Methods of treating fibrosis

Abstract

The present specification provides methods and compositions for treating fibrosis, in particular pulmonary fibrosis. The pulmonary fibrosis may be idiopathic or occur after a pulmonary infection. The pulmonary infection may be caused by SARS-CoV-2. Lung function is stabilized or improved due to treatment.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit and priority of U.S. Patent Application 18 / 115,598, filed February 28, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Treating fibrotic diseases has proven challenging. While some drugs are approved for treating fibrotic diseases, such as pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF), these drugs only moderately slow disease progression, not stop or reverse it. The Hedgehog / GLI signaling pathway is an important regulator of normal embryonic development and has been associated with the development of fibrosis. However, inhibiting the typical Hh signaling pathway, such as by inhibiting the G protein-coupled receptor Smoothened (SMO) in the Hedgehog (Hh) signaling pathway, has failed to produce a clinically viable treatment for pulmonary fibrosis, renal fibrosis, or myelofibrosis. In fact, the SMO inhibitors cyclopamine and IPI-926 have been found to be ineffective in treating renal fibrosis. Furthermore, a phase 2 clinical trial of IPI-926 in myelofibrosis does not support further development. Another SMO inhibitor, vismodegib (in combination with pirfenidone), showed some efficacy in a phase 1b clinical trial for the treatment of IPF, but many patients withdrew from the study because they could not tolerate the drug, and the development of the drug was abandoned due to this indication. Summary of the Invention

[0004] This article discloses methods and compositions for treating fibrotic diseases using hedgehog factor signaling pathway inhibitors, the hedgehog factor signaling pathway inhibitors being potent and tolerable enough to allow for clinical use.

[0005] One aspect is a method for treating fibrosis, which includes administering a Gli1 inhibitor. Gli1 inhibition can be indirect. In some embodiments, an SMO inhibitor is used to indirectly inhibit Gli1.

[0006] One aspect is a method for treating fibrosis, the method comprising administering a means for inhibiting Gli1. Gli1 inhibition can be indirect. In some embodiments, the means for inhibiting SMO is used to indirectly inhibit Gli1. In various embodiments, one or more SMO inhibitors of different genera or species are explicitly excluded.

[0007] With respect to the above, in some embodiments, the Gli1 inhibitor or means for inhibiting Gli1 is an SMO inhibitor (or means for inhibiting SMO). In some embodiments, the SMO inhibitor, Gli1 inhibitor, or means for inhibiting Gli1 or SMO is a compound of Formula I, or a pharmaceutically acceptable salt thereof:

[0008]

[0009] wherein R 1 is hydrogen or methyl; R 2 is hydrogen or methyl; R 3 , R 4 , R 5 , R 6 , or R 7 is independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, or trifluoromethylsulfonyl, provided that at least three of R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen. Under the standard nomenclature used throughout this disclosure, the terminal portion of the specified side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a methylsulfonyl substituent is equivalent to CH3-SO2-. In some embodiments, the compound of Formula I is 4-fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide (CAS 1258861-20-9):

[0010]

[0011] also known as taladegib.

[0012] With respect to the above, in some embodiments, the SMO inhibitor, Gli1 inhibitor, or means for inhibiting Gli1 or SMO is a compound of Formula II, or a pharmaceutically acceptable salt thereof:

[0013]

[0014] wherein R 1 is hydrogen or methyl; R 2 is hydrogen or methyl; R 3 , R 4 , R 5 , R 6 , or R 7Independently, it can be hydrogen, fluorine, chlorine, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, or trifluoromethylsulfonyl, provided that R is present. 3 R 4 R 5 R 6 and R 7 At least three of the components are hydrogen. In some embodiments, the compound of formula II is compound L-4, which has the following structure.

[0015]

[0016] In response to the above aspects, in some embodiments, Gli1 inhibitors or means for inhibiting Gli1 are administered to patients in need, i.e., patients with fibrotic diseases. In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrotic disease is post-infectious pulmonary fibrosis (including bacterial or viral infections). In most cases, fibrosis develops after a chronic infection lasting several years, thus making it impossible to definitively prove the role of infection in causing fibrosis; therefore, this fibrosis is still classified as idiopathic. Covid-19 provides a contrast, as the onset of fibrosis can be very rapid. In some embodiments, pulmonary fibrosis occurs after infection with SARS-CoV-2. In some embodiments, the fibrotic disease is scleroderma. In some cases, the fibrotic disease is systemic scleroderma (also known as systemic sclerosis), and in others, it is systemic scleroderma involving the lungs. In some embodiments, the fibrotic disease is liver fibrosis, such as non-alcoholic steatohepatitis (NASH). In some embodiments, the fibrotic disease is kidney fibrosis. In some implementations, the fibrotic disease is gastric fibrosis. In some implementations, the patient is a person.

[0017] Regarding the above aspects, in some embodiments, a Gli1 inhibitor or means for inhibiting Gli1 is administered in an effective amount. In some embodiments, the effective amount effectively alleviates symptoms. In some embodiments, the effective amount effectively slows or halts disease progression. In some embodiments, the effective amount effectively reduces damage caused by the disease. In some embodiments, the effective amount effectively reverses damage caused by the disease (leading to improvement). Regarding IPF, damage can be measured as a change in lung function, for example, as determined by spirometry. Vigorous capacity measurements that can be used include forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and the lung's carbon monoxide diffusion capacity (DL). CO). The degree of fibrosis can also be assessed by imaging, such as high resolution computed tomography (HRCT). In some embodiments, an effective amount comprises 50-200 mg of a Gli1 inhibitor or means for inhibiting Gli1. In some embodiments, an effective amount comprises 10-300 mg of a Gli1 inhibitor or means for inhibiting Gli1.

[0018] One aspect is a pharmaceutical compound comprising a Gli1 inhibitor or means for inhibiting Gli1. In some embodiments, the Gli1 inhibitor or means for inhibiting Gli1 is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula 1 is taladegib.

[0019] Further aspects include methods of making the disclosed pharmaceutical compositions. For example, the disclosed methods can include removing a solvent component of a solution to produce a solid composition.

[0020] Further aspects include kits comprising the disclosed compositions. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 A comparison of clinical trial results for the following four IPF treatments is depicted: pirfenidone, nintedanib, GLPG1690, and the Hh inhibitor vismodegib. The trials for pirfenidone, nintedanib, GLPG1690 were placebo-controlled, while the vismodegib trial was open-label. The pirfenidone data is the average of three Phase 3 studies at 24 weeks. The nintedanib data is the average of two Phase 3 studies at 24 weeks. The GLPG1690 data is Phase lb data at 12 weeks. The Hh inhibitor (vismodegib) data is Phase lb data at 24 weeks.

[0022] Figure 2 Gli1 mRNA inhibition (%) in skin samples from patients receiving various doses of taladegib is depicted.

[0023] Figure 3 The drug-related discontinuation rates in clinical trials for four drugs considered for IPF treatment are depicted.

[0024] Figures 4A-4B Alpha-SMA protein levels in a bleomycin-induced pulmonary fibrosis model with and without taladegib treatment are depicted. Figure 4A Representative images of lung sections from anti-alpha-SMA immunostaining from sham control, vehicle-treated, and taladegib-treated mice are presented. Figure 4BPercentages of a-SMA positive areas from individual mice are plotted along with the mean and standard deviation for the treatment groups. DETAILED DESCRIPTION

[0025] The general mechanism of fibrotic disease has been understood to involve an initial tissue injury leading to upregulation of hedgehog, which drives the transdifferentiation of cells into myofibroblasts (i.e., differentiated cells (non-stem cells) switch to another type of differentiated cell, in this case myofibroblasts). The physiological function of myofibroblasts is to repair tissue by depositing extracellular matrix and contracting tissue (as in wound closure). Fibrotic diseases, including IPF, are caused by a dysregulated wound remodeling that involves chronic matrix deposition and tissue contraction long after the initial tissue trauma has been resolved. The methods and compositions disclosed herein treat fibrotic disease by inhibiting the Hh signaling pathway so that the upregulated hedgehog no longer drives this pathology, thereby blocking the production of myofibroblasts and halting the chronic remodeling that leads to fibrosis. Despite this mechanism being validated clinically, the prospects for Hh pathway inhibitor treatment of fibrosis have not been realized to date.

[0026] Definitions:

[0027] "Administration" or "to administer" means the step of giving (i.e., administering) a medical device, material, or agent to a subject. The formulations disclosed herein can be administered by a number of suitable routes.

[0028] "Drying" means removal of solvent.

[0029] "Patient" means a human or non-human subject receiving medical or veterinary care.

[0030] "Parenteral administration" and "administered parenterally" are art-recognized terms that refer to modes of administration other than enteral and topical administration, e.g., injection, and include, without limitation, retrobulbar, intraocular, intravenous, intramuscular, intrapleural, intravascular, intrapericardiac, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0031] "Pharmaceutically acceptable" or "therapeutically acceptable" means a material that does not interfere with the effectiveness or biological activity of the active ingredient and that is not toxic to the patient.

[0032] A "pharmaceutically acceptable carrier" is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as, for example, liquids or solid fillers, diluents, excipients, solvents or encapsulating materials, involved in carrying or transporting any subject composition from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the subject composition and not injurious to the patient. In certain embodiments, a pharmaceutically acceptable carrier is pyrogen-free. Exemplary materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethylene glycol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0033] A "pharmaceutical composition" means a formulation containing an active ingredient. The phrase "formulation" means that in addition to the active ingredient, at least one additional ingredient is present in the pharmaceutical composition (such as, but not limited to, albumin [e.g., human serum albumin or recombinant human albumin] and / or sodium chloride). Thus, a pharmaceutical composition is a formulation suitable for diagnostic, therapeutic, or cosmetic administration to a subject, such as a human patient. A pharmaceutical composition can be: a solution formed upon reconstitution of a lyophilized or vacuum-dried pharmaceutical composition with, for example, saline or water, or; a solution that does not require reconstitution. As noted above, a pharmaceutical composition can be a liquid, a semi-solid, or a solid. A pharmaceutical composition can be free of animal proteins.

[0034] "Reduce," "suppress," and "inhibit" have their commonly understood meaning of lessening or decreasing.

[0035] A "therapeutic formulation" means a formulation useful in therapy and thereby lessening a disorder or disease and / or its associated symptoms.

[0036] A "therapeutically effective amount" means the level, quantity or concentration of an agent, material or composition required to achieve a therapeutic goal.

[0037] Compositions

[0038] Disclosed herein are certain 1,4-disubstituted phthalazines that are effective inhibitors of SMO and downstream transcription factors Gli1 and Gli2 and exhibit desirable toxicological properties. Embodiments of the invention provide methods of treatment using a compound of Formula I, or a pharmaceutically acceptable salt thereof:

[0039]

[0040] wherein R 1 is hydrogen or methyl; R 2 is hydrogen or methyl; R 3 , R 4 , R 5 , R 6 or R 7 are independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, or trifluoromethylsulfonyl, provided that at least three of R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen. Under the standard nomenclature used throughout this disclosure, the terminal portion of the specified side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a methylsulfonyl substituent is equivalent to CH3-SO2-. “Pharmaceutically acceptable salt” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds of the present invention.

[0041] Compounds of Formula I and their synthesis are described in U.S. Patent No. 9,000,023, the entire contents of which are hereby incorporated by reference.

[0042] Embodiments of the invention also provide a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient, carrier, or diluent, for use in the methods of treatment. “Pharmaceutically acceptable carrier, diluent, or excipient” is a medium generally accepted in the art for the delivery of a biologically active agent to a mammal (e.g., a human).

[0043] An exemplary compound of Formula I is 4-fluoro-N-methyl-N-(1-(4-(1-methyl-1H- pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide (CAS 1258861-20-9):

[0044]

[0045] Also known as taladegib. Taladegib (also known as LY2940680) is a potent, selective, orally available Smo inhibitor with good safety profile that disrupts the Hh pathway. This molecule has been used in over 192 human subjects and was originally developed with the intent to treat oncology indications, with a focus on lung cancer and basal cell carcinoma (BCC). While primarily in cancer patients, these studies can provide preliminary understanding of dose and tolerability. Taladegib has oral bioavailability. In some embodiments, the mean oral bioavailability is about 72% to about 91%.

[0046] The major metabolite of taladegib, M75, is an oxidized N-desmethyl product that retains activity as an SMO inhibitor. M75 is believed to be formed from the oxidation of R 2 loses the methyl group, so this position is hydrogen rather than methyl.

[0047] Taladegib is well suited for targeting the lung compared to vismodegib. In animal models, taladegib is more than 20-fold more potent than vismodegib at inhibiting Gli1, a downstream effector molecule expressed when the Hh pathway is activated, in the lung. The clinically established MTD for taladegib is 400 mg. At this dose, Gli1 mRNA inhibition in the skin is >85% with a discontinuation rate of about 9%. Taladegib has been clinically evaluated at doses as low as 50 mg, i.e., 8-fold lower than the clinically established MTD, with Gli1 mRNA inhibition still greater than 80%. By contrast, vismodegib inhibits Gli1 mRNA by less than 50% at its MTD of 150 mg. Taladegib has better clinical safety than vismodegib, with a much lower incidence of muscle spasms (40% vs. up to 80%). Thus, while vismodegib proved unsuitable for IPF, clinical studies using vismodegib showed that inhibiting the Hh pathway can improve lung function in patients with IPF.

[0048] Compounds of Formula I inhibit Gli1 activity, typically with an IC 50 <40 nM, as measured in Daoy cells and described in U.S. Patent No. 9,000,023. The IC 50 of taladegib in this assay is about 2.4 nM. Such compounds constitute a means for inhibiting Gli1 activity or a means for inhibiting SMO.

[0049] In addition, U.S. Patent Application Publication No. 20200000784A1 is incorporated by reference herein for all it teaches regarding the use of taladegib to treat fibrosis, particularly idiopathic pulmonary fibrosis.

[0050] Certain analogs of the above phthalazines are potent inhibitors of SMO and downstream transcription factors Gli1 and Gli2, and exhibit desirable toxicological properties. In some embodiments, the SMO inhibitor, Gli1 inhibitor, or means for inhibiting Gli1 or SMO is a compound of Formula II, or a pharmaceutically acceptable salt thereof:

[0051]

[0052] wherein R 1 is hydrogen or methyl; R 2 is hydrogen or methyl; R 3 , R 4 , R 5 , R 6 , or R 7 is independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, or trifluoromethylsulfonyl, provided that at least three of R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen. In some embodiments, the compound of Formula II is N-(1-(4,5-dimethyl-6-(1-methyl-1H-pyrazol-5-yl)pyridazin-3-yl)piperidin-4-yl)-4-fluoro-2-(trifluoromethyl)benzamide, having the structure Also known as L-4.

[0053] L-4 is described in Zhu et al. (L-4, a Well-Tolerated and Orally Active Inhibitor of Hedgehog Pathway, Exhibited Potent Anti-tumor Effects Against Medulloblastoma in vitro and in vivo, Frontiers in Pharmacology 10:89, 2019), the entirety of which is hereby incorporated by reference. Zhu et al. describe L-4 as a promising anticancer agent. It was reported to have similar Hh inhibition ID 50 to taladegib, 2.33 nM vs. 2.26 nM, respectively.

[0054] Like taladegib and the compound of Formula I, L-4 and the compound of Formula II constitute a means for inhibiting Gli1 activity or a means for inhibiting SMO. Various embodiments specifically exclude the compound of Formula I, the compound of Formula II, or a particular subgenus or species of Formula I or Formula II.

[0055] The compounds of the present application are capable of forming pharmaceutically acceptable acid addition salts with, for example, a variety of inorganic acids and organic acids. Such pharmaceutically acceptable salts and the use of common

[0056] The compounds disclosed herein can be formulated into pharmaceutical compositions and administered in a variety of ways using pharmaceutically acceptable carriers, diluents, or excipients. In particular embodiments, such compositions are used for oral or intravenous administration. Such pharmaceutical compositions and processes for preparing them are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro et al. eds., 19th ed., Mack Publishing Co., 1995).

[0057] In some embodiments, the compounds disclosed herein can be formulated into tablets containing 50, 100, 150, 200, 250, 300, or 350 mg of the compound and the following common pharmaceutical ingredients: sodium croscarmellose, HPMCAS-H, mannitol, microcrystalline cellulose, silicon dioxide, and sodium stearyl fumarate. One particular embodiment contains 16.1% of taladegib, 37.6% of HPMCAS-H, 9.3% of mannitol, 28.6% of microcrystalline cellulose, 2.9% of sodium croscarmellose, 1.0% of silicon dioxide, 1.2% of sodium stearyl fumarate, and 3.4% of Opadry® II White. (film coated).

[0058] Additional embodiments can include 5-25% active agent, e.g., Gli1 inhibitor, 20-50% HPMCAS-H, 15-45% mannitol, 15-45% microcrystalline cellulose, 1-5% sodium croscarmellose, 0.5-5% silicon dioxide, 0.5-5% sodium stearyl fumarate, and 1-10% Opadry® II White.

[0059] Methods of use

[0060] IPF is a dysregulated wound healing process that leads to progressive pulmonary fibrotic scarring. Targeting the hedgehog pathway is a rational therapeutic approach to slow, halt, or reverse disease progression. During wound healing, the Hh pathway regulates the activation and transdifferentiation of fibroblasts into myofibroblasts, which when dysregulated are the key drivers of fibrosis. In IPF, myofibroblasts infiltrate the lung where they produce extracellular matrix proteins such as collagen. Myofibroblasts adhere to the extracellular matrix and pull the lung together like closing a wound. The result of myofibroblast activity is a gradual loss of lung function through fibrosis and tissue remodeling.

[0061] Targeting the Hh pathway via Smo inhibition has been validated in both the clinic and preclinically. In the clinical setting, the FDA-approved Smo inhibitor, vismodegib (approved as Erivedge® was evaluated in combination with pirfenidone in a single-arm IPF study. After six months of treatment, patients exhibited an average increase in forced vital capacity (FVC) of about 100 mL. Increases in FVC and lung volume were not found in previous clinical studies interrogating any other target considered for IPF. While Smo inhibition validated the Hh pathway as a therapeutic target for IPF, patients were intolerant to vismodegib because of severe muscle spasms, a major adverse event that led to drug discontinuation in more than 40% of participants. This discontinuation rate was similar to that of BCC patients taking vismodegib. All further development of vismodegib as an IPF therapeutic has been discontinued.

[0062] Inhibition of Gli1 mRNA in the skin is similar to that in the lung. In a lung cancer clinical study, Gli1 mRNA inhibition in skin biopsies has been measured as a surrogate for Gli1 mRNA inhibition in the lung. Nonclinical in vivo models indicate that the kinetics and magnitude of Gli1 mRNA inhibition by orally administered taladegib are very similar in the skin and lung of mice. Furthermore, the degree of Gli1 mRNA inhibition in the skin and lung of mice is similar to the degree of Gli1 mRNA inhibition observed in skin biopsies of human subjects being treated with a clinically relevant dose.

[0063] IPF patient samples have shown elevated levels of Hh pathway components and myofibroblasts. Several studies examined tissue from lung samples of IPF patients and compared them to lung samples of healthy subjects. It became apparent that SHh (an activated ligand of the Hh pathway) and Gli1 were significantly increased. Normal lungs do not have any detectable amount of SHh or Gli1, but IPF samples stained very intensely, indicating significant presence. IPF lung samples also stained very intensely for a-SMA1, a marker that defines myofibroblasts. Normal, healthy lung samples had little to no staining for a-SMA1.

[0064] Disruption of the Hh pathway to inhibit fibrosis has been demonstrated in vitro and in a number of animal models using a variety of Smo inhibitors. These animal models have similar characteristics of fibroblast infiltration and transdifferentiation into myofibroblasts, which then drive progressive fibrosis. Inhibition of Smo was observed to disrupt fibrosis and in some cases reverse the disease. In addition, it has been demonstrated that inhibition of Smo results in increased apoptosis of infiltrating myofibroblasts, reduction of a-SMA1, reduction of Gli1 and SHh, and reduction of collagen.

[0065] Talazoparib's nonclinical toxicity findings were similar to approved drugs in this class, and important potential risks associated with talazoparib's target effect were considered to be liver injury, effects on reproductive organs, rhabdomyolysis, reproductive toxicity, and bone effects. Talazoparib's class effects that have not been observed clinically or nonclinically include amenorrhea.

[0066] Clinically, the mean half-life (t 1 / 2 ) of talazoparib was estimated to be about 16 hours at all doses, allowing for once-daily dosing. The median t max was 2 hours.

[0067] Talazoparib showed good safety profile in 6 industry-sponsored studies that have been conducted primarily in patients with advanced cancers. As a monotherapy for advanced cancer, the most frequently observed adverse events (AEs) were nausea, diarrhea, taste disturbance, fatigue, anorexia, alopecia, vomiting, muscle spasm, constipation, weight loss, and headache.

[0068] The relationship between efficacy and toxicity of a drug is generally expressed in terms of the therapeutic window and the therapeutic index. The therapeutic window is the range of doses from the lowest dose that shows a detectable therapeutic effect up to the maximum tolerated dose (MTD); the MTD is the highest dose that can be reached for the desired therapeutic effect without producing unacceptable toxicity. The most typical therapeutic index is calculated as the LD 50 :ED 50 ratio when based on animal studies and the TD 50 :ED50 The ratio (although this calculation can also be derived from animal studies and is sometimes called the protection index), where LD 50 , TD 50 , and ED 50 are the doses lethal to 50%, toxic, and effective, respectively, in a test population.

[0069] In various aspects of these embodiments, toxicity is observable toxicity, significant toxicity, severe toxicity, or acceptable toxicity, or dose-limiting toxicity (such as, but not limited to, MTD). Observable toxicity refers to an effect that is observed, but is negligible or mild. Significant toxicity means a negative impact on the overall health or quality of life of the patient. In some cases, significant toxicity can be mitigated or resolved by other ongoing medical interventions. Severe toxicity refers to an effect that requires urgent medical intervention and / or dose reduction or treatment pause. Acceptability of toxicity will be influenced by the particular disease being treated and its severity and whether there are palliative medical interventions.

[0070] Toxicity and adverse events are sometimes graded on a 5-point scale. Grade 1 or mild toxicity is asymptomatic or causes only mild symptoms; can be characterized as only clinical or diagnostic observations; and is without indication for intervention. Grade 2 or moderate toxicity can impair activities of daily living (such as preparing meals, shopping, managing finances, using the telephone, etc.), but indicates only minimal, localized, or non-invasive intervention. Grade 3 toxicity is of medical significance, but is not immediately life-threatening; indicates hospitalization or prolongation of hospitalization; and activities of daily living related to self-care (such as bathing, dressing and undressing, feeding self, toileting, taking medications, and out-of-bed) can be impaired. Grade 4 toxicity is life-threatening and indicates urgent intervention. Grade 5 toxicity results in death related to the adverse event. Thus, in various embodiments, use of a drug in a regimen or dose disclosed herein will reduce the toxicity grade associated with treatment by at least one grade compared to use of that drug according to another regimen. In other embodiments, toxicity is limited to Grade 2 or lower, Grade 1 or lower, or results in no observable toxicity by use of the drug according to the specified regimen or dose. In some embodiments, the therapeutic index of a Gli1 or SMO inhibitor disclosed herein is greater than the therapeutic index of Vismodegib (about 0.37). In contrast, the therapeutic index of Taladegib is about 8. In some embodiments, the therapeutic index of a Gli1 or SMO inhibitor disclosed herein is greater than 1, 2, 3, 4, 5, 6, or 7.

[0071] Aspects of the present description provide, in part, for administration of an effective amount (or therapeutically effective amount) of a compound or composition disclosed herein. As used herein, the term “effective amount” is synonymous with “effective dose” and means, when referring to the treatment of IPF, the minimum dose necessary for at least the compound or composition disclosed herein to achieve the desired therapeutic effect. An effective dose or amount of a compound or composition disclosed herein can be readily determined by one of ordinary skill in the art, taking into account all of the standard factors (e.g., excretion rate of the compound or composition used; pharmacokinetics of the compound or composition used; properties of other compounds to be included in the composition; particular route of administration; particular characteristics, medical history, and risk factors of the individual, such as age, weight, general health, etc.; the individual’s response to treatment; or any combination thereof), and representing the best judgment of the individual utilizing the same, especially in light of the exemplary dosages and other information disclosed herein. In some embodiments, an effective dose is 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, or falls within a range bounded by any pair of the foregoing values. In some embodiments, an effective dose is administered once per day.

[0072] In some embodiments, the dose of taladegib, L-4, or related compound is initiated at 200 mg / day. In some embodiments, the dose is provided as a single daily dose. If a Grade 3 or higher AE is observed, the dose is gradually reduced. In some embodiments, the dose is reduced by decrements of 50 mg / day as needed, down to a minimum of 50 mg / day to avoid Grade 3 or higher AEs. In some embodiments, the initial dose (prior to gradual reduction) can be any dose above the minimum dose considered an effective dose. In some embodiments, the initial dose is in the upper half of the effective dose range. In some embodiments, the initial dose is at the top of the effective dose range. For example, if the effective dose range is 50-200 mg, the initial dose can be > 50 mg (e.g., 75 mg), 125-200 mg, or 200 mg. In some cases, the initial dose is in the range of 100-300 mg / day. In some cases, the dose is reduced by 25 mg / day, 50 mg / day, or 100 mg / day.

[0073] In some embodiments, an effective dose of a Gli1 or SMO inhibitor or means for inhibiting Gli1 or SMO results in stabilization or improvement of fibrosis, for example in terms of physical extent of fibrosis, lung function, or other metrics described herein. In further embodiments, the stabilization or improvement of fibrosis is achieved without the patient experiencing drug-related adverse events (toxicity). In particular cases, the drug-related adverse event avoided is a grade 3 or higher toxicity. In some embodiments, the drug-related adverse event that is absent is muscle spasm, QT prolongation, or liver toxicity.

[0074] Aspects are methods of treating fibrosis by administering a Gli1 or SMO inhibitor or means for inhibiting Gli1 or SMO to a patient in need thereof, i.e., a patient with a fibrotic disease. In some embodiments, the Gli1 or SMO inhibitor or means for inhibiting Gli1 or SMO is used as a monotherapy. In some embodiments, the Gli1 or SMO inhibitor or means for inhibiting Gli1 or SMO is used in combination with another anti-fibrotic drug. In some embodiments, the other anti-fibrotic drug is not an Hh pathway inhibitor. In some cases, the anti-fibrotic drug that is not an Hh pathway inhibitor is pirfenidone, nintedanib, GLPG4716, or PRM-151.

[0075] In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrotic disease is post-infection (including bacterial or viral infection) pulmonary fibrosis. In most cases, fibrosis develops after chronic infection for up to several years, thus making it impossible to ultimately prove the role of infection in causing fibrosis; therefore, this fibrosis is still classified as idiopathic. Covid-19 provides a contrast, i.e., the onset of fibrosis can be very rapid. In some embodiments, the pulmonary fibrosis occurs after infection with SARS-CoV-2. In some embodiments, the fibrotic disease is scleroderma. In some cases, the fibrotic disease is systemic scleroderma (also known as systemic sclerosis), and in further cases, is systemic scleroderma involving the lungs. In some embodiments, the fibrotic disease is liver fibrosis, e.g., non-alcoholic steatohepatitis (NASH). In some embodiments, the fibrotic disease is kidney fibrosis, e.g., renal interstitial fibrosis or kidney allograft fibrosis. In some embodiments, the fibrotic disease is stomach fibrosis, e.g., gastric mucosa fibrosis, fundic gland fibrosis, or retroperitoneal fibrosis. In some embodiments, the patient is a human. In some embodiments, the patient is a non-human animal, e.g., a mammal.

[0076] For each treatment method, there are parallel embodiments representing the use of a Gli1 or SMO inhibitor or means for inhibiting Gli1 or SMO in the treatment of fibrotic diseases, or its use in the manufacture of a medicament for the treatment of fibrotic diseases, or a composition or pharmaceutical composition for use in the treatment of fibrotic diseases, etc.

[0077] The term "treatment" and the like, refer to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. The term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, the term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than cure of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of

[0078] Therapeutic activities include, inter alia, administration of the drugs, dosage forms, and pharmaceutical compositions described herein to a patient, either by a healthcare professional, the patient himself or herself, or any other person, in accordance with the various treatment methods disclosed herein. Therapeutic activities include orders, instructions, and recommendations by a healthcare professional (e.g., a physician, physician's assistant, nurse practitioner, etc.) that are then carried out by any other person, including other healthcare professionals or the patient himself or herself. This includes, for example, instructing a patient to undergo or instructing a clinical laboratory to perform a diagnostic procedure, such as an imaging or pulmonary function assessment, so that the patient can ultimately receive an appropriate treatment that is beneficial. In some embodiments, the orders, instructions, and recommendations aspects of therapeutic activities can also include encouraging, inducing, or mandating the selection of a particular drug or combination thereof for the treatment of a condition, and the drug is actually used by being approved for coverage by an insurance company, by denying coverage for an alternative drug, including the drug being on a formulary of drugs or excluding an alternative drug from a formulary of drugs, or by providing a financial incentive for using the drug, as can be done by an insurance company or a pharmacy benefit management company, etc. In some embodiments, therapeutic activities can also include encouraging, inducing, or mandating the selection of a particular drug for the treatment of a disease - and the drug is actually used in accordance with policies or practice standards established by a hospital, clinic, health maintenance organization, medical practice, or group of physicians, etc. All such orders, instructions, and recommendations are considered to be conditional on compliance with the instructions for obtaining the benefits of the treatment. In some cases, the patient also receives a financial benefit for complying with such orders, instructions, or recommendations. In some cases, the healthcare professional also receives a financial benefit for complying with such orders, instructions, or recommendations.

[0079] Treatment efficacy or benefit for pulmonary fibrosis is typically assessed by changes in lung function, e.g., as determined by spirometry. Spirometry measures that can be used include forced vital capacity (FVC), forced expiratory volume in 1 second (FEVi), and diffusing capacity of the lungs for carbon monoxide (DLCO CO ). Other spirometry parameters that can be considered include FEVi / FVC ratio, percent of FVC observed to FVC predicted (FVC% predicted), and percent of FEVi observed to FEVi predicted (FEVi% predicted). The FVC predicted (in liters) is 5.76*height (in meters) - 0.026*age (in years) - 4.34, as published by the Association for Respiratory Technology and Physiology. The FEVi predicted (in liters) is 4.30*height (in meters) - 0.029*age (in years) - 2.49, as published by the Association for Respiratory Technology and Physiology.

[0080] Other assessments include:

[0081] i. appearance of the lungs - quantitative degree of fibrosis (including scarring or remodeling), as a percentage and / or volume, as determined by CT scan, magnetic resonance imaging (MRI), etc.;

[0082] ii. appearance of the lungs - qualitative degree of fibrosis: improved, same, or worse, as determined by CT scan, magnetic resonance imaging (MRI), etc.;

[0083] iii. number of respiratory hospitalizations;

[0084] iv. distance that can be walked in a set time interval, e.g., 6-minute walk distance; and

[0085] v. score on a respiratory health questionnaire, e.g., St. George's Respiratory Questionnaire, UCSD Respiratory Distress Questionnaire, etc.

[0086] Spirometry and other assessments can be performed periodically, e.g., about every 24 weeks, quarterly, semiannually, or annually.

[0087] Treatment efficacy or benefit can be observed as a reduction in disease progression, stabilization of disease, or improvement in the patient's condition. In some embodiments, the progression, stabilization, or improvement is judged by comparison to one or more prior measurements for that patient. In some embodiments, the prior measurement is a baseline measurement prior to the start of treatment. In some embodiments, the progression, stabilization, or improvement is judged based on comparison to actual or historical other patients who did not receive treatment, who received placebo, or who received an alternative treatment. Thus, in some embodiments, the improvement or stabilization is judged by comparison to what would be expected for an untreated patient. For example, in such embodiments, a reduction in scarring includes less of an increase in scarring than would be expected for an untreated patient. Thus, stabilization of lung function does not mean that one or another measure of lung function did not further decline, but rather that any decline did not exceed what would be expected with aging over the time interval under consideration.

[0088] Manufacturing method

[0089] Additional embodiments include methods of making the disclosed pharmaceutical compositions.

[0090] Low-solubility drugs are known in the pharmaceutical arts to often exhibit poor bioavailability or irregular absorption, the degree of irregularity being influenced by factors such as dose level, patient fed state, and drug form.

[0091] In general, it is known that use of water-soluble polymers as matrix materials can increase solubility. Examples of water-soluble polymers that have been employed include polyvinylpyrrolidone (PVP, povidone), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), sodium carboxymethylcellulose (NaCMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), block copolymers of ethylene oxide and propylene oxide (PEO / PPO), and polyethylene glycol (PEG).

[0092] Taladegib is a Biopharmaceutics Classification System (BCS) Class II (high permeability, low solubility) compound. Accordingly, to improve taladegib exposure and reproducibility in humans, HPMCAS spray-dried solid dispersions are disclosed herein.

[0093] For example, crystalline or amorphous forms of the disclosed embodiments can be prepared by one or more techniques such as spray drying, melt quenching, vapor condensation, melt spinning, sol-gel, etc. The disclosed embodiments provide compositions comprising spray-dried solid dispersions comprising a sparingly water-soluble drug (talampanel or L-4) and HPMCAS. In embodiments, it is preferred that the compositions be as amorphous as possible. The disclosed embodiments can include ratios of 80 / 20 amorphous to crystalline form, 85 / 15 amorphous to crystalline form, 90 / 10 amorphous to crystalline form, 95 / 5 amorphous to crystalline form, etc.

[0094] In preferred embodiments, the drug / HPMCAS spray-dried dispersion itself comprises sparingly soluble drug and HPMCAS.

[0095] Other components can be included in the dispersion if inert in the sense that they do not adversely affect the maximum supersaturation solubility concentration (MSSC) achievable by the dispersion in the environment of use. Components that affect the MSSC can also be included, provided that they do not substantially adversely affect (i.e., decrease) the MSSC, meaning that all such components in the dispersion decrease the MSSC by no more than 20% relative to the spray-dried dispersion without such components. Components that do not affect or actually improve the MSSC can be included in any amount. Typically, the amount of HPMCAS and drug in the dispersion (not counting any residual solvent) should be greater than 75% by weight.

[0096] Although the only essential ingredients present in the solid amorphous compositions of the present invention are the drug to be delivered and HPMCAS, it can be useful, and even preferred, to include other excipients in the dispersion.

[0097] For example, a polymer other than HPMCAS that is soluble in aqueous solution over at least a portion of the pH 1.0 to 8.0 range can be included in the dispersion along with the HPMCAS. For example, it has been found that amorphous dispersions of drugs and conventional matrix materials such as PVP, HPC or HPMC can be formed and then milled with HPMCAS to still have superior performance relative to the same dispersion without HPMCAS for some drugs. In this case, it is apparent that the HPMCAS can have the primary benefit of inhibiting precipitation or crystallization of the drug from the supersaturated solution regardless of whether the drug is crystalline or amorphous. Preferred embodiments of the present disclosure include dispersions in which the drug, HPMCAS and one or more other polymers are co-spray dried, with the drug and HPMCAS comprising no more than, for example, 50%, 60% or 75% of the dispersion.

[0098] In addition to drugs and HPMCAS, other conventional formulation excipients can be used in the compositions of the present application, including those well known in the art. Generally, excipients such as fillers, disintegrants, colorants, binders, lubricants, flavorants, glidants, and the like can be used for conventional purposes and in typical amounts that do not affect the properties of the composition. In embodiments, these excipients are used after the HPMCAS / drug dispersion is formed to formulate the dispersion into, for example, tablets or capsules.

[0099] As used herein, spray drying refers generally to a process that involves breaking a liquid mixture into small droplets (atomization) and rapidly removing solvent from the mixture in a vessel (a spray drying apparatus) in which there is a strong driving force for evaporation of the solvent from the droplets. The strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of the solvent in the spray drying apparatus well below the vapor pressure of the solvent at the temperature of the drying droplets. This is achieved by one of two ways:

[0100] i. maintaining the pressure in the spray drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm);

[0101] ii. mixing the droplets with a warm, dry gas; or

[0102] iii. both.

[0103] The solution from which the HPMCAS / drug dispersion is formed by spray drying can contain only the drug and HPMCAS in a solvent. Generally, the ratio of drug to HPMCAS in the solution ranges from 1 :0.2 to 1 : 100, with a preferred range of 1 :0.4 to 1 :20. For taladegib, the preferred ratio is 1 : 1 to 1 :4. However, when the drug dose is low (less than 20 mg), the ratio of drug to HPMCAS can even be higher than 20. Essentially, the solvent suitable for spray drying can be any organic compound in which the drug and HPMCAS are mutually soluble. Preferably, the solvent is also volatile, with a boiling point of 150°C or less.

[0104] Preferred solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, and butanol; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate and propyl acetate; and various other solvents such as acetonitrile, dichloromethane, toluene, and 1,1,1-trichloroethane. Low volatility solvents such as dimethylacetamide or dimethylsulfoxide can also be used. Mixtures of solvents can also be used, as can mixtures with water, as long as the polymer and HPMCAS are sufficiently dissolved for the spray drying process to be viable.

[0105] For the spray-dried embodiments, the temperature and flow rate of the drying gas are selected such that the HPMCAS / drug solution droplets are sufficiently dry by the time they reach the walls of the apparatus so that they are essentially solid, such that they form a fine powder without sticking to the walls of the apparatus.

[0106] After solidification, the solid powder can be held in the spray-drying chamber for 5 to 50 seconds to further evaporate solvent from the solid powder. The final solvent content of the solid dispersion as it exits the dryer should be low, as this reduces the mobility of the drug molecules in the dispersion, thereby increasing its stability. Additional drying steps can be required to further reduce the amount of residual solvent. Typically, the residual solvent content of the dispersion should be less than 2 w / w %, preferably less than 0.2 w / w %.

[0107] The spray-dried dispersions can then be post-processed using methods known in the art, such as roller compaction, fluidized bed agglomeration, or spray coating to prepare them for administration or for further processing.

[0108] The spray-dried solutions and resulting dispersions can also contain various additives that aid in the stability, dissolution, tabletting, or processing of the dispersions. Examples of such additives can include surfactants, pH controlling substances (e.g., acids, bases, buffers), fillers, disintegrants, glidants, or binders. Such additives can be added directly to the spray-dried solution, such that the additive dissolves or suspends in the solution to become a slurry. Alternatively, such additives can be added after the spray-drying process to aid in the formation of the final dosage form.

[0109] Due to the amorphous nature of the spray-dried dispersions, it is critical to protect the tablets from moisture to prevent degradation of the active. This can be improved upon by coating the tablets or capsules with known film coating materials such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, combinations thereof. In embodiments, the final oral dosage form will have to be stored in a low permeability container, for example, with a desiccant to further reduce the effects of moisture.

[0110] The disclosed embodiments can include a filler, such as lactose, HPMCAS, kaolin, powdered cellulose, precipitated calcium carbonate, sorbitol, mannitol, xylitol, microcrystalline cellulose, dicalcium phosphate, starch, combinations thereof, and the like. For example, in embodiments, the filler can comprise 5, 10, 20, 30, or 45% of the disclosed formulation.

[0111] The disclosed embodiments can include a disintegrant, such as sodium starch glycolate, sodium alginate, alginic acid, amberlite, methylcellulose, croscarmellose sodium, combinations thereof, and the like. For example, in embodiments, the disintegrant can comprise 1, 5, 10, or 15% of the disclosed formulation.

[0112] The disclosed embodiments can include a glidant, such as colloidal silicon dioxide, cornstarch, talc, combinations thereof, and the like. For example, in embodiments, the glidant can comprise 0.5, 1, 5, or 10 of the disclosed formulations.

[0113] The disclosed embodiments can include a lubricant, such as magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, zinc stearate, combinations thereof, and the like. For example, in embodiments, the lubricant can comprise 1, 5, 10, or 15% of the disclosed formulations.

[0114] The disclosed embodiments can include a film coating, such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, combinations thereof, and the like.

[0115] The disclosed embodiments can include a binder, such as acacia, alginic acid, methylcellulose, sodium carboxymethylcellulose, compressible sugar (Nu-Tab), microcrystalline cellulose, ethylcellulose, gelatin, povidone, starch, and gums such as guar, tragacanth, combinations thereof, and the like. For example, in embodiments, the binder can comprise 5, 10, 15, 20, 25, 30, or 35% of the disclosed formulations.

[0116] The disclosed embodiments can include a flavoring agent, such as arabian gum syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, combinations thereof, and the like. For example, in embodiments, the flavoring agent can comprise 1, 5, 10, or 15% of the disclosed formulations.

[0117] Commercial products / kit

[0118] According to further embodiments, the disclosed compositions can also be provided in the form of kits in combination with other components required for the administration of the material to a patient.

[0119] Kits are designed in various forms based on the particular deficiency for which they are designed to treat.

[0120] Examples

[0121] The following non-limiting examples are provided for illustrative purposes only, in order to facilitate a more complete understanding of the representative embodiments presently contemplated. These examples should not be construed as limiting any of the embodiments described in this specification.

[0122] Example 1

[0123] In vitro pharmacology of taladegib

[0124] Using an in vitro competitive binding assay, the half maximal inhibitory concentration (IC 50 ) and binding constant (Ki ) was calculated based on competitive displacement of radioligand. Taladegib binds to the hSMO receptor and inhibits 3 H-2406189 (a known hSMO agonist) binds to hSMO with a K i of 76.4 ± 75.3 nM and an IC 50 of 144 ± 143 nM (n = 4, geometric mean ± standard error [SE]).

[0125] To determine the biological activity of taladegib in mouse cells, Gli-luciferase activity was quantified in the mouse mesenchymal C3H10T1 / 2 cell line stimulated with sonic hedgehog conditioned media (SHh-CMs). Taladegib hydrochloride inhibited Hh signaling activity in mouse C3H10T1 / 2 cells with an IC 50 of 11.2 ± 5.33 nM (n = 8, geometric mean ± SE). To determine the biological activity of taladegib in human cells, Gli1 transcript levels were quantified in the human Daoy tumor cell line stimulated with SHh-CMs. Taladegib hydrochloride inhibited Hh signaling activity in human Daoy cells with an IC 50 of 2.22 ± 1.14 nM as determined by measuring Gli1 mRNA using branched DNA assay technology (n = 8, geometric mean ± SE).

[0126] Example 2

[0127] In vivo pharmacology of taladegib

[0128] To understand the PK / PD effects and guide the dosing regimen for efficacy studies, surrogate tissues (lungs, skin, and cerebellum) from Balb / C mice and tumors from Ptch - / + xp53 - / - Key PK / PD studies involving dose response and time course were performed following single oral administration of taladegib in the Balb / c surrogate and Ptch - / + xp53 - / - genetic tumor model, and tumors were harvested, processed, and analyzed using quantitative reverse-transcription polymerase chain reaction Gli1 expression levels were assessed. As summarized in Table 1, taladegib inhibited Hh signaling as measured by mouse Gli1 expression levels in the tissues assessed. A time course study indicated that sustained target inhibition can be maintained for at least 24 hours following a single oral dosing of 8 mg / kg taladegib hydrochloride. Given the parallel PD effect, skin Gli1 is an appropriate PD surrogate for lung tissue Gli1.

[0129] Table 1. TED of taladegib hydrochloride in a mouse pharmacodynamic model 50 and TEC 50 Summary Table

[0130]

[0131] Abbreviations: SE = standard error; TEC50= threshold effective concentration; TED50= threshold effective dose; Tg = transgenic.

[0132] Example 3

[0133] SMO inhibitors improve FVC in IPF patients

[0134] Various clinical trial results for IPF treatment were compared Figure 1 ). The anti-inflammatory drug pirfenidone and the kinase inhibitor nintedanib only slowed the worsening of FVC, while the SMO inhibitor vismodegib (in combination with pirfenidone) was able to produce a significant increase in FVC, indicating a pathological reversal. Autotaxin zirtaxestat (also known as GLPG1690) resulted in a slight increase in FVC in a phase lb trial, however its development was abandoned during phase 3 trials due to a risk-benefit profile that no longer supported its use in an Independent Data Monitoring Committee assessment. All development of zirtaxestat was discontinued. Vismodegib development for IPF treatment was also discontinued due to severe muscle spasms, however these data validated the use of Hh inhibitors in IPF treatment.

[0135] Example 4

[0136] Lower doses of taladegib reduce the severity of muscle spasm adverse events, but maintain

[0137] Degree of Gli1 inhibition

[0138] Taladegib was administered to subjects at doses of 50 mg, 100 mg, 200 mg, 400 mg, and 600 mg. At these doses, the majority of patients exhibited >80% Gli inhibition as measured in skin biopsies Figure 2). While some grade 3 toxicities occurred at 400 mg / day, none occurred at 200 mg / day or 100 mg / day (Table 2). Given that the minimum biological effective dose (BED) was defined in this study as the first dose level with >50% mGli1 inhibition, it can be concluded that taladegib was pharmacologically active at all dose levels tested.

[0139] Table 2. Dose - muscle spasm AE relationship

[0140]

[0141] AE data collected from multiple clinical trials, including a phase lb trial with etoposide and carboplatin. Dose levels with less than 10 patients were excluded due to insufficient efficacy.

[0142] T Taladegib

[0143] V Vismodegib

[0144] Example 5

[0145] Comparison of major AEs of drugs tested for IPF treatment

[0146] Taladegib, vismodegib, pirfenidone, and nintedanib have all been used in clinical trials and have been used to treat IPF or were evaluated for use in treating IPF. With the exception of taladegib, >20% of patients discontinued treatment due to drug-related reasons Figure 3 ). The leading cause of discontinuation was muscle spasm with vismodegib, nausea with pirfenidone, and diarrhea with nintedanib. Taladegib had no prevalent AEs and <10% of patients discontinued treatment due to drug-related reasons when the dose was <200 mg / day.

[0147] Example 6

[0148] Reduction of myofibroblasts in a bleomycin-induced pulmonary fibrosis model

[0149] The bleomycin (BLM)-induced pulmonary fibrosis model is a standard IPF model widely used in pharmacology and basic research. IPF disease is defined as a progressive and irreversible damage localized to the lungs. In IPF patients, loss of lung function is driven by the infiltration and expansion of activated myofibroblasts. The use of Intratracheal administration of bleomycin was performed with a nebulizer. The animals were anesthetized with isoflurane and the nebulizer was connected to the trachea with a catheter. The bleomycin solution was nebulized for 30 min at a flow rate of 0.1 mL / min. The nebulizer administration of bleomycin allows for uniform exposure of the lung and thus reproducible and uniform pathology to develop. In this model, the presence of myofibroblasts was observed by immunohistochemistry when stained for anti-alpha-smooth muscle actin (a-SMA) antibody.

[0150] Animals were exposed to bleomycin and then treated with talabostat on day 7 when fibrosis was present. Animals were examined for pathology on day 21 of the study. Treatment with talabostat at 5 mg / kg orally daily resulted in a reduction of a-SMA protein expression of about 40% indicating a reduction of myofibroblasts Figures 4A-4B ).

[0151] Example 7

[0152] Phase 2 multicenter study to evaluate the safety and efficacy of taladegib in subjects with IPF

[0153] Patients diagnosed with IPF according to the American Thoracic Association, Japanese Respiratory Society, European Respiratory Society, Latin American Thoracic Association guidelines and confirmed by high resolution computed tomography (HRCT) with predicted FVC% > 50% and predicted DLCO% between 35% and 85% were randomly assigned to talabostat and placebo groups. Baseline results from pulmonary function tests (FVC, FEV1 and DL CO ), HRCT and UCSD shortness of breath (SOB) questionnaire were obtained. Talabostat was administered daily for 12 weeks starting at 200 mg / day. Patients were observed for an additional 6 weeks after the pre-scheduled completion of treatment. The dose could be reduced to 100 mg / day if drug related adverse events were experienced. Pulmonary function tests and UCSD SOB questionnaire were repeated at weeks 6, 12 and 18 of the study. HRCT was repeated at week 12. FVC, FEV1, FEV1 / FVC ratio, predicted FVC%, predicted FEV1% and DL COand efficacy in the UCSD SOB questionnaire. Quantitative (% and mL) and qualitative (improved, same, worse) assessments of pulmonary fibrosis by HRCT will be performed at screening and at Week 12. HRCT at screening will serve as the baseline for study HRCT assessments. At Week 12, no or limited dose-limiting toxicities are observed. At Week 12, some efficacy endpoints indicate stabilization or improvement. At Week 18, the durability of response is observed. Patients do not experience serious drug-related adverse events (if any, after adequate dose tapering), including no muscle spasms.

[0154] Example 8

[0155] Covid-19 therapy clinical trial

[0156] SARS-CoV-2 infected patients who have recovered showing pulmonary fibrosis by CT scan are randomized to treatment with standard of care or talabinavir monotherapy. Talabinavir is administered at 200 mg daily. If a drug-related adverse event is experienced, the dose can be reduced in steps of 100 mg to reduce or eliminate the adverse event. Pharmacokinetic data are collected. The primary efficacy endpoint is change in FVC from baseline at 24 weeks. Secondary efficacy endpoints are change in pulmonary fibrosis from baseline CT scan, change in 6-minute walk distance from baseline, number of adjudicated respiratory hospitalizations, and change in St. George’s Respiratory Questionnaire from baseline. At Week 24, some efficacy endpoints indicate stabilization or improvement. Patients do not experience serious drug-related adverse events (if any, after adequate dose tapering), including no muscle spasms.

[0157] Example 9

[0158] Drug manufacturing

[0159] The solution of the low-solubility drug and HPMCAS in acetone is spray dried by spraying the solution at a temperature of 50-70 °C (acetone has a vapor pressure of about 0.8 atm at 50 °C) into a chamber maintained at a total pressure of 0.01 to 0.2 atm by connecting the outlet to a vacuum pump. Alternatively, the acetone solution can be sprayed into a chamber in which the acetone solution is mixed with nitrogen or other inert gas at a temperature of 110-150 °C and a pressure of 1.0-1.2 atm.

[0160] The spray-dried composition is then mixed with fillers, disintegrants, pigments, binders, lubricants, flavoring agents, flow aids, etc., to formulate the dispersion into, for example, tablets or capsules. Tablets or capsules may be made from materials such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, or... The material coating.

[0161] Example 10

[0162] Drug manufacturing

[0163] The formulation containing 16.1% taradiene, 37.6% HPMCAS-H, 9.3% mannitol, 28.6% microcrystalline cellulose, 2.9% croscarmellose sodium, 1.0% silica, 1.2% sodium stearate fumarate, and 3.4% [unclear text - possibly a typo, should be "3.4%"] was prepared using the method of Example 9. Tablets.

[0164] Example 11

[0165] Drug manufacturing

[0166] The preparation method of Example 9 was used to formulate an ingredient comprising 20% ​​L-4, 37.6% HPMCAS-H, 9.3% mannitol, 24.7% microcrystalline cellulose, 2.9% croscarmellose sodium, 1.0% silica, 1.2% sodium stearate fumarate, and 3.4%... Tablets.

[0167] Finally, it should be understood that although various aspects of this specification have been highlighted with reference to specific embodiments, those skilled in the art will readily understand that these disclosed embodiments merely illustrate the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is by no means limited to the specific methods, schemes, and / or reagents described herein. Thus, various modifications, alterations, or alternative configurations can be made to the disclosed subject matter based on the teachings herein without departing from the spirit of this specification. Finally, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which is defined only by the claims. Therefore, the invention is not limited to those precisely shown and described.

[0168] This document describes certain embodiments of the invention, including the best mode known to the inventors for carrying out the invention. Of course, variations of these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors encourage those skilled in the art to appropriately employ such variations, and the inventors intend to practice the invention in ways different from those specifically described herein. Therefore, the invention includes all modifications and equivalents of the subject matter described in the appended claims as permitted by applicable law. Furthermore, unless otherwise stated herein or clearly contradicted by the context, the invention covers any combination of all possible variations of the above embodiments.

[0169] The grouping of alternative embodiments, elements, or steps of the invention should not be construed as limiting. Each member of a group may be mentioned and claimed individually or in any combination with other members of the groups disclosed herein. It is contemplated that one or more members of a group may be included in or removed from the group for convenience and / or patentability reasons. When any such inclusion or removal occurs, this specification is deemed to include the modified group to satisfy the written description of all Markush groups as used in the appended claims.

[0170] Unless otherwise stated, all figures used in this specification and claims to represent features, items, quantities, parameters, properties, terms, etc., should be understood to be modified by the term "about" in all cases. As used herein, the term "about" means that the feature, item, quantity, parameter, property, or period so defined includes a range of ±10% above and below the value of said feature, item, quantity, parameter, property, or period. Therefore, unless indicated to the contrary, the numerical parameters listed in the specification and appended claims are approximate values ​​that may vary. In any case, no attempt is made to limit the application of the principle of equivalents to the scope of the claims, and each numerical indication should be interpreted at least according to the number of significant digits reported and by applying ordinary rounding techniques. Although the numerical ranges and values ​​that illustrate the broad scope of the invention are approximate, the numerical ranges and values ​​listed in the specific embodiments are reported as precisely as possible. However, any numerical range or value inherently contains some error that is necessarily caused by the standard deviation present in their respective test measurements. The description of numerical ranges herein is intended only as a shorthand method for referring to each individual value falling within that range. Unless otherwise stated herein, each individual value of the numerical range is incorporated into this specification as if it were cited separately herein.

[0171] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the application (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the application and does not pose a limitation on the scope of the application unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the application.

[0172] The particular implementations of the application disclosed herein can be further limited, in the claims using the terms "comprising" or "consisting of." When used in the claims, the transitional terms "comprising" and "consisting of" are open-ended transitional terms intended to cover the elements listed following such transitional term, as well as any other item or groups of items not specifically recited. The transitional term "consisting essentially of" limits the scope of a claim to the elements specified in the claim and to other elements that do not materially affect the basic and novel characteristic(s) of the claimed application. Embodiments of the application so claimed are inherently or expressly described and enabled herein.

[0173] All patents, patent publications, and other publications referenced and identified in this specification are individually and expressly incorporated herein by reference for the purpose of describing and disclosing the compositions and methodologies described in such publications that might be used in connection with the present application. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as a representation or admission that the inventors are not entitled to antedate such disclosures or are specifically Adams of same in view of the requirements of 35 U.S.C. § 102. The dates of the publications provided in this regard are believed to be accurate but are not admitted to be true on the basis of independent verification.

Claims

1. A method of formulating a dry pharmaceutical composition comprising an active agent having low aqueous solubility, the method comprising mixing the active agent with a polymer to form a solution or a homogeneous mixture, and drying the mixture to obtain a solid or a finely divided solid.

2. The method of claim 1, wherein the drying comprises spray drying, melt quenching, vapor condensation, or melt spinning.

3. The method of claim 2, wherein the drying comprises spray drying.

4. The method of claim 3, wherein the polymer comprises at least one of polyvinylpyrrolidone (PVP, povidone), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), sodium carboxymethylcellulose (NaCMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), block copolymers of ethylene oxide and propylene oxide (PEO / PPO), and polyethylene glycol (PEG).

5. The method of claim 4, wherein the dry pharmaceutical composition is at least 80% amorphous.

6. The method of claim 5, wherein the dry pharmaceutical composition is at least 90% amorphous.

7. The method of claim 6, wherein the dry pharmaceutical composition is at least 95% amorphous.

8. The method of claim 5, wherein the active agent comprises a Gli1 inhibitor.

9. The method of claim 8, wherein the Gli1 inhibitor comprises a compound of Formula I: wherein, R 1 is hydrogen or methyl; R 2 is hydrogen or methyl; R 3 , R 4 , R 5 , R 6 or R 7 is independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, or trifluoromethylsulfonyl, provided that at least three of R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen; or a pharmaceutically acceptable salt thereof.

10. The method of claim 8, wherein the Gli1 inhibitor comprises a compound of Formula II: wherein R 1 is hydrogen or methyl; R 2 is hydrogen or methyl; R 3 , R 4 , R 5 , R 6 or R 7 is independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, or trifluoromethylsulfonyl, provided that at least three of R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen; or a pharmaceutically acceptable salt thereof.

11. The method of claim 9, wherein the Gli1 inhibitor is a compound of Formula I, and R 1 is methyl, R 2 is methyl, R 3 is trifluoromethyl, R 4 is H, R 5 is fluoro, R 6 is H, and R 7 is H.

12. The method of claim 10, wherein the Gli1 inhibitor of Formula II is L-4.

13. The method of claim 11, wherein the dry pharmaceutical composition comprises 14.5-17.7% taladegib.

14. The method of claim 13, wherein the dry pharmaceutical composition comprises 14.5-17.7% taladegib and 33.9-41.4% HPMCAS-H.

15. The method of claim 14, wherein the dry pharmaceutical composition comprises 14.5-17.7% taladegib, 33.9-41.4% HPMCAS-H, and 8.4-10.2% mannitol.

16. The method of claim 15, wherein the dry pharmaceutical composition comprises 14.5-17.7% taladegib, 33.9-41.4% HPMCAS-H, 8.4-10.2% mannitol, 25.7-31.5% microcrystalline cellulose, and 2.6-3.2% croscarmellose sodium.

17. The method of claim 16, wherein the dry pharmaceutical composition comprises 14.5-17.7% taladegib, 33.9-41.4% HPMCAS-H, 8.4-10.2% mannitol, 25.7-31.5% microcrystalline cellulose, 2.6-3.2% croscarmellose sodium, and 0.9-1.1% silicon dioxide.

18. The method of claim 17, wherein the dry drug composition comprises 14.5-17.7% taladegib, 33.9-41.4% HPMCAS-H, 8.4-10.2% mannitol, and 25.7-31.5% microcrystalline cellulose, 2.6-3.2% croscarmellose sodium, 0.9-1.1% silicon dioxide, and 1.1-1.3% sodium stearyl fumarate.

19. The method of claim 18, wherein the dry pharmaceutical composition comprises 14.5-17.7% taladegib, 33.9-41.4% HPMCAS-H, 8.4-10.2% mannitol, 25.7-31.5% microcrystalline cellulose, 2.6-3.2% croscarmellose sodium, 0.9-1.1% silicon dioxide, 1.1-1.3% sodium stearyl fumarate, and 3.1-3.7% magnesium stearate.

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