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WO2025146262A1 - Obicetrapib destiné à être utilisé dans le traitement d'hémoglobinopathies - Google Patents

Obicetrapib destiné à être utilisé dans le traitement d'hémoglobinopathies Download PDF

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Publication number
WO2025146262A1
WO2025146262A1 PCT/EP2024/080193 EP2024080193W WO2025146262A1 WO 2025146262 A1 WO2025146262 A1 WO 2025146262A1 EP 2024080193 W EP2024080193 W EP 2024080193W WO 2025146262 A1 WO2025146262 A1 WO 2025146262A1
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Prior art keywords
obicetrapib
amorphous
hemicalcium
compound
crystalline
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Inventor
Johannes Jacob Pieter KASTELEIN
Marc DITMARSCH
Eric Niesor
Sheng CUI
Andreas René Rötheli
Christopher J. Borths
Muneki Kishida
Valeriya Nikolayevna Smolenskaya
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NewAmsterdam Pharma NV
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NewAmsterdam Pharma NV
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Publication of WO2025146262A1 publication Critical patent/WO2025146262A1/fr
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    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • red blood cell (RBC) membrane cholesterol content affects the degree of RBC deformability
  • incubation of red blood cells (RBCs) from SCD patients with either high density lipoprotein (HDL) or the HDL-mimetic peptide Fx5A improves the impaired RBC deformability and decreases intracellular reactive oxygen species levels in vitro (Niesor et al. , Membranes 2022, 12, 1134; //doi.org/10.3390/membranesl2111134).
  • HIS was defined as rosuvastatin 20 mg or 40 mg per day or atorvastatin 40 mg or 80 mg per day.
  • FIGs. 36A and 36B there was no significant increase between visits 2 and 4 in pre-betal HDL in the plasma of subjects treated with placebo in the ROSE2 clinical trial, whereas subjects in the obicetrapib treatment group had a statistically significant increase in pre-betal HDL levels between visits 2 and 4.
  • FIG. 37 shows that at visit 4, there was a linear relationship between levels of tocopherol and levels of pre-betal in subjects treated with obicetrapib.
  • NCT 05421078 was a placebo-controlled, double-blind, randomized phase 2 dose-finding study in Japanese patients to evaluate the efficacy, safety and tolerability of obicetrapib as an adjunct to stable statin therapy.
  • a total of 108 patients were randomized to receive placebo, 2.5 mg obicetrapib, 5 mg obicetrapib or 10 mg obicetrapib for an 8-week treatment period. As shown in FIGs.
  • treatment with 2.5, 5 or 10 mg obicetrapib increased the plasma levels of lutein, zeaxanthin and alpha-tocopherol. These results indicate that treatment with 2.5 mg obicetrapib is sufficient to induce a therapeutic effect.
  • methods of treating beta hemoglobinopathies are presented.
  • methods of reducing or preventing vascular symptoms in a patient with a beta hemoglobinopathy are presented.
  • the methods comprise orally administering an HDL- elevating amount of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and optionally co-administering at least one liposoluble antioxidant, to a patient with a beta hemoglobinopathy.
  • the method comprises co-treatment with one or more lipophilic antioxidants, such as, in particular, the oral co-administration of one or more lipophilic antioxidants, such as one or more carotenoids and/or one or more tocopherols.
  • one or more lipophilic antioxidants such as one or more carotenoids and/or one or more tocopherols.
  • compositions are provided, preferably in unit dosage form or solid dosage form, comprising obicetrapib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises a calcium salt of obicetrapib. In some embodiments it is amorphous obicetrapib hemicalcium.
  • the pharmaceutical composition comprises one or more lipophilic antioxidants, such as one or more carotenoids and/or one or more tocopherols.
  • FIG. 1 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.
  • FIG. 2 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.
  • FIG. 21 is 1H-NMR spectrum of Compound ID.
  • FIG. 22 is an x-ray powder diffraction pattern of crystalline obicetrapib hydrochloride Form A.
  • FIG. 28 is an x-ray powder diffraction overlay of the calculated pattern of FIG. 27 and x- ray powder diffraction patterns of Form A crystalline obicetrapib hydrochloride and Form B crystalline obicetrapib hydrochloride.
  • FIG. 29(panels A-E) show the levels of alpha-tocopherol in plasma samples of subjects enrolled in the OCEAN clinical trial, as further described in Example 37.
  • FIG. 30 panels A-E show the levels of alpha-tocopherol in HDL in plasma samples of subjects enrolled in the OCEAN clinical trial, as further described in Example 37.
  • FIG. 31 panels A-E show the levels of lutein in plasma samples of subjects enrolled in the OCEAN clinical trial, as further described in Example 37.
  • FIG. 32 panels A-E show the levels of lutein in HDL in plasma samples of subjects enrolled in the OCEAN clinical trial, as further described in Example 37.
  • FIG. 33 panels A-E show the levels of zeaxanthin in plasma of subjects enrolled in the OCEAN clinical trial, as further described in Example 37.
  • FIG. 34 panels A-E show the levels of zeaxanthin in HDL in plasma samples of subjects enrolled in the OCEAN clinical trial, as further descried in Example 37.
  • FIG. 35 tabulates the level of pre-betal HDL in the plasma of subjects enrolled in the OCEAN clinical trial, as further described in Example 37.
  • FIG. 36 panels A and B show that there was no significant increase between visits 2 and 4 in pre-betal HDL in the plasma of subjects treated with placebo in the ROSE2 clinical trial, whereas subjects in the obicetrapib treatment group had a statistically significant increase in pre- betal HDL levels between visits 2 and 4.
  • FIG. 38 Plasma alpha tocopherol concentrations before and after treatment (NCT05421078) with placebo (A), 2.5 mg obicetrapib (B), 5 mg obicetrapib (C) and 10 mg obicetrapib (D).
  • FIG. 39 Plasma lutein concentrations before and after treatment (NCT05421078) with placebo (A), 2.5 mg obicetrapib (B), 5 mg obicetrapib (C) and 10 mg obicetrapib (D).
  • FIG.40 Plasma zeaxanthin concentrations before and after treatment (NCT05421078) with placebo (A), 2.5 mg obicetrapib (B), 5 mg obicetrapib (C) and 10 mg obicetrapib (D).
  • FIG. 41 shows the percent change from baseline in mean lutein concentration in total plasma, high-density lipoprotein (HDL) fraction, and non-HDL fraction, before and after 8 week treatment with 5 mg obicetrapib as further described in Example 37 (P ⁇ 0.05).
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.25%, 0.2%, 0.1% or 0.05% of a given value or range. Unless otherwise specified, the term “about” means within plus or minus 10% of the explicitly recited value, rounded either up or down to the nearest integer.
  • the term “patient” refers to a human “subject.”
  • treat has the meanings commonly understood in the medical arts, and therefore do not require cure or complete remission, and therefore include any beneficial or desired clinical results.
  • a “therapeutically effective amount” of a compound, composition, or radiation is an amount effective to treat.
  • methods of treating hemoglobinopathies are presented.
  • methods of reducing or preventing vascular symptoms in a patient with a beta hemoglobinopathy are presented.
  • the methods comprise orally administering an HDL-elevating amount of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and optionally co-administering at least one liposoluble antioxidant, to a patient with a beta hemoglobinopathy.
  • the beta-hemoglobinopathy is sickle cell disease (SCD), sickle cell trait (SCT), or P-thalassemia. In specific embodiments, the beta-hemoglobinopathy is SCD.
  • obicetrapib or a pharmaceutically acceptable salt, solvate or cocrystal thereof, is administered daily at a dose sufficient to increase plasma concentration of HDL by at least 10% after 12 weeks of daily administration as compared to the plasma HDL concentration at initiation of obicetrapib treatment (baseline), by at least 20% after 12 weeks of daily administration as compared to the plasma HDL concentration at baseline, by at least 30% after 12 weeks of daily administration as compared to the plasma HDL concentration at baseline, or by at least 40% after 12 weeks of daily administration as compared to the plasma HDL concentration at baseline.
  • obicetrapib or a pharmaceutically acceptable salt, solvate or cocrystal thereof, is administered at a dose sufficient to increase plasma concentration of HDL by more than 20% after 12 weeks of daily administration as compared to the plasma HDL concentration at baseline, by more than 30% after 12 weeks of daily administration as compared to the plasma HDL concentration at baseline, or by more than 40% after 12 weeks of daily administration as compared to the plasma HDL concentration at baseline.
  • obicetrapib is administered orally.
  • obicetrapib is administered as a tablet for oral administration.
  • obicetrapib is administered at a dose of 2.5-25 mg orally per day (2.5-25 mg p.o. QD). In some of these embodiments, obicetrapib is administered at a dose of 2.5 mg p.o. QD, 5 mg p.o. QD, 10 mg p.o. QD, or 25 mg p.o. QD.
  • the dose of obicetrapib or pharmaceutically acceptable salt thereof is 0.5-25 mg orally per day (0.5-25 mg po QD). In some embodiments, the dose of obicetrapib is 1-20 mg orally per day (1-20 mg po QD). In some embodiments, the dose of obicetrapib is 2.5-15 mg orally per day (2.5-15 mg po QD). In some embodiments, the dose of obicetrapib is 1-10 mg orally per day (1-10 mg po QD). In some embodiments, the dose of obicetrapib is 2,5-10 mg orally per day (2.5-10 mg po QD).
  • the dose of obicetrapib or pharmaceutically acceptable salt thereof is equipotent or equivalent to 5-25 mg of obicetrapib orally per day (0.5-25 mg po QD), to 1-20 mg of obicetrapib orally per day (1-20 mg po QD), to 2.5-15 mg of obicetrapib orally per day (2.5-15 mg po QD), to 1-10 mg of obicetrapib orally per day (1-10 mg po QD), or to 2,5-10 of obicetrapib mg orally per day (2.5-10 mg po QD).
  • the dose of obicetrapib is 0.5 mg po QD, 1.0 mg po QD, 1.5 mg po QD, 2.0 mg po QD, 2.5 mg po QD, 3.0 mg po QD, 3.5 mg po QD, 4.0 mg po QD, 4.5 mg po QD, 5 mg po QD, 5.5 mg po QD, 6 mg po QD, 6.5 mg po QD, 7 mg po QD, 7.5 mg po QD, 8 mg po QD, 8.5 mg po QD, 9 mg po QD, 9.5 mg po QD, 10 mg po QD, 10.5 mg po QD,
  • the dose of obicetrapib or salt thereof is equipotent to 5-20 mg of obicetrapib by mouth per day (5-20 mg po QD).
  • obicetrapib is administered as amorphous obicetrapib, and in particularly preferred embodiments, as amorphous obicetrapib hemicalcium.
  • obicetrapib or salt thereof is administered once daily for at least 8 weeks, at least 6 months, at least 12 months, at least 24 months, or at least 36 months.
  • At least one liposoluble antioxidant is co-administered with obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof.
  • at least one of the at least one liposoluble antioxidant is selected from the group consisting of: a xanthophyll, zeaxanthin, lutein, meso-zeaxanthin, astaxanthin, betacryptoxanthin, a tocopherol isomer or derivative thereof selected from alpha-, beta-, gamma- and delta-tocopherol, and a tocotrienol isomer or derivative thereof selected from alpha-, beta-, gamma- and delta-tocotrienol or a mixture thereof.
  • At least one of the at least one liposoluble antioxidant is a xanthophyll, and in particular embodiments, the xanthophyll is lutein.
  • lutein and zeaxanthin are co-administered with obicetrapib.
  • the one or.more lipophilic or liposoluble antioxidants are selected from the group consisting of tocopherols and carotenoids.
  • the methods of the invention in preferred embodiments comprise the concurrent treatment with one or more antioxidants selected from the group consisting of tocopherols, especially alphatocopherol, and xantophylls, especially lutein and zeaxanthin.
  • the methods of the invention further comprises the concurrent treatment with one or more lipophilic antioxidants selected from the group consisting of alpha-tocopherol, lutein and zeaxanthin.
  • methods as defined herein are provided, wherein the one or more lipophilic antioxidant is administered orally, preferably once, twice or three times a day, more preferably once daily.
  • the frequency and administration intervals of obicetrapib and the antioxidant are equal, more preferably each is administered once daily, still more preferably at the same time of the day, sequentially or concurrently.
  • Obicetrapib and (each of) the lipophilic antioxidants may be administered as separate unit dosage forms.
  • obicetrapib and one or more of the lipophilic antioxidants may be administered in the form of the fixed dose combination product as defined herein.
  • the methods comprise the oral administration of a lipophilic antioxidant at a daily dosage of 1000-1 mg, 750-5 mg 500-10 mg, 250-25 mg or 100- 50.
  • RD As established by the (U.S.) national institute of health (‘NTH’), which, currently, uses an RDA for alpha-tocopherol of 15 mg, which corresponds to 22.4 international units (IU), (daily); an RDA for lutein of 10 mg (daily); and an RDA for zeaxanthin of 2 mg (daily).
  • NTH national institute of health
  • the amount of each antioxidant administered is at least 50 %, at least 75 %, at least 80 %, at least 85 %, at least 90 %, at least 95 %, at least 97 %, at least 98 % or at least 99 % and/or less than 200 %, less than 150 %, less than 125 %, less than 120 %, less than 115 %, less than 110 %, less than 105 %, less than 103 %, less than 102 % or less than 101 % of the highest (daily) dose that is safe and recommended/approved for therapeutic and/or prophylactic treatment of subjects suffering from or at risk of suffering from neurodeg enerative diseases.
  • AMD age related macular degeneration
  • the methods comprise the oral administration of lutein at a daily dosage of 1-100 mg, 2-75 mg, 3-50 mg, 4-25 mg, e.g. about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg or about 20 mg, most preferably about 5 mg, about 10 mg, about 15 mg or about 20 mg, most preferably about 10 mg.
  • the methods comprise the oral administration of zeaxanthin at a daily dosage of 0.5-100 mg, 1-50 mg or 1.5-25 mg, e.g. about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg or about 25 mg, most preferably about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg or about 5 mg, most preferably about 2 mg.
  • the methods comprise the oral administration of alphatocopherol at a daily dosage of 1-100 international units (IU), 2-90 IU, 5-80 IU, 100-700 IU, 10- 60 IU , e.g. 15, 17.5, 20, 22.4, 22.5, or 25 IU, more preferably about 22.4 IU.
  • IU international units
  • 2-90 IU 5-80 IU
  • 100-700 IU 10- 60 IU
  • e.g. 15, 17.5, 20, 22.4, 22.5, or 25 IU e.g. 15, 17.5, 20, 22.4, 22.5, or 25 IU, more preferably about 22.4 IU.
  • the methods comprise the oral administration of alphatocopherol at a daily dosage of 0,5-70 mg, 1-60 mg, 3-50 mg, 5-40 mg, 10-40 mg , e.g. 10, 12.5, 15, 17.5 or 20 mg, more preferably about 15 mg.
  • the methods comprise the oral administration of alphatocopherol at a daily dosage of 10-1000 international units (IU), 20-900 IU, 50-800 IU, 100-700 IU, 200-600 IU, e.g. about 200 IU, about 300 IU, about 400 IU, about 500 IU or about 600 IU, most preferably about 200 IU, about 400 IU or about 600 IU.
  • 10-1000 international units IU
  • 20-900 IU 50-800 IU
  • 100-700 IU 200-600 IU
  • 200-600 IU e.g. about 200 IU, about 300 IU, about 400 IU, about 500 IU or about 600 IU, most preferably about 200 IU, about 400 IU or about 600 IU.
  • the methods comprise the oral administration of alphatocopherol at a daily dosage of 5-700 mg, 10-600 mg, 30-500 mg, 50-400 mg, 100-400 mg, e.g. about 134 mg, about 200 mg, about 268 mg, about 335 mg or about 400 mg, most preferably about 134 mg, about 268 mg or about 400 mg.
  • the methods comprise the oral administration of alphatocopherol at a daily dosage of 1000-3000 international units (IU), 1100-2900 IU, 1200-2800 IU, 1300-2700 IU, 1400-2600 IU, 1500-2500 IU, e.g. 1500, 1750, 2000, 2250, 2500 IU, more preferably about 1500, 2000 or 2500 IU, most preferably about 2000 IU.
  • IU international units
  • 1100-2900 IU 1200-2800 IU
  • 1300-2700 IU 1400-2600 IU
  • 1500-2500 IU e.g. 1500, 1750, 2000, 2250, 2500 IU, more preferably about 1500, 2000 or 2500 IU, most preferably about 2000 IU.
  • the methods comprise the oral administration of alpha-tocopherol at a daily dosage of 500-2000 mg, 550-1900 mg, 600-1850 mg, 650-1800 mg, 700-1750 mg, 750- 1700 mg, e.g. 1000, 1173, 1340, 1500, 1675 mg, more preferably about 1000, 1340 or 1675 mg, most preferably about 1340 mg.
  • administration of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, optionally with co-administration of alpha-tocopherol increases plasma concentrations of alpha-tocopherol in HDL.
  • administration of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, optionally with co-administration of lutein increases plasma concentrations of lutein in HDL.
  • administration of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, optionally with co-administration of zeaxanthin increases plasma concentrations of zeaxanthin in HDL.
  • the methods are effective in and/or intended for increasing the plasma level of lutein. More in particular, the methods are effective in and/or intended for increasing the plasma level of lutein, at least 2.5%, from baseline, wherein baseline is defined as start of treatment with obicetrapib, more preferably at least 5%, at least 7.5%, at least 10%, at least 12.5%, or at least 15%.
  • the methods are effective in and/or intended for increasing the plasma level of lutein, with at least 2.5 ng/mL, from baseline, wherein baseline is defined as start of the treatment with obicetrapib, more preferably at least 5 ng/mL, at least 10 ng/mL, at least 12.5 ng/mL, at least 15 ng/mL, at least 17.5 ng/mL, at least 20 ng/mL, at least 22.5 ng/mL, at least 25 ng/mL, at least 27.5 ng/mL, at least 30 ng/mL at least 32.5 ng/mL, at least 35 ng/mL, at least 37.5 ng/mL or at least 40 ng/mL.
  • the methods are effective in and/or intended for increasing the level of lutein carried by HDL and/or Pre-betal HDL. More in particular, the methods are effective in and/or intended for increasing the level of lutein carried by HDL and/or Pre-betal HDL, at least 2.5%, from baseline, wherein baseline is defined as start of treatment with obicetrapib, more preferably at least 5%, at least 7.5%, at least 10%, at least 12.5%, or at least 15%.
  • the methods are effective in and/or intended for increasing the level of lutein carried by HDL and/or Pre-betal HDL, with at least 2.5 ng/mL, from baseline, wherein baseline is defined as start of the treatment with obicetrapib, more preferably at least 5 ng/mL, at least 10 ng/mL, at least 12.5 ng/mL, at least 15 ng/mL, at least 17.5 ng/mL, at least 20 ng/mL, at least 22.5 ng/mL, or at least 25 ng/mL.
  • the methods are effective in and/or intended for increasing the level of lutein carried by HDL and/or Pre-betal HDL, to a level above 50 ng/mL, preferably above 60 ng/mL, above 70 ng/mL, above 90 ng/mL, above 100 ng/mL, above 110 ng/mL, above 120 ng/mL, above 130 ng/mL, above 140 ng/ml or above 150 ng/mL.
  • the methods are effective in and/or intended for increasing the level of zeaxanthin carried by HDL and/or Pre-betal HDL, to a level above 15 ng/mL, preferably above 17.5 ng/mL, above 2 ng/mL, above 22.5 ng/mL, above 25 ng/mL, above 27.5 ng/mL or above 30 ng/mL.
  • the methods are effective in and/or intended for increasing the level of HDL alpha tocopherol. More in particular, the methods are effective in and/or intended for increasing level of HDL alpha tocopherol, with at least 5%, from baseline, wherein baseline is defined as start of treatment with obicetrapib, more preferably with at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%.
  • the methods are effective in and/or intended for increasing level of HDL alpha tocopherol, to a level above 5000 ng/mL, preferably above 5250 ng/mL, above 5500 ng/mL, above 5750 ng/mL, above 6000 ng/mL above 6250 ng/mL, above 6500 ng/mL, above 6750 ng/mL, above 7000 ng/mL, above 7250 ng/mL, above 7500 ng/mL, above 7750 ng/mL or above 8000 ng/mL.
  • the methods are effective in and/or intended for increasing the level of alpha tocopherol carried by HDL and/or Pre-betal HDL. More in particular, the methods are effective in and/or intended for increasing the level of alpha tocopherol carried by HDL and/or Pre-betal HDL, with at least 5%, from baseline, wherein baseline is defined as start of treatment with obicetrapib, more preferably with at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%.
  • the patient is at least 18 years old. In other embodiments, the patient is less than 18 years old. In specific embodiments, the patient is less than 12 years old.
  • compositions are provided, preferably in unit dosage form or solid dosage form, comprising Obicetrapib or a pharmaceutically acceptable salt thereof.
  • composition refers to a composition comprising obicetrapib or a pharmaceutically acceptable salt thereof and one or more additional, non-toxic, ingredients, in particular one or more pharmaceutically acceptable carriers and/or excipients, which composition typically is in a form suitable for administration to a (human) subject, through any route of administration, and which composition is physiologically tolerated upon such administration.
  • the pharmaceutical composition is provided in solid dosage form or unit dosage form.
  • unit dosage form refers to a physically discrete unit suitable as a unitary dosage for human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with any suitable pharmaceutical carrier(s) and/or excipient(s).
  • exemplary, non-limiting unit dosage forms include a tablet, caplet, capsule (e.g., a hard capsule or a soft capsule), lozenge, film, strip, gelcap as well as any metered volume of a solution, suspension, syrup or elixir or the like, which may be contained, for instance in a vial, syringe, applicator device, sachet, spray, micropump etc.
  • the unit dosage form is a unit dosage form that is suitable for oral administration. Most preferably, it is a solid unit dosage form, such as a tablet for oral ingestion.
  • the pharmaceutical composition is provided in a unit dosage form or solid dosage form comprising obicetrapib or a pharmaceutically acceptable salt thereof in a dose of at least 0.5 mg, preferably at least 1 mg, at least 1.5 mg, at least 2 mg, at least 2.5 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, or at least 9 mg, e.g. about 2.5 mg, about 5 mg or about 10 mg.
  • the pharmaceutical composition is provided in a unit dosage form or solid dosage form comprising obicetrapib or a pharmaceutically acceptable salt thereof in a dose of 100 mg or less, more preferably 75 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 15 mg or less, 12.5 mg or less, 10 mg or less, 7.5 mg or less, 5 mg or less, 4 mg or less, 3 mg or less or 2.5 mg or less.
  • the pharmaceutical composition is preferably provided in a unit dosage form or solid dosage form comprising obicetrapib or a pharmaceutically acceptable salt thereof in a dose within the range of 0.5-100 mg, 1-50 mg, 1,5-50 mg, 2-25 mg or 2.5-10 mg.
  • the composition is provided in a unit dosage form or solid dosage form comprising obicetrapib or a pharmaceutically acceptable salt thereof in a dose of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13,
  • the pharmaceutical composition is provided in a unit dosage form or solid dosage form comprising obicetrapib or a pharmaceutically acceptable salt thereof in a dose of 1, 2.5, 5,
  • the pharmaceutical composition further comprises one or more antioxidants, preferably one or more lipophilic antioxidants, more preferably one or more antioxidants selected from the group consisting of tocopherols and carotenoids. More preferably, the pharmaceutical composition comprises one or more lipophilic antioxidants selected from the group consisting of vitamin E, especially alpha-tocopherol, and xantophylls, especially lutein and zeaxanthin. Most preferably the pharmaceutical composition further comprises one or more lipophilic antioxidants selected from the group consisting of alpha-tocopherol, lutein and zeaxanthin.
  • fixed dose combination oral dosage forms comprising: obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; and at least one liposoluble antioxidant.
  • at least one of the at least one liposoluble antioxidants in the FDC oral dosage form is selected from the group consisting of: a xanthophyll, zeaxanthin, meso-zeaxanthin, astaxanthin, beta-cryptoxanthin, a tocopherol isomer or derivative thereof selected from alpha-, beta-, gamma- and delta-tocopherol, and a tocotrienol isomer or derivative thereof selected from alpha-, beta-, gamma- and delta-tocotrienol or a mixture thereof.
  • the oral dosage form comprises amorphous hemicalcium obicetrapib.
  • the oral dosage form comprises amorphous hemicalcium obicetrapib in an amount equivalent to 10 mg obicetrapib.
  • compositions in unit dosage form or solid dosage form comprising said one or more antioxidants, typically in amounts ranging from 1 to 1000 mg.
  • the amount of each antioxidant present in the unit dosage form or solid dosage form is at least 50 %, at least 75 %, at least 80 %, at least 85 %, at least 90 %, at least 95 %, at least 97 %, at least 98 % or at least 99 % and/or less than 200 %, less than 150 %, less than 125 %, less than 120 %, less than 115 %, less than 110 %, less than 105 %, less than 103 % , less than 102 % or less than 101 % of the Recommended Dietary Allowances (RD As), such as the U.S.
  • RD Recommended Dietary Allowances
  • RD As established by the (U.S.) national institute of health (‘NIH’), which, currently, uses an RD A for alpha-tocopherol of 15 mg, which corresponds to 22.4 IU, (daily); an RD A for lutein of 10 mg (daily); and an RDA for zeaxanthin of 2 mg (daily).
  • NASH national institute of health
  • the amount of each lipophilic antioxidant present in the unit dosage form or solid dosage form is at least 50 %, at least 75 %, at least 80 %, at least 85 %, at least 90 %, at least 95 %, at least 97 %, at least 98 % or at least 99 % and/or less than 200 %, less than 150 %, less than 125 %, less than 120 %, less than 115 %, less than 110 %, less than 105 %, less than 103 %, less than 102 % or less than 101 % of the highest (daily) dose that is safe and recommended/approved for therapeutic and/or prophylactic treatment of subjects suffering from or at risk of suffering from neurodegenerative diseases, as discussed herein before.
  • the pharmaceutical composition in unit dosage form or solid dosage form comprises lutein at an amount of 1-100 mg, 2-75 mg, 3-50 mg, 4-25 mg, e.g. 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg or 20 mg, more preferably about 5 mg, 10 mg, 15 mg or 20 mg, most preferably about 10 mg.
  • PLM polarized light microscopy
  • a material is viewed through polarized light, and by viewing the material through cross-polarizers, one can differentiate between materials that are anisotropic (e.g., crystals) or isotropic (e.g., amorphous compounds).
  • Anisotropic materials when exposed to polarized light through cross polarizers, exhibit birefringence which manifests itself by exhibiting color change through cross polarizers.
  • Isotropic materials do not show birefringence and exhibit no color change when exposed to polarized light.
  • the compound of Formula (II) provided in step (a) is a salt of the Formula (II A) or (IIB): wherein A m " is an anion and n is an integer from 1-3.
  • the salts of Formula (IIA) or (IIB), are chosen from salts with an anion A m ' selected from a sulfonate (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate), a sulfate (e.g., methylsulfate), a halogen (e.g., chloride, iodide, or bromide), acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pam
  • the leaving group (X 1 ) is a carbamate. In some embodiments, the leaving group (X 1 ) is a halogen. In certain embodiments, the halogen is chloride.
  • the coupling partner of Formula (III) in step (a) also includes a protecting group (Y 1 ).
  • protecting group refers to any group which when bound to a functional group such as a carboxylic acid moiety of the compounds (including intermediates thereof) prevents reactions from occurring at the functional group and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the functional group e.g., the carboxylic acid moiety.
  • carboxylic acid protecting groups include conventional substituents such as t-butyl esters, methyl esters, ethyl esters, benzyl esters, allyl esters, 1,1 -di ethylallyl esters, 2,2,2-trifluro ethyl esters, phenyl esters, 4- methoxybenzyl esters, silyl esters, ortho esters, esters of 2,6-disubstituted phenols (e.g., 2,6-dimethylphenol) and any other groups that can be introduced chemically onto a carboxylic acid group or like functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
  • substituents such as t-butyl esters, methyl esters, ethyl esters, benzyl esters, allyl esters, 1,1 -di ethylallyl esters, 2,2,2-trifluro ethyl esters
  • any convenient protecting group e.g., ester group
  • a carboxylic acid moiety may find use in the present disclosure for Y 1 , and the selection of appropriate protecting groups can be readily determined by one skilled in the art. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis, 4 th Ed., by T. W. Greene and P. G. M. Wuts (John Wiley & Sons, New York, 1999), in Protecting Group Chemistry, 1st Ed., by Jeremy Robertson (Oxford University Press, 2000); and in March's Advanced Organic chemistry: Reactions Mechanisms, and Structure, 8th Ed., by Michael B.
  • the protecting group (Y 1 ) is selected from an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an allyl group, a substituted allyl group, and a silyl group. In some embodiments, the protecting group (Y 1 ) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluro ethyl, phenyl, 4-methoxybenzyl ester, a 2,6-disubstituted phenol, and a silyl group. In some embodiments, the protecting group (Y 1 ) is a t-butyl group. In some embodiments, the compound of Formula (III) is of the structure IB below:
  • the solvent is selected from toluene, /-butanol, 1 ,4- dioxane, xylene, A-methyl-2-pyrrolidone, dimethylformamide, water, tetrahydrofuran, and combinations thereof.
  • the solvent is a mixture of organic solvent toluene and organic co-solvent t- butanol.
  • steps (pre-al) and (pre-a2) are performed before step (a), the compound of Formula (II) is already present in the required solvent, because the same organic solvents are used in steps (pre-a2) and (a) or because of a solvent swap in step (pre-a2).
  • more organic solvent and for example an organic co-solvent can be added in step (a).
  • an organic co-solvent can also be added during a solvent swap in step (pre-a2).
  • steps (pre-al) and (pre-a2) are performed before step (a) and the compound of Formula (II) is present in toluene.
  • the coupling reaction in step (a) typically is a catalyzed reaction.
  • the reaction is a palladium-catalyzed coupling reaction in the presence of a base.
  • Suitable examples of palladium catalysts are for example tris(dibenzylideneacetone)dipalladium and Pd(II)acetate.
  • Suitable bases include organic bases (e.g., sodium /-butoxide, and potassium t- butoxide) and inorganic bases (e.g., K3PO4, K3PO4 H2O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH, and NaOH).
  • anhydrous K3PO4 is used as a base.
  • the particle size distribution is such that 90% of the particles are smaller than between about 140 and about 307 microns including between about 140 and about 170 microns, including about 160 and about 290 microns, and about 180 and about 220 microns, and about 200 and about 210 microns. In some embodiments, 90% of the particles are less than 205 microns.
  • the compound of Formula (IIA) or (HB) is reacted in step (a) with a compound of Formula (III) in a solvent (e.g., an organic solvent), using a palladium catalyst, a base.
  • a solvent e.g., an organic solvent
  • the reaction mixture further includes a ligand.
  • a salt of Formula (IIA) or (HB) is reacted in step (a) with a compound of Formula (III) in the solvent (e.g., an organic solvent), using Pd(II)acetate, either fS')-BINAP [(5)-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl], (R)- BINAP [(S)-2,2'- bis(diphenylphosphino)- 1,1 '-binaphthyl], or rac-BINAP as a ligand.
  • fS')-BINAP [(5)-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl]
  • R R
  • BINAP [(S)-2,2'- bis(diphenylphosphino)- 1,1 '-binaphthyl]
  • rac-BINAP as a ligand.
  • (5)- BINAP is used as the ligand, and a base selected from sodium /-butoxide, potassium /-butoxide, anhydrous K3PO4, K3PO4-H2O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH and NaOH.
  • the salt of Formula (IIA) is the mesylate salt, Compound 1A.
  • the reaction in step (a) is performed at a temperature from 70°C and 80°C, optionally under a nitrogen atmosphere, for 2 or more hours.
  • the one or more aqueous washing steps comprise one or more washing steps with water, preferably deionized water, followed by separating off the aqueous phase, subsequently one or more washing steps with an aqueous HC1 solution, followed by separating off the aqueous phase, subsequently one or more washing steps with an aqueous sodium chloride solution, followed by separating off the aqueous phase, and finally one or more washing steps with again deionized water, followed by separating off the aqueous phase.
  • water preferably deionized water
  • step (a) If /-butanol is used as an organic co-solvent in step (a), this organic co-solvent is removed from the organic phase during the washing steps.
  • step (a) is performed in an organic solvent different from the solvent used in step (b), the organic solvent used in step (a) is swapped in step (a) with the organic solvent applied in step (b), such that the compound of Formula (IV) remains in solution.
  • the organic solvent used in step (a) is swapped in step (a) with the organic solvent applied in step (b), such that the compound of Formula (IV) remains in solution.
  • at least part of the (organic) solvent used in step (a) is evaporated, such as by using distillation at reduced pressure, and the organic solvent of step (b) is added, such that the compound of Formula (IV) remains in solution during the solvent swap.
  • This process can be performed by continuously evaporating the (organic) solvent used in step (a) and by continuously adding the organic solvent of step (b), for example until the amount of the (organic) solvent used in step (a), based on the total amount of solvent, is below a certain threshold value.
  • this process can be performed batch-wise in more than one steps of evaporating part of the (organic) solvent used in step (a) and subsequently adding part of the organic solvent used in step (b), for example until the amount of the (organic) solvent used in step (a), based on the total amount of solvent, is below a certain threshold value.
  • the solvent used in step (a) is a mixture of organic solvent toluene and organic co-solvent Z-butanol.
  • the /-butanol is removed from the organic phase comprising the compound of Formula (IV) during the washing steps.
  • step (a) the remaining organic solvent toluene is swapped with acetonitrile by distilling off in two or more steps, at a temperature between 50°C and 65°C under reduced pressure, part of the toluene with intermediate addition of acetonitrile, in an amount to obtain a solvent mixture with less than about 20 weight percent toluene, based on the combined weight of the solvents, such that the compound of Formula (IV) remains in solution.
  • Y 1 is t-butyl.
  • step (b) of the method for preparing a compound of Formula (I) according to the disclosure the compound of Formula (IV) is converted to the carbamate of Formula (V) in an organic solvent, and subsequently isolated as a solid salt of Formula (VI) (where Y 1 is a protecting group, e.g., as described herein).
  • the organic solvent used in step (b) is selected from acetonitrile, chlorobenzene, toluene, V-methyl-2-pyrrolidone, xylene, 1,4-di oxane, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, t- butyl methyl ether, and combinations thereof.
  • the organic solvent is acetonitrile or a mixture of chlorobenzene and dichloromethane.
  • the compound of Formula (IV) is already provided in step (a) in the organic solvent used in step (b), either because the same organic solvents are used in steps (a) and (b) or because of a solvent swap in step (a).
  • Y 1 is t-butyl.
  • the organic solvent used in step (b) is a mixture of acetonitrile toluene, with less than about 20 weight percent toluene, based on the combined weight of the organic solvents.
  • the conversion of the compound of Formula (IV) to the corresponding carbamate with Formula (V) in step (b) is performed in acetonitrile with less than about 20 weight percent toluene, based on the combined weight of the organic solvents, with an excess ethyl chloroformate in the presence of pyridine, at a temperature between 10°C and 20°C.
  • step (b) is performed in an organic solvent different from the organic solvent used in step (c)
  • the organic solvent used in step (b) is swapped in step (b) with the organic solvent applied in step (c), such that the compound of Formula (V) remains in solution.
  • step (b) In some embodiments where the organic solvents used in steps (b) and (c) are different, at least part of the organic solvent used in step (b) is evaporated, such as by distillation at reduced pressure, and the organic solvent of step (c) is added, such that the compound of Formula (V) remains in solution during the organic solvent swap.
  • This process can be performed by continuously evaporating the organic solvent used in step (b) and by continuously adding the organic solvent of step (c), for example until the amount of the organic solvent used in step (b), based on the total amount of organic solvent, is below a certain threshold value.
  • this process can be performed batch-wise in more than one steps of evaporating part of the organic solvent used in step (b) and subsequently adding part of the organic solvent used in step (c), for example until the amount of the organic solvent used in step (b), based on the total amount of organic solvent, is below a certain threshold value.
  • the resulting mixture is preferably subjected to one or more treatments with an aqueous sodium chloride and/or HC1 solution, followed by separating off the aqueous phase, and subsequently to one or more treatments with an aqueous bicarbonate solution, followed by separating off the aqueous phase.
  • the conversion of the compound of Formula (IV) to the corresponding carbamate with Formula (V) in step (b) is performed in acetonitrile with an excess of ethyl chloroformate in the presence of pyridine, at a temperature between 10°C and 20°C, and this solvent is swapped in step (b) with isopropyl acetate by distilling off in two or more steps, at a temperature of 60°C or less under reduced pressure, part of the acetonitrile with intermediate addition of isopropyl acetate, in an amount to obtain a solution of the compound of Formula (V) in isopropyl acetate, wherein the solution may be subjected to one or more treatments with an aqueous NaCl/HCl solution, followed by separating off the aqueous phase, and subsequently to one or more treatments with an aqueous bicarbonate solution, followed by separating off the aqueous phase.
  • the salt of Formula (VI) is chosen from salt with an anion A n ' selected from chloride, bromide, bitartrate, and mesylate.
  • XRPD was performed with Panalytical X’Pert 3 Powder diffractometer using an incident beam of Cu radiation produced using an Empyran tube, fine focused source, on a silicon zerobackground holder.
  • a silicon standard (NIST SRM 640d) was analyzed to verify that the Si 111 peak position is consistent with the NIST-certified position.
  • Approximately 5 to 10 mg of sample was placed on a silicon zero-background holder and flattened manually using an aluminum spatula to minimize difference in the overall sample height. The holder was then loaded on the instrument for analysis.
  • the XRPD parameters used are listed in in Table 10. Table 10 Parameters for XRPD test
  • a Rigaku SmartLab X-Ray Diffractometer was configured in Bragg-Brentano reflection geometry equipped with a beam stop and knife edge to reduce incident beam and air scatter. Data collection parameters are shown in Table 11.
  • NMR spectra of a solution made from a sample of amorphous obicetrapib hemicalcium is set forth in Figure 5.
  • the NMR spectrum was obtained using a 600 MHz AVANCE NEO Bruker and in deuterated MeOH as solvent using tetramethylsilane (TMS) as the internal reference for chemical shift at 0.0 ppm.
  • TMS tetramethylsilane
  • Obicetrapib HC1 (approx. 43 mg, prepared consistent as disclosed herein) was combined with CPME/heptane (1:7) (0.8 mL) in a 1-dram vial and the mixture was magnetically stirred at room temperature. After 2 weeks, the solid was separated by centrifugation, the remaining liquid was removed via pipette. The sample was dried in a vacuum desiccator for approx. 30 min to give approximately 25 mg of Form A.
  • Obicetrapib HC1 (approx. 84 mg, prepared consistent as disclosed herein) was dissolved in 3.5 mL of toluene. Approximately 1 molar equivalent of hydrochloric acid (116 pL, 1 M solution in diethyl ether) was added to the solution upon stirring at room temperature. Heptane (4 mL) was then added to the mixture resulting in a cloudy solution within a few minutes. After stirring overnight, the suspension was vacuum filtered and the solid was briefly dried on the filter under reduced pressure to give approximately 40 mg of Form B (weighed after 26 days of ambient storage).
  • Obicetrapib HC1 (approx. 84 mg, prepared consistent as disclosed herein) was dissolved in 1.0 mL of isopropyl acetate. Approximately 1 molar equivalent of hydrochloric acid (116 pL, 1 M solution in diethyl ether) was added to the solution upon stirring at room temperature. Heptane (6 mL) was then added to the mixture resulting in a cloudy solution. After stirring overnight, the suspension was vacuum filtered and the solid was briefly dried on the filter under reduced pressure to give approximately 25 mg of Form C (weighed after 26 days of ambient storage).
  • Obicetrapib HC1 (approx. 46 mg, prepared consistent as disclosed herein) was combined with butyl acetate/heptane (1:5) (0.6 mL) in a 1-dram vial and the mixture was magnetically stirred at room temperature. After 2 weeks, the solid was separated by centrifugation, the remaining liquid was removed via pipette. The sample was dried in a vacuum desiccator for approx. 30 min to give approximately 15 mg of Form D.
  • Obicetrapib HC1 (approximately 10 mg, prepared consistent as disclosed herein) was dissolved in a mixture of cyclopentyl methyl ether and heptane (1:8) (0.232 mL) upon heating at approximately 60°C. The resulting solution was cooled to 50-55°C and left standing at that temperature overnight. The next day, some solids of acicular morphology were observed on the sides of vial. A temperature cycling experiment was conducted via successive heating-cooling: the sample was heated at 55-60°C, then cooled to 45-50°C and held for several hours at that temperature. After approximately 5 days, agglomerated long blades were observed under the microscope and found to be of sufficient size and quality.
  • a colorless long blade-shaped crystal of a single crystal of Example 33 with formula [4(C32H32F9N4O5)-2(C32H3iF9N4O5)-C6Hi2O-C7Hi6-4(Cl)-[+ solvent]] having approximate dimensions of 0.02 * 0.09 * 0.28 mm was mounted on a Mitegen micromesh mount in a random orientation.
  • Data were collected from a shock-cooled single crystal at 150(2) K on a Bruker AXS D8 Quest four circle diffractometer with an I-mu-S microsource X-ray tube using a laterally graded multilayer (Goebel) mirror as monochromator and a PhotonIII_C14 charge-integrating and photon counting pixel array detector.
  • the diffractometer used CuX a radiation
  • the asymmetric part of the structure consists of six major organic molecules, four chloride anions and several solvate molecules (methyl cyclopentyl ether and heptane). Four of the six major fragments are cationic, two are neutral molecules ("free base"). Protonation is at the "N3" nitrogen atom of the pyrimidine ring for all four cations, all four N-H+ units ionized and all four chloride anions ionized - two associated with the two N-H+ units and the other with carboxyl moieties. The equivalent positions for the two free base molecules are not protonated and no close contacts to potential H-bond acceptors are observed.
  • Atomic Displacement Parameters (“ADP”) of the latter were restrained to be close to isotropic. Uij components of ADPs for atoms closer to each other than 2.0 A were restrained to be similar.
  • the position of one N-H+ H atom (H3A 3) was allowed to refine. Hydroxyl H-atoms of the carboxylic acids groups were allowed to rotate. Some were further restrained based on hydrogen bonding considerations. In the initial refinement cycles, a mild damping factor was applied. In the final refinement cycles some hydroxyl H atoms were set to ride on their carrying O atom (H4_l, H4_4, H4B 1), and the damping factor was removed.
  • a methyl cyclopentyl ether solvate molecule was refined as fully occupied. Bond distances and angles were restrained to expected target values and Uij components of ADPs for atoms closer to each other than 2.0 A were restrained to be similar. ADPs were restrained to be close to isotropic. A heptane solvate molecule was refined as disordered over two orientations. Bond distances and angles were restrained to expected target values and Uij components of ADPs for atoms closer to each other than 2.0 A were restrained to be similar. A mild antibumping restraint was applied to avoid close contacts with main molecule atoms. Subject to these conditions, the occupancy ratio refined to 0.460(13) to 0.540(13).
  • the structure contains additional 980 A 3 of solvent-accessible void volume.
  • the two major void spaces (333 A 3 each) likely contain ill-defined highly disordered solvate molecules. No substantial electron density peaks were found in the solvent accessible voids (less than 0.70 electrons per A 3 ) and the residual electron density peaks are not arranged in a recognizable pattern.
  • the structure factors were instead augmented via reverse Fourier transform methods using the SQUEEZE routine (A.L. Spek J. Appl. Cryst. 2003, 36, 7-13) as implemented in the program Platon (P. van der Sluis, & A. L. Spek, Acta Cryst. 1990, A46, 194-201).
  • the SQUEEZE procedure accounted for 229 electrons within this volume , or about one heptane molecule for each of the two larger void spaces (100.2 electrons/heptane).
  • Flack x parameter was determined using 4528 quotients [(!+)- (I- )]/[(!+)+(!“ )] using Parsons’ method and refined to 0.046(17) (S. Parsons, H. Flack, T. Wagner, Acta Cryst. 2013, B69, 249-259). 5.35.
  • Example 35 - X-ray Powder Diffraction Pattern [0536] A Rigaku SmartLab X-Ray Diffractometer was configured in Bragg-Brentano reflection geometry equipped with a beam stop and knife edge to reduce incident beam and air scat-ter. Data collection parameters are shown in the following table (Table 12). This method has not been validated. 5.36.
  • Example 36 Calculated X-ray Powder Diffraction Pattern
  • An x-ray powder diffraction pattern was calculated from the single crystal structure solution of Example 34. The pattern was generated using commercially available software called Mercury 3.3 (Build RC5) from the Cambridge Crystallographic Data Centre (CCDC). [0538] A peak table associated with the calculated pattern is set forth below in Table 13.
  • Example 37 Analysis of blood samples from participants in the OCEAN clinical trial
  • the OCEAN trial was a placebo-controlled, double-blind, randomized, phase 2 study in participants with mild dyslipidemia to evaluate the efficacy, safety, and tolerability of obicetrapib and ezetimibe combination therapy.
  • subjects had fasting LDL-C levels >2.5 mmol/L (>100 mg/dL) and ⁇ 4.5 mmol/L ( ⁇ 175 mg/dL) and triglyceride (TG) levels ⁇ 4.5 mmol/L ( ⁇ 400 mg/dL) (Visit 1).
  • subjects were not taking any lipid-altering therapy.
  • eligible patients were randomized to placebo; 5 mg obicetrapib + 10 mg ezetimibe; 5 mg obicetrapib + placebo; ezetimibe; or placebo obicetrapib + 10 mg ezetimibe, for an 8- week treatment period.
  • patients continued for a 4-week safety follow-up and an 8-week PK follow-up.
  • Example 38 Analysis of blood samples from participants in the ROSE2 clinical trial
  • the ROSE2 trial was a placebo-controlled, double-blind, randomized, phase 2 study to evaluate the efficacy, safety, and tolerability of obicetrapib 10 mg, both in combination with ezetimibe 10 mg and as monotherapy, as an adjunct to high- intensity statin therapy.
  • subjects had LDL-C concentrations of > 70 mg/dL and triglycerides of ⁇ 400 mg/dL while on a high intensity statin (HIS) regimen.
  • HIS was defined as rosuvastatin 20 mg or 40 mg per day or atorvastatin 40 mg or 80 mg per day.
  • subjects were randomized to placebo, 10 mg obicetrapib monotherapy, or 10 mg obicetrapib + 10 mg ezetimibe combination therapy for a 12- week treatment period. After the treatment period, subjects continued for a 4-week safety follow-up.
  • FIGs. 36A and 36B show that subjects in the obicetrapib treatment group in the ROSE2 clinical trial had a statistically significant increase in pre-betal HDL levels between visit 2 and visit 4, whereas there was no significant increase between visits 2 and 4 in pre-betal HDL in the plasma of subjects treated with placebo.
  • FIG. 37 shows that at visit 4, there was a linear relationship between levels of tocopherol and levels of pre-betal in subjects treated with obicetrapib.
  • Example 39 Analysis of blood samples from participants in a phase 2 clinical trial (NCT 05421078)
  • NCT05421078 was designed as a placebo-controlled, double-blind, randomized phase 2 dose-finding study in Japanese patients to evaluate the efficacy, safety and tolerability of obicetrapib as an adjunct to stable statin therapy. A total of 108 patients were randomized to receive placebo, 2.5 mg obicetrapib, 5 mg obicetrapib or 10 mg obicetrapib for an 8- week treatment period.
  • the primary efficacy endpoint was the percent change from start to end of the treatment period in LDL-C for the treatment groups compared to the placebo group.

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Abstract

L'invention concerne des méthodes de réduction ou de prévention de symptômes vasculaires chez un patient atteint d'une hémoglobinopathie bêta. Les méthodes comprennent l'administration par voie orale d'une quantité d'obicetrapib augmentant les HDL, ou d'un sel, d'un solvate ou d'un co-cristal pharmaceutiquement acceptable de celui-ci, et éventuellement la co-administration d'au moins un antioxydant liposoluble à un patient atteint d'une hémoglobinopathie bêta.
PCT/EP2024/080193 2024-01-03 2024-10-25 Obicetrapib destiné à être utilisé dans le traitement d'hémoglobinopathies Pending WO2025146262A1 (fr)

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