Treatment and prevention of sepsis or other dysregulated inflammatory responses using CETP inhibitor obicetrapib

Abstract

This invention relates to methods and compositions useful in subjects suffering from or at risk of suffering from sepsis or other dysregulated inflammatory responses. It has been demonstrated that the CETP inhibitor obicetrapib not only preserved or increased HDL-C and Apo A1 levels, but also reduced an important pro-inflammatory marker, IL-1β, and significantly increased survival, relative to placebo, in a suitable sepsis mouse model. Thus, broadly stated, the present invention concerns the use of CETP inhibitors in the prevention, treatment, management or amelioration of sepsis, or other dysregulated inflammatory responses in a subject.

Description

[0001] TREATMENT AND PREVENTION OF SEPSIS OR OTHER DYSREGULATED INFLAMMATORY RESPONSES USING CETP INHIBITOR OBICETRAPIB

[0002] Field of the Invention

[0003] This invention relates to methods and compositions useful in the prevention, treatment, management or amelioration of sepsis or other dysregulated inflammatory responses. The methods involve administration of a CETP-inhibitor.

[0004] Background of the Invention

[0005] Sepsis is a clinical syndrome that complicates severe infection and is characterized by the systemic inflammatory response syndrome (SIRS), immune dysregulation, microcirculatory derangements, and end-organ dysfunction including acute respiratory distress syndrome (ARDS) and multiple organ failure. SIRS can also be triggered by a variety of non-infectious conditions, such as trauma, bums, hemorrhagic or hypovolemic shock, pancreatitis, and other disease states.

[0006] The sepsis response typically begins with a microbial infection. While the majority of sepsis is caused by bacterial pathogens, there is a significant volume of sepsis caused by fungal and viral agents. In these micro-organisms, there are unique groups of molecules which are not associated with human cells. These unique microbial molecules are called pathogen-associated molecular patterns or PAMPs. Examples of microbial-associated PAMPs include: pathogen-associated lipids (PALs), lipopolysaccharide (LPS) from the outer membrane of the Gram-negative cell wall, bacterial lipoproteins and lipopeptides; double-stranded viral RNA unique to many viruses in some stage of their replication and single-stranded viral RNA from many viruses having an RNA genome.

[0007] The host response to an infection is initiated when innate immune cells, particularly macrophages, recognize and bind to microbial components. This could e.g. occur via the ligation of PAMPs of microorganisms and Pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) on the surface of host immune cells. The Stimulation of PRRs (such as TLRs) by PAMPs triggers the down-stream pathways which will ultimately lead to the activation of mitogen-activated protein kinase (MAPK), nuclear facto(R)-kB (NF-kB) and interferon regulatory factors 3 / 7 (IRF3 / 7), which further leads to transcriptional changes and the secretion of inflammatory cytokines, chemokines and antimicrobial peptides which together function to target and kill pathogen.

[0008] Sepsis develops when the initial, appropriate host response to an infection becomes amplified and subsequently dysregulated, leading to an imbalance between pro- inflammatory and anti-inflammatory responses. In particular, the activation of innate immune response, the “first line of cellular defense”, results in an excessive release of cytokines, chemokines, and other inflammatory regulators from local infection cite to systemic circulation. Furthermore, a dysregulated cytokine release may lead to endothelial dysfunction, characterized by vasodilation and increased capillary permeability. The resulting leakage syndrome is clinically associated with hypotension, macromolecular extravasation, and oedema. The dysfunctional epithelial barriers enable pathogens and their products to further invade the host organism, to disturb regulatory mechanisms, and ultimately, to cause dysfunctions and failure of remote (vital) organs, including the kidneys, lung, liver, and brain. Acute kidney injury (AKI), for example, develops in up to 60% of patients diagnosed with sepsis or septic shock, and septic AKI is associated with an extremely high risk of mortality (-70%). Acute lung injury (ALI), in turn, is one of the leading causes of death in sepsis with very few beneficial treatments available. Indeed, there is no cure for ALI; and the available treatments are just supportive to maintain adequate oxygenation and ventilation while minimizing secondary lung injury. The acute respiratory distress syndrome (ARDS) occurs in 25% to 50% of patients with sepsis. Also in patients with ARDS, there is a high mortality rate.

[0009] Traditionally, sepsis was viewed as an excessive systemic pro-inflammatory reaction (to invasive microbial pathogens). More recently, it has been proposed that the early phase of hyper-inflammation is followed or overlapped by a prolonged state of immunosuppression, referred to as sepsis induced immunoparalysis. This immunoparalytic state is characterized by impaired innate and adaptive immune responses, and may play a central role in the pathogenesis of tissue damage, multiple organ failure, and death induced by sepsis.

[0010] The global burden of sepsis is very high. It affects almost 50 million people per year worldwide. The mortality rate from sepsis is approximately 40% in adults, and 25% in children; 20% of all deaths worldwide are due to sepsis. Septic shock is the 13thleading cause of death in the United States, and the number one cause of deaths in intensive care units.

[0011] Despite the high prevalence of morbidity and mortality, no effective therapies exist yet beyond antibiotic therapy and supportive care. Thus, development of novel therapeutics for treating sepsis, especially those that directly target processes underlying pathogenesis, remains a top priority. It is an objective of the present inventions to provide such therapeutics.

[0012] Summary of the Invention

[0013] The present invention, generally speaking, provides methods for prevention, treatment, management or amelioration of sepsis, or other dysregulated inflammatory responses, said methods comprising the administration of a therapeutically or prophylactically effective amount of a CETP inhibitor, to a subject in need thereof.

[0014] As is shown in the experimental part of the present application, the present inventors have shown that, in an APOE3-Leiden CETP mouse cecal-ligation and puncture model of sepsis, CETP inhibition with obicetrapib preserved or increased HDL-C and Apo A1 levels, reduced an important pro-inflammatory marker, IL-13, and significantly increased survival, relative to placebo.

[0015] Without being bound to theory, the inventors hypothesize that the increase in HDL caused by pharmacological CETP inhibition 1) increases HDL-mediated scavenging of endotoxins, thereby preventing excessive endotoxemia that underlies sepsis-induced mortality, and 2) activates macrophages towards an antibacterial response that is required to combat the underlying infection.

[0016] Sepsis greatly impacts HDL metabolism by causing an acute, large drop in HDL-C. Decreases in HDL-C and several HDL apolipoproteins (apoA1 and apoCi) are associated with increased risk of multiorgan dysfunction, prolonged hospital admission, and mortality. Both apoA1 and apoCi can bind and initiate elimination from plasma of pathogen-associated lipids (PALs), such as lipopolysaccharide (LPS), a component of the outer shell of Gram-negative bacteria. Binding of LPS to HDL particles is thought to be part of the innate immune response. The critical role of HDL and apoA1 in sepsis pathogenesis is supported by preclinical mouse models. Both infusion of HDL and transgenic overexpression of apoA1 reduce inflammation and improve survival rates after intra-abdominal sepsis. In addition to the foregoing, new analyses of samples from the OCEAN trial (NCT04770389, “Randomized Study of Obicetrapib, optionally combined with Ezetimibe”) have demonstrated (see examples herein below) that the CETP inhibitor obicetrapib increased the plasma level of HDL, pre-beta1 HDL, as well as plasma levels of certain antioxidant carotenoids, including lutein, zeaxanthin and tocopherol, and the level of those antioxidants carried by HDL. There is increasing evidence that oxidants and antioxidants play a key role in sepsis. Imbalances of oxidants and antioxidants, in favor of oxidants (called oxidative stress), are believed to contribute to pathogenesis, with vascular permeability impairment, decreased cardiac performance, and mitochondrial malfunction leading to impaired respiration, as the most important consequences. The findings that treatment with obicetrapib increases, total plasma levels of antioxidant (lutein, zeaxanthin and alpha-tocopherol), and the level of HDL carried antioxidants in particular, therefore might constitute additional support for the treatment of using obicetrapib.

[0017] The findings presented herein are particularly unexpected, given that another CETP inhibitor, torcetrapib, that structurally resembles obicetrapib, was associated with increased risk of mortality from infection in humans, increased proinflammatory atherosclerotic lesions in mice, and was suspected to interfere with the elimination of pathogen-associated lipids.

[0018] A first aspect of the invention concerns a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from sepsis or other dysregulated inflammatory responses, said method comprising the administration to said subject of (a pharmaceutical composition comprising) a therapeutically effective amount of a CETP-inhibitor selected from the group consisting of Obicetrapib and pharmaceutically acceptable salts thereof. A further aspect of the invention concerns a method for the prevention, treatment, management or amelioration of sepsis, or other dysregulated inflammatory responses in a subject in need thereof, said method comprising the administration to said subject of (a pharmaceutical composition comprising) a therapeutically effective amount of the CETP-inhibitor, preferably Obicetrapib or a pharmaceutically acceptable salt thereof.

[0019] In a further aspect, the invention provides a CETP inhibitor selected from the group consisting of Obicetrapib and pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising said CETP inhibitor, for use in a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from sepsis or other dysregulated inflammatory responses, said method comprising the administration to said subject of (a pharmaceutical composition comprising) a therapeutically effective amount of the CETP-inhibitor. A further aspect of the invention provides a CETP inhibitor selected from the group consisting of Obicetrapib and pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising said CETP inhibitor, for use in a method for the prevention, treatment, management or amelioration of sepsis, or other dysregulated inflammatory responses in a subject in need thereof, said method comprising the administration to said subject of (a pharmaceutical composition comprising) a therapeutically effective amount of the CETP-inhibitor.

[0020] Yet, a further aspect of the invention concerns the use of a CETP inhibitor selected from the group consisting of Obicetrapib and pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical composition for use in a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from sepsis or other dysregulated inflammatory responses, said method comprising the administration to said subject of (the pharmaceutical composition comprising) a therapeutically effective amount of the CETP inhibitor. A further aspect of the invention provides the use of a CETP-inhibitor selected from the group consisting of Obicetrapib and pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical composition for use in a method for the prevention, treatment, management or amelioration of sepsis, or other dysregulated inflammatory responses in a subject in need thereof, said method comprising the administration to said subject of (the pharmaceutical composition comprising) a therapeutically effective amount of the CETP-inhibitor.

[0021] Other aspects of the invention concern pharmaceutical compositions, preferably in unit dosage form, comprising a CETP inhibitor selected from the group consisting of Obicetrapib and pharmaceutically acceptable salts thereof, and kits comprising a package containing a plurality of one or more of such pharmaceutical unit dosage forms as well as a leaflet containing printed instructions to repeatedly (self)administer said unit dosage forms in order to prevent, treat, manage or ameliorate sepsis, or other dysregulated inflammatory responses.

[0022] Specific details and preferred embodiments of the afore-mentioned methods as well as of the compositions and pharmaceutical kits used therein will become evident to those skilled in the art on the basis of the following detailed description and the appended experimental part.

[0023] Definitions

[0024] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs.

[0025] The terms “subject” or “individual” are used interchangeably and refer to an animal to be treated, including but not limited to humans and non-human primates; rodents, including rats and mice; bovines; equines; ovines; felines; and canines.

[0026] The term “patient” refers to a human subject.

[0027] The phrase “therapeutically effective amount” refers to the amount of a compound that, when administered to a subject for treating a disease, condition, or disorder, is sufficient to effect treatment of the disease, condition, or disorder.

[0028] The term “pharmaceutically acceptable salt” refers to a salt that is acceptable for administration to a subject. Examples of pharmaceutically acceptable salts include, but are not limited to: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate; sulfonic acid salts such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate; organic acid salts such as oxalate, tartrate, citrate, maleate, succinate, acetate, trifluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, and malate; amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate; inorganic salts such as lithium salt, sodium salt, potassium salt, calcium salt, and magnesium salt; and salts with organic bases such as ammonium salt, triethylamine salt, diisopropylamine salt, and cyclohexylamine salt. The term “salt(s)” as used herein encompass hydrate salt(s). Other examples of pharmaceutically acceptable salts include anions of the compounds of the present disclosure compounded with a suitable cation.

[0029] Other interpretational conventions

[0030] Ranges: throughout this disclosure, various aspects of the invention are presented in a range format. Ranges include the recited endpoints. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6, should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc. as well as individual number within that range, for example, 1, 2, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0031] In this disclosure, “comprises”, “comprising”, “containing”, “having”, “includes”, “including” and linguistic variants thereof have the meaning normally ascribed to them in (U.S. and / or European) Patent law, permitting the presence of additional components beyond those explicitly recited.

[0032] Unless specifically stated or apparent from context, as used herein the term “or” is understood to be inclusive.

[0033] Unless specifically stated or apparent from context, as used herein, the terms “a”, “an”, and “the” are understood to be singular or plural. That is, the articles “a” and “an” are used herein to refer to one or to more than one (i.e. , to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0034] Unless specifically stated or otherwise apparent from context, as used herein the term “about” is understood as within range of normal tolerance in the art. Unless otherwise specified, “about” intends ±10% of the stated value. Where a percentage is provided with respect to an amount of a component or material in a composition, the percentage should be understood to be a percentage based on weight, unless otherwise stated or understood from the context.

[0035] Unless the specific stereochemistry is expressly indicated, all chiral, diastereomeric, and racemic forms of a compound are intended. Thus, compounds described herein include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Racemic mixtures of R-enantiomer and S-enantiomer, and enantio-enriched stereomeric mixtures comprising of R- and S-enantiomers, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology. Detailed description of the Invention

[0036] CETP Inhibitors

[0037] The present invention, in one aspect, concerns the use of certain CETP inhibitors in the treatment of sepsis or (other) dysregulated inflammatory response. The term CETP inhibitors refers to a class of compounds that have the capability of inhibiting cholesterylester transfer protein (CETP). Whenever the term ‘CETP inhibitor’ is used herein in general, it refers to the respective compounds in their free base form as well as to any pharmaceutically acceptable derivative thereof, including, in particular, any pharmaceutically acceptable salt, solvate, hydrate, enantiomer, polymorph, etc.

[0038] In accordance with the invention, the CETP inhibitor is obicetrapib or a pharmaceutically acceptable salt thereof.

[0039] “Obicetrapib”, formerly known as TA-8995, is the international non-proprietary name (INN) of the compound with IUPAC name (2R,4S){[3,5Bis(trifluoromethyl)benzyl]-[5(3-carboxypropoxy)pyrimidin-2-yl] amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester, and according to the following formula (I)

[0040] ex n.

[0041] F

[0042] / -F

[0043] F

[0044]

[0045] / F

[0046] (!)■

[0047] Methods of synthesizing obicetrapib are known. See, e.g., U.S. Patent Nos.

[0048] 7,872,126; 8,084,611; and 10,112,904, the disclosures of which are incorporated herein by reference in their entireties.

[0049] In certain preferred embodiments of the invention, the CETP inhibitor is a salt form of obicetrapib, more particularly an amorphous obicetrapib calcium salt, in particular, amorphous obicetrapib hemicalcium. More detailed information containing said salts, including methods of their preparation are is provided herein below.

[0050] Pharmaceutical compositions

[0051] In preferred embodiments of the present invention, the CETP inhibitor is provided in the form of or contained in a pharmaceutical composition. As mentioned herein before, an aspect of the invention relates to said pharmaceutical compositions.

[0052] As used herein, the term "pharmaceutical composition" refers to a composition comprising the CETP inhibitor, typically 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.

[0053] In a preferred embodiment, the composition comprises one or more carriers and / or excipients. As is known by those of average skill in the art, the appropriate choice of excipients is dependent on multiple factors, including the physicochemical properties of the API, the preferred pharmaceutical form, the preferred route of administration, the desired rate of release, etc. The compositions of the invention can be formulated for a variety of routes of administration, oral administration being particularly preferred. It is within the purview of those of average skill in the art to conceive and develop suitable formulations, relying on the common general knowledge as reflected in text books such as Remington’s Pharmaceutical Sciences (Meade Publishing Co., Easton, Pa., 20thEd., 2000), the entire disclosure of which is herein incorporated by reference, and routine development efforts.

[0054] In accordance with the various aspects of the invention, the composition is preferably provided in unit dosage form. The term “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 and / or determined 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. In accordance with particularly preferred embodiments of the invention, 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.

[0055] In accordance with various aspects of the invention, the composition is preferably provided in a unit 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, at least 9 mg or at least 10 mg,. Furthermore, in accordance with the various aspects of the invention, the composition is preferably provided in a unit 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.

[0056] In accordance with the various aspects of the invention, the composition is preferably provided in a unit 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, e.g. about 2.5 mg, about 5 mg or about 10 mg. In certain preferred embodiments, the composition is provided in a unit 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, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 or 20 mg. In certain particularly preferred embodiments, the composition is provided in a unit dosage form comprising obicetrapib or a pharmaceutically acceptable salt thereof in a dose of 1 , 2.5, 5, 7.5, 10, 12.5 or 15 mg.

[0057] In certain embodiments of the invention, 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 antioxidants selected from the group consisting of vitamin E, especially alpha Tocopherol, and xantophylls, especially lutein and zeaxanthin. Most preferably the pharmaceutical composition comprises one or more lipophilic antioxidants selected from the group consisting of alpha Tocopherol , lutein and zeaxanthin. Embodiments are envisaged wherein the composition is a fixed dose combination product comprising the CETP inhibitor, and one or more lipophilic antioxidants.

[0058] Hence, the invention provides compositions as defined herein, provided in unit dosage form, comprising said one or more antioxidants, typically in amounts ranging from 1 to 1000 mg.

[0059] In some embodiments, the amount of each antioxidant present in the unit 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 (RDAs), such as the U.S. RDAs established by the (U.S.) national institute of health (‘NIH’), which, currently, use an RDA for alphatocopherol of 15 mg (daily); an RDA for lutein of 10 mg (daily); and an RDA for zeaxanthin of 2 mg (daily).

[0060] In some embodiments, the invention provides compositions as defined herein, in unit dosage form, comprising 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.

[0061] In some embodiments, the invention provides compositions as defined herein, in unit dosage form, comprising Zeaxanthin or a salt thereof at an amount of 0.5-100 mg, 1-50 mg or 1.5-25 mg, e.g. 1 mg, 1.5 mg, 2 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg, more preferably about 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg or 5 mg, most preferably about 2 mg.

[0062] In some embodiments, the invention provides compositions as defined herein, in unit dosage form, comprising alpha-tocopherol at an amount 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.

[0063] In some embodiments, the invention provides compositions as defined herein, in unit dosage form, comprising alpha-tocopherol at an amount 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.

[0064] In some embodiments, the invention provides compositions as defined herein, in unit dosage form, comprising alpha Tocopherol or a salt thereof at an amount of 10- 1000 international units (IU), 20-900 IU, 50-800 IU, 100-700 IU, 200-600 IU , e.g. 200, 300, 400, 500 or 600 IU, more preferably about 200, 400 or 600 IU, most preferably about 400 IU.

[0065] In some embodiments, the invention provides compositions as defined herein, in unit dosage form, comprising alpha-tocopherol at an amount 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, most preferably about 268 mg.

[0066] In some specific embodiments, the pharmaceutical composition in unit dosage form or solid dosage form, such as the tablet, comprises 0.5 mg, 1 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg of obicetrapib or pharmaceutically acceptable salt thereof. In more specific embodiments, tablets are round, 6 mm in diameter, white film-coated tablets, containing 2,5 mg of obicetrapib as the calcium salt. In other specific embodiments, tablets are round, 6 mm in diameter, white film-coated tablets, containing 5 mg of obicetrapib as the calcium salt. In other specific embodiments, tablets are round, 6 mm in diameter, white film-coated tablets, containing 10 mg of obicetrapib as the calcium salt. In specific embodiments, the excipients present in the tablet cores are microcrystalline cellulose, mannitol, sodium starch glycollate, colloidal silicon dioxide, and magnesium stearate. In specific embodiments, a commercially available film-coating formula (Opadry II white, ex Colorcon) is applied to the cores.

[0067] In preferred embodiments, obicetrapib is present in the compositions and dosage forms as amorphous obicetrapib, and in particularly preferred embodiments, as amorphous obicetrapib hemicalcium.

[0068] Therapeutic Indications

[0069] In one aspect, the present invention relates to methods for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from sepsis or other dysregulated inflammatory responses. In another aspect, the invention relates to methods for the prevention, treatment, management or amelioration of sepsis, or other dysregulated inflammatory responses in a subject in need thereof, The terms "treat", "treating" or "treatment", when used in conjunction with a specific disease or symptom (for example: “method of treating disease ...”) refer to and / or encompass curing, alleviating or abrogating said disease and / or accompanying symptoms, diminishing extent of disease, stabilizing (i.e. not worsening) the state of disease, delaying or slowing of disease progression, ameliorating the disease state, prolonging survival (as compared to expected survival without treatment), etc. Treatment need not mean that the disease, disorder, or condition is totally cured. To be an effective treatment, a useful composition herein needs only to reduce the severity of a disease, disorder, or condition, reduce the severity of symptoms associated therewith, or provide improvement to a patient or subject’s quality of life. The terms “treat”, “treating” or “treatment”, when used in conjunction with or in relation to a patient or subject (for example: “method of treating a subject”), typically refers to the act of administering a therapeutic compound to said patient or subject for whatever therapeutic and / or prophylactic purpose.

[0070] The terms "prevent", "preventing" or "prevention", as used herein, refer to and / or encompass the delay, prevention, suppression, or inhibition of the onset of a disease, disorder, or condition. As used in accordance with the presently described subject matter, the term “prevention” relates to a process of prophylaxis in which a subject is exposed to the presently described compositions or formulations prior to the induction or onset of the disease / disorder process. The term “suppression” is used to describe a condition wherein the disease / disorder process has already begun but obvious symptoms of the condition have yet to manifest. Thus, the cells of an individual may have the disease / disorder, but no outside signs of the disease / disorder have yet been clinically recognized. In either case, the term prophylaxis can be applied to encompass both prevention and suppression.

[0071] The term "sepsis" as used herein refers to a deleterious systemic inflammatory response to infection, formally defined as the presence (probable or documented) of infection together with systemic manifestations of infection. The term sepsis as used herein encompasses complications thereof such as "severe sepsis" and "septic shock". The term “septicemia” is considered to be synonymous to the term “sepsis” and, as such, the two terms may be used herein interchangeably.

[0072] In other specific embodiments, methods as defined herein are provided for the prevention, treatment, management or amelioration of systemic inflammatory response syndrome (SIRS). The term “systemic inflammatory response syndrome” refers to a condition characterized by an exaggerated defense response of the body to a noxious stressor (infection, trauma, surgery, acute inflammation, ischemia or reperfusion, or malignancy, to name a few) to localize and then eliminate the endogenous or exogenous source of the insult. It typically involves the release of acute-phase reactants, which are direct mediators of widespread autonomic, endocrine, hematological, and immunological alteration in the subject. Even though the purpose is defensive, the dysregulated cytokine storm can cause a massive inflammatory cascade leading to reversible or irreversible end-organ dysfunction and even death.

[0073] In case the (suspected) source of infection is infection, the term sepsis is typically used instead of SIRS. Sepsis with one or more end-organ failures is called severe sepsis, and hemodynamic instability despite intravascular volume repletion is called septic shock. Together they represent a physiologic continuum with progressively worsening balance between pro and anti-inflammatory responses of the body.

[0074] Hence, in other specific embodiments, methods as defined herein are provided for the prevention, treatment, management or amelioration of severe sepsis. The term "severe sepsis" as used herein is defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion (in accordance with the "international guidelines for management of severe sepsis and septic shock 2012").

[0075] In other specific embodiments, methods as defined herein are provided for the prevention or treatment of septic shock. Septic shock is defined as sepsis-induced hypotension persisting despite adequate fluid resuscitation (in accordance with the "international guidelines for management of severe sepsis and septic shock 2012").

[0076] In other specific embodiments, methods as defined herein are provided for the prevention, treatment, management or amelioration of one or more symptoms of sepsis.

[0077] In one embodiment, said symptom is sepsis-induced hypertension. Sepsis-induced hypotension is defined as a systolic blood pressure (SBP) < 90 mm Hg or mean arterial pressure (MAP) < 70 mm Hg or a SBP decrease > 40 mm Hg or less than two standard deviations below normal for age in the absence of other causes of hypotension. In one embodiment, said symptom is Sepsis-induced tissue hypoperfusion. Sepsis-induced tissue hypoperfusion is defined as infection-induced hypotension, elevated lactate, or oliguria.

[0078] In other specific embodiments, methods as defined herein are provided for the prevention, treatment, management or amelioration of microcirculatory derangements, typically related to or caused by sepsis. In other specific embodiments, methods as defined herein are provided for the prevention, treatment, management or amelioration of end-organ dysfunction, typically related to or caused by sepsis. In other specific embodiments, methods as defined herein are provided for the prevention, treatment, management or amelioration of Acute Lung Injury (ALI), typically related to or caused by sepsis. In other specific embodiments, methods as defined herein are provided for the prevention, treatment, management or amelioration of acute respiratory distress syndrome (ARDS), typically related to or caused by sepsis. In other specific embodiments, methods as defined herein are provided for the prevention, treatment, management or amelioration of Acute Kidney Injury (AKI), typically related to or caused by sepsis. In other specific embodiments, methods as defined herein are provided for the prevention, treatment, management or amelioration of and multiple organ failure, typically related to or caused by sepsis. In other specific embodiments, methods as defined herein are provided for the prevention, treatment, management or amelioration of multiple-organ dysfunction syndrome (MODS), typically MODS related to or caused by sepsis.

[0079] Regardless of the degree of severity, sepsis can be triggered by a variety of infectious as well as non-infectious conditions. In preferred embodiments of the invention, the sepsis is caused by bacterial, fungal and / or viral infection or has a bacterial, fungal or viral origin. Hence, in some embodiments, the sepsis is microbial septicemia. In a particularly preferred embodiment of the invention, the sepsis is caused by bacterial infection or has a bacterial origin. Hence, in some embodiments, the sepsis is bacterial septicemia. In accordance with the invention, the bacteria causing sepsis may be gram-negative as well as gram-positive bacteria. In preferred embodiments the bacteria causing the sepsis are gram-negative bacteria. In preferred embodiments the bacteria causing the sepsis are bacteria having lipopolysaccharides as an outer membrane component. In a further embodiment, the sepsis is caused by a bacterial or fungal infection, such as an infection by any bacterial or fungal pathogen, that can cause pneumonia. In a further embodiment the sepsis is caused by a nosocomial pathogen, such as a nosocomial species of bacteria or fungus. In a further embodiment, the sepsis is caused by infection with a bacterial pathogen selected from the group consisting of Klebsiella spp., Proteus spp., Enterobacter spp., Serratia spp, Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, Helicobacter pylori, Haemophilus ducreyi, Campylobacter jejuni, Streptococcus pneumoniae, Group A Streptococcus, Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, etc. In some particularly preferred embodiments of the invention, the sepsis is caused by an endotoxin. In some embodiments, the endotoxin giving rise to sepsis is pathogen-associated lipid (PAL), especially lipopolysaccharide (LPS).

[0080] Sepsis may be caused by a single microbial species or by more than one microbial species, which is referred as polymicrobial septicemia, for instance a polymicrobial bacteremia. In some embodiments, the sepsis is caused by more than one microbial species, such as more than one bacteria. Hence, in some embodiments, the sepsis is polymicrobial septicemia.

[0081] In other specific embodiments methods as defined herein are provided for the prevention, treatment, management or amelioration of dysregulated inflammatory responses. In some embodiments, the dysregulated inflammatory response is caused by pathogenic infection, such as bacterial, fungal and / or viral infection, or has a pathogenic origin, such as a bacterial, fungal or viral origin. In particularly preferred embodiments of the invention, the dysregulated immune response is caused by bacterial infection or has a bacterial origin. In preferred embodiments, the dysregulated immune response is caused by infection with any one of the bacterial pathogens recited herein above. In some preferred embodiments of the invention, the dysregulated inflammatory response is caused by an endotoxin. In some embodiments, the endotoxin giving rise to the dysregulated inflammatory response is pathogen-associated lipid (PAL), especially lipopolysaccharide (LPS). The molecular mimicry of some LPS molecules is thought to cause autoimmune-based host responses, such as flareups of multiple sclerosis. Other examples of bacterial mimicry of host structures via LPS are found with the bacteria Helicobacter pylori and Campylobacter jejuni, organisms which cause gastrointestinal disease in humans, and Haemophilus ducreyi which causes chancroid. Certain C. jejuni LPS serotypes (attributed to certain tetra- and pentasaccharide moieties of the core oligosaccharide) have also been implicated with Guillain-Barre syndrome and a variant of Guillain-Barre called Miller-Fisher syndrome. In some embodiments, the dysregulated inflammatory response is selected from any of the aforementioned pathologies / conditions involving LPS.

[0082] In other specific embodiments methods as defined herein are provided for the prevention, treatment, management or amelioration of endotoxemia. The term “endotoxemia” refers to a condition / pathology characterized by the elevation of plasma levels of lipopolysaccharides (LPS), typically due to increased gut permeability, high levels of intestinal LPS-containing bacteria, or both. In preferred embodiments, the endotoxemia is caused by infection with any one of the bacterial pathogens recited herein above.

[0083] Subjects to be treated

[0084] The term “subject” is used interchangeably herein with “patient” to refer to an individual to be treated.

[0085] According to particularly preferred embodiments of the invention, the subject to be treated is a human. The subjects may be male or female and may be of any age, e.g., neonatal, infant, juvenile, adolescent, adult, or geriatric.

[0086] In accordance with the invention, the subject to be treated can have a diagnosis of sepsis, in particular SIRS, sepsis, severe sepsis and / or septic shock, or a dysregulated inflammatory response. The subject to be treated can also be a subject suspected of having or being at risk for having a condition or be diagnosed with a condition that leads to sepsis or a dysregulated inflammatory response. The subject to be treated can also be suspected of having or being at risk for having sepsis or a dysregulated inflammatory response. In particularly preferred embodiments of the invention, the subject to be treated is a human subject that is at increased risk of a severe course of disease following a pathogenic infection. In one specific embodiment, the subject to be treated is an elderly or geriatric person, such as a subject having an age of above 25 years, above 40 years, above 50 years, above 55 years, above 60 years or above 65 years. In some specific embodiment, the subject to be treated is a neonate or infant, especially a neonate. In some specific embodiments, the subject to be treated is a pregnant woman. In some specific embodiments, the subject is hospitalized or a hospitalized person or patient. In some specific embodiments, the subject to be treated is a patient in an intensive care unit. In specific embodiments, the subject to be treated suffers from a pathology that correlates with a severe course of disease or a high risk of a severe course of disease, such as a pathology selected from cardiovascular disease, diabetes, obesity, chronic obstructive pulmonary disease (COPD), high blood pressure, etc. In specific embodiments, the subject to be treated has a weakened immune system, e.g. as a consequence of HIV infection or cancer. In some embodiments, the subject to be treated is a patient suffering from lung trauma or lung injury. In some embodiments, the subject to be treated is a patient suffering from pneumonia. In some embodiments, the subject to be treated is a patient suffering from an infection caused by one or more viruses. In some embodiments, the subject to be treated is a patient suffering from an infection caused by a coronavirus. In some embodiments, the subject to be treated is a patient suffering from an infection caused by SARS-CoV-2. In some embodiments, the subject to be treated is an asymptomatic patient infected with SARS-CoV-2. In some embodiments, the subject to be treated has been diagnosed as having been infected with SARS-CoV-2. In some embodiments, the subject to be treated displays one or more symptoms of SARS-CoV-2 infection. In some embodiments, the subject to be treated is suspected of being infected with SARS-CoV-2. In some embodiments, the subject to be treated is a patient suffering from an infection caused by a coronavirus. In some embodiments, the subject to be treated has been diagnosed with COVID-19. In some embodiments, the subject to be treated displays one or more symptoms of COVID-19.

[0087] In other embodiments, the subject to be treated is a subject that is at increased risk of a severe course of disease due to genetic predisposition; a subject that is at increased risk of a severe course of disease due to certain life-style habits, such as smoking and / or being overweight as a consequence of unhealthy diet; or a subject having a biomarker profile that is indicative of increased risk of a severe course of disease. In certain embodiments, the present methods comprise the step of identifying subjects that are at increased risk of suffering a severe course of disease following the pathogenic infection. In certain embodiments, the present methods comprise the step of diagnosing or establishing whether a subject is at increased risk of suffering a severe course of disease following the pathogenic infection.

[0088] In some embodiments, the subject does not have cardiovascular disease. In some embodiments, the subject is not being treated for cardiovascular disease.

[0089] Administration and dosage (regimens)

[0090] In various embodiments, the CETP inhibitor is administered in an amount and frequency effective to increase levels of total pre-beta1 HDL in blood as compared to the level prior to commencement of treatment. In typical embodiments, blood levels of pre-beta1 HDL are measured in plasma. In preferred embodiments, the CETP inhibitor is administered in an amount effective to increase plasma levels of pre-beta1 HDL.

[0091] In various embodiments, the CETP inhibitor is administered in an amount and frequency effective to cure, alleviate, stabilize disease and / or any accompanying symptom and / or diminish extent of disease, stabilize (i.e. not worsening) the state of disease, and / or delay or slow disease progression.

[0092] In various embodiments, the CETP inhibitor is administered orally and the methods as defined herein before comprise the oral administration of the CETP inhibitor.

[0093] In various embodiments, the dose of obicetrapib or pharmaceutically acceptable salt thereof is 2.5-25 mg by mouth per day (2.5-25 mg po QD). In some embodiments, the dose of the CETP inhibitor is 5-20 mg by mouth per day (5-20 mg po QD). In some embodiments, the dose of the CETP inhibitor is 10-20 mg by mouth per day (10-20 mg po QD). In some embodiments, the dose of the CETP inhibitor is 2.5-15 mg by mouth per day (2.5-15 mg po QD). In some embodiments, the dose of the CETP inhibitor is 5-10 mg by mouth per day (5-10 mg po QD). In some specific embodiments, the dose of the CETP inhibitor is 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, 11 mg po QD, 11.5 mg po QD, 12 mg po QD, 12.5 mg po QD, 13 mg po QD, 13.5 mg po QD, 14 mg po QD, 14.5 mg po QD, 15 mg po QD, 15.5 mg po QD, 16 mg po QD, 16.5 mg po QD, 17 mg po QD, 17.5 mg po QD, 18 mg po QD, 18.5 mg po QD, 19 mg po QD, 19.5 mg po QD, or 20 mg po QD. In some embodiments, the dose of the CETP inhibitor is equipotent to 5-20 mg of obicetrapib by mouth per day (5-20 mg po QD).

[0094] In various embodiments, the dose of obicetrapib or pharmaceutically acceptable salt thereof is 0.5-25 mg by mouth per day (0.5-25 mg po QD). In some embodiments, the dose of the CETP inhibitor is 1-20 mg by mouth per day (1-20 mg po QD). In some embodiments, the dose of the CETP inhibitor is 2.5-15 mg by mouth per day (2.5-15 mg po QD). In some embodiments, the dose of the CETP inhibitor is 1-10 mg by mouth per day (1-10 mg po QD). In some embodiments, the dose of the CETP inhibitor is 2,5-10 mg by mouth per day (2.5-10 mg po QD). In some embodiments, the dose of the CETP inhibitor is 2.5-5 mg by mouth per day (2,5-5 mg po QD). In some specific embodiments, the dose of the CETP inhibitor is 0.5 mg po QD, 1.0 mg po QD, 1.5 mg po QD, 2.0 mg po QD or 2.5 mg po QD.

[0095] In some specific embodiments, the dose of obicetrapib or a pharmaceutically acceptable salt thereof is 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15,1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4.

[0096] 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9. 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5. 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, or 30.0 mg po QD.

[0097] In some specific embodiments, the dose of obicetrapib or a pharmaceutically acceptable salt thereof is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5,1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4. 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0 mg po QD.

[0098] In some specific embodiments, the daily dose of obicetrapib or a pharmaceutically acceptable salt thereof is 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15,1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4. 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9. 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5. 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, or 30.0 mg. In some specific embodiments, the daily dose of obicetrapib or a pharmaceutically acceptable salt thereof is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5,1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4. 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0 mg.

[0099] In various embodiments, the CETP inhibitor is a salt of obicetrapib that is administered at a dose that is equipotent to a certain dose of obicetrapib, administered via the same route. As used herein, the term “equipotent” typically means equally potent or equally capable of producing a pharmacologic effect of certain intensity. It is also common in the art to refer to amounts of a given compound ‘equivalent’ to a specified amountof a reference compound. For example, if the composition comprises a salt of obicetrapib the amount of said salt to be administered and / or to be incorporated into a unit dose form needs to be adjusted to take account of the molecular weight difference between the free base and salt form. For instance, in expressing dose amounts in the label and / or product information of authorized medicinal products comprising a salt form of an active compound that can also be used in free base form, it is customary practice to specify the dose of the free base to which the dose of the salt as used is equivalent. In this context, the term ‘equipotent’ is deemed synonymous to the term ‘equivalent’. In accordance with certain preferred embodiments of the invention the term ‘equipotent’, as used herein, denotes that the salt of obicetrapib is given at a dose containing the same mole amount of obicetrapib as the recited dose of the free base.

[0100] In various embodiments, the CETP inhibitor is a salt of obicetrapib and the (oral) dose is equipotent to 2.5-25 mg po QD of obicetrapib, 5-20 mg po QD of obicetrapib, 10-20 mg po QD of obicetrapib, 2.5-15 mg po QD of obicetrapib, or 5-10 mg po QD of obicetrapib. In some specific embodiments, the CETP inhibitor is a salt of obicetrapib and the (oral) dose is equipotent to 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, 11 mg po QD, 11.5 mg po QD, 12 mg po QD, 12.5 mg po QD, 13 mg po QD, 13.5 mg po QD, 14 mg po QD, 14.5 mg po QD, 15 mg po QD, 15.5 mg po QD, 16 mg po QD, 16.5 mg po QD, 17 mg po QD, 17.5 mg po QD, 18 mg po QD, 18.5 mg po QD, 19 mg po QD, 19.5 mg po QD, or 20 mg po QD of obicetrapib.

[0101] In various embodiments, the CETP inhibitor is a salt of obicetrapib and the (oral) dose is equipotent to 0.5-25 mg po QD, 1-20 mg po QD, 2.5-15 mg po QD, 1-10 mg po QD, 2.5-10 mg po QD, 2,5-5 mg po QD, 0.5 mg po QD, 1.0 mg po QD, 1.5 mg po QD, 2.0 mg po QD or 2.5 mg po QD of obicetrapib.

[0102] In some specific embodiments, the CETP inhibitor is a salt of obicetrapib and the (oral) dose is equipotent to 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15,1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9. 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5. 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, or 30.0 mg po QD of obicetrapib.

[0103] In some specific embodiments, the CETP inhibitor is a salt of obicetrapib and the (oral) dose is equipotent to 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, I.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5,1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4. 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0 mg po QD of obicetrapib.

[0104] In some specific embodiments, the CETP inhibitor is a salt of obicetrapib and the daily dose is equipotent to 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, II.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15,1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4.

[0105] 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9. 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5. 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, or 30.0 mg of obicetrapib.

[0106] In some specific embodiments, the CETP inhibitor is a salt of obicetrapib and the daily dose is equipotent to 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5,1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4. 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0 mg of obicetrapib.

[0107] In various embodiments, the dose is administered once per day. In some embodiments, the dose is divided and total daily dose defined herein, is administered as a plurality of divided doses.

[0108] In various embodiments, obicetrapib is administered as a tablet. In some embodiments, the tablet comprises 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg of obicetrapib or pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains obicetrapib as the calcium salt. In particular embodiments, the tablet contains 5 mg obicetrapib as a calcium salt.

[0109] In various embodiments, obicetrapib is administered as a tablet. In some embodiments, the tablet comprises 0.5 mg, 1 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg of obicetrapib or pharmaceutically acceptable salt thereof.

[0110] In specific embodiments, tablets are round, 6 mm in diameter, white film-coated tablets, containing 2.5 mg of obicetrapib as the calcium salt.

[0111] In other specific embodiments, tablets are round, 6 mm in diameter, white film-coated tablets, containing 5 mg of obicetrapib as the calcium salt.

[0112] In other specific embodiments, tablets are round, 6 mm in diameter, white film-coated tablets, containing 10 mg of obicetrapib as the calcium salt. In specific embodiments, the excipients present in the tablet cores are microcrystalline cellulose, mannitol, sodium starch glycollate, colloidal silicon dioxide, and magnesium stearate. In specific embodiments, a commercially available filmcoating formula (Opadry II white, ex Colorcon) is applied to the cores.

[0113] In some embodiments, the treatment may begin before the subject is diagnosed with sepsis or other dysregulated inflammatory response. In some embodiments, the treatment may begin on the day on which the subject has been diagnosed with sepsis or other dysregulated inflammatory response. In some embodiments, the treatment may begin the day after the subject has been diagnosed with sepsis or other dysregulated inflammatory response. For example, the treatment may begin on days -3, -2, -1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 after the subject has been diagnosed with sepsis or a dysregulated inflammatory response. Thus, in some embodiments, the one or more administrations of the CETP inhibitor begins on 3, 2, or 1 days before the subject has is diagnosed as having sepsis or another dysregulated inflammatory response. In some embodiments, the one or more administrations of the CETP inhibitor begins on the day that the subject is diagnosed as having sepsis or another dysregulated inflammatory response (i.e., day 0). In other embodiments, the one or more administrations of the CETP inhibitor begins on 1, 2, 3, 4, 5, 6, or 7 days after the subject has been diagnosed as having sepsis or another dysregulated inflammatory response. In some embodiments, the one or more administrations of CETP inhibitor begin 1 day after the subject has been diagnosed as having sepsis or another dysregulated inflammatory response. The timing of the administration of the CETP inhibitor may depend on the particular subject (e.g. whether the patient is at high-risk of developing sepsis or another dysregulated inflammatory response) and any additional therapies to be administered or co-administered.

[0114] The CETP inhibitor may be administered as often and as for long as required. In some embodiments, the CETP inhibitor is administered 1-120 times. In some embodiments, the CETP inhibitor is administered for about one day, about two days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, or about 30 days or more. The CETP inhibitor may be administered several times a day, once a day, once every other day, once every three days, once every four days, once every five days, once every six days or once every week. In particularly preferred embodiments, the CETP inhibitor is administered every day for about one week, about two weeks, about three weeks, or about four weeks.

[0115] As a skilled artisan will appreciate, a CETP inhibitor treatment period may vary on a patient-by-patient basis. In some embodiments, a CETP inhibitor treatment period may vary depending on the assessed likelihood of sepsis. In some embodiments, a CETP inhibitor treatment period is determined by monitoring signs and symptoms of sepsis or consequences thereof. For example, if the signs and symptoms of sepsis or consequences thereof are still present after an initial treatment period, CETP inhibitor treatment is continued until resolution of sepsis. In some embodiments, a treatment period lasts from about 1 day to about 1 year, for example about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or more, including all values and ranges in between thereof. In some embodiments, a treatment period lasts 1 week. In various embodiments, the CETP inhibitor 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.

[0116] In order to optimize treatment in subjects suffering from a pathogenic infection, such as a viral or bacterial infection, the method may comprise additional treatment with another pharmacologically active agent, for example other substances displaying antiviral properties and / or other substances with antibiotic or antibacterial properties. In some specific embodiments, the method may comprise the co-administration of or co-treatment with an antibiotic, such as an antibiotic currently used in the management of sepsis, such as, but not limited to an antibiotic selected from the group consisting of carbapenems, tetracyclines, aminoglycosides, polymyxin antibiotics, ceftriaxone, cefuroxime, tobramycin, piperacillin-tazobactam, cefepime, ceftazidime, vancomycin, ciprofloxacin, levofloxacin, Fosfomycin, Aztreonam, Metronidazole, Azithromycin, Doxycycline, Linezolid, Ampicillin, Ertapenem, meropenem, imipenem, tigecycline, colistin, gentamicin, amikacin, streptomycin, paromomycin, streptomycin, plazomicin, some of which may also be used in combination. In certain embodiments, the methods of the invention further comprises the concurrent treatment with one or more antioxidants, preferably one or more lipophilic antioxidants, more preferably one or more lipophilic antioxidants selected from the group consisting of tocopherols and carotenoids. More preferably, the methods of the invention further comprises the concurrent treatment with one or more antioxidants selected from the group consisting of vitamin E, especially alpha Tocopherol, and xantophylls, especially lutein and zeaxanthin. Most preferably 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.

[0117] In certain embodiments, methods and / or compositions for use according to the invention are provided, wherein the methods and / or use comprise the administration, preferably the repeated administration, of the CETP inhibitor, to the subject, at a dose and frequency effective to increase a subject’s total plasma levels of lutein and / or to increase a subject’s total plasma levels of zeaxanthin and / or to increase a subject’s total plasma levels of tocopherol and / or increase the total level of HDL-carried antioxidants, typically to values within the ranges recited herein elsewhere.

[0118] In a preferred embodiment of the invention, 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.

[0119] In preferred embodiments of the invention, the frequency and administration intervals of the CETP inhibitor 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. The CETP inhibitor and (each of) the lipophilic antioxidants may be administered as separate unit dosage forms. In embodiments of the invention, the CETP inhibitor and one or more of the lipophilic antioxidants may be administered in the form of the fixed dose combination product as defined herein.

[0120] In preferred embodiments, the methods of the invention 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.

[0121] In some embodiments, the methods of the invention 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.

[0122] In some embodiments, the methods of the invention 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; or a salt, solvate or co-crystal of Zeaxanthin, in the equipotent dosage, most preferably about 2 mg.

[0123] In some embodiments, the methods of the invention comprise the oral administration of alpha-tocopherol 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.

[0124] In some embodiments, the methods of the invention comprise the oral administration of alpha-tocopherol 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.

[0125] In some embodiments, the methods of the invention comprise the oral administration of alpha-tocopherol 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.

[0126] In some embodiments, the methods of the invention comprise the oral administration of alpha-tocopherol 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.

[0127] Pharmaceutical Kits

[0128] Another aspect of the invention is directed to a pharmaceutical kit comprising a package containing a plurality of unit dosage forms and a leaflet, wherein said unit dosage form is a unit dosage form comprising the CETP inhibitor, such as the unit dosage forms described herein elsewhere, and wherein said leaflet contains printed instructions to repeatedly self-administer said unit dosage forms in order to accomplish any of therapeutic objectives as defined herein, such as to treat and / or prevent sepsis or a dysregulated inflammatory response as defined herein.

[0129] In accordance with embodiments of the invention, the pharmaceutical kit comprises a container, such as a cardboard box, holding one or more blister packs, said one or more blister packs containing a plurality of solid unit dosage forms comprising the CETP inhibitor, such as the unit dosage forms described herein elsewhere, preferably a plurality of tablets as defined herein before. In particularly preferred embodiments of the invention, the pharmaceutical kit comprises at least 5, at least 8, at least 10, at least 12 of at least 15 of said unit dosage forms, e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 of said unit dosage forms. In one embodiment of the invention, the pharmaceutical kit only comprises unit dosage forms as defined herein that contain the CETP inhibitor as the sole active ingredient.

[0130] In accordance with embodiments of the invention, the pharmaceutical kit comprises a first plurality of solid unit dosage forms comprising the CETP inhibitor, such as the unit dosage forms comprising the CETP inhibitor described herein elsewhere, and a second plurality of solid unit dosage forms comprising one or more lipophilic antioxidants, such as the unit dosage forms comprising one or more lipophilic antioxidants described herein elsewhere. Preferably the one or more lipophilic antioxidants is / are selected from the group consisting of alpha Tocopherol, lutein and zeaxanthin. In particularly preferred embodiments of the invention, the pharmaceutical kit comprises at least 5, at least 8, at least 10, at least 12 of at least 15 of said unit dosage forms comprising one or more lipophilic antioxidants, e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 of said unit dosage forms.

[0131] In accordance with the invention, the pharmaceutical kit comprises a leaflet inserted into the container, typically a patient information leaflet containing printed information, which information may include a description of the form and composition of the unit dosage forms contained in the kit, an indication of therapeutic indications for which the product is intended, instructions as to how the product is to be used and information and warnings concerning adverse effects and contraindications associated with the use. It will be understood by those of average skill in the art, based on the information presented herein, that the leaflet that is part of the kit according to the invention, will typically contain the information concerning therapeutic indications, uses, treatment regimens, etc. as described here above in relation to the methods of treatment of the present invention. In particularly preferred embodiments of the invention, the leaflet contains printed instructions to repeatedly (self-)administer the unit dosage forms in order to treat and / or prevent sepsis or a dysregulated inflammatory response, as defined herein.

[0132] The amorphous calcium salt form of obicetrapib

[0133] In certain preferred embodiments of the invention, obicetrapib, as contained in the present pharmaceutical compositions, as used in the present methods, as contained in the unit dosage forms (comprised in the pharmaceutical kit), etc., is a salt form of obicetrapib, more particularly an amorphous obicetrapib calcium salt, in particular, amorphous obicetrapib hemicalcium.

[0134] Amorphous obicetrapib hemicalcium was (first) disclosed in international patent application no. pct / ib2023 / 000392 (published under no. W02024009144). This document describes the preparation of amorphous obicetrapib hemicalcium containing compositions and highly pure forms of amorphous obicetrapib hemicalcium.

[0135] In certain preferred embodiments of the invention, obicetrapib, as contained in the present pharmaceutical compositions, as used in the present methods, as contained in the unit dosage forms (comprised in the pharmaceutical kit), etc., is a salt form of obicetrapib described by one or more of the following non-limiting clauses: Clause 1. An amorphous calcium salt of obicetrapib.

[0136] Clause 2. Amorphous obicetrapib hemicalcium.

[0137] Clause 3. Stable amorphous obicetrapib hemicalcium.

[0138] Clause 4. Substantially pure amorphous obicetrapib hemicalcium.

[0139] Clause 5. The amorphous obicetrapib hemicalcium salt of clauses 2-4, substantially free of any crystalline salt of obicetrapib hemicalcium.

[0140] Clause 6. The amorphous obicetrapib hemicalcium of clauses 2-5, having an x-ray powder diffraction pattern substantially the same as that of Figure 33.

[0141] Clause 7. The amorphous obicetrapib hemicalcium of clauses 2-5, having an x-ray powder diffraction pattern comprising one or more x-ray powder diffraction peaks at about 3.4°20, about 7.O°20, and about 9.2°20.

[0142] Clause 8. The amorphous obicetrapib hemicalcium of clauses 2-7, wherein the amorphous obicetrapib hemicalcium does not birefringe.

[0143] Clause 9. The amorphous obicetrapib hemicalcium of clauses 2-8, having a glass transition temperature at a value between about 107°C and about 112°C. Clause 10. The amorphous obicetrapib hemicalcium of clause 9, wherein the glass transition temperature is measured with modulated differential scanning calorimetry. Clause 11. The amorphous obicetrapib hemicalcium of clause 10, wherein the measurement with modulated differential scanning calorimetry uses a sample pan which is open.

[0144] Clause 12. The amorphous obicetrapib hemicalcium of clause 11, wherein the opening is a pinhole.

[0145] Clause 13. The amorphous obicetrapib hemicalcium of clauses 8-12, wherein the glass transition temperature is at a value between about 110°C and about 112°C. Clause 14. The amorphous obicetrapib hemicalcium of clauses 2-13, having a glass transition temperature of less than about 100°C when measured by differential scanning calorimetry using a closed sample pan.

[0146] Clause 15. The amorphous obicetrapib hemicalcium of clause 14, having a glass transition temperature at a value between about 70°C and about 92°C when measured by differential scanning calorimetry using a closed sample pan.

[0147] Clause 16. The amorphous obicetrapib hemicalcium of clauses 2-15, having a loss in weight of less than about 1% when heated to about 200°C.

[0148] Clause 17. The amorphous obicetrapib hemicalcium of clause 16, wherein the weight loss is between about 0.8% and about 0.95%.

[0149] Clause 18. The amorphous obicetrapib hemicalcium of clause 17, wherein the weight loss is between about 0.84% and about 0.92%.

[0150] Clause 19. The amorphous obicetrapib hemicalcium of clauses 2-18, having a water content of less than about 5%.

[0151] Clause 20. The amorphous obicetrapib hemicalcium of clause 19, having a water content of less than about 4%.

[0152] Clause 21. The amorphous obicetrapib hemicalcium of clause 20, having a water content of less than about 3%.

[0153] Clause 22. The amorphous obicetrapib hemicalcium of clause 19, having a water content of between about 0.5% and about 1.5%.

[0154] Clause 23. The amorphous obicetrapib hemicalcium of clauses 2-22, in a bulk form or formulated composition having a particle size distribution wherein about 90% of the particles have a diameter of about 15 microns or less.

[0155] Clause 24. The amorphous obicetrapib hemicalcium of clause 23, wherein about 90% of the particles have a diameter of between about 6 microns and about 15 microns. Clause 25. The amorphous obicetrapib hemicalcium of clause 24, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 14 microns or less.

[0156] Clause 26. The amorphous obicetrapib hemicalcium of clause 25, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 13 microns or less.

[0157] Clause 27. The amorphous obicetrapib hemicalcium of clause 26, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 12 microns or less.

[0158] Clause 28. The amorphous obicetrapib hemicalcium of clause 27, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 11 microns or less.

[0159] Clause 29. The amorphous obicetrapib hemicalcium of clause 28, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 10 microns or less.

[0160] Clause 30. The amorphous obicetrapib hemicalcium of clause 29, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 9 microns or less.

[0161] Clause 31. The amorphous obicetrapib hemicalcium of clause 30, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 8 microns or less.

[0162] Clause 32. The amorphous obicetrapib hemicalcium of clause 31 , having a particle size distribution wherein about 90% or more of the particles have a diameter of about 7 microns or less.

[0163] Clause 33. The amorphous obicetrapib hemicalcium of clause 32, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 6 microns or less.

[0164] Clause 34. The amorphous obicetrapib hemicalcium of clause 33, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 5 microns or less.

[0165] Clause 35. The amorphous obicetrapib hemicalcium of clause 34, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 4 microns or less. Clause 36. The amorphous obicetrapib hemicalcium of clause 35, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 3 microns or less.

[0166] Clause 37. The amorphous obicetrapib hemicalcium of clauses 2-36, in a bulk form or formulated composition having a particle size distribution wherein about 50% of the particles have a diameter of about 5 microns or less.

[0167] Clause 38. The amorphous obicetrapib hemicalcium of clause 37, having a particle size distribution wherein about 50% of the particles have a diameter of about 4 microns or less.

[0168] Clause 39. The amorphous obicetrapib hemicalcium of clause 38, having a particle size distribution wherein about 50% of the particles have a diameter of about 3 microns or less.

[0169] Clause 40. The amorphous obicetrapib hemicalcium of clauses 2-39, in a bulk form or formulated composition having a particle size distribution wherein about 10% of the particles have a diameter of about 2 microns or less.

[0170] Clause 41. The amorphous obicetrapib hemicalcium of clauses 2-40, having a chemical purity of at least 98.0%.

[0171] Clause 42. The amorphous obicetrapib hemicalcium of clause 41 , having a chemical purity of at least 99.0%.

[0172] Clause 43. The amorphous obicetrapib hemicalcium of clause 42, having a chemical purity of at least 99.5%.

[0173] Clause 44. The amorphous obicetrapib hemicalcium of clause 43, having a chemical purity of at least 99.6%.

[0174] Clause 45. The amorphous obicetrapib hemicalcium of clause 44, having a chemical purity of at least 99.7%.

[0175] Clause 46. The amorphous obicetrapib hemicalcium of clause 45, having a chemical purity of at least 99.8%.

[0176] Clause 47. The amorphous obicetrapib hemicalcium of clause 46, having a chemical purity of at least 99.9%.

[0177] Clause 48. The amorphous obicetrapib hemicalcium of clauses 2-47, having a solid-state13C-NMR spectrum substantially the same as that of Figure 34.

[0178] Clause 49. The amorphous obicetrapib hemicalcium of clauses 2-48, having a solid-state13C-NMR spectrum where no peak is present at about 22.1 ppm. Clause 50. The amorphous obicetrapib hemicalcium of clauses 2-49, having a solid-state13C-NMR spectrum where no peak is present at about 29.5 ppm.

[0179] Clause 51. Unmilled amorphous obicetrapib hemicalcium.

[0180] Clause 52. Milled amorphous obicetrapib hemicalcium.

[0181] Clause 53. The amorphous obicetrapib hemicalcium of clauses 2-50, wherein the amorphous obicetrapib hemicalcium has been milled.

[0182] Clause 54. The amorphous obicetrapib hemicalcium of clauses 2-50 or 53, wherein the amorphous obicetrapib hemicalcium has been jet milled.

[0183] Clause 55. The amorphous obicetrapib hemicalcium of clauses 2-50 or 53-54 wherein the amorphous obicetrapib hemicalcium has been spray dried.

[0184] Thus, the subject method has been described by reference to certain embodiments discussed above. It will be recognized that these embodiments are susceptible to various modifications and alternative forms well known to those of skill in the art.

[0185] Description of the Figures

[0186] Figure 1 : experimental design for assessing the effects of obicetrapib on HDL-C levels, IL-13 levels, and survival in APOE3-Leiden CETP mouse cecal-ligation and puncture model of sepsis.

[0187] Figure 2: effect of pre-treatment with Obicetrapib on HDL-Cholesterol in a mouse model of sepsis .

[0188] Figure 3: effect of pre-treatment with Obicetrapib on IL-13 levels at time=72 hours after onset of sepsis in a mouse model of sepsis.

[0189] Figure 4: effect of pre-treatment with Obicetrapib on survival to 72 hours in a mouse model of sepsis.

[0190] Figure 5: Alpha-Tocopherol in plasma at baseline and after treatment (OCEAN study), in placebo (A) and treatment with obicetrapib (B), ezetimibe (C) and obicetrapib+ezetimibe combination (D). Panel E shows the effect of each treatment, obtained by subtracting baseline values from treated values for each subject. Data are presented in box and whisker diagrams; the boxes correspond to the interquartile range (IQR). The line in the middle of the box is plotted at the median. The whiskers indicate the range of the data within 1.5 X IQR with outliers indicated as circles. The paired t-test was used to determine the p values. * p < 0.05, ** p < 0.01 , *** p < 0.001. Figure 6: Alpha-Tocopherol in HDL at baseline and after treatment (OCEAN study), in placebo (A) and treatment with obicetrapib (B), ezetimibe (C) and obicetrapib+ezetimibe combination (D). Panel E shows the effect of each treatment, obtained by subtracting baseline values from treated values for each subject.

[0191] Figure 7: Lutein in plasma at baseline and after treatment (OCEAN study), in placebo (A) and treatment with obicetrapib (B), ezetimibe (C) and obicetrapib+ezetimibe combination (D). Panel E shows the effect of each treatment , obtained by subtracting baseline values from treated values for each subject.

[0192] Figure 8: Lutein in HDL at baseline and after treatment (OCEAN study), in placebo (A) and treatment with obicetrapib (B), ezetimibe (C) and obicetrapib+ezetimibe combination (D). Panel E shows the effect of each treatment, obtained by subtracting baseline values from treated values for each subject.

[0193] Figure 9: Zeaxanthin in plasma at baseline and after treatment (OCEAN study), in placebo (A) and treatment with obicetrapib (B), ezetimibe (C) and obicetrapib+ezetimibe combination (D). Panel E shows the effect of each treatment, obtained by subtracting baseline values from treated values for each subject.

[0194] Figure 10: Zeaxanthin in HDL at baseline and after treatment (OCEAN study), in placebo (A) and treatment with obicetrapib (B), ezetimibe (C) and obicetrapib+ezetimibe combination (D). Panel E shows the effect of each treatment, obtained by subtracting baseline values from treated values for each subject.

[0195] Figure 11 : HDL vs. Pre-beta1 HDL at baseline in all participants (OCEAN study). Figure 12: triglycerides vs. Pre-beta1 HDL at baseline in all participants (OCEAN study).

[0196] Figure 13: Plasma tocopherol vs. Pre-beta1 HDL at baseline in all participants (OCEAN study).

[0197] Figure 14: Tocopherol in HDL vs. Pre-beta1 HDL at baseline in all participants (OCEAN study).

[0198] Figure 15: Plasma Zeaxanthin vs. Pre-beta1 HDL after treatment in the obicetrapib and obicetrapib+ezetimibe treatment groups (OCEAN study).

[0199] Figure 16: Zeaxanthin in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib and obicetrapib+ezetimibe treatment groups (OCEAN study).

[0200] Figure 17: Tocopherol in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib and obicetrapib+ezetimibe treatment groups (OCEAN study). Figure 18: Plasma Zeaxanthin vs. Pre-beta1 HDL after treatment i the obicetrapib treatment group (OCEAN study).

[0201] Figure 19: Zeaxanthin in HDL vs. Pre-beta1 HDL after treatment i the obicetrapib treatment group (OCEAN study).

[0202] Figure 20: Plasma tocopherol vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0203] Figure 21: Tocopherol in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0204] Figure 22: Tocopherol in non-HDL vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0205] Figure 23: Zeaxanthin in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0206] Figure 24: Pre-beta1 HDL plasma levels at baseline (V2) and after treatment (V4) in placebo group (ROSE2 study).

[0207] Figure 25: Pre-beta1 HDL plasma levels at baseline (V2) and after treatment (V4) in obicetrapib treatment group (ROSE2 study).

[0208] Figure 26: Plasma tocopherol vs. Pre-beta1 HDL at baseline in all participants (ROSE2 study).

[0209] Figure 27: Plasma tocopherol vs. Pre-beta1 HDL at baseline in the obicetrapib treatment group (ROSE2 study).

[0210] Figure 28: Plasma tocopherol vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (ROSE2 study).

[0211] Figure 29: 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).

[0212] Figure 30: 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).

[0213] Figure 31: 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).

[0214] Figure. 32: 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 2 (P<0.05). Figure 33 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.

[0215] Figure 34 is a solid-state13C-NMR spectrum of amorphous obicetrapib hemicalcium.

[0216] Examples

[0217] Example 1: effects of obicetrapib on HDL-C levels and survival in sepsis mouse models

[0218] An animal study was carried out to assess the effects of obicetrapib on HDL-C levels and survival in relevant mouse models of sepsis.

[0219] Background and Introduction

[0220] Sepsis is clinically defined as the life-threatening organ dysfunction caused by a dysregulated host response to infection, and is responsible for tremendous morbidity, mortality, and healthcare expenditure worldwide. A major challenge in the treatment of sepsis caused by bacterial infection is the release of pathogen-associated lipids (PALs) after bacterial death or phagocytosis in the liver and the spleen, which can lead to inappropriate activation of the immune system. To address these challenges, novel sepsis therapies that can be translated to clinical use are urgently needed. The central role of PALs in sepsis is underscored by the observation that total systemic exposure to circulating PALs is directly correlated with the degree of organ failure. PALs can be sequestered and neutralized by lipoproteins. High-density lipoprotein (HDL) demonstrates a greater affinity for binding PALs than low-density lipoprotein (LDL), and the level of HDL decreases precipitously during inflammation, resulting in a reduction in its ApoAl content.

[0221] In fact, recent Mendelian randomization studies implicate a causal role for HDL, but not LDL, in survival from sepsis. In line with this, observational data suggest that lower levels of HDL-cholesterol (HDL-C) are associated with more severe sepsis and a lower chance of survival (7,8). Animal studies have also shown that mice overexpressing human ApoAl, the predominant protein component of HDL, have improved survival from sepsis. Of note, HDL not only sequesters and neutralizes PALs to dampen the excessive endotoxemic response, but also activates macrophages to elicit an antibacterial response. Materials & Methods

[0222] Experiments were performed at the Leiden University Medical Center (LUMC) and at the University of British Colombia (UBC). The experiments were performed on 12-weeks-old female APOE*3-Leiden.CETP mice, which are transgenic for human CETP.

[0223] A pilot study with obicetrapib was first performed at the LUMC to address its HDL-raising properties in this mouse model on a semisynthetic cholesterol-rich diet. For this, 0 vs 0.003% vs 0.01% obicetrapib (w / w) was mixed through the Western-type diet, or vehicle vs obicetrapib will be injected intraperitoneally at 1 mg / kg / day, and CETP activity and HDL-cholesterol will be measured after 1, 3, 7, and 14 days. Per treatment group n=10 mice were used.

[0224] A Streptococcus pneumoniae model of pneumosepsis, mimicking the most common causative microorganism of pneumonia in humans, had been developed and was used by UBC. Pneumococci was introduced into the lungs by direct intratracheal inoculation. After anesthesia was established, the mice were inoculated with 106 CFU in a total volume of 20 pl by a 20-gauge ball-tipped gavage needle.

[0225] In addition, a cecal slurry model of sepsis, which involved injection of cecal contents from a donor mouse into the peritoneal cavity of a recipient mouse to induce polymicrobial sepsis, had been developed and was used by LUMC.

[0226] The effects of pre-treatment with obicetrapib in the two septic models were tested. In pre-treatment experiments, obicetrapib or vehicle was administered mixed in Western diet fed to the mice for 14 days prior to inoculation with Streptococcus pneumoniae.

[0227] The primary end-point was 72-hour survival, while parallel groups will have planned blood draws for secondary endpoints, including 24, 48, and 72 hours changes in serum creatinine and blood urea nitrogen (markers of kidney function), pro-inflammatory cytokines (TNF, IL-6, IL-8), and lipid levels and CETP activity levels.

[0228] In addition, hepatic expression of Saa1 , Saa2 and Saa3 as well as SAA protein levels (Abeam Mouse SAA ELISA Kit; Ab157723) in HDL vs total plasma were determined and associated with circulating pro-inflammatory cytokines as parameters of systemic inflammation. Per treatment group n=20 was used for the survival model, and n=10 per time point was used for the parallel group for secondary outcomes. The power of this experimental design is 85% with a type I error probability of 0.05. The experimental design is summarized in figure 1. Results

[0229] As can be seen in figure 2, pre-treatment with Obicetrapib led to a -50% increase in HDL-Cholesterol (compared to placebo). Figure 3 shows that pretreatment with Obicetrapib was associated with lower levels of IL-1 p at time=72 hours after onset of sepsis (compared to placebo). Figure 4 shows that mice pre-treated with Obicetrapib had significantly greater survival to 72 hours, compare to placebo. Overall, the data show that CETP inhibition with obicetrapib preserved or increased HDL-C and Apo A1 levels, reduced an important pro-inflammatory marker, IL-10, and significantly increased survival, relative to placebo.

[0230] In a subsequent step, an acute, rescue experiment will be conducted, in both models. For this experiment, 6 hours following intratracheal inoculation of Streptococcus pneumoniae or intraperitoneal injection of cecal slurry, mice will be randomly assigned to receive intravenous tail vein injection of 1 mg / kg / day of obicetrapib or vehicle control.

[0231] Example 2: phase 2 clinical trial (OCEAN; NCT04770389)

[0232] OCEAN (NCT04770389) was designed as 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. The screening period for this study will take up to 2 weeks. Following the screening period, eligible patients will be 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. After the treatment period, patients will continue for a 4 week safety follow-up and a 8 week PK follow-up. The primary endpoint was percent change in LDL-C after 8 weeks of treatment, and secondary endpoints are percent change in apoB, HDL-C, and non-HDL-C.

[0233] In addition, the effects of treatment on lipophilic antioxidants (Lutein, zeaxanthin and alpha-tocopherol) were assessed by determining the plasma levels of these lipophilic antioxidants, as well as the levels at which they are carried in HDL and pre-betal HDL in particular, before and after treatment.

[0234] The results of the Lipophilic antioxidants measurements of the samples obtained at baseline and after treatment are summarized in table 1 below. Surprisingly, Obicetrapib treatment alone raised plasma lutein by 37.3% (p<0.04) and the obicetrapib plus ezetimibe combination by 31.1% (p<0.042). Changes in lutein were more dramatic in the HDL fraction (73.5% and (p<0.023) and 90.2% (p<0.008)) for the same groups. Obicetrapib treatment alone raised plasma zeaxanthin by 57.1% (p<0.026) and the obicetrapib plus ezetimibe combination by 33.4% (p<0.037). As observed for lutein the changes in zeaxanthin were more dramatic in the HDL fraction (88.2% and (p<0.013) and 74.9% (p<0.006)) for the same groups. Interestingly, HDL alpha tocopherol was significantly raised in the obicetrapib group (89.1 >% (p<0.010)) and obicetrapib plus ezetimibe group (71.3% (p<0.001)).

[0235] Samples were measured in reflection mode using an Al sample holder without any further preparation (i.e., grinding). The detector measures over the entire angle range from approx. 2°20 to 120° 20 simultaneously; in the case of HCI obicetrapib, discernible signals useful for phase identification are seen up to approx. 45°20. The temperature in the diffractometer is typically around 30 °C during measurements.

[0236] Table 1. Lipophilic antioxidants measured at baseline and after treatment.

[0237] compar unit treatment n baseline min, after min, P change tment max treatment max value %

[0238] Lutein

[0239] plasma ng / ml placebo 9 114.5 71.5, 113.3 59.4, 0.885 -1.1

[0240] 201.2 242.0

[0241] obicetrapib 6 130.1 69.5, 204.4 83.3, 0.026 57.1

[0242] 254.4 533.5

[0243] ezetimibe 9 117.2 74.9, 113.3 79.1, 0.539 -3.3

[0244] 187.1 147.7

[0245] combination 9 109.3 62.3, 143.2 45.3, 0.042 31.1 therapy 160.1 222.7

[0246] HDL ng / ml placebo 8 42.5 17.1, 41.6 15.7, 0.741 -2.2

[0247] 91.9 98.3

[0248] obicetrapib 6 67.6 27.7, 117.3 45.5, 0.023 73.5

[0249] 199.3 295.1

[0250] ezetimibe 7 40.0 23.8, 42.9 34.4, 0.828 7.1

[0251] 61.5 52.3

[0252] combination 8 40.9 15.9, 77.7 15.8, 0.008 90.2 therapy 78.5 110.2

[0253] Zeaxanthin

[0254] plasma ng / ml placebo 9 30.2 17.9, 34.5 16.7, 0.200 14.2

[0255] 59.5 78.5

[0256] obicetrapib 6 31.5 13.6, 43.2 13.8, 0.040 37.3

[0257] 70.4 89.3

[0258] ezetimibe 9 23.5 11.0, 22.4 9.6, 0.493 -4.9

[0259] 38.1 35.5

[0260]

[0261] combination 9 26.4 16.2, 35.2 15.5, 0.037 33.4 therapy 47.5 56.0

[0262] HDL ng / ml placebo 8 12.2 6.2, 13.0 5.9, 0.413 6.7

[0263] 22.8 25.3

[0264] obicetrapib 6 14.2 6.2, 26.6 8.2, 0.013 88.2

[0265] 23.1 40.0

[0266] ezetimibe 7 9.5 4.2, 8.8 4.3, 0.377 -6.9

[0267] 13.7 12.1

[0268] combination 8 10.9 7.0, 19.0 7.4, 0.006 74.9 therapy 18.5 25.1

[0269] alpha Tocopherol

[0270] plasma ng / ml placebo 9 12513 7181, 12710 7885, 0.718 1.6

[0271] 18248 16475

[0272] obicetrapib 6 12284 7745, 13354 8580, 0.451 8.7

[0273] 21232 21413

[0274] ezetimibe 9 13871 9011, 12978 8945, 0.085 -6.4

[0275] 18679 18435

[0276] combination 9 11927 7205, 25820 7836, 0.759 116.5 therapy 16587 25820

[0277] HDL ng / ml placebo 8 3756 1990, 3783 2084, 0.787 0.7

[0278] 5739 5874

[0279] obicetrapib 6 4216 2826, 7974 4383, 0.010 89.1

[0280] 5433 12814

[0281] ezetimibe 7 3901 2988, 4063 2740, 0.766 4.2

[0282] 5184 5905

[0283] combination 8 4087 3339, 7001 4902, 0.001 71.3 therapy 4744 9213

[0284]

[0285] Table 2 below shows the results of the Pre-beta1 HDL analyses.

[0286] Table 2: Pre-beta1 HDL (Ocean trial samples)

[0287] Pre-beta1 HDL Pre-beta1 HDL % change t-Test paired (pg / ml) (pg / ml)

[0288] baseline After treatment

[0289] Placebo 112.6 120.0 6.6 NS Ezetimibe 98.3 94.1 -4.3 NS Obicetrapib 106.9 129.1 20.8 p<0.03 Obicetrapib + 112.3 131.5 17.1 p<0.03 ezetimibe

[0290]

[0291] Further results of antioxidant analyses are presented as figures 5-23. Significant increases in Lutein, Zeaxanthin and Tocopherols were measured in the HDL fractions of the obicetrapib and obicetrapib plus ezetimibe treated subjects. Obicetrapib and obicetrapib plus ezetimibe also increased the plasma level of pre-betal HDL, as well as lutein, zeaxanthin and tocopherol carried by pre-beta1 HDL.

[0292] Example 3: phase 2b clinical trial (ROSE2; NCT05266586)

[0293] ROSE2 (NCT05266586) was designed as a placebo-controlled, double-blind, randomized phase 2 study to evaluate the efficacy, safety and tolerability of obicetrapib 10 mg in combination with ezetimibe 10 mg as an adjunct to high-intensity statin therapy. A total of 119 patients were randomized to receive combination therapy, obicetrapib 10 mg or placebo for an 84-day treatment period. The primary efficacy endpoint was the percent change from Day 1 to Day 84 in LDL-C for the combination treatment group compared to the placebo group and was met. Patients treated with the combination of obicetrapib and ezetimibe achieved a median reduction in LDL-C of 59%, as compared to patients treated with placebo, who achieved a median reduction in LDL-C of 6%. Overall, the combination of obicetrapib and ezetimibe was observed to be well-tolerated, with a safety profile observed to be comparable to placebo.

[0294] Like for the OCEAN study (see example 1), effects of treatment on lipophilic antioxidants (Lutein, zeaxanthin and alpha-tocopherol) were assessed by determining the plasma levels of these lipophilic antioxidants, as well as the levels at which they are carried in HDL and pre-beta1 HDL in particular, before and after treatment. Results of these analyses are presented as figures 24-28. As can be derived from the results presented therein, obicetrapib and obicetrapib plus ezetimibe increased the plasma level of pre-beta-1 HDL, as well as the amount of alpha-tocopherol carried by HDL, in particular pre-beta1 HDL. These results are in line with and confirm the findings based from the OCEAN study samples.

[0295] Example 4: phase 2 clinical trial (NCT 05421078)

[0296] NCT05421078 (A Dose-Finding Study in Japanese Patients to Evaluate the Effect of Obicetrapib as an Adjunct to Stable Statin Therapy) 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.

[0297] 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.

[0298] Like for the OCEAN study (see example 1), effects of treatment on lipophilic antioxidants (lutein, zeaxanthin and alpha-tocopherol) were assessed by determining the plasma levels of these lipophilic antioxidants before and after treatment. Results of these analyses are presented as figures 29-32. As can be derived from the results presented therein, 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 already sufficient to induce a therapeutic effect.

[0299] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.

Claims

Claims1. A CETP inhibitor selected from the group consisting of obicetrapib and pharmaceutically acceptable salts thereof, for use in a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from sepsis or a dysregulated inflammatory response, said method comprising the administration to said subject a therapeutically effective amount of the CETP inhibitor.

2. A CETP inhibitor selected from the group consisting of obicetrapib and pharmaceutically acceptable salts thereof, for use in a method for the prevention, treatment, management or amelioration of sepsis or a dysregulated inflammatory response in a subject in need thereof, said method comprising the administration to said subject a therapeutically effective amount of the CETP inhibitor.

3. The compound for use according to claim 1 or 2, wherein the CETP inhibitor is amorphous obicetrapib hemicalcium.

4. The compound for use according to any one of the preceding claims, wherein the CETP inhibitor is administered orally.

5. The compound for use according to any one of the preceding claims, wherein the dose of obicetrapib or pharmaceutically acceptable salt thereof is 2.5-25 mg by mouth per day (2.5-25 mg po QD)6. The compound for use according to any one of the preceding claims, wherein the method is a method for the prevention, treatment, management or amelioration of microbial septicemia.

7. The compound for use according to claim 6, wherein the method is a method for the prevention, treatment, management or amelioration of bacterial septicemia.

8. The compound for use according to claim 7, wherein the bacteria causing sepsis are gram-negative bacteria.

9. The compound for use according to claim 7 or 8, wherein the sepsis is caused by a nosocomial species of bacteria.

10. The compound for use according to any one of claims 7-9, wherein the sepsis is caused an endotoxin, preferably pathogen-associated lipid (PAL) or lipopolysaccharide (LPS).11.The compound for use according to any one of the preceding claims, wherein the subject to be treated is an elderly or geriatric person.

12. The compound for use according to any one of the preceding claims, wherein the subject to be treated is a patient suffering from an infection caused by one or more viruses.

13. The compound for use according to claim 12, wherein the subject to be treated is a patient suffering from an infection caused by a coronavirus, preferably an infection caused by SARS-CoV-2.

14. A method for the prophylactic and / ortherapeutictreatmentof a subject suffering from or at risk of suffering from sepsis or a dysregulated inflammatory response, said method comprising the administration to said subject a therapeutically effective amount of a CETP inhibitor selected from the group consisting of obicetrapib and pharmaceutically acceptable salts thereof.

15. A method for the prevention, treatment, management or amelioration of sepsis, or a dysregulated inflammatory response in a subject in need thereof, said method comprising the administration to said subject a therapeutically effective amount a CETP inhibitor selected from the group consisting of obicetrapib and pharmaceutically acceptable salts thereof.

16. The method according to claim 14 or 15, wherein the CETP inhibitor is amorphous obicetrapib hemicalcium.

17. The method according to any one of claims 14-16, wherein the CETP inhibitor is administered orally.

18. The method according to any one of claims 14-17, wherein the dose of obicetrapib or pharmaceutically acceptable salt thereof is 2.5-25 mg by mouth per day (2.5-25 mg po QD)19. The method according to any one of claims 14-18, for the prevention, treatment, management or amelioration of microbial septicemia.

20. The method according to claim 19, for the prevention, treatment, management or amelioration of bacterial septicemia.

21. The method according to claim 20, wherein the bacteria causing sepsis are gram-negative bacteria.

22. The method according to claim 20 or 21, wherein the sepsis is caused by a nosocomial species of bacteria.

23. The method according to any one of claims 20-22, wherein the sepsis is caused an endotoxin, preferably pathogen-associated lipid (PAL) or lipopolysaccharide (LPS).

24. The method according to any one of claims 14-23, wherein the subject to be treated is an elderly or geriatric person.

25. The method according to any one of claims 14-24, wherein the subject to be treated is a patient suffering from an infection caused by one or more viruses.

26. The method according to claim 25, wherein the subject to be treated is a patient suffering from an infection caused by a coronavirus, preferably an infection caused by SARS-CoV-2.

27. Use of a CETP inhibitor selected from the group consisting of obicetrapib and pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical composition for use in a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from sepsis or a dysregulated inflammatory response, said method comprising the administration to said subject of a therapeutically effective amount of the CETP inhibitor.

28. Use of a CETP inhibitor selected from the group consisting of obicetrapib and pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical composition for use in a method for the prevention, treatment, management or amelioration of sepsis or a dysregulated inflammatory response in a subject in need thereof, said method comprising the administration to said subject of a therapeutically effective amount of the CETP inhibitor.

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