WO2017200715A1 - Traitement de l'hyperlipidémie sévère - Google Patents

Traitement de l'hyperlipidémie sévère Download PDF

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WO2017200715A1
WO2017200715A1 PCT/US2017/029113 US2017029113W WO2017200715A1 WO 2017200715 A1 WO2017200715 A1 WO 2017200715A1 US 2017029113 W US2017029113 W US 2017029113W WO 2017200715 A1 WO2017200715 A1 WO 2017200715A1
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compound
ldl
seladelpar
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hyperlipidemia
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Robert L. Martin
Charles A. Mcwherter
Patrick J. O'MARA
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CymaBay Therapeutics Inc
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CymaBay Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • This invention relates to the treatment of severe hyperlipidemia.
  • Dyslipidemia is the presence of an abnormal amount of lipids (e.g. cholesterol and/or fat) in the blood.
  • hyperlipidemias include hypercholesterolemia (elevated cholesterol) and hyperglyceridemia (elevated glycerides), with hypertriglyceridemia (elevated triglycerides (TGs)) as a subset of hyperglyceridemia: combined hyperlipidemia refers to an elevation of both cholesterol and triglycerides.
  • Hyperlipoproteinemia refers to the presence of elevated lipoproteins, usually low-density lipoproteins (LDL), otherwise known as
  • hyperchylomicronemia elevated chylomicrons
  • Combined hyperlipidemia refers to elevated TGs and LDL.
  • Familial or primary (i.e., genetically-caused) hyperlipidemias are classified according to the Fredrickson classification, which is based on the pattern of lipoproteins on electrophoresis or ultracentrifugation: Type II includes familial
  • hypercholesterolemia FH, Type Ila
  • familial combined hyperlipidemia Type lib
  • Hyperlipidemias such as hypercholesterolemia, combined hyperlipidemia, and
  • hyperlipoproteinemia generally involve elevated LDL and low-density lipoprotein cholesterol (LDL-C, "bad cholesterol”), and are frequently accompanied by decreased high density lipoproteins (HDL) and high-density lipoprotein cholesterol (HDL-C, "good cholesterol”).
  • LDL-C low-density lipoprotein cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • Chronic hyperlipidemia is recognized to be associated with increased risk of atherosclerotic cardiovascular disease and its associated consequences including acute coronary syndrome, myocardial infarction, heart failure, stroke and death.
  • FH is a genetic disorder characterized by high cholesterol levels, specifically very high levels of LDL-C, in the blood, and a high incidence of cardiovascular disease (CVD) at a young age.
  • the high cholesterol levels in FH are less responsive to the kinds of cholesterol control methods that are usually more effective in people without FH, such as dietary modification and statins, because the body's underlying biochemistry is slightly different in these genetically- linked conditions and the body is often overwhelmed by the magnitude of the abnormal levels of lipids. Nevertheless, treatment (including higher statin doses) can often provide benefit, although with effects that are suboptimal.
  • LDLR gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (apoB), which is the part of LDL that binds with the receptor, both types of mutations leading to elevated LDL-C; mutations in other genes that affect LDL receptor function do occur, but are less frequent.
  • Patients who have one abnormal copy (heterozygous) of the LDLR gene may have premature CVD at the age of 30 to 40.
  • Patients who have two abnormal copies (homozygous) may experience severe CVD in childhood, and without treatment may experience myocardial infarction, ischemic stroke, and death by around the age of 30.
  • Heterozygous FH is a common genetic disorder, inherited in an autosomal dominant pattern, occurring in 1 in 500 people in most countries; homozygous FH (HoFH) is much rarer, occurring in 1 in 1,000,000 people. HeFH is normally treated with statins, cholesterol absorption inhibitors such as ezetimibe, bile acid sequestrants, or other
  • hypolipidemic agents that lower cholesterol levels. New cases are generally offered genetic counseling. HoFH and the more severe forms of HeFH often do not adequately respond to medical therapy and may require other treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and, for HoFH, occasionally liver transplantation. Therapies such as statins work primarily by up-regulating liver LDL receptor expression, thereby increasing LDL receptor-mediated clearance of lipids. Thus patients with HoFH (and severe HeFH), who lack functional LDL receptor activity, will generally respond poorly to such therapies.
  • hyperbetalipoproteinemia or combined primary hyperlipidemia in which the person having the condition fails to achieve adequate control of LDL-C with maximally-tolerated conventional lipid-lowering therapy (dietary modification, apheresis if indicated, and one or more of a statin, a cholesterol absorption inhibitor, and a bile acid sequestrant; but not including therapy with a PCSK9 inhibitor). It refers especially to one of these conditions in which the person fails to achieve adequate control of LDL-C with maximally-tolerated conventional lipid-lowering therapy (as above) and therapy with a PCSK9 inhibitor; and also especially to one of these conditions in which the person exhibits symptoms of clinical atherosclerotic CVD.
  • the National Cholesterol Education Program has established cardiovascular risk categories related to treatment goals pertinent to severe hyperlipidemia as ⁇ 70 mg/dL in patients at very high cardiovascular risk, ⁇ 100 mg/dL in patients at high risk (10-year risk >20%), ⁇ 130 mg/dL in patients at moderately high risk (10-year risk 10-20%) and moderate risk (10-year risk ⁇ 10% but with at least two coronary heart disease risk factors), and ⁇ 160 mg/dL for lower risk.
  • a final LDL-C of not more than 130 mg/dL for example not more than 100 mg/dL, such as not more than 70 mg/dL;
  • PCSK9 is a protein (serine protease) that is synthesized and secreted mainly by the liver and binds to hepatic LDL receptors. It regulates plasma LDL-C levels by diverting cell surface LDL receptors to lysosomes for degradation. In so doing, PCSK9 prevents the normal recycling of LDL receptors back to the cell surface. This process results in reduced LDL receptor density, decreased clearance of LDL-C, and, consequently, accumulation of LDL-C in the circulation.
  • PCSK9 levels tend to correlate directly with LDL-C levels, and this correlation is particularly evident on examination of patient populations with differing degrees of LDL receptor function, including those with HoFH and HeFH (see, for example, Raal et al., "Elevated PCSK9 Levels in Untreated Patients with Heterozygous or Homozygous Familial Hypercholesterolemia and the Response to High-Dose Statin Therapy", /. Am. Heart Assoc. , 2, e000028 (http://jaha.ahajournals.Org/content/2/2e000028), especially Figure 2).
  • PCSK9 inhibitors are therefore considered attractive therapeutic agents for FH, including HoFH.
  • the anti-PCSK9 antibodies i.e.
  • evolocumab antibodies that bind to PCSK9 and prevent it binding to liver LDL receptors
  • evolocumab evolocumab, alirocumab, bococizumab, RG7652, LY3015014, and LGT-209, of which evolocumab and alirocumab are the furthest advanced
  • ALN-PCSsc a GalNAc-modified second generation subcutaneously-administrable agent based on ALN-PCS
  • pegylated adnectin BMS-962476 the pegylated adnectin BMS-962476
  • Evolocumab (REPATHA) has been approved in the United States (August 2015), by the European Medicines Authority (July 2015), and in Canada (September 2015). In the US, evolocumab is indicated as an adjunct to diet and: (a) maximally tolerated statin therapy for treatment of adults with HeFH or clinical atherosclerotic CVD, who require additional lowering of LDL-C; and (b) other LDL- lowering therapies (e.g., statins, cholesterol absorption inhibitors, LDL apheresis) in patients with HoFH who require additional lowering of LDL-C.
  • statins e.g., statins, cholesterol absorption inhibitors, LDL apheresis
  • the approved US dosing is 140 mg every 2 weeks or 420 mg once monthly subcutaneously for hyperlipidemia/HeFH and 420 mg once monthly subcutaneously for HoFH (though 420 mg every 2 weeks subcutaneously has also been tested and proved more effective). Approval was based on data from the PROFICIO program, in which evolocumab reduced LDL-C levels in hypercholesterolemic subjects more than 50%. Evolocumab has also been tested in 331 HeFH patients in the RUTHERFORD-2 trial (Raal et al., "PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a
  • Alirocumab (PRALUENT) has been approved in the United States and by the European Medicines Authority (both in July 2015). In the US, alirocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for treatment of adults with HeFH or clinical atherosclerotic CVD, who require additional lowering of LDL-C.
  • the approved US dosing is 75 mg every 2 weeks subcutaneously, with escalation to 150 mg every 2 weeks subcutaneously if adequate control of LDL-C is not achieved with the lower dose.
  • Alirocumab has also been tested in hypercholesterolemia and in a placebo-controlled Phase 2 study in HeFH using subcutaneous injection at 150 mg every 2 weeks or 150, 200, or 300 mg every 4 weeks, with significant reductions seen in LDL-C (29% for 150 mg/4 weeks to 68% for 150 mg/2 weeks).
  • Bococizumab has been tested in hypercholesterolemia and is under study in HeFH.
  • the Phase 3 trials are using every 2 week dosing, at 75 or 150 mg.
  • ALN-PCS completed a single ascending dose Phase 1 study in hypercholesterolemic subjects, using intravenous doses between 0.015 and 0.040 mg/Kg, with a mean 70% reduction in PCSK9 at the highest dose, while ALN-PCS was said to be well tolerated.
  • BMS-962476 has completed a single ascending dose Phase 1 study in hypercholesterolemic subjects, using subcutaneous doses of 0.01, 0.03, 0.1, and 0.3 mg/Kg and intravenous doses of 0.3 and 1.0 mg/Kg alone, and 0.1 and 0.3 mg/Kg in combination with statins. BMS-962476 was said to be well tolerated, and doses >0.3 mg/Kg reduced PCSK9 by at least 90%.
  • PCSK9 has been found to have additional functions beyond those described for its interactions with the LDL receptor.
  • Sun et al. "Proprotein Convertase
  • Subtilisin/Kexin Type 9 Interacts With Apolipoprotein B and Prevents Its Intracellular Degradation, Irrespective of the Low-Density Lipoprotein Receptor", Arterioscler. Thromb. Vase. Biol, 32, 1585-1595 (2012), studied the role of PCSK9 in mice in which the LDL receptor gene had been deleted. They discovered that increased PCSK9 increases plasma cholesterol and triglycerides in an LDL receptor independent fashion. Their results indicated that PCSK9 interacts with the core protein apoB to increase the secretion of VLDL, the precursor to circulating LDL.
  • PCSK9 Protein Convertase Subtilisin/Kexin Type 9
  • LRP-1 Low Density Lipoprotein Receptor-Related Protein 1
  • Seladelpar has the chemical name (i?)-2-(4-((2-ethoxy-3-(4-(trifluoromethyl)phenoxy)propyl)- thio)-2-methylphenoxy)acetic acid [IUPAC name as generated by CHEMDRAW ULTRA
  • Seladelpar is an orally active, potent (2 nM) agonist of peroxisome proliferator- activated receptor- ⁇ (PPAR5), which is also specific (>600-fold and >2500-fold compared with PPARa and PPARy receptors).
  • PPAR5 activation stimulates fatty acid oxidation and utilization, improves plasma lipid and lipoprotein metabolism, glucose utilization, and mitochondrial respiration, and preserves stem cell homeostasis.
  • PPAR5 agonists such as seladelpar
  • PPAR5-mediated conditions including "diabetes, cardiovascular diseases, Metabolic X syndrome, hypercholesterolemia, hypo-HDL- cholesterolemia, hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, and obesity", with dyslipidemia said to include hypertriglyceridemia and mixed hyperlipidemia.
  • seladelpar reduced LDL-S/VS by 40-48% compared with a 25% decrease with atorvastatin; and seladelpar increased LDL-L by 34-44% compared with a 30% decrease with atorvastatin.
  • seladelpar significantly reduced alkaline phosphatase by 32-43%, compared to reductions of only 4% in the control group and 6% in the ATV group; and significantly reduced ⁇ -glutamyl transpeptidase by 24-28%, compared to a reduction of only 3% in the control group and an increase of 2% in the ATV group.
  • seladelpar corrects all three lipid abnormalities in mixed dyslipidemia - lowers TGs and LDL and raises HDL, selectively depletes small dense LDL particles (92%), reduces cardiovascular inflammation, and improves other metabolic parameters including reducing serum aminotransferases, increases insulin sensitivity (lowers HOMA-IR, fasting plasma glucose, and insulin), lowers ⁇ -glutamyl transpeptidase and alkaline phosphatase, significantly (>2-fold) reduces the percentage of subjects meeting the criteria for metabolic syndrome, and trends towards a decrease in waist circumference and increase in lean body mass.
  • Seladelpar was safe and generally well-tolerated, and also reduced liver enzyme levels. As explained in US Patent Application Publication No.
  • LDL particle size pattern I converts LDL particle size pattern I to pattern A; and from pattern B to pattern I or A, where LDL particle size pattern B is a predominant LDL particle size of less than 25.75 nm, pattern I is a predominant LDL particle size of from 25.75 nm to 26.34nm, and pattern A is a predominant LDL particle size of greater than 26.34 nm, where the LDL particle size is measured by gradient-gel electrophoresis.
  • Watanabe-heritable hyperlipidemic (WHHL) rabbit is a preclinical model of FH that is characterized by low ( ⁇ 5%) hepatic LDL-R activity, highly elevated LDL-C and the accompanying development of atherosclerosis; and is used in studies of candidate compounds for the treatment of hypercholesterolemia and atherosclerosis.
  • CymaBay Therapeutics has reported a study of seladelpar in the WHHL rabbit ("CymaBay Therapeutics Announces Preclinical Data Demonstrating the Potential of MB X- 8025 to Treat Homozygous Familial Hypercholesterolemia", January 28, 2015, http://ir.cymabay.com/press- releases/detail/244/cymabay-therapeutics-announces-preclinical-data-demonstrating-the- potential-of-mbx-8025-to-treat-homozygous-familial-hypercholesterolemia).
  • CymaBay Therapeutics has also reported the results of a pilot Phase 2 clinical study in HoFH patients ("CymaBay Therapeutics Announces Positive Results fromits Pilot Phase2 Clinical Study of MBX-8025 in Patients with Homozygous Familial Hypercholesterolemia", March 17, 2016, http://ir.cymabay.com/press-releases/detail/361/cymabay-therapeutics- announces-positive-results-from-its-pilot-phase-2-clinical-study-of-seladelpar-in-patients-with- homozygous-familial-hypercholesterorectia).
  • This invention is the treatment of severe hyperlipidemia, comprising administration of (i?j-2-(4-((2-ethoxy-3-(4-(trifluoromethyl)phenoxy)propyl)thio)-2-methylphenoxy)acetic acid or a salt thereof (seladelpar or a salt thereof) in combination with a PCSK9 inhibitor.
  • this invention is the treatment of severe hyperlipidemia in persons who fail to achieve adequate control of LDL-C with maximally-tolerated conventional lipid-lowering therapy.
  • this invention includes:
  • seladelpar or a salt thereof in the manufacture of a medicament for treating severe hyperlipidemia where the seladelpar or a salt thereof is administered in combination with a PCSK9 inhibitor.
  • the PCSK9 inhibitor may be an anti-PCSK9 antibody such as evolocumab, alirocumab, bococizumab, RG7652, LY3015014, and LGT-209; an antisense RNAi oligonucleotide such as ALN-PCSsc; or an adnectin such as BMS-962476.
  • an anti-PCSK9 antibody such as evolocumab, alirocumab, bococizumab, RG7652, LY3015014, and LGT-209
  • an antisense RNAi oligonucleotide such as ALN-PCSsc
  • an adnectin such as BMS-962476.
  • seladelpar Because the effects of seladelpar, mediated by PPAR5, do not require an effective LDLR to lower LDL-C and improve other lipid parameters (an effect seen in knockout mice lacking LDLR), seladelpar will have a special benefit in persons with HoFH. Also, because the effect of seladelpar on LDL-C reduction has been seen to increase in dyslipidemic patients with higher starting LDL-C levels, seladelpar is expected to be especially effective in severe
  • PCSK9 inhibitors including anti-PCSK9 antibodies such as evolocumab, alirocumab, bococizumab, RG7652, LY3015014, and LGT-209; antisense RNAi oligonucleotides such as ALN-PCSsc; and adnectins such as BMS-962476, are described in paragraphs [0007] through [0013].
  • Treating" or “treatment” of severe hyperlipidemia in a human includes one or more of:
  • the treatment will be one in which a subject receiving maximally-tolerated conventional lipid-lowering therapy (one or more of a statin, a cholesterol absorption inhibitor, and a bile acid sequestrant) and therapy with a PCSK9 inhibitor exhibits one or more of: (a) an absolute reduction in LDL-C of at least 40 mg/dL, for example at least 100 mg/dL, such as at least 150 mg/dL;
  • a final LDL-C of not more than 130 mg/dL for example not more than 100 mg/dL, such as not more than 70 mg/dL;
  • a "therapeutically effective amount" of each of (seladelpar or a seladelpar salt) and a PCSK9 inhibitor means that amount which, when administered in combination therapy to a human for treating severe hyperlipidemia, is sufficient to effect treatment for severe hyperlipidemia.
  • the therapeutically effective amount for a particular subject varies depending upon the health and physical condition of the subject to be treated, the type and extent of severe hyperlipidemia, the assessment of the medical situation, and other relevant factors. It is expected that the therapeutically effective amount will fall in a relatively broad range, as discussed below, and that this amount can be determined through routine trial based on the ordinary skill in the art and the guidance of this application.
  • Salts for example, pharmaceutically acceptable salts of seladelpar and of the PCSK9 inhibitor are included in this invention and are useful in the compositions, methods, and uses described in this application. These salts are preferably formed with pharmaceutically acceptable acids and bases. See, for example, "Handbook of Pharmaceutically Acceptable Salts", Stahl and Wermuth, eds., Verlag Helvetica Chimica Acta, Zurich, Switzerland, for an extensive discussion of pharmaceutical salts, their selection, preparation, and use. Unless the context requires otherwise, reference to seladelpar and other compounds is a reference both to the compound and to its salts.
  • seladelpar contains a carboxyl group, it may form salts when the acidic proton present reacts with inorganic or organic bases.
  • the seladelpar is treated with an excess of an alkaline reagent, such as hydroxide, carbonate or alkoxide, containing an appropriate cation.
  • Cations such as Na + , K + , Ca 2+ , Mg 2+ , and NH 4 + are examples of cations present in pharmaceutically acceptable salts.
  • Suitable inorganic bases therefore, include calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • Salts may also be prepared using organic bases, such as salts of primary, secondary and tertiary amines, substituted amines including naturally-occurring substituted amines, and cyclic amines including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and the like.
  • organic bases such as salts of primary, secondary and tertiary amines, substituted amines including naturally-occurring substituted amines, and cyclic amines including isopropylamine, trimethylamine, diethylamine, triethy
  • Combination therapy with seladelpar and a PCSK9 inhibitor means administration of seladelpar and a PCSK9 inhibitor during the course of treatment of severe hyperlipidemia.
  • Such combination therapy may involve administration of a PCSK9 inhibitor before, during, and/or after administration of seladelpar, such that therapeutically effective levels of each of the compounds are maintained, seladelpar is typically administered orally once/day.
  • the PCSK9 inhibitors are administered by injection less frequently, such as once every 2 or 4 weeks for the PCSK9 antibodies, it may be convenient to administer the PCSK9 inhibitors, on the day selected for their administration, at the same time as the seladelpar is administered.
  • “Comprising” or “containing” and their grammatical variants are words of inclusion and not of limitation and mean to specify the presence of stated components, groups, steps, and the like but not to exclude the presence or addition of other components, groups, steps, and the like. Thus “comprising” does not mean “consisting of, “consisting substantially of, or “consisting only of; and, for example, a formulation “comprising” a compound must contain that compound but also may contain other active ingredients and/or excipients.
  • the seladelpar, and the PCSK9 inhibitor may be administered by any route suitable to the subject being treated and the nature of the subject's condition.
  • Routes of administration include administration by injection, including intravenous, intraperitoneal, intramuscular, and subcutaneous injection, by transmucosal or transdermal delivery, through topical applications, nasal spray, suppository and the like, or may be administered orally.
  • Formulations may optionally be liposomal formulations, emulsions, formulations designed to administer the drug across mucosal membranes or transdermal formulations.
  • Suitable formulations for each of these methods of administration may be found, for example, in "Remington: The Science and Practice of Pharmacy", 20th ed., Gennaro, ed., Lippincott Williams & Wilkins, Philadelphia, Pa., U.S.A. Because seladelpar is orally available, typical formulations will be oral, and typical dosage forms of seladelpar will be tablets or capsules for oral administration. As mentioned in paragraph [0017], seladelpar has been formulated in capsules for clinical trials.
  • the PCSK9 inhibitors are all formulated as solutions for injection, typically for subcutaneous injection.
  • the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, preferably in unit dosage form suitable for single administration of a precise dosage.
  • the compositions may contain suitable pharmaceutically- acceptable excipients, including adjuvants which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically- acceptable excipient refers to an excipient or mixture of excipients which does not interfere with the effectiveness of the biological activity of the active compound(s) and which is not toxic or otherwise undesirable to the subject to which it is administered.
  • conventional excipients include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmacologically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in water or an aqueous excipient, such as, for example, water, saline, aqueous dextrose, and the like, to form a solution or suspension.
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary excipients such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate,
  • the composition will generally take the form of a tablet or capsule, or it may be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use will generally include one or more commonly used excipients such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent may be combined with emulsifying and suspending excipients. If desired, flavoring, coloring and/or sweetening agents may be added as well. Other optional excipients for incorporation into an oral formulation include preservatives, suspending agents, thickening agents, and the like.
  • kits comprising separate compositions of seladelpar and of a PCSK9 inhibitor, is packaged in a container with a label, or instructions, or both, indicating use of the kit in the treatment of severe hyperlipidemia.
  • seladelpar and a PCSK9 inhibitor are used in combination therapy, a suitable amount of seladelpar (calculated as the free acid) for oral dosing is expected to be
  • suitable amounts of the PCSK9 inhibitor are expected to be similar to the amounts approved or used in clinical trials, as described in paragraphs [0007] through [0013], such as 140 mg every 2 weeks or 420 mg once monthly subcutaneously for hyperlipidemia/HeFH and 420 mg once monthly or every 2 weeks subcutaneously for HoFH for evolocumab and 75 mg or 150 mg every 2 weeks subcutaneously for alirocumab. That is, suitable amounts of seladelpar and the PCSK9 inhibitor to achieve a therapeutically effective amount of the combination therapy are expected to be similar to the amounts employed in clinical trials (and currently approved, in the case of evolocumab and alirocumab). However, it is possible that the therapeutically effective amounts of either may be less in combination therapy than when used as monotherapy because each of seladelpar and the PCSK9 inhibitors is useful in lowering cholesterol, particularly LDL-C.
  • Example 1 Dose escalation study with seladelpar and evolocumab in HoFH
  • the subjects are instructed to maintain a low-fat diet ( ⁇ 20% energy from fat) and to take dietary supplements that provide approximately 400 IU vitamin E, 210 mg a-linolenic acid, 200 mg linoleic acid, 110 mg eicosapentenoic acid, and 80 mg docosahexaenoic acid per day; and are permitted their usual other medications.
  • the subjects are assessed before the study, and at intervals during the study, such as every 1, 2, and 4 weeks after the start of a new dose and 4 weeks after the last dose of the combination therapy, for safety and pharmacodynamic evaluations.
  • MRIs of the subjects' livers are taken after 4 weeks at each dose, and 4 weeks after study completion, to determine hepatic fat.
  • the combination of seladelpar and evolocumab causes dose-dependent lowering of TC, LDL-C, VLDL-C, TG, and apoB, and raising of HDL-C; in particular, increasing the lowering of TC, LDL-C, VLDL-C, TG, and apoB, and raising of HDL-C, beyond that caused by evolocumab alone.
  • Example 2 Dose escalation study with seladelpar and evolocumab in HeFH
  • the subjects are instructed to maintain a low-fat diet ( ⁇ 20% energy from fat) and to take dietary supplements that provide approximately 400 IU vitamin E, 210 mg ⁇ -linolenic acid, 200 mg linoleic acid, 110 mg eicosapentenoic acid, and 80 mg docosahexaenoic acid per day; and are permitted their usual other medications.
  • the subjects are assessed before the study, and at intervals during the study, such as every 1, 2, and 4 weeks after the start of a new dose and 4 weeks after the last dose of the combination therapy, for safety and pharmacodynamic evaluations.
  • MRIs of the subjects' livers are taken after 4 weeks at each dose, and 4 weeks after study completion, to determine hepatic fat.
  • the combination of seladelpar and evolocumab causes dose-dependent lowering of TC, LDL-C, VLDL-C, TG, and apoB, and raising of HDL-C; in particular, increasing the lowering of TC, LDL-C, VLDL-C, TG, and apoB, and raising of HDL-C, beyond that caused by evolocumab alone.
  • Example 3 Dose escalation study with seladelpar and evolocumab in primary hyperlipidemia with clinical atherosclerotic cardiovascular disease
  • the subjects are permitted their usual other medications.
  • the subjects are assessed before the study, and at intervals during the study, such as every 1, 2, and 4 weeks after the start of a new dose and 4 weeks after the last dose of the combination therapy, for safety and pharmacodynamic evaluations.
  • MRIs of the subjects' livers are taken after 4 weeks at each dose, and 4 weeks after study completion, to determine hepatic fat.
  • blood is drawn and urine collected; and a standard metabolic panel, complete blood count, and standard urinalysis are performed. Blood is analyzed for TC, HDL-C, TG, VLDL-C, LDL-C and apoB.
  • the subjects also maintain health diaries, which are reviewed at each visit.
  • the combination of seladelpar and evolocumab causes dose-dependent lowering of TC, LDL-C, VLDL-C, TG, and apoB, and raising of HDL-C; in particular, increasing the lowering of TC, LDL-C, VLDL-C, TG, and apoB, and raising of HDL-C, beyond that caused by evolocumab alone.

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Abstract

Traitement de l'hyperlipidémie sévère par administration de séladelpar ou d'un sel de celui-ci, en combinaison avec un inhibiteur de PCSK9.
PCT/US2017/029113 2016-05-19 2017-04-24 Traitement de l'hyperlipidémie sévère Ceased WO2017200715A1 (fr)

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WO2025036347A1 (fr) * 2023-08-14 2025-02-20 信立泰(成都)生物技术有限公司 Procédé de traitement ou de prévention de maladies liées au cholestérol à l'aide d'un inhibiteur de pcsk9

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10512622B2 (en) 2017-07-14 2019-12-24 Cymabay Therapeutics, Inc. Treatment of intrahepatic cholestatic diseases
US10813896B2 (en) 2017-07-14 2020-10-27 Cymabay Therapeutics, Inc. Treatment of intrahepatic cholestatic diseases
US11224580B2 (en) 2017-07-14 2022-01-18 Cymabay Therapeutics, Inc. Treatment of intrahepatic cholestatic diseases
WO2025036347A1 (fr) * 2023-08-14 2025-02-20 信立泰(成都)生物技术有限公司 Procédé de traitement ou de prévention de maladies liées au cholestérol à l'aide d'un inhibiteur de pcsk9

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