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WO2026035552A1 - Naproxen/pregabalin conjugate dosing regimen - Google Patents

Naproxen/pregabalin conjugate dosing regimen

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Publication number
WO2026035552A1
WO2026035552A1 PCT/US2025/040285 US2025040285W WO2026035552A1 WO 2026035552 A1 WO2026035552 A1 WO 2026035552A1 US 2025040285 W US2025040285 W US 2025040285W WO 2026035552 A1 WO2026035552 A1 WO 2026035552A1
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Prior art keywords
compound
administered
osteoarthritis
amount
day
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PCT/US2025/040285
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French (fr)
Inventor
Feng Xu
Guang Liang Jiang
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Xgene Pharmaceutical Inc
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Xgene Pharmaceutical Inc
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  • a method for improving osteoarthritis symptoms in a subject in need thereof comprising administering 1000 mg per day of a compound that is (3S)-3-((((l- (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
  • the compound is administered in an amount of 500 mg twice a day (BID).
  • Also disclosed herein is a method for improving osteoarthritis symptoms in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3S)-3-((((l- (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
  • the compound is administered in an amount of 250 mg twice a day (BID).
  • Also disclosed herein is a method for improving osteoarthritis symptoms in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)- 3-((((l-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
  • the compound is administered in an amount of less than 750 mg twice a day (BID).
  • the compound is administered in an amount that is less than or equal to 1000 mg per day.
  • the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
  • the compound is administered in an amount that is less than or equal to 500 mg per day.
  • the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
  • the osteoarthritis is osteoarthritis of a joint.
  • the osteoarthritis is osteoarthritis of the knee.
  • the osteoarthritis is osteoarthritis of the hip.
  • the osteoarthritis is osteoarthritis of the ankle.
  • the osteoarthritis is osteoarthritis of the spine joint.
  • the osteoarthritis symptom is pain associated with osteoarthritis.
  • the pain associated with osteoarthritis is decreased.
  • the joint stiffness is lessened.
  • physical functions includes using stairs, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy domestic duties, light domestic duties.
  • Also disclosed herein is a method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3 S)- 3-((((l-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
  • the compound is administered in an amount of 500 mg twice a day (BID).
  • Also disclosed herein is a method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3 S)-3 - ((((l-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
  • the compound is administered in an amount of 250 mg twice a day (BID).
  • Also disclosed herein is a method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)-3 -((((1 -(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)- 5 -methylhexanoic acid.
  • the compound is administered in an amount of less than 750 mg twice a day (BID).
  • the compound is administered in an amount that is less than or equal to 1000 mg per day.
  • the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
  • BID 500 mg twice a day
  • the compound is administered in an amount that is less than or equal to 500 mg per day.
  • the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
  • BID 250 mg twice a day
  • the osteoarthritis is osteoarthritis of a joint.
  • the osteoarthritis is osteoarthritis of the knee.
  • the osteoarthritis is osteoarthritis of the hip.
  • the osteoarthritis is osteoarthritis of the shoulder.
  • the osteoarthritis is osteoarthritis of the ankle.
  • the osteoarthritis is osteoarthritis of the spine joint.
  • Also disclosed herein is a method of treating chronic pain in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
  • the compound is administered in an amount of 500 mg twice a day (BID).
  • Also disclosed herein is a method of treating chronic pain in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
  • the compound is administered in an amount of 250 mg twice a day (BID).
  • Also disclosed herein is a method of treating chronic pain in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)-3-((((l - (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
  • the compound is administered in an amount of less than 750 mg twice a day (BID).
  • the compound is administered in an amount that is less than or equal to 1000 mg per day.
  • the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
  • Also disclosed herein is a method of treating acute pain in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
  • a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid is administered 1000 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
  • the compound is administered in an amount of 500 mg twice a day (BID).
  • Also disclosed herein is a method of treating acute pain in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)-3-((((l - (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
  • the compound is administered in an amount of less than 750 mg twice a day (BID).
  • the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
  • the acute pain is post-surgical pain, post-trauma soft tissue pain, post fracture pain, post-sprain, bum wound, toothache, menstrual pain, or visceral organ pain.
  • Also disclosed herein is a method for treating postoperative sleep disturbances in a subject in need thereof; the method comprising administering a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
  • the compound is administered in an amount of between 1000 mg and 3000 mg a day.
  • the compound is administered in an amount of between 1500 mg and 2500 mg a day.
  • the compound is administered in an amount of less than or equal to 1250 mg twice a day (BID).
  • the compound is administered in an amount of 1250 mg twice a day (BID).
  • the compound is administered in an amount of less than or equal to 750 mg twice a day (BID).
  • the compound is administered in an amount of 750 mg twice a day (BID).
  • the postoperative sleep disturbances comprise decreased sleep time, increased awakenings, lowered sleep quality, nightmares, and Loss of REM or SWS sleep.
  • the postoperative sleep disturbance is measured by the Sleep Interference Score (SIS) questionnaire 24h post-surgery, 48h post-surgery, and 72h post-surgery.
  • SIS Sleep Interference Score
  • the 24h post-surgery SIS score is about 3 times better than when administered a placebo.
  • the 48h post-surgery SIS score is about 3 times better than when administered a placebo.
  • the 72h post-surgery SIS score is about 3 times better than when administered a placebo.
  • the 24h post-surgery SIS score is about 2 times better than when administered a placebo.
  • the 48h post-surgery SIS score is about 2 times better than when administered a placebo.
  • the 72h post-surgery SIS score is about 2 times better than when administered a placebo.
  • Also disclosed herein is a method for improving post-surgery sleep quality in a subject in need thereof; the method comprising administering a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
  • the compound is administered in an amount of between 1000 mg and 3000 mg a day.
  • the compound is administered in an amount of between 1500 mg and 2500 mg a day.
  • the compound is administered in an amount of less than or equal to 1250 mg twice a day (BID).
  • the compound is administered in an amount of 1250 mg twice a day (BID).
  • the compound is administered in an amount of less than or equal to 750 mg twice a day (BID).
  • BID 750 mg twice a day
  • the compound is administered in an amount of 750 mg twice a day (BID).
  • the improvement in post-surgery sleep quality is measured by the Sleep Interference Score (SIS) questionnaire 24h post-surgery, 48h post-surgery, and 72h post-surgery.
  • SIS Sleep Interference Score
  • the 24h postsurgery SIS score is about 3 times better than when administered a placebo.
  • the 48h postsurgery SIS score is about 3 times better than when administered a placebo.
  • the 72h postsurgery SIS score is about 3 times better than when administered a placebo.
  • the 24h postsurgery SIS score is about 2 times better than when administered a placebo.
  • the 72h postsurgery SIS score is about 2 times better than when administered a placebo.
  • FIG. 1 shows the change from baseline of WOMAC pain subscore over time after administration of Compound A for 4 weeks.
  • FIG. 2. shows the change from baseline of WOMAC stiffness subscore over time after administration of Compound A for 4 weeks.
  • FIG. 3. shows the change from baseline of WOMAC joint function subscore over time after administration of Compound A for 4 weeks.
  • FIG. 4 shows the change from Baseline of Compound A vs. placebo in weekly average of Sleep Interference Score for 4 weeks.
  • GABA gamma (y)-aminobutyric acid
  • WSGR Docket No. 50048-714.601 baclofen, antidepressants, such as serotonin-norepinephrine reuptake inhibitors (SNRIs), and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to display limited pain alleviating properties in the clinic and in various animal models.
  • Narcotic analgesics such as morphine
  • CNS central nervous system
  • Another concern of the current pain treatment regimens relates to their effectiveness.
  • Many single active ingredients such as antidepressant agents, such as serotonin-norepinephrine reuptake inhibitors (SNRIs), or GABA analogs employed in current pain relief regimens cannot achieve adequate pain alleviation even at their maximum approved therapeutic doses in certain severe pain states.
  • SNRIs serotonin-norepinephrine reuptake inhibitors
  • GABA analogs employed in current pain relief regimens cannot achieve adequate pain alleviation even at their maximum approved therapeutic doses in certain severe pain states.
  • increasing the drug dose may produce an increase in unwanted side effects such as cognitive impairment, dizziness, somnolence, nausea, and constipation.
  • Narcotics have been reported to be ineffective in control chronic painful conditions, such as pain associated with osteoarthritis (OA).
  • GABA analogs and many narcotic analgesics relate to their less favorable pharmacokinetic and physiological properties.
  • Many orally administrated opioid molecules are extensively metabolized by digestive organs before reaching systemic circulation. Rapid systemic clearance and saturable absorption of some of the GABA analogs have limited these drugs to reach their full potential in treatment of pain and other CNS disorders. These sub-optimal properties often lead to less than adequate efficacy and unwanted side effects in patients.
  • Sustained released formulations are a conventional method to address the issue of rapid systemic clearance, as it is well known to those skilled in the art (e.g., “Remington’s Pharmaceutical Sciences,” Philadelphia College of Pharmacy and Science, 17 th Edition, 1985).
  • GABA analogs such as baclofen, gabapentin and pregabalin are not absorbed through the large intestine. Rather, these compounds are typically absorbed in the small intestine by the neutral amino transporter systems (Jezyk et al., Pharm. Res., 1999, 16, 519-526). The rapid passage of conventional tract has prevented the successful application of sustained release approach to these GABA analogs.
  • Non-steroidal anti-inflammatory drugs are widely used for the management of pain often as first line therapy.
  • Naproxen approved by the FDA in 1976 and approved as OTC drug in 1994 is one of the most commonly used NSAIDs for the management of both acute and chronic pain.
  • OTC drug approved as OTC drug in 1994 is one of the most commonly used NSAIDs for the management of both acute and chronic pain.
  • PCT/US25/40285 01 August 2025 01.08.2025
  • WSGR Docket No. 50048-714.601 naproxen with systemic exposure is often associated with serious gastrointestinal (GI) side effects such as ulcers or bleeding (Aleve USPI ref; Kyremateng 2019; Solomon 2017).
  • GI gastrointestinal
  • Neuropathic pain is actual injury to the nerves and nervous system itself.
  • Neuropathic pain also known as nerve pain, is a type of chronic pain that occurs when nerves in the central nervous system become injured or damaged.
  • Neuropathic Pain is a complex, chronic pain state that usually is accompanied by tissue injury or damage.
  • tissue injury or damage In neuropathic pain, the nerve fibers themselves might be damaged, dysfunctional, or injured. These damaged nerve fibers send out pain signals when there might, in fact, be no actual tissue injury, other than to the nerve fibers.
  • Nerve fiber injury can include a change in nerve function both at the site of injury and areas around the injury.
  • Naproxen is marketed products for the treatment of various types of pain (due to rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendinitis, bursitis, and acute gout) and pregabalin is marketed for the treatment of neuropathic pain, neuralgia, and fibromyalgia.
  • Naproxen was initially approved by the United States (US) Food and Drug Administration (FDA) in 1976 and approved as over-the-counter over- the-counter (OTC) drug in 1994.
  • FDA Food and Drug Administration
  • OTC over-the-counter over- the-counter
  • Naproxen is a propionic acid derivative related to the arylacetic acid group of non-steroidal anti-inflammatory drugs (NSAIDs).
  • naproxen non-selectively and reversibly inhibits both COX-1 and COC-2 enzymes, resulting in the inhibition of prostaglandin synthesis and leukocyte activation.
  • COX-1/2 Through inhibiting COX-1/2, naproxen induces an anti-inflammatory and analgesic effect.
  • Pregabalin was approved by the US FDA in 2004, and generic versions are available since 2018. The topical formulation of naproxen that aimed to delivery naproxen topically has been developed to reduce the side effects and improving patient compliance (Patwardhan et al. 2017).
  • Topical formulation of naproxen gel 10% w/v is approved in several European countries (Momendol Gel).
  • the various product formulation development studies for pregabalin were completed to develop pregabalin controlled transdermal alternative to the conventional oral route (Arafa and Ayoub 2017 Arafa and Ayoub 2017; Bhatia et al. 2012) to minimize its CNS side effects. It could be a useful treatment option to avoid or minimize the central nervous system (CNS) -mediated side effects of orally administered pregabalin (Fukasawa et al. 2014).
  • CNS central nervous system
  • Multimodal therapeutic approaches for pain are recommended to minimize the adverse effects of individual drugs as well as to target different mechanisms of pain, including nociception, inflammation, and neuropathic (Finnerup 2019; American Pain Society monograph on PCT/US25/40285 01 August 2025 (01.08.2025)
  • Using such an approach may lead to better efficacy and lower opioid use for pain management in both acute and chronic pain syndromes.
  • Addition of pregabalin, an agent known to target neuropathic pain to a NSAID may result in improved pain control in both acute (Wang et al. 2010, bunionectomy model) and chronic pain (Sofat et al. 2017 - hand osteoarthritis, Derry et al 2017-acute and chronic neuropathic pain, Lambrechts et al. 2013 - chronic post thoracotomy pain).
  • Compound A is (S)-3-(((((R)-l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid:
  • Compound B is (S)-3-(((((S)-l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid:
  • Compound C is (3S)-3-((((l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid:
  • Pregabalin is (S)-3-(aminomethyl)-5-methylhexanoic acid
  • Naproxen is (S)-2-(6-methoxynaphthalen-2-yl)propanoic acid PCT/US25/40285 01 August 2025 (01.08.2025)
  • Drug conjugate refers to the biologically active drugs linked by chemical linkers with labile chemical bonds. Typically, the linker will be attached to the drugs via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.
  • the term “patient,” “subject” or “individual” are used interchangeably. As used herein, they refer to individuals suffering from a disorder, and the like, encompasses mammals and non-mammals. None of the terms require that the individual be under the care and/or supervision of a medical professional. Mammals are any member of the Mammalian class, including but not limited to humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like.
  • the individual is a mammal. In preferred embodiments, the individual is a human.
  • the terms “treat,” “treating” or “treatment,” and other grammatical equivalents as used herein, include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, notwithstanding that the individual is still be afflicted with the underlying disorder.
  • WOMAC Western Ontario and McMaster Universities Arthritis Index
  • the WOMAC has also been used to assess back pain, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, and fibromyalgia. It can be self-administered and was developed at Western Ontario and McMaster Universities in PCT/US25/40285 01 August 2025 (01.08.2025)
  • the WOMAC measures five items for pain (score range 0-20 Likert scale or 0-50 NRS), two for stiffness (score range 0-8 Likert scale, 0-20 NRS), and 17 for functional limitation (score range 0-68 Likert scale, or 0-170 NRS).
  • Physical functioning questions cover everyday activities such as stair use, standing up from a sitting or lying position, standing, bending, walking, getting in and out of a car, shopping, putting on or taking off socks, lying in bed, getting in or out of a bath, sitting, and heavy and light household duties.
  • scoring scales such as 0-4 semi-quantitative Likert scale or 0-10 numerical rating scale.
  • a method for improving osteoarthritis symptoms in a subject in need thereof comprising administering 1000 mg per day of a compound that is (3 S)-3- ((((l-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
  • the compound is administered in an amount of 500 mg twice a day (BID).
  • Also disclosed herein is a method for improving osteoarthritis symptoms in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3 S)-3 - ((((l-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
  • the compound is administered in an amount of 250 mg twice a day (BID).
  • Also disclosed herein is a method for improving osteoarthritis symptoms in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)-3 -((((1 -(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)- 5 -methylhexanoic acid (Compound C).
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount of less than 750 mg twice a day (BID).
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 1000 mg per day.
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg twice a day (BID).
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg per day.
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg per day.
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 250 mg per day.
  • the osteoarthritis is osteoarthritis of a joint.
  • the osteoarthritis is osteoarthritis of the knee.
  • the osteoarthritis is osteoarthritis of the hip.
  • the osteoarthritis is osteoarthritis of the hand.
  • the osteoarthritis is osteoarthritis of the shoulder.
  • the osteoarthritis is osteoarthritis of the ankle.
  • the osteoarthritis is osteoarthritis of the spine joint.
  • the osteoarthritis is osteoarthritis of the elbow.
  • the osteoarthritis symptom is pain associated with osteoarthritis.
  • the pain associated with osteoarthritis is decreased. In some embodiments of a method for improving osteoarthritis symptoms, the pain associated with osteoarthritis is decreased as measured by a WOMAC score.
  • the osteoarthritis symptom is joint stiffness.
  • the joint stiffness is lessened. In some embodiments of a method for improving osteoarthritis symptoms, the joint stiffness is lessened as measured by a WOMAC score.
  • physical functions includes using stairs, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy domestic duties, light domestic duties.
  • the physical functions are improved. In some embodiments of a method for improving osteoarthritis symptoms, the physical functions are improved as measured by a WOMAC score.
  • the methods described herein result in a decrease in WOMAC total score in a subject. In some embodiments of a method of improving osteoarthritis symptoms, the methods described herein result in a decrease in WOMAC total score in the subject from baseline.
  • WOMAC total score of 10 NRS (i.e., sum of all item scores on 0-10 NRS scale/24).
  • 0-4 WOMAC Likert scale the maximum WOMAC total score will be 4 (i.e., sum of all item scores on 0-4 scale/24) and the above corresponding points will be divided by 2.5.
  • 0-100 WOMAC VAS scale the maximum WOMAC total score will be 100 (i.e., sum of all item scores on 0-100 VAS scale/24) and the above corresponding points will be multiplied by 10.
  • the methods described herein result in a decrease in WOMAC total score in the subject from baseline.
  • a decrease in WOMAC total score in the subject of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% in the subject from baseline.
  • the methods provided herein result in a decrease in WOMAC total score one day after administration, two days after administration, three days after administration, four days after administration, five days after administration, six days after administration, one week after administration, two weeks after administration, three weeks after administration, four weeks after administration, five weeks after administration, or six weeks after administration.
  • the WOMAC score is broken down into individual pain, stiffness, and physical function scores.
  • the methods described herein result in a decrease in WOMAC physical function score in the subject from baseline.
  • WOMAC physical function score 10 NRS (i.e., sum of all function item scores on 0-10 NRS scale/17).
  • NRS i.e., sum of all function item scores on 0-10 NRS scale/17.
  • the maximum WOMAC function score will be 4 (i.e., sum of all function item scores on 0-4 scale/17) and the above corresponding points will be divided by 2.5.
  • the maximum WOMAC physical function score will be 100 (i.e., sum of all item scores on 0-100 VAS scale/17) and the above corresponding points will be multiplied by 10.
  • the methods described herein result in a decrease in WOMAC physical function score in the subject from baseline.
  • a decrease in WOMAC physical function score in the subject of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% in the subject from baseline.
  • the methods provided herein result in a decrease in WOMAC physical function score one day after administration, two days after administration, three days after administration, four days after administration, five days after administration, six days after administration, one week after administration, two weeks after administration, three weeks after administration, four weeks after administration, five weeks after administration, or six weeks after administration.
  • the methods described herein result in a decrease in WOMAC pain score in the subject from baseline.
  • the above points are based on maximum WOMAC pain score of 10 NRS (i.e., sum of all pain item scores on 0-10 NRS scale/5).
  • maximum WOMAC pain score will be 4 (i.e., sum of all pain item scores on 0-4 scale/5) and the above corresponding points PCT/US25/40285 01 August 2025 (01.08.2025)
  • WSGR Docket No. 50048-714.601 will be divided by 2.5.
  • the maximum WOMAC pain score will be 100 (i.e., sum of all pain item scores on 0-100 VAS scale/5) and the above corresponding points will be multiplied by 10.
  • the methods described herein result in a decrease in WOMAC pain score in the subject from baseline.
  • a decrease in WOMAC pain score in the subject of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% in the subject from baseline.
  • the methods provided herein result in a decrease in WOMAC pain score one day after administration, two days after administration, three days after administration, four days after administration, five days after administration, six days after administration, one week after administration, two weeks after administration, three weeks after administration, four weeks after administration, five weeks after administration, or six weeks after administration.
  • the methods described herein result in a decrease in WOMAC stiffness score in the subject from baseline.
  • the above points are based on maximum WOMAC stiffness score of 10 NRS (i.e., sum of all stiffness item scores on 0-10 NRS scale/2).
  • maximum WOMAC stiffness score will be 4 (i.e., sum of all stiffness item scores on 0-4 scale/2) and the above corresponding points will be divided by 2.5.
  • maximum WOMAC stiffness score will be 100 (i.e., sum of all item scores on 0-100 VAS scale/2) and the above corresponding points will be multiplied by 10.
  • the methods described herein result in a decrease in WOMAC stiffness score in the subject from baseline.
  • a decrease in WOMAC stiffness score in the subject of at least 5%, 10%,
  • the methods provided herein result in a decrease in WOMAC stiffness score one day after administration, two days after administration, three days after administration, four days after administration, five days after administration, six days after administration, one week after administration, two weeks after administration, three weeks after administration, four weeks after administration, five weeks after administration, or six weeks after administration.
  • the dose administered results in high efficacy and reduced side effects, such as gastrointestinal sides effects or CNS side effects, as compared to a higher dose of the compound or as compared to an efficacious dose of naproxen and/or pregabalin.
  • Also disclosed herein is a method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3 S)-3 -((((1 -(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
  • the compound is administered in an amount of 500 mg twice a day (BID).
  • Also disclosed herein is a method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3 S)-3 -((((1 -(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
  • the compound is administered in an amount of 250 mg twice a day (BID).
  • Also disclosed herein is a method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
  • the compound is: (Compound A) .
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount of less than 750 mg twice a day (BID).
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 1000 mg per day.
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg twice a day (BID).
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg per day.
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg per day.
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
  • the compound is administered in an amount that is less than or equal to 250 mg per day.
  • the osteoarthritis is osteoarthritis of a joint.
  • the osteoarthritis is osteoarthritis of the knee.
  • the osteoarthritis is osteoarthritis of the hip.
  • the osteoarthritis is osteoarthritis of the hand.
  • the osteoarthritis is osteoarthritis of the shoulder.
  • the osteoarthritis is osteoarthritis of the ankle.
  • the osteoarthritis is osteoarthritis of the spine joint.
  • the osteoarthritis is osteoarthritis of the elbow.
  • a decrease in WOMAC pain score in the subject from baseline results in a decrease in WOMAC pain score in the subject from baseline.
  • a decrease in WOMAC pain score in the subject of at least 0.5 point from baseline results in a decrease in WOMAC pain score in the subject of at least 1 point from baseline; a decrease in WOMAC pain score of at least 1.5 points from baseline; a decrease in WOMAC pain score of at least 2 points from baseline, a decrease in WOMAC pain score of at least 2.5 points from baseline, a decrease in WOMAC pain score of at least 3 points from baseline, a decrease in WOMAC pain score of at least 3.5 points from baseline, a decrease in WOMAC pain score of at least 4 points from baseline, a decrease in WOMAC pain score of at least 5 points from baseline, a decrease in WOMAC pain score of at least 5.5 points from baseline, a decrease in WOMAC pain score of at least 6 points from baseline, a decrease in WOMAC pain score of at least
  • the above points are based on maximum WOMAC pain score of 10 NRS (i.e., sum of all pain item scores on 0-10 NRS scale/5).
  • maximum WOMAC pain score will be 4 (i.e., sum of all pain item scores on 0-4 scale/5) and the above corresponding points will be divided by 2.5.
  • maximum WOMAC pain score will be 100 (i.e., sum of all pain item scores on 0-100 VAS scale/5) and the above corresponding points will be multiplied by 10.
  • the methods described herein result in a decrease in WOMAC pain score in the subject from baseline.
  • a decrease in WOMAC pain score in the subject of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% in the subject from baseline.
  • the methods provided herein result in a decrease in WOMAC pain score one day after administration, two days after administration, three days after administration, four days after administration, five days after administration, six days after administration, one week after administration, two weeks after administration, three weeks after administration, four weeks after administration, five weeks after administration, or six weeks after administration.
  • the dose administered results in high efficacy and reduced side effects, such as gastrointestinal sides effects or CNS side effects, as compared to a higher dose of the compound or as compared to an efficacious dose of naproxen and/or pregabalin.
  • Also disclosed herein is a method of treating chronic pain in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3 S)-3 -((((1 - (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
  • the compound is administered in an amount of 500 mg twice a day (BID).
  • Also disclosed herein is a method of treating chronic pain in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3S)-3 -((((1 - (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
  • the compound is administered in an amount of 250 mg twice a day (BID).
  • Also disclosed herein is a method of treating chronic pain in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)- 3-((((l-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
  • the compound is: (Compound A) .
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount of less than 750 mg twice a day (BID).
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 1000 mg per day.
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg twice a day (BID).
  • BID 750 mg twice a day
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg per day.
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg per day.
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
  • Chronic pain is pain that lasts longer than the usual recovery period or persists alongside a chronic health condition. It can be continuous or intermittent, and can range from mild to severe. Chronic pain is different from acute pain, which develops quickly and doesn't usually last long, like pain from an injury.
  • the chronic pain comprises migraine, headache, trigeminal neuralgia, cervical radiculopathy, thoracic outlet syndrome, spinal pain, peripheral nerve compression, diabetic neuropathy, herpes neuralgia, carpal tunnel syndrome, frozen shoulder, sciatic, back pain, cancer pain, hip impingement syndrome, shoulder impingement syndrome, rotator cuff tear, irritable bowel syndrome, and chronic visceral organ pain.
  • the chronic pain is pain caused by osteoarthritis.
  • the dose administered results in high efficacy and reduced side effects, such as gastrointestinal sides effects or CNS side effects, as compared to a higher dose of the compound or as compared to an efficacious dose of naproxen and/or pregabalin.
  • Also disclosed herein is a method of treating acute pain in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
  • the compound is administered in an amount of 500 mg twice a day (BID).
  • Also disclosed herein is a method of treating acute pain in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6-)
  • the compound is administered in an amount of 250 mg twice a day (BID).
  • Also disclosed herein is a method of treating acute pain in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)-3-((((l - (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
  • the compound is: (Compound A) .
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount of less than 750 mg twice a day (BID).
  • the compound is administered in an amount that is less than or equal to 1000 mg per day.
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg twice a day (BID).
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg per day.
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg per day.
  • the compound for example Compound A or Compound C
  • the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
  • Acute pain is a sudden or urgent pain that is usually severe but lasts a relatively short time, often less than a month. It can be caused by injury, trauma, surgery, or other medical treatments. Acute pain is expected and common after surgery, and it serves as a warning of disease or a threat to the body.
  • the acute pain is post- surgical pain, post-trauma soft tissue pain, post fracture pain, post-sprain, bum wound, toothache, menstrual pain, or visceral organ pain.
  • the acute pain is following bunionectomy.
  • the dose administered results in high efficacy and reduced side effects, such as gastrointestinal sides effects or CNS side effects, as compared to a higher dose of the compound or as compared to an efficacious dose of naproxen and/or pregabalin.
  • Also disclosed herein is a method of treating acute pain, (e.g., following bunionectomy), in a subject in need thereof; the method comprising administering 1500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
  • the compound is: (Compound A) .
  • the compound for example Compound A or Compound C
  • BID twice a day
  • a method of treating acute pain comprising administering 2500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
  • a compound that is (3S)-3-((((l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid Compound C
  • the compound is: (Compound A) .
  • the compound for example Compound A or Compound C
  • BID 1250 mg twice a day
  • Also disclosed herein is a method for treating postoperative sleep disturbances in a subject in need thereof; the method comprising administering a compound that is (3S)-3-((((l-(((S)- 2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
  • a compound that is (3S)-3-((((l-(((S)- 2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid Compound C.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount of between 1000 mg and 3000 mg a day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount of between 1500 mg and 2500 mg a day.
  • the compound for example Compound A, Compound B, or Compound C
  • BID 1250 mg twice a day
  • the compound for example Compound A, Compound B, or Compound C
  • BID twice a day
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 3000 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 2500 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 1250 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg twice a day (BID).
  • BID 750 mg twice a day
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 1000 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
  • the compound is administered in an amount that is less than or equal to 250 mg per day.
  • the postoperative sleep disturbances comprise decreased sleep time, increased awakenings, lowered sleep quality, nightmares, and Loss of REM or SWS sleep.
  • the postoperative sleep disturbance is measured by the Sleep Interference Score (SIS) questionnaire (or other sleep assessment measurements) 24h post-surgery, 48h post-surgery, and 72h post-surgery.
  • SIS Sleep Interference Score
  • the 24h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
  • the 48h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
  • the 72h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
  • the 24h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
  • the 48h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
  • the 72h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
  • Also disclosed herein is a method for improving post-surgery sleep quality in a subject in need thereof; the method comprising administering a compound that is (3 S)-3-((((l -(((S)- 2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount of between 1000 mg and 3000 mg a day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount of between 1500 mg and 2500 mg a day.
  • the compound for example Compound A, Compound B, or Compound C
  • BID 1250 mg twice a day
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 3000 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 2500 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 1250 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 1000 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
  • the compound is administered in an amount that is less than or equal to 250 mg per day.
  • the improvement in post-surgery sleep quality is measured by the Sleep Interference Score (SIS) questionnaire (or other sleep assessment measurements) 24h post-surgery, 48h post-surgery, and 72h post-surgery.
  • SIS Sleep Interference Score
  • the 24h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
  • the 48h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
  • the 72h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
  • the 24h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
  • the 48h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
  • the 72h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
  • Also disclosed herein is a method for improving post-surgery sleep impairment in a subject in need thereof; the method comprising administering a compound that is (3 S)-3-((((l -(((S)-
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount of between 1000 mg and 3000 mg a day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount of between 1500 mg and 2500 mg a day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount of 1250 mg twice a day (BID).
  • BID 1250 mg twice a day
  • the compound for example Compound A, Compound B, or Compound C
  • BID twice a day
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 3000 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 2500 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 1250 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 1000 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 250 mg per day.
  • the improvement in post-surgery sleep impairment is measured by the Sleep Interference Score (SIS) PCT/US25/40285 01 August 2025 (01.08.2025)
  • WSGR Docket No. 50048-714.601 questionnaire (or other sleep assessment measurements) 24h post-surgery, 48h post-surgery, and 72h post-surgery.
  • the 24h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
  • the 48h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
  • the 72h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
  • the 24h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
  • the 48h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
  • the 72h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
  • Also disclosed herein is a method for improving post-surgery sleep interference in a subject in need thereof; the method comprising administering a compound that is (3S)-3-((((l-(((S)- 2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount of between 1000 mg and 3000 mg a day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount of between 1500 mg and 2500 mg a day.
  • the compound for example Compound A, Compound B, or Compound C
  • BID 1250 mg twice a day
  • the compound for example Compound A, Compound B, or Compound C
  • BID twice a day
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 3000 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 2500 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 1250 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 1000 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 250 mg per day.
  • the improvement in post-surgery sleep interference is measured by the Sleep Interference Score (SIS) questionnaire (or other sleep assessment measurements) 24h post-surgery, 48h post-surgery, and 72h post-surgery.
  • SIS Sleep Interference Score
  • the 24h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
  • the 48h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
  • the 72h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
  • the 24h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
  • the 48h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
  • the 72h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
  • Also disclosed herein is a method for treating sleep disturbances in a subject with chronic pain; the method comprising administering a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
  • a compound that is (3S)-3-(((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid Compound C.
  • the compound is: (Compound
  • the compound is: (Compound
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount of between 1000 mg and 3000 mg a day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount of between 1500 mg and 2500 mg a day.
  • the compound for example Compound A, Compound B, or Compound C
  • BID 1250 mg twice a day
  • the compound for example Compound A, Compound B, or Compound C
  • BID twice a day
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 3000 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 2500 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 1250 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg twice a day (BID).
  • BID 750 mg twice a day
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 750 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 1000 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 500 mg per day.
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
  • the compound for example Compound A, Compound B, or Compound C
  • the compound is administered in an amount that is less than or equal to 250 mg per day.
  • the sleep disturbances comprise decreased sleep time, increased awakenings, lowered sleep quality, nightmares, and Loss of REM or SWS sleep.
  • the sleep disturbance is measured by the Sleep Interference Score (SIS) questionnaire (or other sleep assessment measurements).
  • SIS Sleep Interference Score
  • the SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
  • the SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
  • the chronic pain comprises migraine, headache, trigeminal neuralgia, cervical radiculopathy, thoracic outlet syndrome, spinal pain, peripheral nerve compression, diabetic neuropathy, herpes neuralgia, carpal tunnel syndrome, frozen shoulder, sciatic, back pain, cancer pain, hip impingement syndrome, shoulder impingement syndrome, rotator cuff tear, irritable bowel PCT/US25/40285 01 August 2025 (01.08.2025)
  • the chronic pain is pain caused by osteoarthritis.
  • Study Design and Results A 3-arm, double-blind, placebo-controlled, parallel-group, randomized and multiple center study was conducted to investigate the safety and efficacy of Compound A in patients with moderate to severe pain of osteoarthritis (OA) of the knee. Subject’s eligibility was established based on screening evaluations and post -washout period baseline evaluations. Eligible subjects were randomized, titrated as shown in the table 1 and then given study drug of either Compound A at 500 mg BID, 750 mg BID, or placebo BID for total 4 weeks. Subjects were assessed at 1, 2 and 4 weeks after randomization at office visits, followed by a safety follow-up phone call by the end of the fifth week.
  • OA osteoarthritis
  • WOMAC is a questionnaire that contains 24 questions for patients to assess the severity of joint pain (5 questions), stiffness (2 questions) and functional limitation (17 questions).
  • FIG. 4 shows the weekly sleep disturbance scores as measured by the Sleep Interference Score (SIS) questionnaire.

Abstract

Described herein are method of treating pain associated with osteoarthritis (OA) using a low dose of an oral drug conjugate of naproxen and pregabalin. Described herein are method of addressing sleep disturbance in a subject in pain using an oral drug conjugate of naproxen and pregabalin.

Description

PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
NAPROXEN/PREGABAEIN CONJUGATE DOSING REGIMEN
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63/679,569 filed August 5, 2024 and U.S. Provisional Application Serial No. 63/722,764 filed November 20, 2024; which are hereby incorporated by reference in their entirety.
BACKGROUND
[0002] A number of treatments involving the administration of single drugs are currently recommended for relief of pain including neurological pain. The single administration of narcotic analgesics, gamma (y)-aminobutyric acid (GABA) analogs such as gabapentin, pregabalin and baclofen, antidepressants, and non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to display pain alleviating properties in the clinic and in various animal models.
SUMMARY OF THE INVENTION
[0003] Disclosed herein is a method for improving osteoarthritis symptoms in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3S)-3-((((l- (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
[0004] In some embodiments of a method for improving osteoarthritis symptoms, the compound is administered in an amount of 500 mg twice a day (BID).
[0005] Also disclosed herein is a method for improving osteoarthritis symptoms in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3S)-3-((((l- (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
[0006] In some embodiments of a method for improving osteoarthritis symptoms, the compound is administered in an amount of 250 mg twice a day (BID).
[0007] Also disclosed herein is a method for improving osteoarthritis symptoms in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)- 3-((((l-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
[0008] In some embodiments of a method for improving osteoarthritis symptoms, the compound is administered in an amount of less than 750 mg twice a day (BID).
[0009] In some embodiments of a method for improving osteoarthritis symptoms, the compound is administered in an amount that is less than or equal to 1000 mg per day. PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[0010] In some embodiments of a method for improving osteoarthritis symptoms, the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
[0011] In some embodiments of a method for improving osteoarthritis symptoms, the compound is administered in an amount that is less than or equal to 500 mg per day.
[0012] In some embodiments of a method for improving osteoarthritis symptoms, the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
[0013] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of a joint.
[0014] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of the knee.
[0015] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of the hip.
[0016] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of the hand.
[0017] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of the shoulder.
[0018] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of the ankle.
[0019] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of the spine joint.
[0020] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis symptom is pain associated with osteoarthritis.
[0021] In some embodiments of a method for improving osteoarthritis symptoms, the pain associated with osteoarthritis is decreased.
[0022] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis symptom is joint stiffness.
[0023] In some embodiments of a method for improving osteoarthritis symptoms, the joint stiffness is lessened.
[0024] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis symptom is loss of physical functions.
[0025] In some embodiments of a method for improving osteoarthritis symptoms, physical functions includes using stairs, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy domestic duties, light domestic duties.
[0026] In some embodiments of a method for improving osteoarthritis symptoms, the physical functions are improved. PCT/US25/40285 01 August 2025 (01.08.2025)
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[0027] Also disclosed herein is a method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3 S)- 3-((((l-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
[0028] In some embodiments of a method of treating pain associated with osteoarthritis, the compound is administered in an amount of 500 mg twice a day (BID).
[0029] Also disclosed herein is a method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3 S)-3 - ((((l-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
[0030] In some embodiments of a method of treating pain associated with osteoarthritis, the compound is administered in an amount of 250 mg twice a day (BID).
[0031] Also disclosed herein is a method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)-3 -((((1 -(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)- 5 -methylhexanoic acid.
[0032] In some embodiments of a method of treating pain associated with osteoarthritis, the compound is administered in an amount of less than 750 mg twice a day (BID).
[0033] In some embodiments of a method of treating pain associated with osteoarthritis, the compound is administered in an amount that is less than or equal to 1000 mg per day.
[0034] In some embodiments of a method of treating pain associated with osteoarthritis, the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID). [0035] In some embodiments of a method of treating pain associated with osteoarthritis, the compound is administered in an amount that is less than or equal to 500 mg per day.
[0036] In some embodiments of a method of treating pain associated with osteoarthritis, the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID). [0037] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of a joint.
[0038] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of the knee.
[0039] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of the hip.
[0040] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of the hand.
[0041] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of the shoulder. PCT/US25/40285 01 August 2025 (01.08.2025)
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[0042] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of the ankle.
[0043] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of the spine joint.
[0044] Also disclosed herein is a method of treating chronic pain in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid. [0045] In some embodiments of a method of treating chronic pain, the compound is administered in an amount of 500 mg twice a day (BID).
[0046] Also disclosed herein is a method of treating chronic pain in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid. [0047] In some embodiments of a method of treating chronic pain, the compound is administered in an amount of 250 mg twice a day (BID).
[0048] Also disclosed herein is a method of treating chronic pain in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)-3-((((l - (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
[0049] In some embodiments of a method of treating chronic pain, the compound is administered in an amount of less than 750 mg twice a day (BID).
[0050] In some embodiments of a method of treating chronic pain, the compound is administered in an amount that is less than or equal to 1000 mg per day.
[0051] In some embodiments of a method of treating chronic pain, the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
[0052] In some embodiments of a method of treating chronic pain, the compound is administered in an amount that is less than or equal to 500 mg per day.
[0053] In some embodiments of a method of treating chronic pain, the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
[0054] In some embodiments of a method of treating chronic pain, the chronic pain comprises migraine, headache, trigeminal neuralgia, cervical radiculopathy, thoracic outlet syndrome, spinal pain, peripheral nerve compression, diabetic neuropathy, herpes neuralgia, carpal tunnel syndrome, frozen shoulder, sciatic, back pain, cancer pain, hip impingement syndrome, shoulder impingement syndrome, rotator cuff tear, irritable bowel syndrome, and chronic visceral organ pain.
[0055] Also disclosed herein is a method of treating acute pain in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid. PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[0056] In some embodiments of a method of treating acute pain, the compound is administered in an amount of 500 mg twice a day (BID).
[0057] Also disclosed herein is a method of treating acute pain in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid. [0058] In some embodiments of a method of treating acute pain, the compound is administered in an amount of 250 mg twice a day (BID).
[0059] Also disclosed herein is a method of treating acute pain in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)-3-((((l - (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
[0060] In some embodiments of a method of treating acute pain, the compound is administered in an amount of less than 750 mg twice a day (BID).
[0061] In some embodiments of a method of treating acute pain, the compound is administered in an amount that is less than or equal to 1000 mg per day.
[0062] In some embodiments of a method of treating acute pain, the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
[0063] In some embodiments of a method of treating acute pain, the compound is administered in an amount that is less than or equal to 500 mg per day.
[0064] In some embodiments of a method of treating acute pain, the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
[0065] In some embodiments of a method of treating acute pain, the acute pain is post-surgical pain, post-trauma soft tissue pain, post fracture pain, post-sprain, bum wound, toothache, menstrual pain, or visceral organ pain.
[0066] Also disclosed herein is a method for treating postoperative sleep disturbances in a subject in need thereof; the method comprising administering a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
[0067] In some embodiments of a method for treating postoperative sleep disturbances, the compound is administered in an amount of between 1000 mg and 3000 mg a day.
[0068] In some embodiments of a method for treating postoperative sleep disturbances, the compound is administered in an amount of between 1500 mg and 2500 mg a day.
[0069] In some embodiments of a method for treating postoperative sleep disturbances, the compound is administered in an amount of less than or equal to 1250 mg twice a day (BID). [0070] In some embodiments of a method for treating postoperative sleep disturbances, the compound is administered in an amount of 1250 mg twice a day (BID). PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[0071] In some embodiments of a method for treating postoperative sleep disturbances, the compound is administered in an amount of less than or equal to 750 mg twice a day (BID).
[0072] In some embodiments of a method for treating postoperative sleep disturbances, the compound is administered in an amount of 750 mg twice a day (BID).
[0073] In some embodiments of a method for treating postoperative sleep disturbances, the postoperative sleep disturbances comprise decreased sleep time, increased awakenings, lowered sleep quality, nightmares, and Loss of REM or SWS sleep.
[0074] In some embodiments of a method for treating postoperative sleep disturbances, the postoperative sleep disturbance is measured by the Sleep Interference Score (SIS) questionnaire 24h post-surgery, 48h post-surgery, and 72h post-surgery.
[0075] In some embodiments of a method for treating postoperative sleep disturbances, the 24h post-surgery SIS score is about 3 times better than when administered a placebo.
[0076] In some embodiments of a method for treating postoperative sleep disturbances, the 48h post-surgery SIS score is about 3 times better than when administered a placebo.
[0077] In some embodiments of a method for treating postoperative sleep disturbances, the 72h post-surgery SIS score is about 3 times better than when administered a placebo.
[0078] In some embodiments of a method for treating postoperative sleep disturbances, the 24h post-surgery SIS score is about 2 times better than when administered a placebo.
[0079] In some embodiments of a method for treating postoperative sleep disturbances, the 48h post-surgery SIS score is about 2 times better than when administered a placebo.
[0080] In some embodiments of a method for treating postoperative sleep disturbances, the 72h post-surgery SIS score is about 2 times better than when administered a placebo.
[0081] Also disclosed herein is a method for improving post-surgery sleep quality in a subject in need thereof; the method comprising administering a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
[0082] In some embodiments of a method for improving post-surgery sleep quality, the compound is administered in an amount of between 1000 mg and 3000 mg a day.
[0083] In some embodiments of a method for improving post-surgery sleep quality, the compound is administered in an amount of between 1500 mg and 2500 mg a day.
[0084] In some embodiments of a method for improving post-surgery sleep quality, the compound is administered in an amount of less than or equal to 1250 mg twice a day (BID).
[0085] In some embodiments of a method for improving post-surgery sleep quality, the compound is administered in an amount of 1250 mg twice a day (BID).
[0086] In some embodiments of a method for improving post-surgery sleep quality, the compound is administered in an amount of less than or equal to 750 mg twice a day (BID). PCT/US25/40285 01 August 2025 (01.08.2025)
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[0087] In some embodiments of a method for improving post-surgery sleep quality, the compound is administered in an amount of 750 mg twice a day (BID).
[0088] In some embodiments of a method for improving post-surgery sleep quality, the improvement in post-surgery sleep quality is measured by the Sleep Interference Score (SIS) questionnaire 24h post-surgery, 48h post-surgery, and 72h post-surgery.
[0089] In some embodiments of a method for improving post-surgery sleep quality, the 24h postsurgery SIS score is about 3 times better than when administered a placebo.
[0090] In some embodiments of a method for improving post-surgery sleep quality, the 48h postsurgery SIS score is about 3 times better than when administered a placebo.
[0091] In some embodiments of a method for improving post-surgery sleep quality, the 72h postsurgery SIS score is about 3 times better than when administered a placebo.
[0092] In some embodiments of a method for improving post-surgery sleep quality, the 24h postsurgery SIS score is about 2 times better than when administered a placebo.
[0093] In some embodiments of a method for improving post-surgery sleep quality, the 48h postsurgery SIS score is about 2 times better than when administered a placebo.
[0094] In some embodiments of a method for improving post-surgery sleep quality, the 72h postsurgery SIS score is about 2 times better than when administered a placebo.
BRIEF DESCRIPTION OF THE FIGURES
[0095] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:
[0096] FIG. 1 shows the change from baseline of WOMAC pain subscore over time after administration of Compound A for 4 weeks.
[0097] FIG. 2. shows the change from baseline of WOMAC stiffness subscore over time after administration of Compound A for 4 weeks.
[0098] FIG. 3. shows the change from baseline of WOMAC joint function subscore over time after administration of Compound A for 4 weeks.
[0099] FIG. 4 shows the change from Baseline of Compound A vs. placebo in weekly average of Sleep Interference Score for 4 weeks.
DETAILED DESCRIPTION
[00100] A number of treatments involving the administration of single drugs are currently recommended for relief of pain including neurological pain. The single administration of narcotic analgesics, gamma (y)-aminobutyric acid (GABA) analogs such as gabapentin, pregabalin and PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601 baclofen, antidepressants, such as serotonin-norepinephrine reuptake inhibitors (SNRIs), and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to display limited pain alleviating properties in the clinic and in various animal models.
[00101] Despite the limited benefits derived from the current single drug pain relief regimens, these regimens have disadvantages. One area of concern relates to the incidence of unwanted side effects caused by many of the pain treatment regimens available today. Narcotic analgesics, such as morphine, are sparingly prescribed for chronic pain, such as pain associated with osteoarthritis (OA), because of the well-known addictive effects and central nervous system (CNS) side effects and gastrointestinal side effects resulting from their single administration.
[00102] Another concern of the current pain treatment regimens relates to their effectiveness. Many single active ingredients such as antidepressant agents, such as serotonin-norepinephrine reuptake inhibitors (SNRIs), or GABA analogs employed in current pain relief regimens cannot achieve adequate pain alleviation even at their maximum approved therapeutic doses in certain severe pain states. In addition to not achieving adequate pain alleviation, increasing the drug dose may produce an increase in unwanted side effects such as cognitive impairment, dizziness, somnolence, nausea, and constipation. Narcotics have been reported to be ineffective in control chronic painful conditions, such as pain associated with osteoarthritis (OA).
[00103] Furthermore, other concerns of GABA analogs and many narcotic analgesics relate to their less favorable pharmacokinetic and physiological properties. Many orally administrated opioid molecules are extensively metabolized by digestive organs before reaching systemic circulation. Rapid systemic clearance and saturable absorption of some of the GABA analogs have limited these drugs to reach their full potential in treatment of pain and other CNS disorders. These sub-optimal properties often lead to less than adequate efficacy and unwanted side effects in patients. [00104] Sustained released formulations are a conventional method to address the issue of rapid systemic clearance, as it is well known to those skilled in the art (e.g., “Remington’s Pharmaceutical Sciences,” Philadelphia College of Pharmacy and Science, 17th Edition, 1985). GABA analogs, such as baclofen, gabapentin and pregabalin are not absorbed through the large intestine. Rather, these compounds are typically absorbed in the small intestine by the neutral amino transporter systems (Jezyk et al., Pharm. Res., 1999, 16, 519-526). The rapid passage of conventional tract has prevented the successful application of sustained release approach to these GABA analogs.
[00105] Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the management of pain often as first line therapy. Naproxen, approved by the FDA in 1976 and approved as OTC drug in 1994 is one of the most commonly used NSAIDs for the management of both acute and chronic pain. Though generally well tolerated, the oral use of NSAIDs such as PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601 naproxen with systemic exposure is often associated with serious gastrointestinal (GI) side effects such as ulcers or bleeding (Aleve USPI ref; Kyremateng 2019; Solomon 2017).
[00106] In view of these concerns, it is evident that there is a need for an improved pain regimen that provides an improved therapeutic benefit (i.e., reduced severity and/or frequency of pain) and/or reduces the incidence of unwanted side effects caused by many of the current regimens. In addition, improving pharmacokinetic profile of GABA analogs will also lead to more customized dosing regimens according to patients’ need.
[00107] Neuropathic pain is actual injury to the nerves and nervous system itself. Neuropathic pain, also known as nerve pain, is a type of chronic pain that occurs when nerves in the central nervous system become injured or damaged. Neuropathic Pain is a complex, chronic pain state that usually is accompanied by tissue injury or damage. In neuropathic pain, the nerve fibers themselves might be damaged, dysfunctional, or injured. These damaged nerve fibers send out pain signals when there might, in fact, be no actual tissue injury, other than to the nerve fibers. Nerve fiber injury can include a change in nerve function both at the site of injury and areas around the injury.
[00108] Naproxen is marketed products for the treatment of various types of pain (due to rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendinitis, bursitis, and acute gout) and pregabalin is marketed for the treatment of neuropathic pain, neuralgia, and fibromyalgia. Naproxen was initially approved by the United States (US) Food and Drug Administration (FDA) in 1976 and approved as over-the-counter over- the-counter (OTC) drug in 1994. Naproxen is a propionic acid derivative related to the arylacetic acid group of non-steroidal anti-inflammatory drugs (NSAIDs). Like other NSAIDs, naproxen non-selectively and reversibly inhibits both COX-1 and COC-2 enzymes, resulting in the inhibition of prostaglandin synthesis and leukocyte activation. Through inhibiting COX-1/2, naproxen induces an anti-inflammatory and analgesic effect.
[00109] Pregabalin was approved by the US FDA in 2004, and generic versions are available since 2018. The topical formulation of naproxen that aimed to delivery naproxen topically has been developed to reduce the side effects and improving patient compliance (Patwardhan et al. 2017).
Topical formulation of naproxen gel 10% w/v is approved in several European countries (Momendol Gel). Similarly, the various product formulation development studies for pregabalin were completed to develop pregabalin controlled transdermal alternative to the conventional oral route (Arafa and Ayoub 2017 Arafa and Ayoub 2017; Bhatia et al. 2012) to minimize its CNS side effects. It could be a useful treatment option to avoid or minimize the central nervous system (CNS) -mediated side effects of orally administered pregabalin (Fukasawa et al. 2014).
[00110] Multimodal therapeutic approaches for pain are recommended to minimize the adverse effects of individual drugs as well as to target different mechanisms of pain, including nociception, inflammation, and neuropathic (Finnerup 2019; American Pain Society monograph on PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601 pain; Hsu et al. 2019). Using such an approach may lead to better efficacy and lower opioid use for pain management in both acute and chronic pain syndromes. Addition of pregabalin, an agent known to target neuropathic pain to a NSAID may result in improved pain control in both acute (Wang et al. 2010, bunionectomy model) and chronic pain (Sofat et al. 2017 - hand osteoarthritis, Derry et al 2017-acute and chronic neuropathic pain, Lambrechts et al. 2013 - chronic post thoracotomy pain).
Compound A
[00111] Compound A is (S)-3-(((((R)-l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid:
Compound B
[00112] Compound B is (S)-3-(((((S)-l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid:
Compound C
[00113] Compound C is (3S)-3-((((l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid:
[00114] Pregabalin is (S)-3-(aminomethyl)-5-methylhexanoic acid
[00115] Naproxen is (S)-2-(6-methoxynaphthalen-2-yl)propanoic acid PCT/US25/40285 01 August 2025 (01.08.2025)
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Definitions
[00116] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. [00117] As used in the specification and claims, the singular form “a,” “an” and “the” includes plural references unless the context clearly dictates otherwise.
[00118] “Drug conjugate” refers to the biologically active drugs linked by chemical linkers with labile chemical bonds. Typically, the linker will be attached to the drugs via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.
[00119] The term “patient,” “subject” or “individual” are used interchangeably. As used herein, they refer to individuals suffering from a disorder, and the like, encompasses mammals and non-mammals. None of the terms require that the individual be under the care and/or supervision of a medical professional. Mammals are any member of the Mammalian class, including but not limited to humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In some embodiments of the methods and compositions provided herein, the individual is a mammal. In preferred embodiments, the individual is a human.
[00120] The terms “treat,” “treating” or “treatment,” and other grammatical equivalents as used herein, include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. The terms further include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, notwithstanding that the individual is still be afflicted with the underlying disorder.
[00121] Western Ontario and McMaster Universities Arthritis Index" or "WOMAC" refers to a widely used, proprietary set of standardized questionnaires used by health professionals to evaluate the condition of patients with osteoarthritis of the knee and hip, including pain, stiffness, and physical functioning of the joints. The WOMAC has also been used to assess back pain, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, and fibromyalgia. It can be self-administered and was developed at Western Ontario and McMaster Universities in PCT/US25/40285 01 August 2025 (01.08.2025)
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1982. The WOMAC measures five items for pain (score range 0-20 Likert scale or 0-50 NRS), two for stiffness (score range 0-8 Likert scale, 0-20 NRS), and 17 for functional limitation (score range 0-68 Likert scale, or 0-170 NRS). Physical functioning questions cover everyday activities such as stair use, standing up from a sitting or lying position, standing, bending, walking, getting in and out of a car, shopping, putting on or taking off socks, lying in bed, getting in or out of a bath, sitting, and heavy and light household duties. Various versions of WOMAC have been validated and used in clinical studies, with difference in scoring scales, such as 0-4 semi-quantitative Likert scale or 0-10 numerical rating scale.
Method of Treating
[00122] Disclosed herein is a method for improving osteoarthritis symptoms in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3 S)-3- ((((l-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
[00123] In some embodiments of a method for improving osteoarthritis symptoms, the compound is administered in an amount of 500 mg twice a day (BID).
[00124] Also disclosed herein is a method for improving osteoarthritis symptoms in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3 S)-3 - ((((l-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
[00125] In some embodiments of a method for improving osteoarthritis symptoms, the compound is administered in an amount of 250 mg twice a day (BID).
[00126] Also disclosed herein is a method for improving osteoarthritis symptoms in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)-3 -((((1 -(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)- 5 -methylhexanoic acid (Compound C).
[00127] In some embodiments of a method for improving osteoarthritis symptoms, the
[00128] In some embodiments of a method for improving osteoarthritis symptoms, the compound (for example Compound A or Compound C) is administered in an amount of less than 750 mg twice a day (BID).
[00129] In some embodiments of a method for improving osteoarthritis symptoms, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 1000 mg per day. PCT/US25/40285 01 August 2025 (01.08.2025)
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[00130] In some embodiments of a method for improving osteoarthritis symptoms, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 750 mg twice a day (BID).
[00131] In some embodiments of a method for improving osteoarthritis symptoms, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 750 mg per day.
[00132] In some embodiments of a method for improving osteoarthritis symptoms, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 500 mg twice a day (BID).
[00133] In some embodiments of a method for improving osteoarthritis symptoms, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 500 mg per day.
[00134] In some embodiments of a method for improving osteoarthritis symptoms, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 250 mg twice a day (BID).
[00135] In some embodiments of a method for improving osteoarthritis symptoms, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 250 mg per day.
[00136] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of a joint.
[00137] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of the knee.
[00138] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of the hip.
[00139] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of the hand.
[00140] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of the shoulder.
[00141] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of the ankle.
[00142] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of the spine joint.
[00143] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis is osteoarthritis of the elbow.
[00144] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis symptom is pain associated with osteoarthritis. PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00145] In some embodiments of a method for improving osteoarthritis symptoms, the pain associated with osteoarthritis is decreased. In some embodiments of a method for improving osteoarthritis symptoms, the pain associated with osteoarthritis is decreased as measured by a WOMAC score.
[00146] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis symptom is joint stiffness.
[00147] In some embodiments of a method for improving osteoarthritis symptoms, the joint stiffness is lessened. In some embodiments of a method for improving osteoarthritis symptoms, the joint stiffness is lessened as measured by a WOMAC score.
[00148] In some embodiments of a method for improving osteoarthritis symptoms, the osteoarthritis symptom is loss of physical functions.
[00149] In some embodiments of a method for improving osteoarthritis symptoms, physical functions includes using stairs, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy domestic duties, light domestic duties.
[00150] In some embodiments of a method for improving osteoarthritis symptoms, the physical functions are improved. In some embodiments of a method for improving osteoarthritis symptoms, the physical functions are improved as measured by a WOMAC score.
[00151] In some embodiments of a method of improving osteoarthritis symptoms, the methods described herein result in a decrease in WOMAC total score in a subject. In some embodiments of a method of improving osteoarthritis symptoms, the methods described herein result in a decrease in WOMAC total score in the subject from baseline. For example, a decrease in WOMAC total score in the subject of at least 0.5 point from baseline; a decrease in WOMAC total score in the subject of at least 1 point from baseline; a decrease in WOMAC total score of at least 1.5 points from baseline; a decrease in WOMAC total score of at least 2 points from baseline, a decrease in WOMAC total score of at least 2.5 points from baseline, a decrease in WOMAC total score of at least 3 points from baseline, a decrease in WOMAC total score of at least 3.5 points from baseline, a decrease in WOMAC total score of at least 4 points from baseline, a decrease in WOMAC total score of at least 5 points from baseline, a decrease in WOMAC total score of at least 5.5 points from baseline, a decrease in WOMAC total score of at least 6 points from baseline, a decrease in WOMAC total score of at least 6.5 points from baseline, a decrease in WOMAC total score of at least 7 points from baseline, a decrease in WOMAC total score of at least 7.5 points from baseline, a decrease in WOMAC total score of at least 8 points from baseline, a decrease in WOMAC total score of at least 8.5 points from baseline, a decrease in WOMAC total score of at least 9 points from baseline, a decrease in WOMAC total score of at least 9.5 points from baseline, or a decrease in WOMAC total score of at least 10 points from baseline. The above points are based on maximum PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
WOMAC total score of 10 NRS (i.e., sum of all item scores on 0-10 NRS scale/24). When 0-4 WOMAC Likert scale is used, the maximum WOMAC total score will be 4 (i.e., sum of all item scores on 0-4 scale/24) and the above corresponding points will be divided by 2.5. When 0-100 WOMAC VAS scale is used, the maximum WOMAC total score will be 100 (i.e., sum of all item scores on 0-100 VAS scale/24) and the above corresponding points will be multiplied by 10.
[00152] In some embodiments of a method of improving osteoarthritis symptoms, the methods described herein result in a decrease in WOMAC total score in the subject from baseline. For example, a decrease in WOMAC total score in the subject of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% in the subject from baseline.
[00153] In some embodiments of a method of improving osteoarthritis symptoms, the methods provided herein result in a decrease in WOMAC total score one day after administration, two days after administration, three days after administration, four days after administration, five days after administration, six days after administration, one week after administration, two weeks after administration, three weeks after administration, four weeks after administration, five weeks after administration, or six weeks after administration.
[00154] The WOMAC score is broken down into individual pain, stiffness, and physical function scores.
[00155] In some embodiments of a method of improving osteoarthritis symptoms, the methods described herein result in a decrease in WOMAC physical function score in the subject from baseline. For example, a decrease in WOMAC physical function score in the subject of at least 0.5 point from baseline; a decrease in WOMAC physical function score in the subject of at least 1 point from baseline; a decrease in WOMAC physical function score of at least 1.5 points from baseline; a decrease in WOMAC physical function score of at least 2 points from baseline, a decrease in WOMAC physical function score of at least 2.5 points from baseline, a decrease in WOMAC physical function score of at least 3 points from baseline, a decrease in WOMAC physical function score of at least 3.5 points from baseline, a decrease in WOMAC physical function score of at least 4 points from baseline, a decrease in WOMAC physical function score of at least 5 points from baseline, a decrease in WOMAC physical function score of at least 5.5 points from baseline, a decrease in WOMAC physical function score of at least 6 points from baseline, a decrease in WOMAC physical function score of at least 6.5 points from baseline, a decrease in WOMAC physical function score of at least 7 points from baseline, a decrease in WOMAC physical function score of at least 7.5 points from baseline, a decrease in WOMAC physical function score of at least 8 points from baseline, a decrease in WOMAC physical function score of at least 8.5 points from baseline, a decrease in WOMAC physical function score of at least 9 points from baseline, a decrease in WOMAC physical function score of at least 9.5 points from baseline, or a decrease in WOMAC physical function score of at least 10 points from baseline. The above points are based on PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601 maximum WOMAC physical function score of 10 NRS (i.e., sum of all function item scores on 0-10 NRS scale/17). When 0-4 WOMAC Likert scale is used, the maximum WOMAC function score will be 4 (i.e., sum of all function item scores on 0-4 scale/17) and the above corresponding points will be divided by 2.5. When 0-100 WOMAC VAS scale is used, the maximum WOMAC physical function score will be 100 (i.e., sum of all item scores on 0-100 VAS scale/17) and the above corresponding points will be multiplied by 10.
[00156] In some embodiments of a method of improving osteoarthritis symptoms, the methods described herein result in a decrease in WOMAC physical function score in the subject from baseline. For example, a decrease in WOMAC physical function score in the subject of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% in the subject from baseline.
[00157] In some embodiments of a method of improving osteoarthritis symptoms, the methods provided herein result in a decrease in WOMAC physical function score one day after administration, two days after administration, three days after administration, four days after administration, five days after administration, six days after administration, one week after administration, two weeks after administration, three weeks after administration, four weeks after administration, five weeks after administration, or six weeks after administration.
[00158] In some embodiments of a method of improving osteoarthritis symptoms, the methods described herein result in a decrease in WOMAC pain score in the subject from baseline. For example, a decrease in WOMAC pain score in the subject of at least 0.5 point from baseline; a decrease in WOMAC pain score in the subject of at least 1 point from baseline; a decrease in WOMAC pain score of at least 1.5 points from baseline; a decrease in WOMAC pain score of at least 2 points from baseline, a decrease in WOMAC pain score of at least 2.5 points from baseline, a decrease in WOMAC pain score of at least 3 points from baseline, a decrease in WOMAC pain score of at least 3.5 points from baseline, a decrease in WOMAC pain score of at least 4 points from baseline, a decrease in WOMAC pain score of at least 5 points from baseline, a decrease in WOMAC pain score of at least 5.5 points from baseline, a decrease in WOMAC pain score of at least 6 points from baseline, a decrease in WOMAC pain score of at least 6.5 points from baseline, a decrease in WOMAC pain score of at least 7 points from baseline, a decrease in WOMAC pain score of at least 7.5 points from baseline, a decrease in WOMAC pain score of at least 8 points from baseline, a decrease in WOMAC pain score of at least 8.5 points from baseline, a decrease in WOMAC pain score of at least 9 points from baseline, a decrease in WOMAC pain score of at least 9.5 points from baseline, or a decrease in WOMAC pain score of at least 10 points from baseline. The above points are based on maximum WOMAC pain score of 10 NRS (i.e., sum of all pain item scores on 0-10 NRS scale/5). When 0-4 WOMAC Likert scale is used, the maximum WOMAC pain score will be 4 (i.e., sum of all pain item scores on 0-4 scale/5) and the above corresponding points PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601 will be divided by 2.5. When 0-100 WOMAC VAS scale is used, the maximum WOMAC pain score will be 100 (i.e., sum of all pain item scores on 0-100 VAS scale/5) and the above corresponding points will be multiplied by 10.
[00159] In some embodiments of a method of improving osteoarthritis symptoms, the methods described herein result in a decrease in WOMAC pain score in the subject from baseline. For example, a decrease in WOMAC pain score in the subject of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% in the subject from baseline.
[00160] In some embodiments of a method of improving osteoarthritis symptoms, the methods provided herein result in a decrease in WOMAC pain score one day after administration, two days after administration, three days after administration, four days after administration, five days after administration, six days after administration, one week after administration, two weeks after administration, three weeks after administration, four weeks after administration, five weeks after administration, or six weeks after administration.
[00161] In some embodiments of a method of improving osteoarthritis symptoms, the methods described herein result in a decrease in WOMAC stiffness score in the subject from baseline. For example, a decrease in WOMAC stiffness score in the subject of at least 0.5 point from baseline; a decrease in WOMAC stiffness score in the subject of at least 1 point from baseline; a decrease in WOMAC stiffness score of at least 1.5 points from baseline; a decrease in WOMAC stiffness score of at least 2 points from baseline, a decrease in WOMAC stiffness score of at least 2.5 points from baseline, a decrease in WOMAC stiffness score of at least 3 points from baseline, a decrease in WOMAC stiffness score of at least 3.5 points from baseline, a decrease in WOMAC stiffness score of at least 4 points from baseline, a decrease in WOMAC stiffness score of at least 5 points from baseline, a decrease in WOMAC stiffness score of at least 5.5 points from baseline, a decrease in WOMAC stiffness score of at least 6 points from baseline, a decrease in WOMAC stiffness score of at least 6.5 points from baseline, a decrease in WOMAC stiffness score of at least 7 points from baseline, a decrease in WOMAC stiffness score of at least 7.5 points from baseline, a decrease in WOMAC stiffness score of at least 8 points from baseline, a decrease in WOMAC stiffness score of at least 8.5 points from baseline, a decrease in WOMAC stiffness score of at least 9 points from baseline, a decrease in WOMAC stiffness score of at least 9.5 points from baseline, or a decrease in WOMAC stiffness score of at least 10 points from baseline. The above points are based on maximum WOMAC stiffness score of 10 NRS (i.e., sum of all stiffness item scores on 0-10 NRS scale/2). When 0-4 WOMAC Likert scale is used, the maximum WOMAC stiffness score will be 4 (i.e., sum of all stiffness item scores on 0-4 scale/2) and the above corresponding points will be divided by 2.5. When 0-100 WOMAC VAS scale is used, the maximum WOMAC stiffness score will be 100 (i.e., sum of all item scores on 0-100 VAS scale/2) and the above corresponding points will be multiplied by 10. PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00162] In some embodiments of a method of improving osteoarthritis symptoms, the methods described herein result in a decrease in WOMAC stiffness score in the subject from baseline. For example, a decrease in WOMAC stiffness score in the subject of at least 5%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% in the subject from baseline.
[00163] In some embodiments of a method of improving osteoarthritis symptoms, the methods provided herein result in a decrease in WOMAC stiffness score one day after administration, two days after administration, three days after administration, four days after administration, five days after administration, six days after administration, one week after administration, two weeks after administration, three weeks after administration, four weeks after administration, five weeks after administration, or six weeks after administration.
[00164] In some embodiments of a method of improving osteoarthritis symptoms, the dose administered results in high efficacy and reduced side effects, such as gastrointestinal sides effects or CNS side effects, as compared to a higher dose of the compound or as compared to an efficacious dose of naproxen and/or pregabalin.
[00165] Also disclosed herein is a method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3 S)-3 -((((1 -(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
[00166] In some embodiments of a method of treating pain associated with osteoarthritis, the compound is administered in an amount of 500 mg twice a day (BID).
[00167] Also disclosed herein is a method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3 S)-3 -((((1 -(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
[00168] In some embodiments of a method of treating pain associated with osteoarthritis, the compound is administered in an amount of 250 mg twice a day (BID).
[00169] Also disclosed herein is a method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
[00170] In some embodiments of a method of treating pain associated with osteoarthritis, the compound is: (Compound A) . PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00171] In some embodiments of a method of treating pain associated with osteoarthritis, the compound (for example Compound A or Compound C) is administered in an amount of less than 750 mg twice a day (BID).
[00172] In some embodiments of a method of treating pain associated with osteoarthritis, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 1000 mg per day.
[00173] In some embodiments of a method of treating pain associated with osteoarthritis, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 750 mg twice a day (BID).
[00174] In some embodiments of a method of treating pain associated with osteoarthritis, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 750 mg per day.
[00175] In some embodiments of a method of treating pain associated with osteoarthritis, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 500 mg twice a day (BID).
[00176] In some embodiments of a method of treating pain associated with osteoarthritis, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 500 mg per day.
[00177] In some embodiments of a method of treating pain associated with osteoarthritis, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 250 mg twice a day (BID).
[00178] In some embodiments of a method of treating pain associated with osteoarthritis, the compound is administered in an amount that is less than or equal to 250 mg per day.
[00179] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of a joint.
[00180] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of the knee.
[00181] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of the hip.
[00182] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of the hand.
[00183] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of the shoulder.
[00184] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of the ankle. PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00185] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of the spine joint.
[00186] In some embodiments of a method of treating pain associated with osteoarthritis, the osteoarthritis is osteoarthritis of the elbow.
[00187] In some embodiments of a method of treating pain associated with osteoarthritis, the methods described herein result in a decrease in WOMAC pain score in the subject from baseline. For example, a decrease in WOMAC pain score in the subject of at least 0.5 point from baseline; a decrease in WOMAC pain score in the subject of at least 1 point from baseline; a decrease in WOMAC pain score of at least 1.5 points from baseline; a decrease in WOMAC pain score of at least 2 points from baseline, a decrease in WOMAC pain score of at least 2.5 points from baseline, a decrease in WOMAC pain score of at least 3 points from baseline, a decrease in WOMAC pain score of at least 3.5 points from baseline, a decrease in WOMAC pain score of at least 4 points from baseline, a decrease in WOMAC pain score of at least 5 points from baseline, a decrease in WOMAC pain score of at least 5.5 points from baseline, a decrease in WOMAC pain score of at least 6 points from baseline, a decrease in WOMAC pain score of at least 6.5 points from baseline, a decrease in WOMAC pain score of at least 7 points from baseline, a decrease in WOMAC pain score of at least 7.5 points from baseline, a decrease in WOMAC pain score of at least 8 points from baseline, a decrease in WOMAC pain score of at least 8.5 points from baseline, a decrease in WOMAC pain score of at least 9 points from baseline, a decrease in WOMAC pain score of at least 9.5 points from baseline, or a decrease in WOMAC pain score of at least 10 points from baseline. The above points are based on maximum WOMAC pain score of 10 NRS (i.e., sum of all pain item scores on 0-10 NRS scale/5). When 0-4 WOMAC Likert scale is used, the maximum WOMAC pain score will be 4 (i.e., sum of all pain item scores on 0-4 scale/5) and the above corresponding points will be divided by 2.5. When 0-100 WOMAC VAS scale is used, the maximum WOMAC pain score will be 100 (i.e., sum of all pain item scores on 0-100 VAS scale/5) and the above corresponding points will be multiplied by 10.
[00188] In some embodiments of a method of treating pain associated with osteoarthritis, the methods described herein result in a decrease in WOMAC pain score in the subject from baseline. For example, a decrease in WOMAC pain score in the subject of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% in the subject from baseline. [00189] In some embodiments of a method of treating pain associated with osteoarthritis, the methods provided herein result in a decrease in WOMAC pain score one day after administration, two days after administration, three days after administration, four days after administration, five days after administration, six days after administration, one week after administration, two weeks after administration, three weeks after administration, four weeks after administration, five weeks after administration, or six weeks after administration. PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00190] In some embodiments of a method of treating pain associated with osteoarthritis, the dose administered results in high efficacy and reduced side effects, such as gastrointestinal sides effects or CNS side effects, as compared to a higher dose of the compound or as compared to an efficacious dose of naproxen and/or pregabalin.
[00191] Also disclosed herein is a method of treating chronic pain in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3 S)-3 -((((1 - (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
[00192] In some embodiments of a method of treating chronic pain, the compound is administered in an amount of 500 mg twice a day (BID).
[00193] Also disclosed herein is a method of treating chronic pain in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3S)-3 -((((1 - (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
[00194] In some embodiments of a method of treating chronic pain, the compound is administered in an amount of 250 mg twice a day (BID).
[00195] Also disclosed herein is a method of treating chronic pain in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)- 3-((((l-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
[00196] In some embodiments of a method of treating chronic pain, the compound is: (Compound A) .
[00197] In some embodiments of a method of treating chronic pain, the compound (for example Compound A or Compound C) is administered in an amount of less than 750 mg twice a day (BID).
[00198] In some embodiments of a method of treating chronic pain, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 1000 mg per day.
[00199] In some embodiments of a method of treating chronic pain, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 750 mg twice a day (BID). PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00200] In some embodiments of a method of treating chronic pain, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 750 mg per day.
[00201] In some embodiments of a method of treating chronic pain, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 500 mg twice a day (BID).
[00202] In some embodiments of a method of treating chronic pain, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 500 mg per day.
[00203] In some embodiments of a method of treating chronic pain, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 250 mg twice a day (BID).
[00204] Chronic pain is pain that lasts longer than the usual recovery period or persists alongside a chronic health condition. It can be continuous or intermittent, and can range from mild to severe. Chronic pain is different from acute pain, which develops quickly and doesn't usually last long, like pain from an injury.
[00205] In some embodiments of a method of treating chronic pain, the chronic pain comprises migraine, headache, trigeminal neuralgia, cervical radiculopathy, thoracic outlet syndrome, spinal pain, peripheral nerve compression, diabetic neuropathy, herpes neuralgia, carpal tunnel syndrome, frozen shoulder, sciatic, back pain, cancer pain, hip impingement syndrome, shoulder impingement syndrome, rotator cuff tear, irritable bowel syndrome, and chronic visceral organ pain. In some embodiments of a method of treating chronic pain, the chronic pain is pain caused by osteoarthritis.
[00206] In some embodiments of a method of treating chronic pain, the dose administered results in high efficacy and reduced side effects, such as gastrointestinal sides effects or CNS side effects, as compared to a higher dose of the compound or as compared to an efficacious dose of naproxen and/or pregabalin.
[00207] Also disclosed herein is a method of treating acute pain in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
[00208] In some embodiments of a method of treating acute pain, the compound is administered in an amount of 500 mg twice a day (BID).
[00209] Also disclosed herein is a method of treating acute pain in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6-
- 1 - PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601 methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
[00210] In some embodiments of a method of treating acute pain, the compound is administered in an amount of 250 mg twice a day (BID).
[00211] Also disclosed herein is a method of treating acute pain in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)-3-((((l - (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid (Compound C).
[00212] In some embodiments of a method of treating acute pain, the compound is: (Compound A) .
[00213] In some embodiments of a method of treating acute pain, the compound (for example Compound A or Compound C) is administered in an amount of less than 750 mg twice a day (BID).
[00214] In some embodiments of a method of treating acute pain, the compound is administered in an amount that is less than or equal to 1000 mg per day.
[00215] In some embodiments of a method of treating acute pain, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 750 mg twice a day (BID).
[00216] In some embodiments of a method of treating acute pain, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 750 mg per day.
[00217] In some embodiments of a method of treating acute pain, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 500 mg twice a day (BID).
[00218] In some embodiments of a method of treating acute pain, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 500 mg per day.
[00219] In some embodiments of a method of treating acute pain, the compound (for example Compound A or Compound C) is administered in an amount that is less than or equal to 250 mg twice a day (BID).
[00220] Acute pain is a sudden or urgent pain that is usually severe but lasts a relatively short time, often less than a month. It can be caused by injury, trauma, surgery, or other medical treatments. Acute pain is expected and common after surgery, and it serves as a warning of disease or a threat to the body. PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00221] In some embodiments of a method of treating acute pain, the acute pain is post- surgical pain, post-trauma soft tissue pain, post fracture pain, post-sprain, bum wound, toothache, menstrual pain, or visceral organ pain.
[00222] In some embodiments of a method of treating acute pain, the acute pain is following bunionectomy.
[00223] In some embodiments of a method of treating acute pain, the dose administered results in high efficacy and reduced side effects, such as gastrointestinal sides effects or CNS side effects, as compared to a higher dose of the compound or as compared to an efficacious dose of naproxen and/or pregabalin.
[00224] Also disclosed herein is a method of treating acute pain, (e.g., following bunionectomy), in a subject in need thereof; the method comprising administering 1500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
[00225] In some embodiments of a method of treating acute pain, the compound is: (Compound A) .
[00226] In some embodiments of a method of treating acute pain, the compound (for example Compound A or Compound C) is administered in an amount of 750 mg twice a day (BID).
[00227] Also disclosed herein is a method of treating acute pain, (e.g., following bunionectomy), in a subject in need thereof; the method comprising administering 2500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C). In some embodiments of a method of treating acute pain, the compound is: (Compound A) .
[00228] In some embodiments of a method of treating acute pain, the compound (for example Compound A or Compound C) is administered in an amount of 1250 mg twice a day (BID).
[00229] Also disclosed herein is a method for treating postoperative sleep disturbances in a subject in need thereof; the method comprising administering a compound that is (3S)-3-((((l-(((S)- 2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C). PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00230] In some embodiments of a method for treating postoperative sleep disturbances, the (Compound A) .
[00231] In some embodiments of a method for treating postoperative sleep disturbances, the (Compound B) .
[00232] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of between 1000 mg and 3000 mg a day.
[00233] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of between 1500 mg and 2500 mg a day.
[00234] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of 1250 mg twice a day (BID).
[00235] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of 750 mg twice a day (BID).
[00236] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 3000 mg per day.
[00237] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 2500 mg per day.
[00238] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 1250 mg twice a day (BID).
[00239] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 750 mg twice a day (BID). PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00240] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 750 mg per day.
[00241] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 1000 mg per day.
[00242] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 500 mg twice a day (BID).
[00243] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 500 mg per day.
[00244] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 250 mg twice a day (BID).
[00245] In some embodiments of a method for treating postoperative sleep disturbances, the compound is administered in an amount that is less than or equal to 250 mg per day.
[00246] In some embodiments of a method for treating postoperative sleep disturbances, the postoperative sleep disturbances comprise decreased sleep time, increased awakenings, lowered sleep quality, nightmares, and Loss of REM or SWS sleep.
[00247] In some embodiments of a method for treating postoperative sleep disturbances, the postoperative sleep disturbance is measured by the Sleep Interference Score (SIS) questionnaire (or other sleep assessment measurements) 24h post-surgery, 48h post-surgery, and 72h post-surgery.
[00248] In some embodiments of a method for treating postoperative sleep disturbances, the 24h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
[00249] In some embodiments of a method for treating postoperative sleep disturbances, the 48h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
[00250] In some embodiments of a method for treating postoperative sleep disturbances, the 72h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
[00251] In some embodiments of a method for treating postoperative sleep disturbances, the 24h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo. PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00252] In some embodiments of a method for treating postoperative sleep disturbances, the 48h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
[00253] In some embodiments of a method for treating postoperative sleep disturbances, the 72h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
[00254] Also disclosed herein is a method for improving post-surgery sleep quality in a subject in need thereof; the method comprising administering a compound that is (3 S)-3-((((l -(((S)- 2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
[00255] In some embodiments of a method for improving post-surgery sleep quality, the (Compound A) .
[00256] In some embodiments of a method for improving post-surgery sleep quality, the (Compound B) .
[00257] In some embodiments of a method for improving post-surgery sleep quality, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of between 1000 mg and 3000 mg a day.
[00258] In some embodiments of a method for improving post-surgery sleep quality, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of between 1500 mg and 2500 mg a day.
[00259] In some embodiments of a method for improving post-surgery sleep quality, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of 1250 mg twice a day (BID).
[00260] In some embodiments of a method for improving post-surgery sleep quality, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of 750 mg twice a day (BID).
[00261] In some embodiments of a method for improving post-surgery sleep quality, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 3000 mg per day. PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00262] In some embodiments of a method for improving post-surgery sleep quality, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 2500 mg per day.
[00263] In some embodiments of a method for improving post-surgery sleep quality, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 1250 mg twice a day (BID).
[00264] In some embodiments of a method for improving post-surgery sleep quality, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 1000 mg per day.
[00265] In some embodiments of a method for improving post-surgery sleep quality, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 750 mg twice a day (BID).
[00266] In some embodiments of a method for improving post-surgery sleep quality, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 750 mg per day.
[00267] In some embodiments of a method for improving post-surgery sleep quality, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 500 mg twice a day (BID).
[00268] In some embodiments of a method for improving post-surgery sleep quality, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 500 mg per day.
[00269] In some embodiments of a method for improving post-surgery sleep quality, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 250 mg twice a day (BID).
[00270] In some embodiments of a method for improving post-surgery sleep quality, the compound is administered in an amount that is less than or equal to 250 mg per day.
[00271] In some embodiments of a method for improving post-surgery sleep quality, the improvement in post-surgery sleep quality is measured by the Sleep Interference Score (SIS) questionnaire (or other sleep assessment measurements) 24h post-surgery, 48h post-surgery, and 72h post-surgery.
[00272] In some embodiments of a method for improving post-surgery sleep quality, the 24h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
[00273] In some embodiments of a method for improving post-surgery sleep quality, the 48h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo. PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00274] In some embodiments of a method for improving post-surgery sleep quality, the 72h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
[00275] In some embodiments of a method for improving post-surgery sleep quality, the 24h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
[00276] In some embodiments of a method for improving post-surgery sleep quality, the 48h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
[00277] In some embodiments of a method for improving post-surgery sleep quality, the 72h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
[00278] Also disclosed herein is a method for improving post-surgery sleep impairment in a subject in need thereof; the method comprising administering a compound that is (3 S)-3-((((l -(((S)-
2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
[00279] In some embodiments of a method for improving post-surgery sleep impairment, the (Compound A) .
[00280] In some embodiments of a method for improving post-surgery sleep impairment, the (Compound B) .
[00281] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of between 1000 mg and 3000 mg a day.
[00282] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of between 1500 mg and 2500 mg a day.
[00283] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of 1250 mg twice a day (BID). PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00284] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of 750 mg twice a day (BID).
[00285] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 3000 mg per day.
[00286] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 2500 mg per day.
[00287] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 1250 mg twice a day (BID).
[00288] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 1000 mg per day.
[00289] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 750 mg twice a day (BID).
[00290] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 750 mg per day.
[00291] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 500 mg twice a day (BID).
[00292] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 500 mg per day.
[00293] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 250 mg twice a day (BID).
[00294] In some embodiments of a method for improving post-surgery sleep impairment, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 250 mg per day.
[00295] In some embodiments of a method for improving post-surgery sleep impairment, the improvement in post-surgery sleep impairment is measured by the Sleep Interference Score (SIS) PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601 questionnaire (or other sleep assessment measurements) 24h post-surgery, 48h post-surgery, and 72h post-surgery.
[00296] In some embodiments of a method for improving post-surgery sleep impairment, the 24h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
[00297] In some embodiments of a method for improving post-surgery sleep impairment, the 48h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
[00298] In some embodiments of a method for improving post-surgery sleep impairment, the 72h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
[00299] In some embodiments of a method for improving post-surgery sleep impairment, the 24h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
[00300] In some embodiments of a method for improving post-surgery sleep impairment, the 48h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
[00301] In some embodiments of a method for improving post-surgery sleep impairment, the 72h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
[00302] Also disclosed herein is a method for improving post-surgery sleep interference in a subject in need thereof; the method comprising administering a compound that is (3S)-3-((((l-(((S)- 2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C).
[00303] In some embodiments of a method for improving post-surgery sleep interference, the
[00304] In some embodiments of a method for improving post-surgery sleep interference, the PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00305] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of between 1000 mg and 3000 mg a day.
[00306] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of between 1500 mg and 2500 mg a day.
[00307] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of 1250 mg twice a day (BID).
[00308] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of 750 mg twice a day (BID).
[00309] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 3000 mg per day.
[00310] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 2500 mg per day.
[00311] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 1250 mg twice a day (BID).
[00312] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 1000 mg per day.
[00313] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 750 mg twice a day (BID).
[00314] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 750 mg per day.
[00315] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 500 mg twice a day (BID).
[00316] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 500 mg per day. PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00317] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 250 mg twice a day (BID).
[00318] In some embodiments of a method for improving post-surgery sleep interference, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 250 mg per day.
[00319] In some embodiments of a method for improving post-surgery sleep interference, the improvement in post-surgery sleep interference is measured by the Sleep Interference Score (SIS) questionnaire (or other sleep assessment measurements) 24h post-surgery, 48h post-surgery, and 72h post-surgery.
[00320] In some embodiments of a method for improving post-surgery sleep interference, the 24h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
[00321] In some embodiments of a method for improving post-surgery sleep interference, the 48h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
[00322] In some embodiments of a method for improving post-surgery sleep interference, the 72h post-surgery SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
[00323] In some embodiments of a method for improving post-surgery sleep interference, the 24h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
[00324] In some embodiments of a method for improving post-surgery sleep interference, the 48h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
[00325] In some embodiments of a method for improving post-surgery sleep interference, the 72h post-surgery SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
[00326] Also disclosed herein is a method for treating sleep disturbances in a subject with chronic pain; the method comprising administering a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid (Compound C). PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00327] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound is: (Compound
A) .
[00328] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound is: (Compound
B) .
[00329] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of between 1000 mg and 3000 mg a day.
[00330] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of between 1500 mg and 2500 mg a day.
[00331] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of 1250 mg twice a day (BID).
[00332] In some embodiments of a method for treating postoperative sleep disturbances, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount of 750 mg twice a day (BID).
[00333] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 3000 mg per day.
[00334] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 2500 mg per day.
[00335] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 1250 mg twice a day (BID).
[00336] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 750 mg twice a day (BID). PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601
[00337] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 750 mg per day.
[00338] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 1000 mg per day.
[00339] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 500 mg twice a day (BID).
[00340] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 500 mg per day.
[00341] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 250 mg twice a day (BID).
[00342] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the compound (for example Compound A, Compound B, or Compound C) is administered in an amount that is less than or equal to 250 mg per day.
[00343] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the sleep disturbances comprise decreased sleep time, increased awakenings, lowered sleep quality, nightmares, and Loss of REM or SWS sleep.
[00344] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the sleep disturbance is measured by the Sleep Interference Score (SIS) questionnaire (or other sleep assessment measurements).
[00345] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the SIS score (or other sleep assessment measurements) is about 3 times better than when administered a placebo.
[00346] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the SIS score (or other sleep assessment measurements) is about 2 times better than when administered a placebo.
[00347] In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the chronic pain comprises migraine, headache, trigeminal neuralgia, cervical radiculopathy, thoracic outlet syndrome, spinal pain, peripheral nerve compression, diabetic neuropathy, herpes neuralgia, carpal tunnel syndrome, frozen shoulder, sciatic, back pain, cancer pain, hip impingement syndrome, shoulder impingement syndrome, rotator cuff tear, irritable bowel PCT/US25/40285 01 August 2025 (01.08.2025)
WSGR Docket No. 50048-714.601 syndrome, and chronic visceral organ pain. In some embodiments of a method for treating sleep disturbances in a subject with chronic pain, the chronic pain is pain caused by osteoarthritis.
[00348] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
EXAMPLES
[00349] The following examples are provided to further illustrate some embodiments of the present disclosure, but are not intended to limit the scope of the disclosure; it will be understood by their exemplary nature that other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.
Example 1
[00350] Study Design and Results: A 3-arm, double-blind, placebo-controlled, parallel-group, randomized and multiple center study was conducted to investigate the safety and efficacy of Compound A in patients with moderate to severe pain of osteoarthritis (OA) of the knee. Subject’s eligibility was established based on screening evaluations and post -washout period baseline evaluations. Eligible subjects were randomized, titrated as shown in the table 1 and then given study drug of either Compound A at 500 mg BID, 750 mg BID, or placebo BID for total 4 weeks. Subjects were assessed at 1, 2 and 4 weeks after randomization at office visits, followed by a safety follow-up phone call by the end of the fifth week.
Table 1. Dose Titration
[00351] Total 318 subjects were randomized at 2: 1 :2 ratio into 750 mg, 500 mg, or placebo arm, respectively, from 22 study sites across China. The trial included the widely used assessment tool for OA clinical research, namely, the Western Ontario and McMaster Universities Osteoarthritis PCT/US25/40285 01 August 2025 (01.08.2025)
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Index (WOMAC). WOMAC is a questionnaire that contains 24 questions for patients to assess the severity of joint pain (5 questions), stiffness (2 questions) and functional limitation (17 questions).
• Pain (5 items): during walking, using stairs, in bed, sitting or lying, and standing upright.
• Stiffness (2 items): after first waking and later in the day.
• Physical Function (17 items): using stairs, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy domestic duties, light domestic duties.
[00352] Demographics and baseline conditions were comparable across the different arms.
[00353] The results showed that 500 mg BID Compound A was as effective as 750 mg BID in relieving pain, improving joint stiffness and functional limitation, with statistically significant difference from those of placebo (FIG. 1, FIG. 2, and FIG. 3). 250 mg QD and BID for the first 2 days during titration period also improved daily walking pain significantly greater than placebo (Changes from Baseline in Daily Walking Pain score (LSM±SE) were -0.23±0.06 and -0.05±0.0652 for active arm and placebo, respectively, P=0.0467) - see table 2. The active metabolites from one 250 mg Compound A tablet are approximately equivalent to 120 mg naproxen and 65 mg pregabalin blood exposures (AUC), respectively. While currently naproxen is prescribed at 1000 mg/day with gastrointestinal, renal, and cardiovascular side effects; and pregabalin is currently prescribed up to 600 mg/day, which is associated with side effects of dizziness, somnolence, etc. Thus, Compound A at 500 mg BID or lower dose offer sufficient pain relief with potential improvement in drug safety. [00354] Subjects were also asked to record any sleep interference caused by knee pain every day.
[00355] FIG. 4 shows the weekly sleep disturbance scores as measured by the Sleep Interference Score (SIS) questionnaire.
Table 2. Compound A administered at 250 mg BID showed early onset of pain suppression effect during titration phase.
Change from Baseline in Daily Walking Pain on Day 2 when drug was given at 250 mg BID
750+500 mg groups Placebo
(N=185) (N=131)
Change from Baseline in Daily Walking Pain
Mean(SD) -0.281(0.8155) -0.099(0.7465)
Q1,Q3 -0.667,0.000 -0.429,0.143
Mm, Max -5.14,2.29 -2.71,2.29 PCT/US25/40285 01 August 2025 (01.08.2025)
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Least Square Mean -0.23 -0.05 (95% CI) (-0.36,-0.10) (-0.20,0.10)
Difference over Placebo -0.18
(95% CI) (-0.35,-0.00)
P Value vs. Placebo 0.0467
Example 2
[00356] Trial description: A multiple-center, placebo-controlled, dose-ranging Phase 2b study in patients undergoing bunionectomy was conducted to evaluate the safety and efficacy of the Compound A oral tablet on acute pain. Total 450 patients were randomized in a 1 : 1 : 1 ratio into either placebo, 750 mg, or 1250 mg of Compound A groups. The study drug or placebo was administered twice a day (bid) starting one hour prior to surgery to 72 hours post-surgery. Sleep quality was assessed at 24-, 48- and 72-hours post-surgery by using the Sleep Interference Score (SIS) questionnaire, along with other efficacy measurements (see Tables 3, 4, and 5). The SIS questionnaire is a validated tool: On a scale of 0-10, please rate how the pain at the operation site has interfered with your sleep during the last 24 hours (0=no interference, 10=worst interference imaginable).
[00357] Results: SIS score of the 1250 mg groups was statistically significantly lower than in the placebo group (1.49, 1.22, and 1.06 versus 4.81, 3.42, 3.30 at 24h, 48h, and 72h respectively, P< 0.0001). SIS of the 750 mg group was statistically significantly lower than in the placebo group (1.98, 1.43, and 1.58 versus 4.95, 3.45, and 3.36 at 24h, 48h, and 72h respectively, P< 0.0001). It can be concluded that treatment with Compound A significantly reduced sleep disturbance caused by surgery.
Table 3 PCT/US25/40285 01 August 2025 (01.08.2025)
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Table 4
Table 5

Claims

WSGR Docket No. 50048-714.601 CLAIMS WHAT IS CLAIMED IS:
1. A method for improving osteoarthritis symptoms in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
2. The method of claim 1, wherein the compound is administered in an amount of 500 mg twice a day (BID).
3. A method for improving osteoarthritis symptoms in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
4. The method of claim 3, wherein the compound is administered in an amount of 250 mg twice a day (BID).
5. A method for improving osteoarthritis symptoms in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)-3-((((l - (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
6. The method of claim 5, wherein the compound is administered in an amount of less than 750 mg twice a day (BID).
7. The method of claim 5, wherein the compound is administered in an amount that is less than or equal to 1000 mg per day.
8. The method of claim 5, wherein the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
9. The method of claim 5, wherein the compound is administered in an amount that is less than or equal to 500 mg per day.
10. The method of claim 5, wherein the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
11. The method of any one of claims 1-10, wherein the compound is: (Compound A) .
12. The method of any one of claims 1-11, wherein the osteoarthritis is osteoarthritis of a joint.
13. The method of any one of claims 1-11, wherein the osteoarthritis is osteoarthritis of the knee.
14. The method of any one of claims 1-11, wherein the osteoarthritis is osteoarthritis of the hip. WSGR Docket No. 50048-714.601
15. The method of any one of claims 1-11, wherein the osteoarthritis is osteoarthritis of the hand.
16. The method of any one of claims 1-11, wherein the osteoarthritis is osteoarthritis of the shoulder.
17. The method of any one of claims 1-11, wherein the osteoarthritis is osteoarthritis of the ankle.
18. The method of any one of claims 1-11, wherein the osteoarthritis is osteoarthritis of the spine joint.
19. The method of any one of claims 1-18, wherein the osteoarthritis symptom is pain associated with osteoarthritis.
20. The method of claim 18, wherein the pain associated with osteoarthritis is decreased.
21. The method of any one of claims 1-18, wherein the osteoarthritis symptom is joint stiffness.
22. The method of claim 21, wherein the joint stiffness is lessened.
23. The method of any one of claims 1-18, wherein the osteoarthritis symptom is loss of physical functions.
24. The method of claim 23, wherein physical functions includes using stairs, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy domestic duties, light domestic duties.
25. The method of claim 23 or 24, wherein the physical functions are improved.
26. A method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3S)-3-((((l-(((S)- 2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
27. The method of claim 26, wherein the compound is administered in an amount of 500 mg twice a day (BID).
28. A method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3S)-3-((((l-(((S)-2- (6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid.
29. The method of claim 28, wherein the compound is administered in an amount of 250 mg twice a day (BID).
30. A method of treating pain associated with osteoarthritis in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3S)-3- ((((l-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5- methylhexanoic acid. WSGR Docket No. 50048-714.601
31. The method of claim 30, wherein the compound is administered in an amount of less than 750 mg twice a day (BID).
32. The method of claim 30, wherein the compound is administered in an amount that is less than or equal to 1000 mg per day.
33. The method of claim 30, wherein the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
34. The method of claim 30, wherein the compound is administered in an amount that is less than or equal to 500 mg per day.
35. The method of claim 30, wherein the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
36. The method of any one of claims 25-34, wherein the compound is: (Compound A) .
37. The method of any one of claims 26-36, wherein the osteoarthritis is osteoarthritis of a joint.
38. The method of any one of claims 26-36, wherein the osteoarthritis is osteoarthritis of the knee.
39. The method of any one of claims 26-36, wherein the osteoarthritis is osteoarthritis of the hip.
40. The method of any one of claims 26-36, wherein the osteoarthritis is osteoarthritis of the hand.
41. The method of any one of claims 26-36, wherein the osteoarthritis is osteoarthritis of the shoulder.
42. The method of any one of claims 26-36, wherein the osteoarthritis is osteoarthritis of the ankle.
43. The method of any one of claims 26-36, wherein the osteoarthritis is osteoarthritis of the spine joint.
44. A method of treating chronic pain in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
45. The method of claim 44, wherein the compound is administered in an amount of 500 mg twice a day (BID).
46. A method of treating chronic pain in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- WSGR Docket No. 50048-714.601 methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
47. The method of claim 46, wherein the compound is administered in an amount of 250 mg twice a day (BID).
48. A method of treating chronic pain in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3 S)-3-((((l -(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
49. The method of claim 48, wherein the compound is administered in an amount of less than 750 mg twice a day (BID).
50. The method of claim 48, wherein the compound is administered in an amount that is less than or equal to 1000 mg per day.
51. The method of claim 48, wherein the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
52. The method of claim 48, wherein the compound is administered in an amount that is less than or equal to 500 mg per day.
53. The method of claim 48, wherein the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
54. The method of any one of claims 44-53, wherein the compound is: (Compound A) .
55. The method of any one of claims 44-54, wherein the chronic pain comprises migraine, headache, trigeminal neuralgia, cervical radiculopathy, thoracic outlet syndrome, spinal pain, peripheral nerve compression, diabetic neuropathy, herpes neuralgia, carpal tunnel syndrome, frozen shoulder, sciatic, back pain, cancer pain, hip impingement syndrome, shoulder impingement syndrome, rotator cuff tear, irritable bowel syndrome, and chronic visceral organ pain.
56. A method of treating acute pain in a subject in need thereof; the method comprising administering 1000 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
57. The method of claim 56, wherein the compound is administered in an amount of 500 mg twice a day (BID). WSGR Docket No. 50048-714.601
58. A method of treating acute pain in a subject in need thereof; the method comprising administering 500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
59. The method of claim 58, wherein the compound is administered in an amount of 250 mg twice a day (BID).
60. A method of treating acute pain in a subject in need thereof; the method comprising administering less than 1500 mg per day of a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
61. The method of claim 60, wherein the compound is administered in an amount of less than 750 mg twice a day (BID).
62. The method of claim 60, wherein the compound is administered in an amount that is less than or equal to 1000 mg per day.
63. The method of claim 60, wherein the compound is administered in an amount that is less than or equal to 500 mg twice a day (BID).
64. The method of claim 60, wherein the compound is administered in an amount that is less than or equal to 500 mg per day.
65. The method of claim 60, wherein the compound is administered in an amount that is less than or equal to 250 mg twice a day (BID).
66. The method of any one of claims 56-65, wherein the compound is: (Compound A) .
67. The method of any one of claims 56-66, wherein the acute pain is post-surgical pain, posttrauma soft tissue pain, post fracture pain, post-sprain, bum wound, toothache, menstrual pain, or visceral organ pain.
68. A method for treating postoperative sleep disturbances in a subject in need thereof; the method comprising administering a compound that is (3S)-3-((((l-(((S)-2-(6- methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
69. The method of claim 68, wherein the compound is administered in an amount of between 1500 mg and 2500 mg a day.
70. The method of claim 68 or 69, wherein the compound is administered in an amount of less than or equal to 1250 mg twice a day (BID). WSGR Docket No. 50048-714.601
71. The method of any one of claims 68-70, wherein the compound is administered in an amount of less than or equal to 750 mg twice a day (BID).
72. The method of any one of claims 68-70, wherein the postoperative sleep disturbances comprise decreased sleep time, increased awakenings, lowered sleep quality, nightmares, and Loss of REM or SWS sleep.
73. The method of any one of claims 68-72, wherein the postoperative sleep disturbance is measured by the Sleep Interference Score (SIS) questionnaire 24h post-surgery, 48h postsurgery, and 72h post-surgery.
74. The method of claim 73, wherein the 24h post-surgery SIS score is about 3 times better than when administered a placebo.
75. The method of claim 73, wherein the 48h post-surgery SIS score is about 3 times better than when administered a placebo.
76. The method of claim 73, wherein the 72h post-surgery SIS score is about 3 times better than when administered a placebo.
77. The method of claim 73, wherein the 24h post-surgery SIS score is about 2 times better than when administered a placebo.
78. The method of claim 73, wherein the 48h post-surgery SIS score is about 2 times better than when administered a placebo.
79. The method of claim 73, wherein the 72h post-surgery SIS score is about 2 times better than when administered a placebo.
80. A method for improving post-surgery sleep quality in a subject in need thereof; the method comprising administering a compound that is (3S)-3-((((l-(((S)-2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.
81. The method of claim 80, wherein the compound is administered in an amount of between 1500 mg and 2500 mg a day.
82. The method of claim 80 or 81, wherein the compound is administered in an amount of less than or equal to 1250 mg twice a day (BID).
83. The method of any one of claims 80-82, wherein the compound is administered in an amount of less than or equal to 750 mg twice a day (BID).
84. The method of any one of claims 80-83, wherein the improvement in post-surgery sleep quality is measured by the Sleep Interference Score (SIS) questionnaire 24h post-surgery, 48h post-surgery, and 72h post-surgery.
85. The method of claim 84, wherein the 24h post-surgery SIS score is about 3 times better than when administered a placebo.
86. The method of claim 84, wherein the 48h post-surgery SIS score is about 3 times better than when administered a placebo. WSGR Docket No. 50048-714.601
87. The method of claim 84, wherein the 72h post-surgery SIS score is about 3 times better than when administered a placebo.
88. The method of claim 84, wherein the 24h post-surgery SIS score is about 2 times better than when administered a placebo.
89. The method of claim 84, wherein the 48h post-surgery SIS score is about 2 times better than when administered a placebo.
90. The method of claim 84, wherein the 72h post-surgery SIS score is about 2 times better than when administered a placebo.
91. The method of any one of claims 68-90, wherein the compound is: (Compound A) .
92. The method of any one of claims 68-90, wherein the compound is: (Compound B) .
PCT/US2025/040285 2024-08-05 2025-08-01 Naproxen/pregabalin conjugate dosing regimen Pending WO2026035552A1 (en)

Applications Claiming Priority (2)

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US63/722,764 2024-11-20

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