WO2020092376A1 - Traitement de la stéatohépatite non alcoolique (shna) - Google Patents

Traitement de la stéatohépatite non alcoolique (shna) Download PDF

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WO2020092376A1
WO2020092376A1 PCT/US2019/058575 US2019058575W WO2020092376A1 WO 2020092376 A1 WO2020092376 A1 WO 2020092376A1 US 2019058575 W US2019058575 W US 2019058575W WO 2020092376 A1 WO2020092376 A1 WO 2020092376A1
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compound
patient
liver
fasn
administered
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PCT/US2019/058575
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George Luke
Duncan Walker
Patrick J. Kelly
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Forma Therapeutics, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • NASH non-alcoholic steatohepatitis
  • FASN fatty acid synthase
  • Nonalcoholic fatty liver disease is the most common source of chronic liver disease in the United States. Clinical features of NAFLD include dysregulated fatty acid metabolism and subsequent liver steatosis associated with an asymptomatic metabolic illness.
  • Non-alcoholic steatohepatitis is a chronic liver disease characterized pathologically by lipid accumulation in the liver with evidence of cellular damage, inflammation, and fibrosis. Progression of NAFLD to non-alcoholic steatohepatitis (NASH) involves lobular inflammation and fibrosis. Patients with NASH have increased risks of cardiovascular death, cirrhosis, hepatitis, end-stage liver disease, and hepatocellular carcinoma. Currently, there are no effective treatments approved for NASH. There are at least 16 million patients in the U.S. with NASH, and it is the second leading cause of liver transplants in the U.S. NASH presents a significant healthcare burden with a high, unmet medical need. Ideally, treatment approaches to NASH would target multiple pathogenic axes of the disease (steatosis, inflammation, and fibrosis).
  • DNL hepatic de novo lipogenesis
  • TG triglyceride
  • liver resident cells hepatocytes, Kupffer cells and hepatic stellate cells (HSC).
  • ROS reactive oxygen species
  • ER endoplasmic reticulum
  • HSC hepatic stellate cells
  • FASN catalyzes the final step of DNL, converting acetyl- Coenzyme-A (acetyl-CoA) and malonyl-Coenzyme-A (malonyl-CoA) to the fatty acid palmitate, which can then undergo further modifications to other fatty acids and TG.
  • FASN gene expression is elevated in liver biopsies from NASH patients as compared to healthy volunteers.
  • One clinical hypothesis for intervention is that inhibition of FASN may reduce the rate of DNL and steatosis, thereby lowering lipid accumulation in the liver and leading to decreases in cellular damage, inflammation, and fibrosis that are associated with NASH pathology.
  • FASN inhibition attenuates the production of lipid metabolites that can stimulate release of pro-inflammatory cytokines, activate hepatic stellate cells (HSC), and regulate differentiation of T helper 17 (TH17) immune cells by mechanisms that are incompletely understood. Therefore, modulation of FASN offers a promising approach to treating NASH.
  • Compound 1 is a potent, selective, orally bioavailable, small-molecule inhibitor of Fatty Acid Synthase (FASN) in development for patients with NASH, useful in reducing the rate of de novo lipogenesis (DNL).
  • Fatty Acid Synthase Fatty Acid Synthase
  • NASH de novo lipogenesis
  • the inhibition of DNL can affect lipid accumulation in the liver that can cause cellular damage, inflammation, and fibrosis that characterizes the pathology in non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • Preclinical repeat-dose toxicity and toxicokinetic studies conducted in rat and monkey subjects support further investigation of compound 1 in humans.
  • a phase 1 clinical study of compound 1 to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy volunteers is presented in the below examples.
  • the compound (4-(2-fluoro-4-(l-methyl-lH-benzo[d]imidazol-5-yl)benzoyl)piperazin-l- yl)(l-hydroxycyclopropyl)methanone (Compound 1), and pharmaceutically acceptable salts and solid forms thereof, is a small molecule inhibitor of fatty acid synthase (FASN).
  • FASN fatty acid synthase
  • Compound 1 unexpectedly demonstrates effects on all three key pathogenic axes of NASH (steatosis, inflammation, and fibrosis).
  • Compound 1 is a FASN inhibitor.
  • Compound l is a low nanomolar inhibitor of the ketoreductase (KR) domain of FASN.
  • KR ketoreductase
  • Compound 1 is active in a variety of cellular assays: for example, Compound 1 inhibits T helper 17 (TH17) cell differentiation and interleukin-l7 (IL-17) secretion without affecting the viability of TH17 cells.
  • Compound 1 also inhibits the proliferation of rat hepatic stellate cells (HSC).
  • Compound 1 demonstrates FASN target engagement in vivo in rats and mice as evidenced by elevated levels of malonyl-CoA, malonyl-carnitine, and reduced triglycerides (TG) in the liver.
  • Compound 1 produces effects on steatosis in a diet-induced obesity (DIO) rat model utilizing a high fat diet (HFD).
  • DIO diet-induced obesity
  • HFD high fat diet
  • anti-inflammatory activity is observed in the THl7-driven experimental autoimmune encephalomyelitis (EAE) mouse model with significantly reduced clinical scores, inflammation, and markers of TH17 differentiation. Together these effects suggest that Compound 1 has activity against steatosis and inflammation, which are hallmarks of NASH.
  • Compound 1 has suitable oral bioavailability in preclinical species for daily administration to human patients diagnosed with NASH, preferably in the range of about 1.5 mg to about 3.0 mg per day.
  • Compound 1 can be administered to subjects in one or more consecutive treatment cycles comprising the intermittent daily administration of a pharmaceutical composition to the subject.
  • Compound 1 is orally administered once daily to the subject in a pharmaceutically acceptable amount of 1.5 mg - 4.5 mg QD (e.g., 1.5 mg QD, 3.0 mg QD or 4.5 mg QD).
  • the treatment cycle preferably comprises the consecutive daily administration of Compound 1 to the subject for a series of multiple days (preferably, 2 weeks) followed by multiple days without administration to the patient of any Compound 1 (preferably, 1 week).
  • a three-week treatment cycle can consist of the administration of a FASN inhibitor therapy consisting of 1.5 - 4.5 mg of Compound 1 (or a pharmaceutically acceptable salt thereof) once daily for 14 consecutive days, followed by 7 consecutive days without administering a FASN Inhibitor to the subject.
  • a course of therapy can include multiple (e.g., 4 or more) consecutive 3-week treatment cycles.
  • Figure 1 is a schematic pathway showing the role of Fatty Acid Synthase in de novo Lipogenesis.
  • FIG. 2 is a scheme of the CPM assay utilizing full-length FASN enzyme (Example 1). CoA was monitored by covalent coupling with non-fluorescent reagent CPM to yield a fluorescent CPM-CoA conjugate.
  • Figure 3 is a graph showing inhibition by Compound 1 of IL-17 production in human TH17 cells differentiated from CD4+ T cells isolated from healthy donors (Example 2).
  • Figure 4 is a graph showing cellular potency of Compound 1 in blocking IL-17 production in human TH17 cells.
  • Figure 5 is a graph of IL-17 secretion as a function of Compound 1 concentration in the TH17 cell differentiation assay described in Example 3.
  • Figure 6 is a plot of hepatic malonyl-CoA level as a function of free Compound 1 concentration in the liver in a Normal Diet Rat Model, as described in Example 5.
  • Figure 7 is a graph showing the results from evaluation of hematoxylin and eosin stained liver slides. Slides were evaluated for steatosis store by Kleiner scoring system as described in Example 6.
  • Figure 8 is a plot of body weight over time at various doses of Compound 1 in a High-Fat Diet Rat Model.
  • Figures 9A and 9B are plots of the percentage increase in malonyl-carnitine (Fig. 9A) and malonyl-CoA (Fig. 9B) over time and as a function of the dose of Compound 1 in a High-Sucrose Diet (HSD) Rat Model, as described in Example 9.
  • Figure 10 is a graph of the percentage increase in malonyl-carnitine levels after peak liver and plasma Compound 1 concentrations across the dose range of Compound 1 evaluated in a High- Sucrose Diet Rat Model, as described in Example 9.
  • Figure 11 is a graph showing the reduction of gene expression level of mRORc in splenic cells from EAE model after treatment with Compound 1 (Example 10).
  • Figure 12A and Figure 12B are graphs showing that Compound 1 reduced the population of IL17+ CD4+ cells in lymph node (12A) and spinal cord and brain tissue samples in the second EAE study (12B) (Example 10).
  • Figure 13 summarizes the Phase 1 clinical study design of Example 11.
  • Figure 14 is a scheme showing the Phase 1 clinical study events and timelines of Example 11.
  • Figure 15 is a graph showing the pharmacokinetic profile of Compound 1 following a single oral dose.
  • Figure 16 is a series of graphs showing the inhibition of hepatic fractional de novo lipogenesis after a single dose of Compound 1 versus placebo.
  • Figures 16A, 16B, and 16C are for the 3mg, 6 mg, and 9 mg cohorts of the Phase 1 clinical study of Example 11, respectively.
  • Figure 17 is a series of graphs showing the effects of Compound 1 on inhibition of hepatic fractional de novo lipogenesis in a dose-dependent manner following a single oral dose.
  • Figure 17A shows normalized fructose-stimulated DNL over time for the various dosing cohorts and
  • Figure 17B is a histogram showing the inhibition of DNL (AEiCo-12) at three doses.
  • Figure 18 is a synthetic scheme suitable for the manufacture of Compound 1.
  • compositions comprising (or providing, e.g., as a prodrug, salt, or other solid form) the active moiety of Compound 1 provide a novel therapy, which simultaneously target multiple pathological processes, such as steatosis, inflammation, and fibrosis, and therefore, may effectively manage NASH.
  • Compound 1 provides a multi-modal approach for treating NASH, by reducing steatosis as well as TH! 7-dependent inflammation and fibrosis.
  • Steatosis which plays a central role in NASH pathogenesis, is caused by deposition of triglycerides (TG) in the liver and can be driven by the excessive synthesis of TG from increased de novo lipogenesis (DNL).
  • TG triglycerides
  • a key enzyme in the DNL pathway is Fatty Acid Synthase (FASN).
  • FASN catalyzes the final step of DNL, converting acetyl-CoA and malonyl-CoA into the fatty acid (FA) palmitate, which can then undergo further modifications to other fatty acids and TG.
  • FASN Fatty Acid Synthase
  • FASN catalyzes the final step of DNL, converting acetyl-CoA and malonyl-CoA into the fatty acid (FA) palmitate, which can then undergo further modifications to other fatty acids and TG.
  • Chronic activation of hepatic DNL and increased traffic of free fatty acids within hepatocytes can lead to the generation of toxic lipid metabolites.
  • These lipotoxic metabolites act as reactive oxygen species (ROS), triggering endoplasmic reticulum (ER) stress, apoptosis, and necrosis in the liver resident cells, hepatocytes, Kupffer cells, and
  • FASN activity may be a major contributor to NASH through lipotoxicity mediated tissue injury and cell death.
  • the gene expression of FASN in liver biopsies from NASH patients is elevated up to l7-fold as compared to healthy volunteers. Therefore, elevated FASN activity may be a major contributor to NASH through lipotoxicity-mediated tissue injury and cell death.
  • Liver-specific ablation of the gene encoding FASN in mice results in malonyl-CoA increases and palmitate decreases in liver.
  • FASNLKO mice on a standard diet show normal liver TG content, suggesting DNL may be dispensable in healthy liver and FASN inhibition may evade negative impact on non-diseased liver function. Inhibition of FASN reduces DNL and should reduce steatosis.
  • FASN In addition to FASN’s role in steatosis and lipotoxicity, it may contribute to inflammation and the processes of fibrosis. Palmitate, the end product of the fatty acid synthesis pathway, upregulates toll-like receptor 4 (TLR4), pro-inflammatory cytokines, and tumor necrosis factor-a (TNF-a) production in primary hepatocytes and Kupffer cells. Hence, DNL generates fatty acids necessary for TH17 cell differentiation and function. Recent studies strengthen the role of TH17 cells and interleukin- 17 (IL-17) in NASH progression since increased levels of TH17 cells in human liver are associated with the progression from non-alcoholic fatty liver (NAFL) to NASH.
  • IL-17 interleukin- 17
  • IL-17 also promotes liver fibrosis in a mouse model of liver disease (carbon tetrachloride (CCL)- induced liver injury model) through hepatic stellate cell activation and subsequent collagen production. Stimulation of HSC activation occurs both by elevation of IL-17 and by palmitate in mice. Accordingly, FASN inhibition attenuates the production of lipid metabolites that can stimulate release of pro-inflammatory cytokines, activate hepatic stellate cells (HSC), and regulate TH17 differentiation. Therefore, modulation of FASN offers a promising approach to treating NASH.
  • CCL carbon tetrachloride
  • HSC hepatic stellate cells
  • ACC1 is an enzyme directly upstream from FASN that catalyzes the production of malonyl-CoA from acetyl-CoA.
  • Small molecule inhibitors of ACC 1/2 such as NDI-010976 (Nimbus Therapeutics/Gilead), reduced steatosis and fibrosis in preclinical NASH models, but they may carry a risk of undesired fatty acid b -oxidation.
  • Compound 1 selectively targets the ketoreductase (KR) domain of FASN. Inhibition of the KR domain is sufficient to shut down activity of the enzyme.
  • KR ketoreductase
  • Compound 1 inhibits the enzymatic activity of human FASN (ICso ⁇ 50 nM) and rat FASN (ICso ⁇ 100 nM).
  • ICso ⁇ 50 nM human FASN
  • rat FASN ICso ⁇ 100 nM
  • TH17 cell differentiation and IL-17 secretion ICso ⁇ 10 nM
  • Compound 1 inhibited TH17 cell differentiation and IL-17 secretion (ICso ⁇ 10 nM) without affecting the viability of TH17 cells (ICso >10 mM), suggesting it may block TH17- mediated inflammation.
  • Compound 1 inhibited the proliferation of rat HSC (ICso ⁇ 1 mM), supporting the hypothesis that the inhibition of fatty acid synthesis may directly inhibit
  • the in vivo anti-inflammatory activity of Compound 1 was investigated in the TH17 driven EAE mouse model. Attenuated spinal cord demyelination/inflammation, reduced brain inflammation, and improved disease severity in this THl7-driven inflammation model were observed at the lowest dose tested of 1 mg/kg twice-daily administration. These doses and exposures were associated with inhibition of markers of murine TH17 differentiation and reduced IL-17+ CD4+ T cells in the lymph node, spinal cord, and brain.
  • the drug exposure for minimal activity in the EAE model was similar to the exposures associated with significantly reduced steatosis in the HFD rat, suggesting that the effects of Compound 1 on inflammation and steatosis can be achieved at the same low exposure.
  • FASN ATP-citrate lyase
  • SCD stearoyl-CoA desaturase
  • GPAT glyceraldehyde-3 -phosphate acyltransferase
  • Compound 1 is a potent, selective, orally bioavailable, small-molecule inhibitor of FASN useful as a treatment for patients with NASH.
  • Compound 1 demonstrated a dose-dependent increase in hepatic malonyl-CoA levels with a low nM calculated fifty percent effective concentration (EC50) for FASN inhibition in rat liver correlating with the potency seen in in vitro studies.
  • EC50 fifty percent effective concentration
  • liver malonyl-carnitine accumulation with daily administration of Compound 1 could be achieved at exposures [area under the curve over 24 hr (AUC0-24)] below the no observed adverse effect level (NOAEL) in rats, the most sensitive preclinical species.
  • Compound 1 treatment lowered liver triglycerides (TG) and improved liver steatosis across a dose range of Compound 1 exposures below the rat NOAEL, with optimal inhibition of steatosis associated with once daily dosing.
  • FASN is a key enzyme for exacerbated DNL. Palmitate, the end product of the reaction catalyzed by FASN, induces expression of toll-like receptor (TLR) and pro- inflammatory cytokines in Kupffer cells and hepatocytes.
  • TLR toll-like receptor
  • the DNL pathway is required for the differentiation of TH17 cells, which plays a critical role in the inflammation and fibrosis aspects of NASH. Therefore, a FASN inhibitor offers a potential broad based mechanism to block NASH pathophysiology by simultaneously blocking three key pathologic axes of NASH, namely steatosis, inflammation, and fibrosis.
  • One aspect of this disclosure is a method of treating a patient diagnosed with non-alcoholic steatohepatitis (NASH).
  • a method of treating a patient diagnosed with NASH comprises administering to the patient a therapeutically effective amount of Compound 1.
  • NASH is characterized by hepatic steatosis, inflammation, and fibrosis.
  • a total daily human dose of Compound 1 in a method of treating a patient diagnosed with NASH can be 1.5 mg or 3.0 mg. In some embodiments, the total daily dose is 3.0 mg.
  • Compound 1 in a method of treating a patient diagnosed with NASH, can be administered orally.
  • Compound 1 can be administered orally as the Form B solid form.
  • Compound 1 can be administered orally in a capsule, optionally further comprising one or more pharmaceutically acceptable excipients.
  • the capsule is a unit dosage form.
  • Another aspect of this disclosure is a method of treating a patient diagnosed with NASH, the method comprising diagnosing the patient as having NASH prior to administering Compound 1 to the patient. Diagnosing the patient as having NASH can be by analysis of a liver biopsy from the patient, analyzing the concentration of one or more liver enzymes relating to the diagnosis of NASH in the blood of the patient, or measuring elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • a novel, intermittent dosing regimen for the administration of Compound 1 was developed, based on studies of Compound 1.
  • the use of a FASN inhibitor in an intermittent dosing regimen refers to the administration of the FASN inhibitor to a patient at regular intervals (e.g., once per day) during a treatment period, interrupted by one or more rest periods wherein the FASN inhibitor is either not administered to the patient or is administered to the patient during the rest period at a lower dose than during the treatment period.
  • a method of treating a patient can comprise the administration of a FASN inhibitor to the patient in need thereof for a treatment cycle comprising a treatment period followed by a rest period (e.g., where no FASN inhibitor is administered to the patient during the rest period).
  • the treatment cycle can comprise one or more treatment period with at least one rest period before, during or after the treatment cycle.
  • the intermittent dosing regimen comprises one or more consecutive treatment cycles, each comprising (a) the daily administration of a therapeutically effective amount of Compound 1 to a subject in need thereof (in single or multiple doses) on consecutive days for 2 weeks, followed by (b) 1 week without administering Compound 1.
  • the treatment cycle can comprise the administration of Compound 1 to a subject once daily for 14 consecutive days followed by 7 consecutive days without administration of Compound 1 to the subject (2- weeks on/l-week off).
  • a method of treatment comprises administering a therapeutically effective amount (e.g., 3.0 mg) of Compound 1 to a subject in need thereof (e.g., a patient diagnosed with NASH) in one or more consecutive 3 -week treatment cycles, where each treatment cycle comprises administering the therapeutically effective dose of Compound 1 once daily to the subject on consecutive days for 2 weeks, followed by one week without treatment with Compound 1.
  • the method can comprise 4 consecutive treatment cycles.
  • the therapeutically effective dose of Compound 1 administered to a patient in need thereof during the treatment cycle can be 1.5 mg, 3 mg or 4.5 mg administered daily to the subject for 2 weeks during the beginning of a treatment cycle prior to a rest period, followed by a 1 week rest period without administering Compound 1, repeated through a course of treatment.
  • the course of treatment can be 12 or more consecutive weeks.
  • a method comprises administering Compound 1 to a patient in multiple consecutive 3-week treatment cycles each comprising (a) administering 1.5 mg of Compound 1 to a patient diagnosed with NASH once daily for 2 weeks, followed (b) by 1 week without administering Compound 1 to the patient.
  • the method can comprise repeating the 3-week treatment cycle for 12 consecutive weeks.
  • a method comprises administering Compound 1 to a patient in multiple consecutive 3-week treatment cycles each comprising (a) administering 3.0 mg of Compound 1 to a patient diagnosed with NASH once daily for 2 weeks, followed (b) by 1 week without administering Compound 1 to the patient.
  • the method can comprise repeating the 3-week treatment cycle for 12 consecutive weeks.
  • a method comprises administering Compound 1 to a patient diagnosed with NASH in multiple consecutive 3-week treatment cycles, each comprising (a) administering 4.5 mg of Compound 1 to a patient once daily for 2 weeks, followed (b) by 1 week without administering Compound 1.
  • the method can comprise repeating the 3-week treatment cycle for 12 consecutive weeks.
  • the treatment cycle is 3 weeks (21 days) long and comprises the administration of a therapeutically effective amount of the FASN inhibitor (such as Compound 1 or a pharmaceutically acceptable salt there) once per day (QD) for 2 weeks (14 consecutive days), followed by one week (7 consecutive days) where no FASN Inhibitor (e.g. Compound 1 or a pharmaceutically acceptable salt thereof) is administered to the patient.
  • the FASN inhibitor such as Compound 1 or a pharmaceutically acceptable salt there
  • subjects can take the Compound 1 at home once a day (QD) as instructed.
  • QD QD
  • Dosing will be intermittent, with 2 weeks of QD dosing of Compound 1 treatment followed by 1 week without any Compound 1.
  • the aim is to dose the patient with Compound 1 at approximately the same clock time on every dosing day.
  • the preclinical in vivo pharmacology data in the below examples show the modulation of FASN activity leading to inhibition of DNL by Compound 1 was demonstrated in different preclinical models including diet-induced obesity (DIO) models.
  • DIO diet-induced obesity
  • the examples describe experiments demonstrating an impact of Compound 1 on each of three key aspects of NASH (steatosis, inflammation, and fibrosis). Importantly, inhibition of steatosis was achieved at exposures suggesting a therapeutic window for Compound 1 in treating NASH patients.
  • the examples herein evaluated Compound 1 using endpoints of steatosis and inflammation in preclinical models.
  • Compound 1 inhibited IL-17 production in human TH17 cells differentiated from CD4+ T cells isolated from healthy donors, and Compound 1 blocked IL-17 production in human TH17 cells during cellular potency determination.
  • Compound 1 potently inhibited TH17 cell differentiation and IL-17 secretion suggesting it may block THl7-mediated inflammation.
  • Compound 1 inhibited the proliferation of rat HSC, supporting the hypothesis that the inhibition of fatty acid synthesis may directly inhibit fibrosis.
  • Compound 1 inhibited FASN activity in HSD rat liver samples as demonstrated by accumulation of malonyl- carnitine and/or malonyl-CoA.
  • the compound reduced the levels of early markers of steatosis, including liver and plasma TG.
  • the exposure associated with the reduction of early steatosis markers is well below maximal inhibition of FASN, suggesting that incomplete and/or intermittent FASN inhibition may be sufficient for therapeutic activity.
  • Compound 1 was well- tolerated in all dose levels (0.125 - 1.2 mg/kg) in a 4-week HFD rat model study. Treatment with Compound 1 resulted in significant reduction in liver steatosis at the lowest dose evaluated of 0.125 mg/kg QD.
  • the exposure associated anti-steatosis activity is well below maximal inhibition of FASN, suggesting that low and sustained FASN inhibition may be sufficient for therapeutic activity.
  • inhibition of steatosis in the HFD rat model occurred at exposures suggesting a therapeutic window for Compound 1 in treating NASH patients.
  • Compound 1 The in vivo anti-inflammatory activity of Compound 1 was investigated in the THl7-driven EAE mouse model.
  • Compound 1 inhibited the gene expression level of splenic Retinoic acid Receptor-Related Orphan Receptor C (RORc) (a key regulator for murine TH17 differentiation) and reduced the population of IL-17+ CD4+ T cells in the lymph node, spinal cord, and brain. Consequently, treatment with Compound 1 attenuated spinal cord demyelination/inflammation, reduced brain inflammation and improved disease severity in this THl7-driven inflammation model at the lowest dose of 1 mg/kg twice daily administration.
  • RORc splenic Retinoic acid Receptor-Related Orphan Receptor C
  • Projected human doses of Compound 1 based on pharmacologically active preclinical exposures are in the range of about 0.3 mg to about 9.0 mg per day.
  • the values for total oral dose are projected by matching the exposure (area under the curve, AUC) observed for in vivo preclinical pharmacology to an estimation of human AUC modeled on PK parameters based on in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) and preclinical PK studies.
  • AUC area under the curve
  • Example 13 summarizes the synthesis of (4-(2-fluoro-4-(l-methyl-lH-benzo[d]imidazol- 5-yl)benzoyl)piperazin-l-yl)(l-hydroxycyclopropyl)methanone (“Compound 1”), which was reported previously in PCT Application Publication No. WO 2014/164749.
  • Example 14 describes the preparation of solid Form B of Compound 1.
  • the potency of Compound 1 against human FASN protein was determined by in vitro biochemical assay using purified full-length FASN recombinant enzyme.
  • FASN activity was detected using 7-diethylamino-3-(4’-maleimidylphenyl)-4-methylcoumarin (CPM), where the production of CoA was measured by the formation of a fluorescent CPM-CoA conjugate from the non-fluorescent CPM reagent ( Figure 2).
  • Compound 1 inhibited the enzymatic activity of human FASN protein with a fifty percent inhibitory concentration (ICso) value of 39.8 nM.
  • ICso inhibitory concentration
  • the cellular potency of Compound 1 in inhibiting de novo lipogenesis (DNL) was evaluated with 14 C-acetate incorporation into fatty acids in HepG2 cells, a human hepatocellular carcinoma line.
  • HepG2 cells were treated with various concentrations of Compound 1 or dimethyl sulfoxide (DMSO) as a control in the presence of 14 C-acetate for 5 hr.
  • DMSO dimethyl sulfoxide
  • the lipid fraction was extracted from cell pellets and resolved by thin layer chromatography (TLC). Fatty acid synthesis was measured by the radioactivity from 14 C-acetate incorporated into free fatty acids.
  • Compound 1 inhibited DNL in HepG2 cells with a fifty percent effective concentration (ECso) of 61.7 nM.
  • TH17 cell differentiation De novo fatty acid synthesis is required for TH17 cell differentiation.
  • the activity of Compound 1 on human TH17 cell differentiation was determined using isolated naive T cells under TH17 differentiation conditions. Briefly, CD4+ T cells were isolated from peripheral blood mononuclear cells of healthy donors, activated with CD3/CD28 microbeads, and then cultured in the presence of PMb, IL-6, 11-21, 11-23 and TGFP for 7-10 days to promote TH17 cell differentiation. Compound 1 or DMSO as control was present in the media during TH17 cell differentiation process, which was monitored through the detection of secreted IL-17 in the supernatant by enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • HSC hepatic stellate cells
  • Compound 1 inhibited proliferation of rat HSC in a concentration-dependent manner with IC50 of 0.42 mM.
  • ND Normal diet fed rats were used to assess the in vivo activity of Compound 1 to modulate FASN.
  • Male Sprague-Dawley (SD) rats received a single oral (QD) or two oral (BID) administrations of Compound 1 or vehicle control (N 4/group).
  • Compound 1 treatment resulted in a similar total concentration of Compound 1 in plasma and liver tissues that was dose-proportional, suggesting that Compound 1 is not accumulated in liver in the ND rat model.
  • Treatment with Compound 1 resulted in a dose-dependent increase in hepatic malonyl-CoA level as compared to the vehicle group, indicating increasing inhibition of FASN at increasing doses.
  • the calculated EC50 for FASN inhibition in rat liver was less than 25 nM ( Figure 6), which correlated well with the potency values for FASN inhibition in in vitro pharmacology experiments.
  • HFD rat model In order to investigate the relationship between dose and exposure and the corresponding changes in clinical activity, Compound 1 was evaluated in a HFD rat model.
  • the HFD model is widely used in preclinical animal models to induce hepatic steatosis as one key pathological component of NASH. Steatosis is caused by the accumulation of TG in the liver, and as such, decreases in TG may represent a potential marker that Compound 1 acts on steatosis.
  • the obese phenotype of the HFD model is dependent on the incorporation of high dietary fat and DNL- derived fat.
  • the first HFD study was designed as a dose-range finding study to define tolerable doses for further analysis and to demonstrate preliminary activity of Compound 1 on markers of liver steatosis.
  • the second HFD study investigated lower exposures and alternative dosing schedules on the endpoints of steatosis and liver and plasma markers of lipogenesis, including triglyceride (TG) and free fatty acid (FFA) levels.
  • TG triglyceride
  • FFA free fatty acid
  • DIO diet-induced obesity
  • HFD study 2 a lower range of dose levels of Compound 1 in established obese HFD rats was evaluated. Rats were orally administered Compound 1 at 0.125, 0.4 and 1.2 mg/kg QD for 4 weeks. This study also investigated dose ranging on both a BID (0.2 and 0.6 mg/kg BID) and Q2D (2.4 and 12 mg/kg every other day) schedules in order to assess the impact of schedule on the activity of Compound 1.
  • BID 0.2 and 0.6 mg/kg BID
  • Q2D 2.4 and 12 mg/kg every other day
  • the effect of Compound 1 on steatosis was determined by evaluating liver histology post treatment. An independent pathologist evaluated liver specimens in a blinded manner. The E&S stained liver slides were evaluated for steatosis store by Kleiner scoring system (See Kleiner, D.E., et al. (2005),“Design and validation of a histological scoring system for nonalcoholic fatty liver disease,” Hepatol. Baltim. Md 41 , 1313-1321). Steatosis scores were assessed by medium-power evaluation of parenchymal involvement by steatosis.
  • Severity of steatosis was defined as follows: SO: no steatosis, ⁇ 5% parenchymal involvement; Sl : mild steatosis, 5-33% parenchymal involvement; S2: moderate steatosis, >33-66% parenchymal involvement; S3 : severe steatosis, >66% parenchymal involvement.
  • liver TG were significantly elevated compared to normal diet controls, consistent with accumulation of TG in the liver and the presence of steatosis in this disease model.
  • Steatosis is caused by the accumulation of TG in the liver, and as such, decreases in TG may represent a potential marker for steatosis.
  • liver TG were significantly elevated in HFD controls compared to normal diet controls, consistent with accumulation of TG in the liver and the presence of steatosis in this disease model. Decreases in liver TG were demonstrated in all QD dosing groups and, consistent with the steatosis scores; no clear dose- dependent effect was observed (Table 2).
  • liver TG As noted above for the steatosis measurements, the lack of a dose-dependent response of Compound 1 on liver TG may be due to the variation within the model and the smaller sample size, but also reflects a significant activity of Compound 1 at low doses and exposures in the livers of HFD animals.
  • plasma TG levels were not significantly elevated in this model, when compared to normal diet controls; however, a dose-dependent decrease in plasma TG was demonstrated with daily dosing (Table 2). Although there are differences between the liver and plasma TG changes following Compound 1 treatment, it may be that liver DNL is more sensitive to FASN inhibition. These data demonstrate that lowering of plasma TG even from normal levels is possible with FASN inhibition.
  • treatment with daily Compound 1 reduced plasma leptin levels (a marker of total body fat levels) to similar levels as the age-matched non-diseased control group. There were no apparent changes in plasma ketone body levels following Compound 1 treatment, which indicates that there were no changes in fatty acid oxidation with daily dosing.
  • the high-fat-diet (HFD) rat model was used to further evaluate the in vivo activity of Compound 1.
  • the HFD model is widely used in preclinical animal models to induce hepatic steatosis as one key pathological component of NASH. Steatosis is caused by the accumulation of TG in the liver, and as such, decreases in TG may represent a potential marker for activity toward steatosis.
  • the obese phenotype of the HFD model is dependent on the incorporation of high dietary fat and DNL-derived fat. Since these animals have large amounts of exogenous fat from the diet, this model would have a high bar of success for an inhibitor of DNL and activity of Compound 1 would demonstrate the importance of FASN as a key mediator of steatosis.
  • HFD high-fat diet
  • ND normal diet
  • QD once daily
  • BID twice dai y
  • QQ2D every ot ler day.
  • Severity of steatosis was defined as follows: SO, no steatosis, ⁇ 5% parenchymal involvement; Sl, mild steatosis, 5-33%; S2, moderate steatosis, > 33-66%; S3, severe steatosis, > 66%.
  • HSD fed rats represent an alternative experimental model for obesity and steatosis.
  • 60-70% of the caloric intake is from simple carbohydrates, and thus, the primary source of increased TG is from DNL.
  • Inhibition of FASN and, thus, DNL by Compound 1 can have a significant impact on TG production and steatosis in this model.
  • the goal of the HSD study was to evaluate the in vivo potency of Compound 1 for blocking fatty acid (FA) synthesis in order to reduce fat deposition in the liver, as monitored by steatosis scores, as well as changes in liver and plasma TG and liver FFA.
  • An additional single administration PK/PD study in HSD rats was also used to determine the relationship between the induction of liver and plasma malonyl-camitine and Compound 1 in this diseased model.
  • HSD Research Diets Inc.
  • the HSD vehicle treatment group had significantly lower liver TG levels as compared to HFD vehicle group at the end of the study (14.5 ⁇ 2.0 pmol/g in HSD vs. 57.3 ⁇ 7.7 pmol/g in HFD).
  • Treatment with Compound 1 with doses as low as 0.3 mg/kg resulted in reduction of liver TG to levels near those observed in normal diet animals, consistent with DNL as the primary source of excess TG in this model (Table 6).
  • Table 6 shows data showing the effect of Compound 1 on plasma and liver triglycerides from HSD rat model. The data are presented as Mean ⁇ SEM.
  • the high-sucrose diet (HSD) rat model is an experimental model for obesity and steatosis. In this model, 60-70% of the caloric intake is from simple carbohydrates, and thus, the primary source of increased TG is through DNL.
  • HSD rats were treated orally with a dose range of Compound 1 or vehicle as single dose or once daily for 4 weeks. Plasma and liver samples were collected at the end of the study for the measurement of FASN inhibition and TG levels.
  • FASN inhibition was measured by changes in the level of malonyl-CoA and malonyl- carnitine, which is converted from malonyl-CoA by carnitine palmitoyltransferase (CPT).
  • CPT carnitine palmitoyltransferase
  • a single administration of Compound 1 resulted in a small (up to 2-fold), but reproducible dose- and time- dependent increase of malonyl-camitine and malonyl-CoA (Figure 9).
  • the peak plasma and liver concentrations of Compound 1 occurred at 2 hr following treatment, whereas the maximal increase in malonyl-camitine was observed at 24 hr.
  • liver malonyl- carnitine levels over the period measured was more pronounced at the lower doses of Compound 1, with equivalent increases in liver malonylcamitine over vehicle treated animals 8 hr post Compound 1 dosing (a 2.5- to 3-fold increase).
  • treatment with Compound 1, including doses as low as 0.3 mg/kg resulted in reduction of liver TGto levels near those observed in ND animals, consistent with DNL as the primary source of excess TG in this model (Table 7).
  • HSD high-sucrose diet
  • QD once daily. * p ⁇ 0.05 relative to vehicle treated group.
  • splenic mRNAs were measured for expression of mRORc, which encodes key transcription factor RAR-related orphan receptor gamma, thymus-specific isoform (RORxT) essential for murine TH17 cell differentiation.
  • EAE Study 1 Two mouse EAE studies were conducted. The first study was designed to assess the anti inflammatory effects of Compound 1 in terms of reducing EAE clinical scores and pathology at the conclusion of the study on Day 29. In addition, Compound 1 exposure, PD, and clinical activity relationships were assessed. In EAE Study 1, the impacts of Compound 1 on EAE clinical score and pathology were assessed at doses of 2, 6, and 20 mg/kg QD and at 1, 3, and 10 mg/kg. BID. To better demonstrate PD effects of Compound 1 on TH17 biomarkers in the relevant tissues, a second EAE study was conducted in which lymph nodes and CNS tissues were analyzed for the presence of IL-17+ CD4+ cells at the peak of the disease (based on clinical scores) on Day 15. In the EAE model, disease-induced weight loss and sporadic animal deaths are expected due to the severity of the disease. Thus, it was important to monitor for significant body weight changes and mortality of the animals treated with Compound 1.
  • the impact of treatment on the disease states in the EAE model is characterized by the degree of inflammatory cell infiltration into tissues of the CNS.
  • demyelination in the spinal cords and CNS inflammation of treated animals were by evaluated.
  • the spinal cords of Compound 1 treated animals showed significantly reduced visible signs of demyelinating lesions or inflammation as judged by cellular infiltrates with Luxol fast blue staining and H&E staining (Table 8).
  • Table 8 provides data on the effect of Compound 1 on spinal cord demyelination, spinal cord inflammation and brain inflammation in EAE model. Data were presented as Mean ⁇ SD. The grading scales for each measurement are listed in Table 9. Table 9
  • lymph nodes and spinal cords were collected for flow cytometry analysis of IL-17+ CD4+ cells at the peak of the EAE disease.
  • the EAE disease state was induced in animals as described above, and animals were sacrificed on Day 15. Mice were treated on a BID schedule with vehicle control or Compound 1 at 0.3, 1, 3, and 10 mg/kg from Day 4 to Day 15. In this study, two deaths occurred; one in the vehicle treatment group and one in the 3 mg/kg BID group.
  • FIG. 12 Compound 1 reduced the population of IL-17+ CD4+ T cells in lymph nodes and CNS at doses as low as 0.3 mg/kg BID and achieved statistical significance at 3 and 10 mg/kg BID (Figure 12).
  • Figure 12A and Figure 12B are graphs showing the reduction by Compound 1 of the population of IL17+ CD4+ cells in lymph node ( Figure 12A) and spinal cord and brain tissue samples in the second EAE study ( Figure 12B). The data were presented as Mean ⁇ SD. * P ⁇ 0.05 ** P ⁇ 0.0l as compared to vehicle control.
  • Compound 1 reduced disease progression and severity in the mouse EAE model, with evidence of decreased CNS inflammation, as well as systemic PD effects on TH17 relevant biomarkers, as evidenced by reduced gene expression of mRORc in spleen, decreased IL- 17+ and CD4+ T cells in lymph nodes and CNS tissues.
  • these data lend further support for the therapeutic utility of Compound 1, at least by dampening THl7-driven inflammation and potentially the resultant fibrosis.
  • Example 11 Inhibition of Fatty FASN with Compound 1 Reduces hepatic de novo Lipogenesis in Healthy Adult Subjects
  • Hepatic fractional DNL (% new palmitate in plasma TG) was measured for 12 hours during fructose stimulation using an infusion of [l- 13 Ci]-acetate, which is incorporated into palmitate in plasma TG, and mass isotopomer distribution analyses (Figure 14).
  • the [l- 13 Ci]-acetate infusion and fructose stimulation were stopped after the collection of the 12 HR sample, a standardized dinner was consumed and DNL assessment continued for another 12 hours.
  • Fructose-stimulated DNL was calculated by subtraction of pre-fructose DNL values from each post-fructose DNL value.
  • Compound 1 concentrations at each sampling point were used for calculation of plasma compound 1 pharmacokinetic (PK) parameters.
  • Safety was assessed via adverse event (AE) reporting by the investigators and clinical laboratory anomalies.
  • PK parameters were calculated from the plasma Compound 1 concentration-time data using Phoenix WinNonlin Version 6.3. Actual sample times were used in the calculation of PK parameters.
  • the PD parameter DNL area under the curve from 0 to 12 hours (AUCo-i2h) was calculated by cohort and treatment with the use of normalized fructose-stimulated DNL data. For each subject, the percent PD change from placebo (or DNL inhibition) for fructose-stimulated DNL at each dose level was calculated as follows:
  • DNL AUCs were calculated using results obtained prior (AUCO-I2HR) and after discontinuation of the acetate infusion (AUCo-24h).
  • Plasma Compound 1 concentrations increased rapidly with peak values occurring at the first sampling point 1 hour after dosing in most subjects (Table 15). Apparent elimination ti/2 values, calculated when sufficient data were available, varied between 11 and 17 hours in subjects treated with Compound 1. Exposure to Compound 1 increased in a dose-proportional manner (Table 11).
  • Example 12 A study of Compound 1 in Overweight/Obese Participants with NASH
  • This randomized, double-blind, placebo-controlled Phase 1/2 interventional study evaluates safety, efficacy, PK, and PD of Compound 1 as a single agent in overweight/obese subjects with NASH.
  • the study may be conducted with 30 participants in multiple dosing cohorts that will overlap. Subjects in each cohort are randomized to Compound 1 or placebo.
  • Cohort A will assess the administration of a dose of 1.5 mg Compound 1 given for 2 weeks, alternating with a 1 week of no investigational product (IP), continued for 12 weeks. This design leads to 4 dosing cycles (2 -week daily IP followed by 1 week of no IP).
  • Cohort A (1.5 mg Compound 1) received 6 weeks of treatment (2 dosing cycles)
  • Cohort B (3.0 mg Compound 1) will only be approved after the safety and tolerability data from Cohort A (1.5 mg Compound 1) are determined to be acceptable.
  • Cohort B will be administered up to 3.0 mg Compound 1 with the same dosing design as in Cohort A.
  • Cohort C will be administered up to 4.5 mg Compound 1 with the same dosing design as in Cohort A.
  • Safety, tolerability, PK and PD assessments will be performed throughout the study. Hepatic steatosis will be assessed by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF).
  • MRI-PDFF magnetic resonance imaging-estimated proton density fat fraction
  • Hepatic and sebum de novo lipogenesis will be assessed using a 2-week deuterated water labelling protocol.
  • Deuterated water will be provided as individual ready -to-use, single dose bottles each containing 50 mL of deuterated water (70%).
  • Sebum and blood samples for additional pharmacodynamic (PD) and pharmacokinetic (PK) assessments will be collected throughout the study.
  • ECG electrocardiogram
  • ALT Alanine aminotransferase
  • AST Aspartate aminotransferase
  • yGT Gammaglutamyl transferase
  • Alkaline phosphatase Alkaline phosphatase
  • Time to maximum concentration (Time Frame: Blood samples for PK analysis to be collected at multiple visits, up to 9 study visits over the course of approximately 20 weeks]
  • Sebum fatty acid concentrations & Sebum DNL [Time Frame: Sebum lipids to be measured using Sebutape at multiple visits, up to 5 study visits over the course of approximately 20 weeks]
  • Circulating biomarkers of liver injury and fibrosis Enhanced liver fibrosis (ELF) score, Cytokeratin-l8 fragments, FibroSure®, PRO-C3) [Time Frame: Blood samples for PD analysis to be collected at multiple visits, up to 4 study visits over the course of approximately 20 weeks]
  • Circulating metabolic parameters (Fasting Lipids, Glycemic parameters, Adiponectin, FGF-21, Malonyl carnitine) [Time Frame: Blood samples for PD analysis to be collected at multiple visits]
  • CAP Steatosis
  • LSM liver stiffness
  • Imaging parameters (Liver Volume [L], Liver Fat Volume Index [L]) assessed by MRI-PDFF [Time Frame: Imaging parameters to be assessed at multiple visits, up to 3 study visits over the course of approximately 20 weeks]
  • Eligibility Criteria may include:
  • LSM > 7-12 kPa and CAP > 300 dB/m by FibroScan® OR Liver biopsy within 24 months, consistent with NASH (defined as the presence of steatosis, inflammation, and ballooning) with stage 2-3 fibrosis according to the NASH Clinical Research Network (CRN) classification (or equivalent); and Screening MRI-PDFF with > 10% steatosis;
  • Stable body weight defined as no weight gain or weight loss > 5% over the previous 3 months.
  • T2DM Type diabetes
  • Subject with T2DM is on stable doses of metformin monotherapy (subjects on combination therapy of metformin and sulfonylurea (SU) need to undergo washout period of 7 days of SU prior to dosing) with no changes in medication within the previous 6 months;
  • Type 1 diabetes and type 2 diabetic subjects on insulin therapy 1. Type 1 diabetes and type 2 diabetic subjects on insulin therapy;
  • Diabetic complications such as acute proliferative retinopathy
  • Uncontrolled hypertension defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg at screening (reading may be repeated on a different day). (Subjects with uncontrolled hypertension may be rescreened after 3 months, following initiation or adjustment of antihypertensive therapy);
  • Pacemaker implanted electronic devices, metal fragments, aneurysm clips in the brain or any other device that could interfere with the MRI examination;
  • HBV Ab hepatitis B surface antigen
  • HCV Ab hepatitis C antibody
  • HCV-l human immunodeficiency virus type 1
  • HV-2 type 2 antibody
  • Step 2 (4-(4-(ter t-butoxycar bony I) piperazine- 1 -car bony I)-3-fluoropheny I) boronic acid
  • the aqueous (product containing) phase was diluted with fresh 2-methyltetrahydrofuran (1400 mL), and the pH was adjusted to 1.0 with 6 M HC1.
  • the phases were separated, and the organic (product containing) phase was filtered through celite and added to a 5 L multi-neck round bottom flask fitted with nitrogen inlet and overhead stirring, containing water (1400 mL) and sodium periodate (110 g, 516 mmol). The mixture was stirred for 1 hour, followed by the addition of 1 M HC1 (980 ml). The mixture was stirred at rt and monitored for completion by LC/MS.
  • Compound 1 can be obtained in a free base solid form suitable for use in a pharmaceutical composition (e.g., disclosed herein as Compound 1 solid Form B).
  • An Active Pharmaceutical Ingredient consisting essentially of Compound 1 free base in solid Form B can be combined with pharmaceutically acceptable excipients to form an oral unit dosage form (e.g., a capsule or tablet) that can be administered to patients in need thereof.
  • Compound 1 can be obtained as a crystalline solid form that is a highly stable and non- hygroscopic substance.
  • a thermodynamically stable polymorph (Form B) with well-defined characteristics was selected based on a solid form stability evaluation of several polymorphs.
  • Form B solid form of Compound l is a free base, anhydrate form (Form B polymorph) with a DSC onset: 224 °C; peak: 226 °C.
  • Form B is a stable form of the anhydrous polymorphs at both RT and 50 °C.
  • the conditions for step 5 in Figure 18 were modified such that (/-R NE ⁇ was replaced with aq. NaOH and DMF was replaced with ethanol (EtOH).
  • the solid Compound 1 that was isolated directly from this reaction mixture is of the desired Form B polymorph and is of excellent purity (> 99% LCAP).
  • Form B was non-hygroscopic, with 0.46% weight gain from 0% to 95% RH at 25 °C.
  • Form B is a stable physical form at both RT and 50 °C.
  • Form B showed 0.06 mg/mL solubility in 24 hours in the formulation of 0.5% MC and 0.5% Tween 80 in water, with no form change or significant degradation found in the formulation.
  • Form B is non-hygroscopic, and remains stable after exposure to humidity in DVS analysis.

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Abstract

La présente invention concerne l'administration thérapeutique d'un inhibiteur d'acide gras synthase (FASN) (composé 1), y compris via des schémas posologiques intermittents, à des patients diagnostiqués avec une stéatohépatite non alcoolique (SHNA) caractérisée par une stéatose hépatique, une inflammation et une fibrose.
PCT/US2019/058575 2018-10-29 2019-10-29 Traitement de la stéatohépatite non alcoolique (shna) WO2020092376A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160002188A1 (en) * 2013-03-13 2016-01-07 Forma Therapeutics, Inc. Novel compounds and compositions for inhibition of fasn
US20170312273A1 (en) * 2016-04-25 2017-11-02 Forma Therapeutics, Inc. Methods of using fasn inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160002188A1 (en) * 2013-03-13 2016-01-07 Forma Therapeutics, Inc. Novel compounds and compositions for inhibition of fasn
US20170312273A1 (en) * 2016-04-25 2017-11-02 Forma Therapeutics, Inc. Methods of using fasn inhibitors
WO2017189613A1 (fr) * 2016-04-25 2017-11-02 Forma Therapeutics, Inc. Procédés d'utilisation d'inhibiteurs de fasn

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