Classifications

• • 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
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• • 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
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• fibrotic diseases have proved challenging. Although there are approved drugs of the treatment of some fibrotic diseases, such as pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF). However, these drugs only modestly slow progression of the disease, but do not stop or reverse it.
• IPF idiopathic pulmonary fibrosis
• Hedgehog/GLI signaling pathway is an important regulator of normal embryonic development and had been implicated in the development of fibrosis as well.
• One aspect is a method of treating fibrosis comprising administering an inhibitor of Gli1.
• Inhibition of Gli1 can be indirect.
• an inhibitor of SMO is used to indirectly inhibit Gli1.
• One aspect is a method of treating fibrosis comprising administering means for inhibiting Gli1.
• Inhibition of Gli1 can be indirect.
• means for inhibiting SMO are used to indirectly inhibit Gli1.
• one or another genus or species of SMO inhibitor is specifically excluded.
• the inhibitor of G li 1 or the means for inhibiting Gli1 is an inhibitor of SMO (or means for inhibiting SMO).
• the inhibitor of SMO, the inhibitor of Gli1 , or the means for inhibiting Gli1 or SMO is 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 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; or a pharmaceutically acceptable salt thereof.
• the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
• a methylsulfonyl substituent is equivalent to CH3-SO2-.
• the compound of Formula I is 4-Fluoro-N-methyl-N-(1-(4-(1-methyl-1 H-pyrazol-5- yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide (CAS 1258861-20-9): also known as taladegib.
• the inhibitor of SMO, the inhibitor of Gli 1 , or the means for inhibiting G li 1 or SMO is 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 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; or a pharmaceutically acceptable salt thereof.
• the compound of Formula II is compound L-4, having the structure
• the inhibitor of G li 1 or the means for inhibiting Gli 1 is administered to a patient in need thereof, that is, a patient having a fibrotic disease.
• the fibrotic disease is idiopathic pulmonary fibrosis (IPF).
• the fibrotic disease is pulmonary fibrosis following infection, including a bacterial or viral infection.
• the fibrosis develops after years-long chronic infections so that the role of the infection in causing the fibrosis cannot be conclusively demonstrated; such fibrosis is therefore still classified as idiopathic.
• Covid-19 provides a counterpoint, in that onset of fibrosis can be very rapid.
• the pulmonary fibrosis follows infection with SARS-CoV-2.
• the fibrotic disease is scleroderma.
• the fibrotic disease is systemic scleroderma (also known as systemic sclerosis) and in further instances, systemic scleroderma involving the lung.
• the fibrotic disease is liver fibrosis, such as in non-alcoholic steatohepatitis (NASH).
• the fibrotic disease is kidney fibrosis.
• the fibrotic disease is gastric fibrosis.
• the patient is a human.
• the inhibitor of G li 1 or the means for inhibiting Gli1 is administered in an effective amount.
• the effective amount is effective for reducing symptoms.
• the effective amount is effective for slowing or halting progression of the disease.
• the effective amount is effective for reducing impairment due to the disease.
• the effective amount is effective for reversing impairment due to the disease (causing improvement).
• impairment can be measured as changes in lung function, for example, as determined by spirometry.
• the effective amount comprises 50-200 mg of the inhibitor of Gli 1 or the means for inhibiting Gli1.
• One aspect is a pharmaceutical compound comprising the inhibitor of Gli1 or the means for inhibiting Gli 1 .
• the inhibitor of Gli 1 orthe means for inhibiting Gli1 is a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
• the compound of Formula 1 is taladegib.
• Figuere 1 depicts a comparison of clinical trial results for four IPF treatments: 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 mean of three phase 3 studies at 24 weeks.
• the nintedanib data is the mean of two phase 3 studies at 24 weeks.
• the GLPG1690 data is phase 1b data at 12 weeks.
• the Hh inhibitor (vismodegib) data is phase 1 b data as 24 weeks.
• Figure 2 depicts Gli1 mRNA inhibition (%) in skin samples from patients receiving various doses of taladegib.
• Figure 3 depicts the rate of drug-related discontinuations in clinical trials for four drugs considered for IPF treatment.
• Figures 4A-B portray a-SMA protein levels with and without taladegib treatment in a bleomycin-induced pulmonary fibrosis model.
• Figure 4A presents representative images of anti-a-SMA immunostained lung sections from sham control, vehicle-treated, and taldegib- treated mice.
• Figure 4B depicts the percent a-SMA positive area from the individual mice and the mean and standard deviation for the treatment groups.
• fibrotic disease has been understood to involve an initial tissue insult causing an upregulation of hedgehog, driving transdifferentiation of cells into myofibroblasts (that is, the conversion of differentiated cells (non-stem cells) into another type of differentiated cell, in this case myofibroblasts).
• myofibroblasts that is, the conversion of differentiated cells (non-stem cells) into another type of differentiated cell, in this case myofibroblasts.
• the physiologic function of myofibroblasts is to repair tissue by depositing extracellular matrix and contracting tissue, as in wound closing.
• Fibrotic diseases, including IPF arise from dysregulated wound remodeling involving chronic matrix deposition and tissue contraction long after initial tissue trauma has been resolved.
• the herein disclosed methods and compositions treat fibrotic disease by inhibiting the Hh signaling pathway so that upregulated hedgehog can no longer drive this pathology, blocking the generation of myofibroblasts and stopping the chronic remodeling that causes fibrosis. Although this mechanism has been clinically validated, the promise of Hh pathway inhibitors to treat fibrosis has so far not been realized. [0016] It is disclosed herein that certain 1 ,4-disubstituted phthalizines that are potent inhibitors of SMO and the downstream transcription factors Gli 1 and Gli2, and that exhibit a desirable toxicology profile, fulfill this promise.
• the present embodiments provide methods of treatment using compounds 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 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; or a pharmaceutically acceptable salt thereof.
• the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
• a methylsulfonyl substituent is equivalent to CH3-SO2-.
• “Pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic salts of compounds of the present invention.
• the present embodiments also provide a pharmaceutical composition
• 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.
• a pharmaceutically acceptable carrier, diluent, or excipient is a medium generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans.
• a paradigmatic 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): also known as taladegib.
• Taladegib also referred to as LY2940680
• LY2940680 is a potent, selective, and orally available Smo inhibitor with a favorable safety profile, capable of disrupting the Hh pathway.
• This molecule has been in over 192 human subjects and developed initially with the intention of treating oncologic indications with a focus on lung cancer and basal cell carcinoma (BCC). Although primarily cancer patients, these studies allowed for a preliminary understanding of dose and tolerability.
• Taladegib is orally bioavailable. In some embodiments, the mean oral bioavailability is from about 72% to about 91%.
• M75 The major metabolite of taladegib, M75, an oxidative N-desmethylation product, retains activity as an inhibitor of SMO. M75 is understood to have lost the methyl group at R 2 of Formula I, so that position is hydrogen instead of methyl.
• Taladegib is well-suited to target the lung compared to vismodegib. In animal models, taladegib is greater than 20-fold more potent than vismodegib at inhibiting Gli 1 in the lungs, a downstream effector molecule that is expressed when the Hh pathway is activated.
• the clinically established MTD for taladegib is 400 mg. At this dose, Gli1 mRNA inhibition is >85% in skin with a discontinuation of approximately 9%.
• Taladegib has been evaluated clinically at a dose as low as 50mg (i.e., 8-fold lowerthan the clinically established MTD) where inhibition of Gli1 mRNA was still greater than 80%.
• vismodegib inhibits Gli1 mRNA less than 50% at its MTD of 150mg.
• Taladegib has a better clinical safety profile than vismodegib, with substantially lower occurrence of muscle spasms (40% versus up to 80%).
• vismodegib proved unsuitable for IPF, clinical studies with vismodegib indicated inhibition of the Hh pathway can improve lung function in IPF patients.
• Compounds of Formula I inhibit Gli1 activity, generally with an IC 5 o of ⁇ 40 nM, as measured in Daoy cells and described in U.S. Patent No. 9,000,023.
• Taladegib has an IC 5 o of about 2.4 nM in this assay.
• Such compounds constitute means for inhibiting Gli1 activity or means for inhibiting SMO.
• the inhibitor of SMO, the inhibitor of Gli1 , or the means for inhibiting Gli 1 or SMO is 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 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; or a pharmaceutically acceptable salt thereof.
• the compound of Formula II is N-(1-(4,5-dimethyl-6-(1-methyl-1 H-pyrazol-5- yl)pyridazin-3-yl)piperidin-4-yl)-4-fluoro-2-(trifluoromethyl)benzamide, having the structure also known as L-4.
• 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), which is hereby incorporated by reference in its entirety.
• Zhu et al. describe L-4 as a promising anti-cancer agent. It is reported to have a similar ID 5 o for Hh inhibition as taladegib, 2.33 nM versus 2.26 nM, respectively.
• L-4 and compounds of Formula II constitute means for means for inhibiting Gli1 activity or means for inhibiting SMO.
• Various embodiments specifically exclude compounds of Formula I, compounds of Formula II, or particular sub-genera or species of Formula I or Formula II.
• the compounds of the present invention are capable of reaction, for example, with a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts.
• pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2002); S. M. Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol 66, No. 1 , January 1977.
• compositions can be formulated as pharmaceutical compositions using a pharmaceutically acceptable carrier, diluent, or excipient and administered by a variety of routes.
• such compositions are 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., 19.sup.th ed., Mack Publishing Co., 1995).
• the herein disclosed compounds of can be formulated as tablets containing 50 or 100 mg of the compound and the common pharmaceutical ingredients: croscarmellose sodium, HPMCAS-H, mannitol, microcrystalline cellulose, silicon dioxide, and sodium stearyl fumarate.
• One particular embodiment contains 16.1% taladegib, 37.6% HPMCAS-H, 9.3% mannitol, 28.6% microcrystalline cellulose, 2.9% croscarmellose sodium, 1.0% silicon dioxide, 1.2 % sodium stearyl fumarate, and 3.4% Opadry (Film Coating).
• IPF is a dysregulated wound healing process causing progressive fibrotic lung scarring.
• Targeting the Hedgehog pathway is a logical therapeutic approach to slow, halt or reverse progression of the disease.
• the Hh pathway regulates the activation of fibroblasts and transdifferentiation into myofibroblasts which when dysregulated become key drivers of fibrosis.
• myofibroblasts infiltrate the lung where they produce extracellular matrix proteins such as collagen. The myofibroblasts adhere to the extracellular matrix and pull the lung closed similar to pulling a wound closed. The result of the myofibroblast activity is progressive loss of lung function through fibrosis and tissue remodeling.
• Gli1 mRNA inhibition in skin biopsies has been measured as a surrogate for G li 1 mRNA inhibition in lungs in clinical studies of lung cancer.
• Nonclinical in vivo models demonstrated that the kinetics and magnitude of Gli1 mRNA inhibition by orally administered taladegib were very similar in the skin and lungs of mice.
• the extent of G li 1 mRNA inhibition in the skin and lungs of mice was similar to the extent of Gli 1 mRNA inhibition observed in the skin biopsies of human subjects being treated with clinically relevant doses.
• IPF patient samples have shown increased levels of Hh pathway components and myofibroblasts.
• SHh the activating ligand of the Hh pathway
• Gli1 the activating ligand of the Hh pathway
• Normal lungs did not present with any detectable amount of either SHh or Gli 1 , but IPF samples stained very strongly indicating a significant presence.
• IPF lung samples also stained very strongly for a-Smooth Muscle Actin 1 (a-SMA1) which is a marker that defines myofibroblasts. Normal healthy lung samples had little to no staining of a-SMA1 .
• a-SMA1 a-Smooth Muscle Actin 1
• Hh pathway disruption to inhibit fibrosis has been demonstrated in vitro and in a number of animal models using several Smo inhibitors. These animal models have similar features that capitulate fibroblast infiltration and transdifferentiation into myofibroblasts that then drive progressive fibrosis. Inhibition of Smo was observed to disrupt fibrosis and in some cases reverse the disease. Additionally, it has been demonstrated that inhibition of Smo resulted in increased apoptosis of infiltrated myofibroblasts, reduction of a-SMA1 , reduction of Gli1 and SHh, and reduction of collagen.
• Nonclinical toxicity findings for taladegib are similar to approved drugs in this class, with the important potential risks associated with on target effects of taladegib considered to be hepatic injury, effects on the reproductive organs, rhabdomyolysis, reproductive toxicity and bone effects. Class effects not yet observed with taladegib, clinically or nonclinically, include amenorrhea.
• Taladegib has demonstrated a favorable safety profile in 6 industry-sponsored studies that have been conducted, primarily in advanced cancer patients.
• AEs adverse events
• Therapeutic window is the dose range from the lowest dose that exhibits a detectable therapeutic effect up to the maximum tolerated dose (MTD); the highest dose that will the desired therapeutic effect without producing unacceptable toxicity.
• Most typically therapeutic index is calculated as the ratio of LD 5 o:ED 5 o when based on animal studies and TD 5 o:EDso when based on studies in humans (though this calculation could also be derived from animal studies and is sometime called the protective index), where LD 5 o, TD 5 o, and ED 5 o are the doses that are lethal, toxic, and effective in 50% of the tested population, respectively.
• the toxicity is an observable toxicity, a substantial toxicity, a severe toxicity, or an acceptable toxicity, or a dose-limiting toxicity (such as but not limited to a MTD).
• an observable toxicity it is meant that while a change is observed the effect is negligible or mild.
• substantial toxicity it is meant that there is a negative impact on the patient’s overall health or quality of life. In some instances a substantial toxicity may be mitigated or resolved with other ongoing medical intervention.
• a severe toxicity it is meant that the effect requires acute medical intervention and/or dose reduction or suspension of treatment. The acceptability of the toxicity will be influenced by the particular disease being treated and its severity and the availability of mitigating medical intervention.
• Toxicities and adverse events are sometimes graded according to a 5 point scale.
• a grade 1 or mild toxicity is asymptomatic or induces only mild symptoms; may be characterized by clinical or diagnostic observations only; and intervention is not indicated.
• a grade 2 or moderate toxicity may impair activities of daily living (such as preparing meals, shopping, managing money, using the telephone, etc.) but only minimal, local, or non-invasive interventions are indicated.
• Grade 3 toxicities are medically significant but not immediately lifethreatening; hospitalization or prolongation of hospitalization is indicated; activities of daily living related to self-care (such as bathing, dressing and undressing, feeding oneself, using the toilet, taking medications, and not being bedridden) may be impaired.
• Grade 4 toxicities are life-threatening and urgent intervention is indicated.
• Grade 5 toxicity produces an adverse event-related death.
• use of a drug in the herein disclosed regimen or dosage reduces the grade of a toxicity associated with treatment by at least one grade as compared to use of that drug according to another regimen.
• a toxicity is confined to grade 2 or less, grade 1 or less, or produces no observation of the toxicity.
• a therapeutic index of a herein disclosed inhibitor of Gli1 or SMO is greater than that of vismodegib (approximately 0.37). In comparison, the therapeutic of taladegib is approximately 8.
• a therapeutic index of a herein disclosed inhibitor of Gli 1 or SMO is greater than 1 , 2, 3, 4, 5, 6, or 7.
• aspects of the present specification provide, in part, administering an effective amount (or therapeutically effective amount) of a compound ora composition disclosed herein.
• an effective amount or therapeutically effective amount
• the term “effective amount” is synonymous with “effective dose” and when used in reference to treating IPF means at least the minimum dose of a compound or composition disclosed herein necessary to achieve the desired therapeutic effect.
• an effective dosage or amount of a compound or a composition disclosed herein can readily be determined by the person of ordinary skill in the art considering all criteria (for example, the rate of excretion of the compound or composition used, the pharmacodynamics of the compound or composition used, the nature of the other compounds to be included in the composition, the particular route of administration, the particular characteristics, history and risk factors of the individual, such as, e.g., age, weight, general health and the like, the response of the individual to the treatment, or any combination thereof) and utilizing his best judgment on the individual’s behalf, especially in light of the exemplary dosages and other information disclosed herein.
• an effective dose is 25, 50, 75, 100, 150, 200, 250, 300, 350, or 400 mg, or falls in a range bound by any pair of the preceding values.
• the effective dose is administered once a day.
• the dosage of taladegib, L-4, or related compounds is begun at 200 mg/day.
• the dosage is provided in a single daily dose. If grade 3 or higher AEs are observed, dosing is stepped down. In some embodiments, the dosage is stepped down in decrements of 50 mg/day as needed to avoid grade 3 or higher AEs, to as little as 50 mg/day.
• an initial dosage (before step-down) can be any dosage higher than the lowest dosage deemed an effective dose. In some embodiments, the initial dosage in is the top half of the effective dose range. In some embodiments, the initial dosage is at the top of the effective dose range.
• an initial dose could be >50 mg (e.g., 75 mg), 125-200 mg, or 200 mg.
• the initial dosage is in a range of 100-300 mg/day.
• the stepdown in dosage is 25, 50, or 100 mg/day.
• an effective dose of the inhibitor of Gli1 or SMO, or means for inhibiting Gli1 or SMO results in stabilization or improvement of fibrosis, such as with respect to the physical extent of fibrosis, lung function, or other measure as described herein.
• the stabilization or improvement of fibrosis is achieved without the patient experiencing drug-related adverse events (toxicities).
• the avoided drug-related adverse events are grade 3 or higher toxicities.
• the absent drug-related adverse events are muscle spasms, QT elongation or a liver toxicity.
• Various aspects are methods of treating fibrosis by administering an inhibitor of G I i 1 or SMO, or means for inhibiting Gli1 or SMO, to a patient in need thereof, that is, a patient having a fibrotic disease.
• the inhibitor of G li 1 or SMO, or means for inhibiting Gli1 or SMO is used as monotherapy.
• the inhibitor of Gli 1 or SMO, or means for inhibiting Gli1 or SMO is used in combination with another anti-fibrosis drug.
• the other anti-fibrosis drug is not a Hh pathway inhibitor.
• the non-Hh pathway inhibitor anti-fibrosis drug is pirfenidone, nintedanib, GLPG4716 or PRM-151.
• the fibrotic disease is idiopathic pulmonary fibrosis (IPF).
• the fibrotic disease is pulmonary fibrosis following infection, including a bacterial or viral infection.
• the fibrosis develops after years-long chronic infections so that the role of the infection in causing the fibrosis cannot be conclusively demonstrated; such fibrosis is therefore still classified as idiopathic.
• Covid-19 provides a counterpoint, in that onset of fibrosis can be very rapid.
• the pulmonary fibrosis follows infection with SARS-CoV-2.
• the fibrotic disease is scleroderma.
• the fibrotic disease is systemic scleroderma (also known as systemic sclerosis) and in further instances, systemic scleroderma involving the lung.
• the fibrotic disease is liver fibrosis, such as in non-alcoholic steatohepatitis (NASH).
• the fibrotic disease is kidney fibrosis, for example, renal interstitial fibrosis or renal allograft fibrosis.
• the fibrotic disease is gastric fibrosis, for example, gastric mucosal fibrosis, glandular stomach fibrosis, or retroperitoneal fibrosis.
• the patient is a human.
• the patient is a non-human animal, for example a mammal.
• treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
• This 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.
• this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
• palliative treatment that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder
• preventative treatment that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder
• supportive treatment that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
• Various embodiments may specifically include or exclude one or more of these modes of treatment.
• Treatment activity includes the administration of the medicaments, dosage forms, and pharmaceutical compositions described herein to a patient, especially according to the various methods of treatment disclosed herein, whether by a healthcare professional, the patient his/herself, or any other person.
• Treatment activities include the orders, instructions, and advice of healthcare professionals such as physicians, physician’s assistants, nurse practitioners, and the like, that are then acted upon by any other person including other healthcare professionals or the patient him/herself. This includes, for example, direction to the patient to undergo, or to a clinical laboratory to perform, a diagnostic procedure, such as imaging or an evaluation of lung function, so that ultimately the patient may receive the benefit appropriate treatment.
• the orders, instructions, and advice aspect of treatment activity can also include encouraging, inducing, or mandating that a particular medicament, or combination thereof, be chosen for treatment of a condition - and the medicament is actually used - by approving insurance coverage for the medicament, denying coverage for an alternative medicament, including the medicament on, or excluding an alternative medicament, from a drug formulary, or offering a financial incentive to use the medicament, as might be done by an insurance company or a pharmacy benefits management company, and the like.
• treatment activity can also include encouraging, inducing, or mandating that a particular medicament be chosen for treatment of a condition - and the medicament is actually used - by a policy or practice standard as might be established by a hospital, clinic, health maintenance organization, medical practice or physicians group, and the like. All such orders, instructions, and advice are to be seen as conditioning receipt of the benefit of the treatment on compliance with the instruction.
• a financial benefit is also received by the patient for compliance with such orders, instructions, or advice.
• a financial benefit is also received by the healthcare professional for compliance with such orders, instructions, or advice.
• Treatment efficacy or benefit for pulmonary fibrosis is commonly assessed by changes in lung function for example, as determined by spirometry.
• Spirometry measures that can be used include forced vital capacity (FVC), forced expiratory volume in 1 second (FEVi), and diffusion capacity of the lungs for carbon monoxide (DLco).
• Further spirometry parameters that can be considered include FEVi/FVC ratio, observed FVC as a percentage of predicted FVC (FVC % predicted), and observed FE i as a percentage of predicted FE i (FE i % predicted).
• the predicted value of FVC (in liters) as published by the Association for Respiratory Technology and Physiology is 5.76*height (in meters) - 0.026*age (in years) - 4.34.
• the predicted value of FEVi (in liters) as published by the Association for Respiratory Technology and Physiology is 4.30*height (in meters) - 0.029*age (in years) ⁇ 2.49.
• the spirometry and other assessments may be made at regular intervals, for example, about every 24 weeks, quarterly, semi-annually, or annually.
• Treatment efficacy or benefit may be observed as a decrease in the progression of the disease, a stabilization of the disease, or improvement in the patient’s condition.
• progression, stabilization, or improvement is judged in comparison to a previous measurement or measurements of that patient.
• the previous measurement is a baseline measurement prior to initiation of treatment.
• progression, stabilization, or improvement is judged based in comparison with other patients, actual or historical, receiving no treatment, placebo, or alternative treatment.
• improvement or stabilization is judged by comparison to what would be expected in an untreated patient.
• decreased scarring includes an increase in scarring that is less than would be expected in an untreated patient.
• a stabilization of lung function does not imply no further decrease in one or another measure of lung function but rather that any decrease does not exceed that expected with aging for the time interval considered.
• IC 5 o half-maximal inhibitory concentration
• Kj binding constant
• Gli-Luciferase activity was quantified in a mouse mesenchymal C3H10T 1 /2 cell line stimulated with sonic hedgehog conditioned media (SHh-CM).
• Gli 1 transcript levels were quantified in a human Daoy tumor cell line stimulated with SHh-CM.
• taladegib inhibited Hh signaling as measured by mouse Gli 1 expression levels in tissues evaluated.
• the time course study demonstrated that sustained target inhibition can be maintained for at least 24 hours following a single oral dose of taladegib hydrochloride at 8 mg/kg.
• skin G li 1 is an appropriate PD surrogate for lung tissue Gli 1 .
• Table 1 Summary Table of TED50 and TEC50 of Taladegib Hydrochloride in Mouse Pharmacodynamic Models
• SE standard error
• TEC50 threshold effective concentration
• TED50 threshold effective dose
• Tg transgenic.
• Taldegib was administered to subjects at doses of 50, 100, 200, 400 and 600 mg. At these doses most patients exhibited >80% inhibition of Gli as measured in skin biopsies ( Figure 2). While some grade 3 toxicities were seen at 400 mg/day, there were none at 200 or 100 mg/day (Table 2). Given that the minimal biological effective dose (BED) was defined in this study as the first dose level at which the inhibition of rnGlil was >50%, it was concluded that taladegib was pharmacologically active at all dose levels tested.
• BED minimal biological effective dose
• Taladegib, vismodegib, pirfenidone, and nintedanib have all been used in clinical trials and have been used or evaluated for use in treating IPF. Except for taladegib, >20% of patients discontinued treatment for drug related reasons (Figure 3). The predominant AE causing discontinuation was muscle spasms for vismodegib, nausea for pirfenodone, and diarrhea for nintedanib. There was no prevalent AE for taladegib and ⁇ 10% patients discontinued treatment for drug related reasons when the dosage was ⁇ 200 mg/day.
• the Bleomycin (BLM) induced pulmonary fibrosis model is a standard IPF model, widely used in pharmacology and fundamental research.
• the disease IPF is defined as injury confined to the lungs that is progressive and irreversible.
• loss of lung function is driven by the infiltration and expansion of activated myofibroblasts.
• a Microsprayer® Aerosolizer was used to perform intratracheal administration of bleomycin. By administering bleomycin via Microsprayer® Aerosolizer, it can be evenly exposed to the lungs and thus, develops a reproducible and uniform pathology. In this model, the presence of myofibroblasts are observed by immunohistochemistry when stained with anti-alpha-smooth muscle actin (a- SMA) antibodies.
• a- SMA anti-alpha-smooth muscle actin
• Patients recovered from SARS-CoV-2 infection showing lung fibrosis by CT scan are randomized for treatment with standard of care or taladegib monotherapy.
• Taladegib is administered daily starting at 200 mg. If medication-related adverse events are experienced, the dosage may be reduced in steps of 100 mg to reduce or eliminate adverse events.
• Phamacokinetic data is collected.
• the primary efficacy endpoint is FVC change from baseline at 24 weeks.
• Secondary efficacy endpoints are change in lung fibrosis from baseline CT scan, change from baseline in 6-minute walk distance, the number of adjudicated respiratory hospitalizations, and change from baseline in St. George’s Respiratory Questionnaire. At 24 weeks some efficacy endpoints demonstrate stabilization or improvement.

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