WO2018029505A1 - Cer-001 therapy for treating familial primary hypoalphalipoproteinemia - Google Patents

Abstract

Methods for treating a subject by administering CER-001 to the subject according to an induction regimen comprising multiple doses of CER-001 administered five or more days apart and subsequently administering CER-001 to the subject according to a maintenance regimen.

Description

CER-001 THERAPY FOR TREATING FAMILIAL PRIMARY

HYPOALPHALIPOPROTEINEMIA

1. BACKGROUND

1.1. Familial primary hypoalphalipoproteinemia (FPHA)

[0001 ] ATP binding cassette transporter A1 (ABCA1 ) and apolipoprotein Al (ApoA-l) deficiencies are underlying causes of familial primary hypoalphalipoproteinemia (FPHA). FPHA is caused by genetic defect in one or more of the genes responsible for high- density lipoprotein (HDL) synthesis/maturation, such as ATP-binding cassette transporter 1 (ABCA1 ) and apolipoprotein A-l (ApoA-l), and is associated with a very low number of HDL particles, also reflected in a very low plasma concentration of ApoA-l. The disease is also generally associated with a positive family history of low HDL-cholesterol (HDL-C) or premature cardiovascular disease.

[0002] The underlying etiology for all clinical phenotypes of ABCA1 and ApoA-l deficiencies is the imbalance in cholesterol metabolism. The major carriers for cholesterol in the blood are lipoproteins, including the low-density lipoprotein (or LDL) particles, and the HDL particles. In a healthy human body, there is a balance between the delivery and removal of cholesterol. The LDL particles deliver cholesterol to organs, where it can be used to produce hormones, maintain healthy cells, and be transformed into natural products that assist in the digestion of lipids. The HDL particles remove cholesterol from arteries and tissues to transport it back to the liver for storage, recycling, and elimination through a pathway called reverse lipid transport (RLT).

[0003] Mutations in the key HDL gene products, like ABCA1 , ApoA-l and lecithin :cholesterol acyltransferase (LCAT), result in low circulating levels of HDL particles in these patients and, as such, an absent or deficient RLT capacity which is insufficient to prevent the accumulation of cholesterol in the peripheral tissues. The accumulation of cholesterol in the peripheral tissues can result in the development of premature cardiovascular disease.

[0004] Current management of patients with FPHA is very limited and is focused on diet control and aggressive LDL-cholesterol (LDL-C)-directed pharmacotherapy. There is no treatment currently available that can directly restore normal HDL levels or function.

[0005] Epidemiological studies have consistently shown that decreased HDL-C levels (hypoalphalipoproteinemia) are strongly associated with an increased risk of developing Coronary Arterial Disease (CAD) (Vega and Grundy, 1996, Curr Opin Lipidol. 7(4):209-16; Calabresi and Franceschini, 1997, Curr Opin Lipidol. 8(4):219-24). 1.2. Mutations in ApoA-l

[0006] Several mutation variants of ApoA-l have been identified. Homozygous patients have almost undetectable plasma ApoA-l and HDL-C levels. Heterozygosity often results in approximately half-normal plasma ApoA-l and HDL-C concentrations (Calabresi and Franceschini, 1997, Curr Opin Lipidol. 8(4):219-24). However, there are also many heterozygous variants that do not seem to affect HDL-C levels. Class I mutations prevent the synthesis of ApoA-l and are associated with accumulation of cholesterol in tissues, manifesting clinically as xanthomatosis, corneal opacity and premature atherosclerosis in the affected individuals. Class II mutations lead to the production of truncated proteins and are variably associated with coronary risk. Class III mutations cause the synthesis of an ApoA-l species with a grossly altered conformation that is not able to associate with LCAT, thus causing corneal opacity but not necessarily premature coronary heart disease (CHD).

[0007] Approximately 25 patients with complete ApoA-l deficiency have been reported by different authors (Ikewaki et ai, 2004, Atherosclerosis 172(1 ):39-45; Yokota et ai, 2002,

Atherosclerosis 162(2):399-407; Pisciotta et ai, 2003, Atherosclerosis 167(2):335-45).

Almost all cases were characterized by the absence of or low levels of HDL-C, and CAD was present in 1 1 of these patients; 13 of the remaining cases were below age 50, perhaps before clinical atherosclerosis could become manifest. A family clustering of ApoA-l deficiency in Brazil caused by intermarriage has been reported, where a detailed description of two brothers indicated significant cardiovascular disease by their early 40s

(Santos et al., 2008, J Lipid Res. 49(2):349-57).

1.3. Mutations in ABCA1

[0008] In humans, homozygous mutations in the ABCA1 gene leading to defective or non- functional ABCA1 receptors result in Tangier disease, characterized by profoundly decreased HDL-C, ApoA-l and ApoA-ll levels, reduced total and LDL-C and ApoB, and elevated plasma triglyceride levels. With ABCA1 deficiency, ApoA-l is rapidly cleared before it is able to acquire cholesterol. The cholesterol storage disorder that occurs with ABCA1 mutations might thus possibly be more a consequence of HDL deficiency than a direct consequence of dysfunctional ABCA1 (Attie et ai, 2001 , J Lipid Res. 42(1 1 ):1717- 26).

[0009] Homozygous (Tangier disease) patients develop peripheral neuropathy and premature CHD, caused by cholesteryl ester (CE) deposition in a variety of cell types, although the CHD risk differs from one kindred to another, probably because of the reported genetic heterogeneity of the disease (Calabresi and Franceschini, 1997 Curr Opin Lipidol. 8(4):219-24). Even in heterozygote ABCA1 deficiency patients, radiolabeled HDL was more rapidly catabolized than in healthy controls. Therefore, the metabolic basis of Tangier disease is a rapid catabolism of ApoA-l and HDL, rather than a defect in their biosynthesis (Puntoni et al., 2012, Am J Cardiovasc Drugs. 1 ;12(5):303-1 1 ). This condition results in an accumulation of CE in many tissues throughout the body, and fibroblasts are characterized by defective efflux capacity. The deposition of CE in the reticuloendothelial organs results in orange-colored tonsils.

[0010] The overall data emerging from studies evaluating patients with ABCA1 mutations are indicative of a link with the development of atherosclerosis and increased vascular disease risk (Clee et al., 2000, J Clin Invest. 106(10):1263-70; van Dam et al., 2002, Lancet 359(9300):37-42).

1.4. Atherosclerosis in FPHA

[0011 ] Atherosclerosis is thought to develop following an imbalance in which there is too much cholesterol delivery by LDL particles relative to the amount of removal by HDL particles.

[0012] In animal studies, increasing HDL-C in transgenic mice and rabbits by overexpressing ApoA-l, a major protein in HDL-C, was associated with protection against diet-induced atherosclerosis (Paszty et al, 1994, J Clin Invest. 94(2):899-903; Plump et al., 1994, PNAS 91 (20):9607-1 1 ; Duverger et al., 1996, Circulation 94(4):713-7).

[0013] In humans, FPHA has been reported as highly correlated with higher incidence of premature CAD (Genest et al., 1992, Circulation (6):2025-33; Genest et al., 1993, Arterioscler Thromb. (12):1728-37) and tissue cholesterol efflux was decreased in patients with FPHA which coincided with accelerated and premature atherosclerosis (Kootte et al., 2015, J Lipid Res. 56(3):703-12).

1.5. CER-001

[0014] CER-001 , a negatively charged lipoprotein complex, comprises recombinant human ApoA-l, sphingomyelin (SM), and 1 , 2-dihexadecanoyl-sn-glycero-3-phospho-(1 '- rac-glycerol) (Dipalmitoylphosphatidyl-glycerol; DPPG). It mimics natural, nascent discoidal pre-beta HDL, which is the form that HDL particles take prior to acquiring cholesterol.

[0015] A proof-of-concept study with seven subjects having ApoA-l, ABCA1 , or LCAT mutations (termed SAMBA) found that CER-001 regressed carotid artery inflammation and atherosclerosis and increased elimination of cholesterol from the body (Kootte et al., 2015, J Lipid Res. 56(3):703-12; WO/2015/173633). In the SAMBA study, subjects received 9 infusions of CER-001 over 4 weeks (one week after the first infusion, the second to ninth infusions were given every 3 days over a 3 week period) followed by 1 1 infusions every 2 weeks.

[0016] The encouraging efficacy results seen to date in clinical studies with CER-001 indicate that CER-001 can bring substantial benefit to patients with FHPA. New methods for using CER-001 that increase patient compliance are needed.

2. SUMMARY

[0017] The present disclosure provides new dosing regimens for CER-001 therapy that are more amenable with patient compliance than prior regimens.

[0018] The new dosing regimens typically entail administering CER-001 at a reduced frequency and/or reduced overall dose than previously used for patients with familial primary hypoalphalipoproteinemia (FPHA).

[0019] The dosing regimens of the disclosure typically entail administering CER-001 to a subject according to an initial "induction" regimen, followed by administering CER-001 to the subject according to a less intense "maintenance" regimen.

[0020] The induction regimens typically comprise administering multiple doses of CER- 001 to the subject with a period of 5 days or greater, e.g., a period of one week, between each dose. In some embodiments, the induction regimens comprise three or more doses of CER-001 .

[0021 ] The maintenance regimens comprise administering multiple doses of CER-001 to the subject on a less frequent basis than during the induction regimen, for example a period of 10 days or greater. In certain aspects, the multiple doses of CER-001 are administered once every two weeks during the maintenance regimens.

[0022] In certain aspects, the disclosure provides methods of treating a subject with CER- 001 using an induction regimen comprising administering three or four doses of CER-001 to the subject with one week between each dose followed by a maintenance comprising administering a dose of CER-001 to the subject once every 10 days to two weeks.

[0023] The subject treated according to the dosing regimens of the disclosure can be any patient in need of long-term HDL therapy. In some embodiments, the subject treated according to the dosing regimens of the disclosure has lower than normal HDL-C levels. Preferably, the subject treated according to the dosing regimens of the disclosure is suffering from FPHA. 3. BRIEF DESCRIPTION OF THE FIGURES

[0024] FIG. 1 shows the design of the study described in Example 1 .

4. DETAILED DESCRIPTION

[0025] The disclosure provides improved dosing regimens for treating a subject with CER-001 . The methods of the disclosure comprise administering CER-001 to a subject in two phases. First, CER-001 is administered in an initial, more intense "induction" regimen. The induction regimen is followed by a less intense "maintenance" regimen. Induction regimens that can be used in the methods of the disclosure are described in Section 4.1 and maintenance regimens that can be used in the methods of the disclosure are described in Section 4.3. The dosing regimens of the disclosure comprise administering CER-001 as monotherapy or as part of a combination therapy with one or more medications. Combination therapies are described in Section 4.4. Populations and subpopulations of patients who can be treated using the methods of the disclosure are described in Section 4.5.

4.1. CER-001

[0026] CER-001 as used in the literature and in Example 1 below refers to a complex described in Example 4 of WO 2012/109162. WO 2012/109162 refers to CER-001 as a complex having a 1 :2.7 lipoprotein weight:total phospholipid weight ratio with a SM:DPPG weight:weight ratio of 97:3. Example 4 of WO 2012/109162 also describes a method of its manufacture.

[0027] When used in the context of a dosing regimen of the disclosure, CER-001 refers to a lipoprotein complex whose individual constituents can vary from CER-001 as described in Example 4 of WO 2012/109162 by up to 20%. In certain embodiments, the constituents of the lipoprotein complex vary from CER-001 as described in Example 4 of WO 2012/109162 by up to 10%. Preferably, the constituents of the lipoprotein complex are those described in Example 4 of WO 2012/109162 (plus/minus acceptable manufacturing tolerance variations).

4.2. Induction Regimen

[0028] A significant drawback to the induction regimen used in the SAMBA trial (Kootte et a/., 2015, J Lipid Res. 56(3):703-12) discussed in Section 1 .5 is the requirement for an infusion of CER-001 once every three days. Such an induction regimen can be inconvenient for patients, for example, because some patients may find it difficult to remember the schedule for their infusions given that the infusions cannot be scheduled for the same days each week. Other patients may find it difficult to arrange their schedules to accommodate the once every three day dosing schedule. The methods of the disclosure overcome this drawback by decreasing the frequency of the dosing in the induction regimen. Thus, it is expected that use of the treatment methods described herein will provide greater patient compliance compared to the method of treatment described in the SAMBA trial.

[0029] Induction regimens suitable for use in the methods of the disclosure entail administering multiple doses of CER-001 separated by 5 or more days (e.g., one week) between each administration.

[0030] The induction regimens typically include at least two dosings of CER-001 but can include three or more dosings of CER-001 , e.g., four, five, six, seven, eight, nine or ten dosings.

[0031 ] The induction regimens can last two or more weeks, three or more weeks, four or more weeks, five or more weeks, six or more weeks, seven or more weeks, eight or more weeks, nine or more weeks, or ten or more weeks.

[0032] For example, the induction regimen can comprise administering:

- three doses of CER-001 over two weeks;

three doses of CER-001 over three weeks;

four doses of CER-001 over three weeks;

four doses of CER-001 over four weeks;

five doses of CER-001 over three weeks;

- five doses of CER-001 over four weeks;

five doses of CER-001 over five weeks;

six doses of CER-001 over four weeks;

six doses of CER-001 over five weeks;

six doses of CER-001 over six weeks;

- seven doses of CER-001 over five weeks;

seven doses of CER-001 over six weeks;

seven doses of CER-001 over seven weeks;

eight doses of CER-001 over six weeks;

eight doses of CER-001 over seven weeks;

- eight doses of CER-001 over eight weeks;

nine doses of CER-001 over six weeks;

nine doses of CER-001 over seven weeks;

nine doses of CER-001 over eight weeks;

nine doses of CER-001 over nine weeks; - ten doses of CER-001 over seven weeks;

- ten doses of CER-001 over eight weeks;

- ten doses of CER-001 over nine weeks; or

- ten doses of CER-001 over ten weeks.

[0033] In a preferred embodiment, the induction regimen comprises administering nine doses of CER-001 over eight weeks.

[0034] In practice, an administration window can be provided, for example, to accommodate slight variations to a weekly dosing schedule. For example, a window of ± 2 days or ± 1 day around the weekly date can be used.

[0035] The dose of CER-001 administered in the induction regimen can range from 4 to 15 mg/kg on a protein weight basis (e.g., 4, 5, 6, 7, 8, 9, 1 0, 1 2 or 1 5 mg/kg). As used herein, the expression "protein weight basis" means that a dose of CER-001 to be administered to a subject is calculated based upon the amount of ApoA-l in the CER-001 to be administered and the weight of the subject. For example, a subject who weighs 70 kg and is to receive an 8 mg/kg dose of CER-001 would receive an amount of CER-001 that provides 560 mg of ApoA-l (70 kg x 8 mg/kg). In some embodiments, the dose of CER-001 used in the induction regimen is 8 mg/kg. In some embodiments, the induction regimen comprises nine doses of CER-001 administered over eight weeks at a dose of 8 mg/kg.

[0036] In yet other aspects, CER-001 can be administered on a unit dosage basis. The unit dosage used in the induction phase can vary from 300 mg to 1500 mg per administration.

[0037] In particular embodiments, the dosage of CER-001 used during the induction phase is 400 mg to 1500 mg, 500 mg to 1200 mg, or 500 mg to 1000 mg per administration.

[0038] CER-001 is preferably administered as an IV infusion. For example, a stock solution of CER-001 can be diluted in normal saline to a volume of 250 ml and administered over a one-hour period using an infusion pump at a fixed rate of 250 ml/hr. Depending on the needs of the subject, administration can be by slow infusion with a duration of more than one hour (e.g., up to two hours), by rapid infusion of one hour or less, or by a single bolus injection.

4.3. Maintenance Regimen

[0039] The methods of the disclosure comprise a maintenance regimen in which CER- 001 is administered to the subject on a less frequent basis than during the induction phase. Typically, CER-001 is administered once every 10 or more days, for example once every two weeks, during the maintenance regimen.

[0040] The maintenance regimen can entail administering CER-001 for one month or longer, two months or longer, three months or longer, six months or longer, nine months or longer, a year or longer, 18 months or longer, two years or longer, or indefinitely.

[0041 ] In some embodiments, the maintenance regimen comprises administering CER- 001 once every 10 days to two weeks for at least 16 weeks. In other embodiments, the maintenance regimen comprises administering CER-001 once every two weeks for at least 20 weeks, for at least 30 weeks, or for at least 40 weeks.

[0042] Similar to the administration window described above in Section 4.2, an administration window can also be used in the maintenance regimen to accommodate slight variations to a biweekly dosing schedule. For example, a window of ± 2 days or ± 1 day around the biweekly date can be used. As used herein, the term "biweekly" means once every two weeks.

[0043] The dose of CER-001 administered in the maintenance regimen is typically lower than is used during the induction phase. Typically, the dose of CER-001 administered in the maintenance regimen ranges from 0.5 mg/kg to 8 mg/kg on a protein weight basis (e.g., 0.5, 1 , 2, 3, 4, 5, 6, 7 or 8 mg/kg). In some embodiments, the dose of CER-001 administered in the maintenance regimen is 8 mg/kg.

[0044] In yet other aspects, CER-001 can be administered on a unit dosage basis. The unit dosage used in the maintenance phase can vary from 200 mg to 1000 mg per administration.

[0045] In particular embodiments, the dosage of CER-001 used during the induction phase is 200 mg to 1000 mg, 300 mg to 900 mg or 400 mg to 800 mg per administration

[0046] CER-001 can be administered during the maintenance phase in the same manner as described in Section 4.1 , e.g., as an IV infusion over a one-hour period.

4.4. Combination therapies

[0047] The subjects can be treated with CER-001 as a monotherapy or a part of a combination therapy regimen, e.g., with one or more lipid control medications such as a statin (e.g., atorvastatin, rosuvastatin, simvastatin, fluvastatin, lovastatin, pravastatin), a cholesterol absorption inhibitor (e.g., ezetimibe), niacin, aspirin, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (e.g., an antibody such as alirocumab, bococizumabevolocumab, 1 D05-lgG2 (Ni et ai, 201 1 , J Lipid Res. 52(1 ):78-86), and LY3015014 (Kastelein et al., 2016, Eur Heart J 37(17):1360-9) or an RNAi therapeutic such as ALN-PCSSC (the Medicines Company)).

[0048] A combination therapy regimen can entail administering CER-001 in combination with one or more of the foregoing medicines and/or one or more of the foregoing classes of medications. In some embodiments, the subject is treated with CER-001 in combination with atorvastatin. In some embodiments, the subject is treated with CER-001 in combination with ezetimibe. In some embodiments, the subject is treated with CER-001 in combination with niacin. In some embodiments, the subject is treated with CER-001 in combination with rosuvastatin. In some embodiments, the subject is treated with CER-001 in combination with simvastatin. In some embodiments, the subject is treated with CER- 001 in combination with aspirin. In some embodiments, the subject is treated with CER- 001 in combination with fluvastatin. In some embodiments, the subject is treated with CER-001 in combination with lovastatin. In some embodiments, the subject is treated with CER-001 in combination with pravastatin. In some embodiments, the subject is treated with CER-001 in combination with aiirocumab. In some embodiments, the subject is treated with CER-001 in combination with evolocumab. In some embodiments, the subject is treated with CER-001 in combination with ALN-PCSsc. In each of the foregoing embodiments, the lipid control medicine can be the only lipid control medicine that the subject receives in combination with CER-001 therapy, or can be part of a combination of lipid control medicines administered in combination with CER-001 therapy.

[0049] Therapy with CER-001 can be added to a background lipid lowering therapy started before therapy with CER-001 .

[0050] In some embodiments, the subject is treated with a stable dose of a lipid control medication for at least 6 weeks (e.g., 6 weeks, 8 weeks, 2 months, 6 months, 1 year, or more than one year) before beginning therapy with CER-001 according to a dosing regimen of the disclosure. Alternatively, CER-001 therapy can be started before or concurrently with treatment with one or more lipid control medications.

4.5. Patient populations

[0051 ] The subject treated according to the dosing regimens of the disclosure can be any patient in need of long-term HDL therapy. In some embodiments, the subject treated according to the dosing regimens of the disclosure has low HDL-C levels prior to starting CER-001 therapy (e.g., less than 60 mg/dL, less than 50 mg/dL, less than 40 mg/dL, less than 30 mg/dL, less than 20 mg/dL, or less than 10 mg/dL). In some embodiments, the subject's HDL-C level is 0 mg/dL to less than 40 mg/dL, 10 mg/dL to less than 40 mg/dL, 20 mg/dL to less than 40 mg/dL, 30 mg/dL to less than 40 mg/dL, 10 mg/dL to 20 mg/dL, 10 mg/dL to 30 mg/dL, or any range bounded by any two of the foregoing values (e.g., 20 mg/dL to 30 mg/dL) prior to starting HDL therapy. Preferably, the subject treated according to the dosing regimens of the disclosure is suffering from FPHA.

[0052] ApoA-l deficiency, ABCA1 deficiency, and LCAT deficiency are underlying causes of FPHA (Kootte et ai, 2015, J Lipid Res. 56(3)703-12). Accordingly, subjects having a mutation in one or more of their ApoA-l, ABCA1 , and LCAT genes can be treated by the therapeutic methods described herein. The subject can have a mutation in one, two, or all three of their ApoA-l, ABCA1 , and LCAT genes, and the subject can be independently homozygous or heterozygous for each mutation.

[0053] In some embodiments, the subject to be treated according to a therapeutic method described herein is homozygous or heterozygous for an ABCA1 mutation. In some embodiments, the subject to be treated according to a therapeutic method described herein is homozygous or heterozygous for an ApoA-l mutation. In some embodiments, the subject to be treated according to a therapeutic method described herein is homozygous or heterozygous for a LCAT mutation.

[0054] In some embodiments, the subject to be treated according to a therapeutic method described herein has an ABCA1 and/or ApoA-l mutation but does not have a LCAT mutation. In some embodiments, the subject to be treated according to a therapeutic method described herein has an ABCA1 mutation but does not have an ApoA-l mutation or a LCAT mutation. In some embodiments, the subject to be treated according to a therapeutic method described herein has an ApoA-l mutation but does not have an ABCA1 mutation or a LCAT mutation.

[0055] Mutations in ApoA-l, ABCA1 , and LCAT are known to affect HDL-C concentrations. In some embodiments, the subject has very low plasma ApoA-l concentration prior to starting CER-001 therapy, e.g., less than 70 mg/dL, less than 60 mg/dL, less than 50 mg/dL, less than 40 mg/dL, less than 30 mg/dL, less than 20 mg/dL, or less than 10 mg/dL. In some embodiments, the subject's plasma ApoA-l concentration is 0 mg/dL to less than 70 mg/dL, 10 mg/dL to less than 70 mg/dL, 20 mg/dL to less than 70 mg/dL, 30 mg/dL to less than 70 mg/dL, 40 mg/dL to less than 70 mg/dL, 50 mg/dL to less than 70 mg/dL, 60 mg/dL to less than 70 mg/dL, or any range bounded by any two of the foregoing values (e.g., 10 mg/dL to 50 mg/dL).

[0056] Subjects having FPHA can have symptomatic or asymptomatic cardiovascular disease prior to being treated with a therapeutic method as described herein. For example, a subject having symptomatic cardiovascular disease can have a history of cardiovascular events (e.g., a heart attack, angina), a history of cerebrovascular events (e.g., stroke, transient ischemic attack), diagnosed CAD, diagnosed carotid or peripheral stenosis, have had a previous myocardial revascularization (e.g., percutaneous coronary intervention (PCI), coronary artery bypass graft (CAGB)), or any combination of the foregoing. Asymptomatic cardiovascular disease can be diagnosed by an imaging method, such as Doppler ultrasound, B-mode ultrasonography measurement of carotid intima media thickness, intravascular ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI).

[0057] Subjects who do show any signs of cardiovascular disease can also be treated with a therapeutic method as described herein, e.g., a baby, child, or young adult who has a family history of FPHA.

5. EXAMPLE 1 : CLINICAL TESTING OF CER-001 IN PATIENTS WITH FAMILIAL PRIMARY HYPOALPHALIPOPROTEINEMIA

5.1. Study Rationale

[0058] The encouraging efficacy results seen to date in clinical trials with CER-001 indicate a potential for CER-001 to bring substantial benefit to patients with FHPA.

Despite the efforts made on diet control and aggressive LDL-C directed pharmacotherapy,

FHPA patients remain at high risk for developing cardiovascular events and there is no treatment currently approved that can directly restore functional HDL.

5.2. Study Design Overview

[0059] This is a Phase I I I, multi-center, randomized, 48 weeks, double-blind, parallel- group, placebo controlled study to evaluate efficacy and safety of CER-001 on ApoA-l and vessel wall area in patients with genetically defined FPHA and receiving background optimized lipid therapy. Following the SAMBA trial, Cerenis received two orphan drug designations from the European Medicines Agency (EMA) for the use of CER-001 in the treatment of patients with ApoA-l and ABCA1 deficiencies, two FPHA subpopulations who are treated in this study.

[0060] After obtaining written informed consent and provided the patient fulfills the selection criteria, he/she is randomized to receive twenty-nine doses of CER-001 (8 mg/kg (on a protein weight basis)) or placebo, weekly during the first 8 weeks (9 doses) and then every two weeks during the following 40 weeks (20 doses). Dosing visits have a window of +/- 2 days around the strict weekly or biweekly date.

[0061 ] The study design is shown schematically in FIG. 1 . 5.3. Study Population

[0062] Patients with ApoA-l < 70 mg/dL and with homozygous or heterozygous mutation in the ABCA1 , and/or ApoA-l genes confirmed by genetic testing, are eligible for this study. Additionally, background symptomatic or asymptomatic cardiovascular disease should be present. Patients having symptomatic cardiovascular disease have at least one of (i) history of cardio or cerebrovascular events, (ii) diagnosed (CAD), (iii) diagnosed carotid or peripheral stenosis, or (iv) previous myocardial revascularization (percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG)). Patients having asymptomatic cardiovascular disease have subclinical atherosclerosis diagnosed using an imaging method such as (i) Doppler ultrasound, ii) B-mode ultrasonography (measurement of carotid intima media thickness, iii) intravascular ultrasonography, iv) Computed Tomography (CT), or v) Magnetic Resonance Imaging (MRI).

[0063] Patients, who fulfill all inclusion/exclusion criteria, including confirmation of a genetic defect, are enrolled in the study. Patients are randomized into the active treatment group and placebo group in a 2:1 ratio.

5.4. Study Objectives

[0064] The primary objectives of the study are to evaluate the effect of 24 week treatment with CER-001 on carotid Mean Vessel Wall Area (MVWA) as compared to placebo using 3T magnetic resonance imaging (3T-MRI) and to evaluate the safety and tolerability of CER-001 administered for 24 weeks.

[0065] The secondary objectives of the study are: to evaluate the effect of 8 week and 48 week treatment with CER-001 on carotid MVWA as compared to placebo using 3T-MRI; to evaluate the effect of 8 week, 24 week and 48 week treatment with CER-001 on femoral artery MVWA as compared to placebo using 3T-MRI; to evaluate the effect of 24 week treatment with CER-001 in the target (plaque) to background (blood) ratio (TBR) from an index vessel (either right carotid or left carotid) based on the standardized ⁸FDG uptake measured with PET/CT; and to evaluate safety and tolerability of 48 week treatment with CER-001 .

5.5. Imaging Assessments

[0066] Patients have 3T-MRI imaging performed at Baseline, Week 8, Week 24 and Week 48 for carotid and femoral Mean Vessel Wall Area (MVWA) and carotid normalized wall index (NVWI) measurements.

[0067] Patients have two PET/CT scans with labelled glucose ( ⁸F-deoxyglucose) at Baseline and Week 24 (only at sites appropriately equipped to perform the scans). 5.6. CER-001 Administration

[0068] The first dose administration occurs at the randomization/first infusion visit (visit 2), and weekly scheduled visits for the first nine doses induction period. During the maintenance and extension periods, dosing occurs every 2 weeks for the following twenty doses until the end of the week 48 treatment period.

[0069] At each of these visits, patient is given a single intravenous infusion of either placebo or CER-001 (8mg/kg) diluted in normal saline to a volume of 250 ml over a one hour period using an infusion pump at a fixed rate of 250 ml/hr. Study drug administration may be extended up to a period of 120 minutes if deemed medically necessary for the patient by the Investigator.

5.7. Results

[0070] After 8, 24, and 48 weeks of treatment with CER-001 according to the administration regimen described above and shown in FIG. 1 , patients' carotid artery MVWA decreases as compared to placebo when measured using 3T magnetic resonance imaging (3T-MRI). After 8, 24, and 48 weeks of treatment with CER-001 , patients' femoral artery MVWA decreases as compared to placebo when measured using 3T-MRI. After 24 week treatment with CER-001 , patients' TBR is reduced as compared to placebo. 24 and 48 week treatment with CER-001 is found to be safe and well tolerated.

6. SPECIFIC EMBODIMENTS

[0071 ] Various aspects of the present disclosure are described in the embodiments set forth in the following numbered paragraphs.

1 . A method for treating a subject in need of long term HDL therapy, comprising:

(a) administering CER-001 to the subject according to an induction regimen comprising administering at least three doses of CER-001 to the subject separated by 5 or more days; and, subsequently

(b) administering CER-001 to the subject according to a maintenance regimen comprising administering a dose of CER-001 to the subject once every 10 or more days. 2. The method of embodiment 1 , wherein the doses of the induction regimen are administered weekly.

3. The method of embodiment 2, wherein the weekly dosings are administered +/- 2 days around the strict weekly date. 4. The method of any one of embodiment 1 to 3, wherein the doses of the maintenance regimen are administered biweekly.

5. The method of embodiment 4, wherein the biweekly dosings are administered +/- 2 days around the strict biweekly date. 6. The method of any one of embodiments 1 to 5, wherein the induction regimen comprises administering three or more doses of CER-001 to the subject.

7. The method of any one of embodiments 1 to 5, wherein the induction regimen comprises administering four or more doses of CER-001 to the subject.

8. The method of any one of embodiments 1 to 5, wherein the induction regimen comprises administering five or more doses of CER-001 to the subject.

9. The method of any one of embodiments 1 to 5, wherein the induction regimen comprises administering six or more doses of CER-001 to the subject.

10. The method of any one of embodiments 1 to 5, wherein the induction regimen comprises administering seven or more doses of CER-001 to the subject. 1 1 . The method of any one of embodiments 1 to 5, wherein the induction regimen comprises administering eight or more doses of CER-001 to the subject.

12. The method of any one of embodiments 1 to 5, wherein the induction regimen comprises administering nine or more doses of CER-001 to the subject.

13. The method of embodiment 12, wherein the induction regimen comprises administering nine doses of CER-001 to the subject.

14. The method of any one of embodiments 1 to 5, wherein the induction regimen comprises administering ten or more doses of CER-001 to the subject.

15. The method of any one of embodiments 1 to 14, wherein the maintenance regimen comprises administering CER-001 to the subject for at least one month. 16. The method of any one of embodiments 1 to 14, wherein the maintenance regimen comprises administering CER-001 to the subject for at least two months.

17. The method of any one of embodiments 1 to 14, wherein the maintenance regimen comprises administering CER-001 to the subject for at least three months. 18. The method of any one of embodiments 1 to 14, wherein the maintenance regimen comprises administering CER-001 to the subject for least six months.

19. The method of any one of embodiments 1 to 14, wherein the maintenance regimen comprises administering CER-001 to the subject for at least nine months. 20. The method of any one of embodiments 1 to 14, wherein the maintenance regimen comprises administering CER-001 to the subject for at least a year.

21 . The method of any one of embodiments 1 to 14, wherein the maintenance regimen comprises administering CER-001 to the subject for at least 18 months.

22. The method of any one of embodiments 1 to 14, wherein the maintenance regimen comprises administering CER-001 to the subject for at least 2 years.

23. The method of any one of embodiments 1 to 14, wherein the maintenance regimen comprises administering CER-001 to the subject indefinitely.

24. The method of any one of embodiments 1 to 14, wherein the maintenance regimen comprises administering CER-001 for 16 or more weeks. 25. The method of any one of embodiments 1 to 14, wherein the maintenance regimen comprises administering CER-001 for 20 or more weeks.

26. The method of any one of embodiments 1 to 14, wherein the maintenance regimen comprises administering CER-001 for 30 or more weeks.

27. The method of any one of embodiments 1 to 14, wherein the maintenance regimen comprises administering CER-001 for 40 or more weeks.

28. The method of any one of embodiments 1 to 27, wherein the dose of CER- 001 administered in the induction regimen is 4 to 15 mg/kg (on a protein weight basis).

29. The method of embodiment 28, wherein the dose of CER-001 administered in the induction regimen is 8 mg/kg (on a protein weight basis). 30. The method of any one of embodiments 1 to 27, wherein the dose of CER-

001 administered in the induction regimen is 300 mg to 1500 mg.

31 . The method of embodiment 30, wherein the dose of CER-001 administered in the induction regimen is 400 mg to 1500 mg. 32. The method of embodiment 30, wherein the dose of CER-001 administered in the induction regimen is 500 mg to 1200 mg.

33. The method of embodiment 30, wherein the dose of CER-001 administered in the induction regimen is 500 mg to 1000 mg. 34. The method of any one of embodiments 1 to 33, wherein the dose of CER-

001 administered in the maintenance regimen is 0.5 to 8 mg/kg (on a protein weight basis).

35. The method embodiment 34, wherein the dose of CER-001 administered in the maintenance regimen is 8 mg/kg (on a protein weight basis). 36. The method of any one of embodiments 1 to 33, wherein the dose of CER-

001 administered in the maintenance regimen is 100 mg to 1000 mg.

37. The method embodiment 36, wherein the dose of CER-001 administered in the maintenance regimen is 200 mg to 1000 mg.

38. The method embodiment 36, wherein the dose of CER-001 administered in the maintenance regimen is 300 mg to 900 mg.

39. The method embodiment 36, wherein the dose of CER-001 administered in the maintenance regimen is 400 mg to 800 mg.

40. The method of any one of embodiments 1 to 39, wherein the dose of CER- 001 administered in the induction regimen and in the maintenance regimen is the same. 41 . The method of any one of embodiments 1 to 40, wherein the subject has low HDL-C levels prior to starting CER-001 therapy.

42. The method of embodiment 41 , wherein the subject's HDL-C level is less than 70 mg/dL prior to starting CER-001 therapy.

43. The method of embodiment 41 , wherein the subject's HDL-C level is less than 60 mg/dL prior to starting CER-001 therapy.

44. The method of embodiment 41 , wherein the subject's HDL-C level is less than 50 mg/dL prior to starting CER-001 therapy. 45. The method of embodiment 41 , wherein the subject's HDL-C level is less than 40 mg/dL prior to starting CER-001 therapy.

46. The method of embodiment 41 , wherein the subject's HDL-C level is less than 30 mg/dL prior to starting CER-001 therapy. 47. The method of embodiment 41 , wherein the subject's HDL-C level is less than 20 mg/dL prior to starting CER-001 therapy.

48. The method of embodiment 41 , wherein the subject's HDL-C level is less than 10 mg/dL prior to starting CER-001 therapy.

49. The method of embodiment 41 , wherein the subject's HDL-C level ranges between 0 mg/dL and less than 40 mg/dL prior to starting CER-001 therapy.

50. The method of embodiment 41 , wherein the subject's HDL-C level ranges between 10 mg/dL and less than 40 mg/dL prior to starting CER-001 therapy.

51 . The method of embodiment 41 , wherein the subject's HDL-C level ranges between 20 mg/dL and less than 40 mg/dL prior to starting CER-001 therapy. 52. The method of embodiment 41 , wherein the subject's HDL-C level ranges between 30 mg/dL and less than 40 mg/dL prior to starting CER-001 therapy.

53. The method of embodiment 41 , wherein the subject's HDL-C level ranges between 10 mg/dL and 20 mg/dL prior to starting CER-001 therapy.

54. The method of embodiment 41 , wherein the subject's HDL-C level ranges between 10 mg/dL and 30 mg/dL prior to starting CER-001 therapy.

55. The method of any one of embodiments 1 to 54, wherein the subject has familial primary hypoalphalipoproteinemia (FPHA).

56. The method of embodiment 55, wherein the subject is homozygous for an ABCA1 mutation. 57. The method of embodiment 55, wherein the subject is heterozygous for an

ABCA1 mutation.

58. The method of any one of embodiments 55 to 57, wherein the subject is homozygous for an ApoA-l mutation. 59. The method of any one of embodiments 55 to 57, wherein the subject is heterozygous for an ApoA-l mutation.

60. The method of any one of embodiments 55 to 59, wherein the subject is homozygous for a LCAT mutation. 61 . The method of any one of embodiments 55 to 59, wherein the subject is heterozygous for a LCAT mutation.

62. The method of any one of embodiments 55 to 59, wherein the subject does not have a LCAT mutation.

63. The method of any one of embodiments 1 to 62, which further comprises genetically testing the subject for one or more FPHA mutations prior to initiating therapy.

64. The method of embodiment 63, wherein the subject is tested for an ABCA1 mutation, an ApoA-l mutation, a LCAT mutation, or any combination of two or all three of the foregoing.

65. The method of any one of embodiments 1 to 64, wherein the subject has symptomatic cardiovascular disease.

66. The method of embodiment 65, wherein the subject has a history of cardiovascular or cerebrovascular events.

67. The method of embodiment 65 or embodiment 66, wherein the subject has diagnosed coronary artery disease (CAD). 68. The method of any one of embodiments 65 to 67, wherein the subject has diagnosed carotid or peripheral stenosis.

69. The method of any one of embodiments 65 to 68, wherein the subject had a previous myocardial revascularization.

70. The method of embodiment 69, wherein the previous myocardial revascularization is a percutaneous coronary intervention (PCI).

71 . The method of embodiment 69, wherein the previous myocardial revascularization is a coronary artery bypass graft (CAGB). 72. The method of any one of embodiments 1 to 64, wherein the subject has asymptomatic cardiovascular disease.

73. The method of embodiment 72, wherein the subject has subclinical atherosclerosis diagnosed by an imaging method. 74. The method of embodiment 73, wherein the imaging method is Doppler ultrasound.

75. The method of embodiment 73, wherein the imaging method is B-mode ultrasonography measurement of carotid intima media thickness.

76. The method of embodiment 73, wherein the imaging method is intravascular ultrasonography.

77. The method of embodiment 73, wherein the imaging method is computed tomography (CT).

78. The method of embodiment 73, wherein the imaging method is magnetic resonance imaging (MRI). 79. The method of any one of embodiments 1 to 64, wherein the subject does not have symptomatic cardiovascular disease or asymptomatic cardiovascular disease.

80. The method of any one of embodiments 1 to 79, wherein the subject is also treated with a lipid control medication.

81 . The method of embodiment 80, wherein the lipid control medication comprises a statin.

82. The method of embodiment 81 , wherein the statin is atorvastatin, rosuvastatin, simvastatin, fluvastatin, lovastatin, or pravastatin.

83. The method of any one of embodiments 80 to 82, wherein the lipid control medication comprises a cholesterol absorption inhibitor. 84. The method of embodiment 83, wherein the cholesterol absorption inhibitor is ezetimibe.

85. The method of any one of embodiments 80 to 84, wherein the lipid control medication comprises niacin. 86. The method of any one of embodiments 80 to 85, wherein the lipid control medication comprises aspirin.

87. The method of any one of embodiments 80 to 86, wherein the lipid control medication comprises a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. 88. The method of embodiment 87, wherein the PCSK9 inhibitor is an antibody.

89. The method of embodiment 88, wherein the antibody is alirocumab, bococizumabevolocumab, 1 D05-lgG2 or LY3015014.

90. The method of embodiment 87, wherein the PCSK9 inhibitor is RNAi therapeutic.

91 . The method of embodiment 90, wherein the RNAi therapeutic is ALN- PCSSC.

92. The method of any one of embodiments 80 to 91 , further comprising administering a therapeutically effective amount of the lipid control medication to the subject.

[0072] While various specific embodiments have been illustrated and described, it will be appreciated that various changes can be made without departing from the spirit and scope of the disclosure(s).

7. INCORPORATION BY REFERENCE

[0073] All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes.

[0074] Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the present disclosure. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed anywhere before the priority date of this application.

Claims

WHAT IS CLAIMED IS:

1 . A method for treating a subject in need of long term HDL therapy, comprising:

(a) administering CER-001 to the subject according to an induction regimen comprising administering at least three doses of CER-001 to the subject separated by 5 or more days; and, subsequently

(b) administering CER-001 to the subject according to a maintenance regimen comprising administering a dose of CER-001 to the subject once every 10 or more days.

2. The method of claim 1 , wherein the doses of the induction regimen are administered weekly.

3. The method of claim 2, wherein the weekly dosings are administered +/- 2 days around the strict weekly date.

4. The method of any one of claims 1 to 3, wherein the doses of the maintenance regimen are administered biweekly.

5. The method of claim 4, wherein the biweekly dosings are administered +/- 2 days around the strict biweekly date.

6. The method of any one of claims 1 to 5, wherein the induction regimen comprises administering three or more doses of CER-001 to the subject.

7. The method of any one of claims 1 to 6, wherein the maintenance regimen comprises administering CER-001 to the subject for at least six months.

8. The method of any one of claims 1 to 7, wherein the dose of CER-001 administered in the induction regimen is 4 to 15 mg/kg (on a protein weight basis).

9. The method of claim 8, wherein the dose of CER-001 administered in the induction regimen is 8 mg/kg (on a protein weight basis).

10. The method of any one of claims 1 to 9, wherein the dose of CER-001 administered in the maintenance regimen is 0.5 to 8 mg/kg (on a protein weight basis).

1 1 . The method of claim 10, wherein the dose of CER-001 administered in the maintenance regimen is 8 mg/kg (on a protein weight basis).

12. The method of any one of claims 1 to 1 1 , wherein the subject has low HDL-C levels prior to starting CER-001 therapy.

13. The method of claim 12, wherein the subject's HDL-C level is less than 70 mg/dL prior to starting CER-001 therapy.

14. The method of claim 13, wherein the subject's HDL-C level ranges between 0 mg/dL and less than 40 mg/dL prior to starting CER-001 therapy.

15. The method of any one of claims 1 to 14, wherein the subject has familial primary hypoalphalipoproteinemia (FPHA).

16. The method of claim 15, wherein the subject has an ABCA1 mutation, an ApoA-l mutation or a LCAT mutation.

17. The method of any one of claims 1 to 16, wherein the subject has symptomatic cardiovascular disease.

18. The method of any one of claims 1 to 16, wherein the subject has asymptomatic cardiovascular disease.

19. The method of any one of claims 1 to 18, wherein the subject is also treated with a lipid control medication.

20. The method of claim 19, wherein the lipid control medication comprises a statin, a cholesterol absorption inhibitor, niacin, aspirin, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, or a combination of any two or more of the foregoing.