Treatment and prevention of basal cell carcinoma with topical compositions containing pachydegib

Abstract

Disclosed herein are methods for treating and / or preventing basal cell carcinoma lesions, comprising topically administering a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein (i) the subject must have at least six facial BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH.

Description

[Technical Field]

[0001] In some embodiments, the present invention relates to methods for treating and / or preventing basal cell carcinoma (BCC) lesions, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein (i) the subject has at least six facial BCC lesions, or (ii) the subject has a genetically mutated PTCH, or (iii) the subject has at least six BCC lesions and a genetically mutated PTCH. [Background technology]

[0002] Basal cell carcinoma (BCC) is a common form of skin cancer and a subtype of nonmelanoma skin cancer (NMSC). BCC arises from abnormal and uncontrolled proliferation of basal cells and is driven by the Hedgehog (HH) signaling pathway, which is thought to be a major signaling pathway during embryonic development but is normally shut down after birth. Activated HH signaling, driven by mutations in the tumor suppressor gene Patched (PTCH) and / or the G protein-coupled receptor Smoothened (SMO), is known to promote oncogenic signaling and drive BCC growth. Mutations in human Patch genes, such as PTCH1 and PTCH2, are associated with nevoid basal cell carcinoma syndrome and basal cell carcinoma [1].

[0003] A variety of surgical and non-surgical treatments are available for BCC. Non-surgical treatments include radiation therapy, chemotherapy, and immunotherapy. These therapies can be useful for definitively treating primary and some recurrent BCC tumors, as well as alleviating symptoms associated with inoperable tumors. However, some of these therapies can also have significant and unpleasant side effects. The side effects of radiation therapy and certain chemotherapy are well documented. One form of immunotherapy involves intralesional injections of interferon. While interferon therapy can be effective against BCC, multiple intralesional injections can require clinic visits several times a week for several weeks and are painful.

[0004] The most common topical treatments for BCC are 5-fluorouracil (5FU) and / or imiquimod, which are highly effective but cause painful sores in the treatment area.

[0005] There are genetic disorders associated with an increased risk of developing BCC early and increased prevalence. Such disorders include:

[0006] Nevoid Basal Cell Carcinoma Syndrome - Nevoid basal cell carcinoma syndrome (NBCCS), also known as basal cell nevus syndrome or Gorlin syndrome, is a rare, autosomal dominant, multisystem disorder caused in most, but not all, cases by germline mutations in human patch gene-1 (PTCH1) and, more rarely, SMO, SUFU (a negative regulator of SUFU in Hedgehog signaling), and / or PTCH2 [1, 2a, 2b]. Affected patients present with both developmental abnormalities and postnatal tumors, including multiple BCCs, odontogenic keratocysts, and medulloblastomas, at a mean age of 20–21 years [3]. Gorlin syndrome affects individuals who develop multiple (tens to thousands) microscopic and macroscopic BCCs, various benign follicular hamartomas, palmar and plantar pits, as well as skeletal abnormalities (bifid ribs and syndactyly), central nervous system abnormalities (calcification of the falx cerebri and agenesis of the corpus callosum), craniofacial features (enlarged skull, sequestration, and frontal bossing), and benign odontogenic keratocysts of the jaws.

[0007] Rombo syndrome - Rombo syndrome was first described in a family with vermiculate atrophoderma and telangiectasia, associated with cyanosis in childhood, milia, trichoepithelioma, and hypotrichosis in adulthood, and BCC that developed in the third and fourth decades.[4] Rombo syndrome appears to be transmitted in a predominant pattern, but the causative mutations had not been identified.

[0008] Bazex-Dupre-Christol syndrome - Bazex-Dupre-Christol syndrome (also known as Bazex syndrome or follicular atrophy of the cutis and basal cell carcinoma) is an X-linked dominant disorder characterized by congenital hypotrichosis, follicular atrophy of the cutis, milia, and multiple BCCs.[5]

[0009] Xeroderma pigmentosum - Xeroderma pigmentosum is a rare autosomal recessive disorder caused by mutations in any of eight genes involved in the repair of UV-induced DNA damage.[6] Clinical findings include early-onset pigmented skin changes and early-onset skin cancer. SCC and BCC occur at a mean age of 9 years.

[0010] Muir-Torre syndrome - Muir-Torre syndrome is a rare autosomal dominant condition caused by mutations in the DNA mismatch repair genes MLH1, MSH2, and MSH6. Patients present with sebaceous neoplasms, including sebaceous adenomas and carcinomas, keratoacanthomas, BCCs, and malignancies of the colon and genitourinary tract.[4]

[0011] Oculocutaneous albinism - Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders of melanin biosynthesis that present with a spectrum of visual impairment and hypopigmentation of the skin and hair. Individuals with OCA are at high risk for early-onset skin cancer, possibly by the teenage years. SCC is the most common type of cancer occurring in patients with OCA, although BCC and melanoma also occur.[7]

[0012] BCC is typically observed in the general population on sun-exposed areas of the skin.

[0013] Additionally, there is an increased risk of developing BCC for immunosuppressed subjects or subjects exposed to radiation, asbestos, sunlight, or tanning salons. Thus, there remains a need for non-surgical therapies for BCC that offer better treatment.

[0014] Pachidegibu

[0015] The patidegib compound, also known in the art as "salidegib" and "IPI-926," has the following structure:

[0016] [ka]

[0017] Patidegib is included in U.S. Pat. No. 8,785,635 (U.S. Pat. No. 635) entitled "Cyclopamine analogs." Patidegib is a member of a class of anticancer compounds known as hedgehog (HH) pathway inhibitors. Patidegib exerts its pharmacological effects through inhibition of the G protein-coupled receptor Smoothened, a component of the hedgehog (HH) signaling pathway.

[0018] References [1] "Yang, Xin-Hua, et al."Inherited rare and common variants in PTCH1 and PTCH2 contributing to the predisposition to reproductive cancers."Gene 814(2022):146157." [2a] "Farndon PA, Del Mastro RG, Evans DG, Kilpatrick MW. Location of gene for Gorlin syndrome. Lancet 1992;339:581." [2b] "Peris, K, et al. 'Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines.' European Journal of cancer 118(2019):10-34." [3] "MacDonald DS. A systematic review of the literature of nevoid basal cell carcinoma syndrome affecting East Asians and North Europeans. Oral Surg Oral Med Oral Pathol Oral Radiol 2015;120:396." [4] "Schierbeck J, Vestergaard T, Bygum A. Skin Cancer Associated Genodermatoses: A Literature Review. Acta Derm Venereol 2019;99:360." [5] "Torrelo A, Sprecher E, Mediero IG, et al. What syndrome is this? Bazex-Dupre-Christol syndrome. Pediatr Dermatol 2006;23:286." [6] "DiGiovanna JJ, Kraemer KH. Shining a light on xeroderma pigmentosum. J Invest Dermatol 2012;132:785." [7] "Kiprono SK, Chaula BM, Beltraminelli H. Histological review of skin cancers in African Albinos: a 10-year retrospective review. BMC Cancer 2014;14:157."

Summary of the Invention

Means for Solving the Problems

[0019] The present invention is directed to methods for treating and / or preventing basal cell carcinoma lesions, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six facial BCC lesions; or (ii) the subject must have genetically mutated PTCH; or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. [Brief explanation of the drawings]

[0020] The subject matter which is regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of this specification. However, the invention, both as to organization and method of operation, together with its objects, features, and advantages, may best be understood by reference to the following detailed description when read in connection with the accompanying drawings.

[0021] [Figure 1] 1 is a graphical representation of the number of new basal cell carcinoma (BCC) lesions, excluding BCCs that are no longer suspicious, observed in subjects with PTCH1 mutations. Based on the study described in Example 2. [Figure 2] 1 is a graphical representation of the number of new BCCs, excluding BCCs no longer suspicious, observed for subjects with PTCH1 mutations and at least six facial BCC lesions at baseline, based on the study described in Example 2. [Figure 3] 1 is a graphical representation of the number of new BCCs, excluding BCCs no longer suspicious, observed for subjects with PTCH1 mutations and at least eight facial BCC lesions at baseline, based on the study described in Example 2. [Figure 4]1 is a graphical representation of the number of new BCCs, excluding BCCs no longer suspicious, observed for subjects with PTCH1 mutations and at least 10 facial BCC lesions at baseline, based on the study described in Example 2. [Figure 5] 1 is a graphical representation of the number of eligible new surgically eligible BCCs (nSEBs) observed for subjects with PTCH1 mutations, based on the study described in Example 2. [Figure 6] 1 is a graphical representation of the number of qualifying nSEBs observed for subjects with a PTCH1 mutation and at least six facial BCC lesions at baseline, based on the study described in Example 2. [Figure 7] 1 is a graphical representation of the number of qualifying nSEBs observed for subjects with a PTCH1 mutation and at least eight facial BCC lesions at baseline, based on the study described in Example 2. [Figure 8] 1 is a graphical representation of the number of qualifying nSEBs observed for subjects with a PTCH1 mutation and at least 10 facial BCC lesions at baseline, based on the study described in Example 2. [Figure 9] 1 is a graphical representation of the rate of clinically resolved and observed SEB in subjects with PTCH1 mutations, based on the study described in Example 2. [Figure 10] 1 is a graphical representation of the rate of clinically resolved and observed SEB in subjects with PTCH1 mutations and at least six facial BCC lesions at baseline, based on the study described in Example 2. [Figure 11] 1 is a graphic representation of the rate of clinically resolved and observed SEB in subjects with PTCH1 mutations and at least eight facial BCC lesions at baseline, based on the study described in Example 2. [Figure 12] 1 is a graphical representation of the rate of clinically resolved and observed SEB in subjects with a PTCH1 mutation and at least 10 facial BCC lesions at baseline, based on the study described in Example 2. [Figure 13]1 is a graphic representation of the proportion of clinically resolved and observed SEB in the intent-to-treat population (ITT), based on the study described in Example 3.

[0022] It will be understood that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements. DETAILED DESCRIPTION OF THE INVENTION

[0023] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0024] In some embodiments, the present invention provides a method for treating and / or preventing basal cell carcinoma (BCC) lesions, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein (i) the subject must have at least six facial BCC lesions, or (ii) the subject must have a genetic mutation, or (iii) the subject must have at least six BCC lesions and a genetic mutation. In another embodiment, the genetic mutation comprises PATCH, PATCH1, PATCH2, SMO, SUFU, or any combination thereof.

[0025] In some embodiments, the present invention provides methods for treating and / or preventing basal cell carcinoma (BCC) lesions, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions; (ii) the subject must have a genetically mutated PTCH; or (iii) the subject must have at least six BCC lesions and a genetically mutated PTCH. In another embodiment, the PTCH is PTCH1. In another embodiment, the PTCH is PTCH2. In another embodiment, the PTCH is PTCH1 and / or PTCH2. In another embodiment, the subject must have at least eight BCC lesions. In another embodiment, the subject must have at least 10 BCC lesions. In another embodiment, the subject must have at least 12 BCC lesions. In another embodiment, the subject must have at least four facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least eight facial BCC lesions. In another embodiment, the subject must have at least ten facial BCC lesions. In another embodiment, the subject must have at least twelve facial BCC lesions.

[0026] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC) lesions, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pachydegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH, and wherein the composition comprises pachydegib in an amount of about 0.1% w / w to about 6% w / w. In another embodiment, the composition comprises patydegib in an amount of about 0.1-2% w / w, 0.1-3% w / w, 0.1-4% w / w, 0.1-5% w / w, 1-2% w / w, 1.5-3% w / w, 1-3% w / w, 1-4% w / w, 1-5% w / w, 2-4% w / w, 2-5% w / w, 2-6% w / w, or 0.1-6% w / w. In another embodiment, the composition comprises patydegib in an amount of about 1% w / w, 2% w / w, 3% w / w, 4% w / w, 5% w / w, or 6% w / w. In another embodiment, the composition comprises patydegib in an amount of about 2% w / w, 3% w / w, or 4% w / w. In another embodiment, the composition comprises patydegib in an amount of about 2%.

[0027] In some embodiments, the present invention provides methods for treating and / or preventing basal cell carcinoma (BCC) lesions, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six facial BCC lesions; or (ii) the subject must have genetically mutated PTCH; or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH.

[0028] In another embodiment, the PTCH is PTCH1. In another embodiment, the PTCH is PTCH2. In another embodiment, the PTCH is PTCH1 and / or PTCH2.

[0029] In another embodiment, the subject must have at least 8 facial BCC lesions. In another embodiment, the subject must have at least 10 facial BCC lesions. In another embodiment, the subject must have at least 12 facial BCC lesions. In another embodiment, the subject must have at least 8 BCC lesions and a genetically mutated PTCH. In another embodiment, the subject must have at least 10 BCC lesions and a genetically mutated PTCH. In another embodiment, the subject must have at least 12 BCC lesions and a genetically mutated PTCH.

[0030] In another embodiment, a subject must have at least six facial BCC lesions and a genetically mutated PTCH. In another embodiment, a subject must have at least eight facial BCC lesions and a genetically mutated PTCH. In another embodiment, a subject must have at least ten facial BCC lesions and a genetically mutated PTCH. In another embodiment, a subject must have at least twelve facial BCC lesions and a genetically mutated PTCH.

[0031] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC) lesions, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pachydegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH, and the composition comprises pachydegib in an amount of about 0.1% w / w to about 6% w / w. In another embodiment, the composition comprises patydegib in an amount of about 0.1-2% w / w, 0.1-3% w / w, 0.1-4% w / w, 0.1-5% w / w, 1-2% w / w, 1.5-3% w / w, 1-3% w / w, 1-4% w / w, 1-5% w / w, 2-4% w / w, 2-5% w / w, 2-6% w / w, or 0.1-6% w / w. In another embodiment, the composition comprises patydegib in an amount of about 1% w / w, 2% w / w, 3% w / w, 4% w / w, 5% w / w, or 6% w / w. In another embodiment, the composition comprises patydegib in an amount of about 2% w / w, 3% w / w, or 4% w / w. In another embodiment, the composition comprises patydegib in an amount of about 2%.

[0032] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC) lesions, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pachydegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six facial BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six facial BCC lesions and genetically mutated PTCH, and wherein the composition comprises pachydegib in an amount of about 0.1% w / w to about 6% w / w. In another embodiment, the composition comprises patydegib in an amount of about 0.1-2% w / w, 0.1-3% w / w, 0.1-4% w / w, 0.1-5% w / w, 1-2% w / w, 1.5-3% w / w, 1-3% w / w, 1-4% w / w, 1-5% w / w, 2-4% w / w, 2-5% w / w, 2-6% w / w, or 0.1-6% w / w. In another embodiment, the composition comprises patydegib in an amount of about 1% w / w, 2% w / w, 3% w / w, 4% w / w, 5% w / w, or 6% w / w. In another embodiment, the composition comprises patydegib in an amount of about 2% w / w, 3% w / w, or 4% w / w. In another embodiment, the composition comprises patydegib in an amount of about 2%.

[0033] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pachydegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six facial BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH, and wherein the composition comprises pachydegib in an amount of about 2% w / w.

[0034] According to some embodiments, the pachydegib composition of the present invention is selected from a cream, ointment, gel, lotion, spray, patch, or foam, hi some embodiments, the pachydegib topical composition of the present invention is a gel.

[0035] In another embodiment, patidegib is formulated as a gel formulation.

[0036] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pachydegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six facial BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH; wherein the pachydegib is in an amount of about 0.1% w / w to about 6% w / w; and the pachydegib is formulated as a gel formulation. In another embodiment, the pachydegib is formulated as shown in Example 1.

[0037] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six BCC lesions.

[0038] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six facial BCC lesions.

[0039] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have a genetically mutated PTCH.

[0040] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six BCC lesions and a genetically mutated PTCH.

[0041] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six facial BCC lesions and a genetically mutated PTCH.

[0042] In some embodiments, provided herein are methods of treating basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein subjects eligible for treatment are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH.

[0043] In some embodiments, provided herein are methods of treating basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein subjects eligible for treatment are selected according to any one of the following criteria: (i) the subject must have at least six facial BCC lesions; or (ii) the subject must have genetically mutated PTCH; or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In some embodiments, provided herein are methods of treating basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein subjects eligible for treatment are selected according to any one of the following criteria: (i) the subject must have at least six facial BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0044] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein eligible subjects are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions; (ii) the subject must have genetically mutated PTCH; or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH; and the subject has Gorlin syndrome. In another embodiment, the subject must have at least six facial lesions. In another embodiment, the subject must have genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0045] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six BCC lesions, and the subject is afflicted with Gorlin syndrome.

[0046] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six facial BCC lesions, and the subject is afflicted with Gorlin syndrome.

[0047] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have a genetically mutated PTCH gene, and the subject is afflicted with Gorlin syndrome.

[0048] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six BCC lesions and a genetically mutated PTCH, and the subject is afflicted with Gorlin syndrome.

[0049] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six facial BCC lesions and a genetically mutated PTCH, and the subject is afflicted with Gorlin syndrome.

[0050] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six BCC lesions, and the subject must be immunosuppressed or have been exposed to radiation, asbestos, sunlight, or tanning salons. In another embodiment, the subject must have at least eight BCC lesions. In another embodiment, the subject must have at least ten BCC lesions. In another embodiment, the subject must have at least twelve BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least eight facial BCC lesions. In another embodiment, the subject must have at least ten facial BCC lesions. In another embodiment, the subject must have at least twelve facial BCC lesions.

[0051] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six facial BCC lesions, the subject suffers from immunosuppression, or the subject has been exposed to radiation, asbestos, sunlight, or a tanning salon.

[0052] In some embodiments, provided herein are methods of treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six BCC lesions, and the subject is afflicted with a disorder consisting of non-melanoma skin cancer, Rombo syndrome, Bazex-Dupre-Christol syndrome, xeroderma pigmentosum, Muir-Torre syndrome, oculocutaneous albinism, or Gorlin syndrome.

[0053] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pachydegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six facial BCC lesions, and the subject is afflicted with a disorder consisting of non-melanoma skin cancer, Rombo syndrome, Bazex-Dupre-Christol syndrome, xeroderma pigmentosum, Muir-Torre syndrome, oculocutaneous albinism, or Gorlin syndrome.

[0054] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six BCC lesions, and the subject is afflicted with Rombo syndrome, Bazex-Dupre-Christol syndrome, xeroderma pigmentosum, Muir-Torre syndrome, or oculocutaneous albinism.

[0055] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least six BCC lesions, and the subject is afflicted with Rombo syndrome, Bazex-Dupre-Christol syndrome, xeroderma pigmentosum, Muir-Torre syndrome, or oculocutaneous albinism.

[0056] In some embodiments, the methods of treating BCC of the present invention result in a reduction in the size of the BCC lesion or clinical resolution over time. In another embodiment, the methods of treating BCC of the present invention result in a reduction in the size of the BCC lesion. In another embodiment, the size of the BCC lesion is reduced by about 1-100%. In another embodiment, the size of the lesion is reduced by about 5%. In another embodiment, the size of the BCC lesion is reduced by about 10%. In another embodiment, the size of the BCC lesion is reduced by about 20%. In another embodiment, the size of the lesion is reduced by about 30%. In another embodiment, the size of the BCC lesion is reduced by about 40%. In another embodiment, the size of the BCC lesion is reduced by about 50%. In another embodiment, the size of the BCC lesion is reduced by about 60%. In another embodiment, the size of the BCC lesion is reduced by about 70%. In another embodiment, the size of the lesion is reduced by about 75%. In another embodiment, the size of the BCC lesion is reduced by about 80%. In another embodiment, the size of the BCC lesion is reduced by about 85%. In another embodiment, the size of the BCC lesion is reduced by about 90%. In another embodiment, the size of the BCC lesion is reduced by about 95%. In another embodiment, the size of the BCC lesion is reduced by about 100%.

[0057] In another embodiment, treating a BCC results in a clinically resolved BCC, particularly where the BCC disappears completely. In another embodiment, treating a BCC lesion results in a clinically resolved BCC, where the lesion is no longer suspected as a BCC.

[0058] In some embodiments, the methods of the invention prevent the formation of new BCCs, and subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0059] In some embodiments, the methods of the invention prevent the formation of nSEB, and subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0060] In some embodiments, the methods of the invention prevent the formation of nSEB, and the subject is selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0061] In some embodiments, the present invention provides methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH, and wherein the composition is topically administered once daily, twice daily, three times daily, every other day, or three times weekly.

[0062] In some embodiments, the present invention provides methods for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six facial BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH, and the composition is topically administered once daily, twice daily, three times daily, every other day, or three times weekly. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0063] In some embodiments, provided herein are methods of treatment and / or prevention comprising topical application of a composition comprising a therapeutically effective amount of pasidegib or a pharmaceutically acceptable salt thereof once daily, twice daily, three times daily, every other day, or three times per week.

[0064] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising topically applying a therapeutically effective amount of a composition comprising pasidegib or a pharmaceutically acceptable salt thereof to the facial skin of a subject in need thereof once daily, twice daily, three times daily, every other day, or three times weekly until the BCC is cured, prevented, or ameliorated, or as directed by a physician; subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0065] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising topically applying a therapeutically effective amount of a composition described herein to an affected skin area of ​​a subject in need thereof once daily, twice daily, three times daily, every other day, or three times weekly until the BCC is cured, prevented, or alleviated, or as directed by a physician; wherein subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions; (ii) the subject must have genetically mutated PTCH; or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0066] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising topically applying a therapeutically effective amount of a composition described herein to an affected skin area of ​​a subject in need thereof once daily, twice daily, three times daily, every other day, or three times weekly until the BCC is cured, prevented, or ameliorated, or as directed by a physician; subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six facial BCC lesions; (ii) the subject must have genetically mutated PTCH; or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0067] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising topically applying a therapeutically effective amount of a composition described herein to any area of ​​a subject's body in need thereof once daily, twice daily, three times daily, every other day, or three times weekly until the BCC is cured, prevented, or ameliorated, or as directed by a physician; wherein subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions; (ii) the subject must have genetically mutated PTCH; or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0068] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising topically applying a therapeutically effective amount of the composition to the entire body of a subject in need thereof once daily, twice daily, three times daily, every other day, or three times weekly until the BCC is cured, prevented, or ameliorated, or as directed by a physician; wherein subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions; (ii) the subject must have genetically mutated PTCH; or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0069] In some embodiments, provided herein are methods of treating BCC lesions, comprising topically applying a therapeutically effective amount of the composition to BCC lesions in a subject in need thereof once daily, twice daily, three times daily, every other day, or three times weekly until the BCC is cured, prevented, or ameliorated, or as directed by a physician; wherein (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH.

[0070] In some embodiments, provided herein are methods for treating and / or preventing BCC lesions, comprising topically applying a therapeutically effective amount of the composition to BCC lesions and the skin surrounding the BCC lesions in a subject in need thereof once daily, twice daily, three times daily, every other day, or three times weekly until the BCC is cured, prevented, or alleviated, or as directed by a physician; wherein (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0071] In some embodiments, provided herein are methods of treating BCC lesions, comprising topically applying a therapeutically effective amount of the composition to BCC lesions in a subject in need thereof once daily, twice daily, three times daily, every other day, or three times weekly until the BCC is cured, prevented, or ameliorated, or as directed by a physician, wherein the subject has (i) at least six facial BCC lesions, or (ii) genetically mutated PTCH, or (iii) at least six BCC lesions and genetically mutated PTCH.

[0072] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is topically administered for about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, about 24 months, about 36 months, chronically, or lifelong; and wherein (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. Each represents a separate embodiment of the invention. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0073] In another embodiment, the composition is topically administered for a period of about 6 months. In another embodiment, the composition is topically administered for a period of about 9 months. In another embodiment, the composition is topically administered for a period of about 12 months. In another embodiment, the composition is topically administered for a period of more than 12 months. In another embodiment, the composition is topically administered for a period of life. In another embodiment, the composition is topically administered chronically.

[0074] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is administered for more than 12 months, more than 18 months, more than 24 months, more than 36 months, at least 1-10 years, more than 1 year, more than 2 years, more than 3 years, more than 4 years, more than 5 years, more than 6 years, more than 7 years, more than 8 years, more than 9 years, more than 10 years, or a chronic or lifelong administration period; and subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions; (ii) the subject must have genetically mutated PTCH; or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. Each represents a separate embodiment of the present invention. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and a genetically mutated PTCH. In another embodiment, the subject has not developed drug resistance. In another embodiment, the subject has not developed drug resistance after a period of discontinuation of treatment.

[0075] In some embodiments, the subject of the methods provided herein does not develop drug resistance, hi other embodiments, the subject of the methods provided herein does not develop drug resistance after a period of discontinuation of treatment.

[0076] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is topically administered for a period of greater than 12 months, and subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions; or (ii) the subject must have genetically mutated PTCH; or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH; and the subject has not developed drug resistance. Each represents a separate embodiment of the invention. In another embodiment, the composition is administered for a period of greater than 18 months. In another embodiment, the composition is administered for a period of greater than 24 months. In another embodiment, the composition is administered for a lifelong period. In another embodiment, the composition is administered chronically. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and a genetically mutated PTCH. In another embodiment, the subject has not developed drug resistance after a period of treatment discontinuation.

[0077] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma, comprising topically administering to a subject a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein subjects eligible for treatment and / or prevention are selected according to any one of the following criteria: (i) the subject must have at least six BCC lesions; (ii) the subject must have genetically mutated PTCH; or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH; and the subject has not developed drug resistance. In another embodiment, the subject has not developed drug resistance after a period of cessation of treatment. In some embodiments, the duration of administration of the methods of the present invention does not affect drug efficacy. In another embodiment, drug efficacy is not affected after a period of cessation of treatment.

[0078] In some embodiments, provided herein are methods for treating and / or preventing basal cell carcinoma, comprising topically administering to a subject a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein (i) the subject must have at least six facial BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH, and wherein the efficacy of the drug is not affected after a period of discontinuation of administration during treatment.

[0079] In some embodiments, in the methods provided herein, the administration period comprises at least 12 consecutive months of administration.

[0080] In some embodiments, in the methods provided herein, the administration period comprises (i) 12 consecutive months of administration, (ii) followed by a withdrawal period, and (iii) followed by continued administration, wherein the efficacy of the drug is not affected by the period of withdrawal during treatment. In other embodiments, the withdrawal period is 1, 2, 3, 4, 5, 6, 7, or 8 months, or 1 to 3 months, 1 to 24 months, 2 to 12 months, 3 to 12 months, 3 to 8 months, or 3 to 10 months.

[0081] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is topically administered for a period of at least 9 months, and after 9 months of administration, the efficacy in treating and / or preventing BCC is improved compared to administration of a vehicle, and wherein (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0082] In some embodiments, provided herein are methods for treating SEB clinically, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is topically administered for a period of at least 9 months, and after 9 months of administration, the efficacy in treating and / or preventing BCC is improved compared to administration of a vehicle, and subjects eligible for treatment and / or prevention are selected according to one of the following criteria: (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0083] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is topically administered for a period of at least 12 months, and wherein after 12 months of administration, the efficacy in treating and / or preventing BCC is improved compared to administration of a vehicle, and wherein (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0084] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pachydegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is topically administered for a period of at least 12 months, and after 12 months of administration, the efficacy in treating and / or preventing BCC is unaffected compared to the efficacy in treating / preventing BCC following the initial 12-month topical administration of the pharmaceutical composition comprising pachydegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and wherein (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and genetically mutated PTCH.

[0085] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is topically administered for a period of at least 18 months, and wherein after 18 months of administration, the effectiveness in treating and / or preventing BCC is unaffected, and wherein (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH.

[0086] In another embodiment, the subject must have at least six facial BCC lesions. In another embodiment, the subject must have at least six facial BCC lesions and a genetically mutated PTCH.

[0087] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is topically administered for about 3 months, about 6 months, about 9 months, about 12 months, chronically, or lifelong, and wherein (i) the subject must have at least six facial BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH.

[0088] In some embodiments, provided herein are methods for treating and / or preventing BCC, comprising locally administering to a subject in need thereof a pharmaceutical composition comprising pasidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the number of BCC surgeries is reduced, and (i) the subject must have at least six BCC lesions, or (ii) the subject must have genetically mutated PTCH, or (iii) the subject must have at least six BCC lesions and genetically mutated PTCH. In another embodiment, BCC surgeries are reduced after 12 months of treatment (Example 2, Table 14).

[0089] In some embodiments, the pharmaceutically acceptable carrier of the compositions of the present invention comprises DGME (diethylene glycol monoethyl ether), HPC (hydroxypropyl cellulose), borate buffer, dehydrated alcohol, propylene glycol, phenoxyethanol, or any combination thereof. In another embodiment, the pharmaceutically acceptable carrier of the compositions of the present invention includes carriers, excipients, and diluents, which refers to materials, compositions, or vehicles such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that are involved in carrying or transporting a pharmaceutical agent across the stratum corneum.

[0090] In some embodiments, the methods of the present invention comprise topically applying a composition comprising patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0091] In another embodiment, the pacydegib or pharmaceutically acceptable salt thereof compound may be formulated with any pharmaceutically acceptable carrier, and may be a liquid, semi-solid, or solid composition. Pharmaceutical and cosmetic carriers or vehicles suitable for topical administration of compositions to the skin or mucosa are known to those skilled in the art, and the pacydegib compound may be included in the carrier in an amount sufficient to provide a therapeutically useful effect in the treatment and / or prevention of BCC. In one embodiment, the composition containing pacydegib or a pharmaceutically acceptable salt thereof is liquid. Liquid dosage forms for topical administration include emulsions, solutions, and suspensions containing diluents commonly used in the art, such as alcohols, glycols, oils, and water. The composition may also include wetting agents, emulsifying agents, and suspending agents.

[0092] The composition may be in the form of a solution, suspension, emulsion, ointment, lotion, gel, etc. Oil-in-water or water-in-oil emulsions are contemplated. Gels are formed by entrapping a large amount of aqueous or aqueous-alcoholic liquid within a network of polymeric or colloidal solid particles. Such polymers or colloids are typically present at concentrations less than 10% w / w and are also referred to as gelling agents or thickeners. Examples of suitable gelling agents include carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, sodium alginate, alginic acid, pectin, tragacanth, carrageen, agar, clay, aluminum silicate, carbomer, etc.

[0093] Creams and ointments may also be utilized. They are emulsions of oily substances and water (i.e., carrier). Creams may be water-in-oil (w / o), where an aqueous phase is dispersed in an oily phase, or oil-in-water (o / w), where oil is dispersed within an aqueous base. Ointments are also contemplated and are typically thicker than oil-in-water creams. Traditional ointment bases (i.e., carriers) include hydrocarbons (such as petrolatum and beeswax), vegetable oils, fatty alcohols (such as cholesterol, lanoilin, wool alcohol, and stearyl alcohol), or silicones. Pastes are a type of ointment containing a high proportion of insoluble particulate solids, up to 50% by weight. Insoluble solids such as starch, zinc oxide, calcium carbonate, or talc may also be used.

[0094] Aerosols may also be utilized. The compound may be dissolved in a propellant and co-solvent such as ethanol, acetone, hexadecyl alcohol, etc. Foaming agents may also be incorporated to produce mousses.

[0095] Emollients or lubricating vehicles that help hydrate the skin can also be used. Examples of suitable bases or vehicles for preparing hydrating compositions for use on human skin are petrolatum, petrolatum with volatile silicones, lanolin, cold cream (USP), and hydrophilic ointment (USP).

[0096] A variety of methods may be used to prepare the above formulations. Generally, the formulations may be prepared by combining the components of the formulation as described herein at a temperature and for a time sufficient to provide a pharmaceutically acceptable composition. The term "combining together," as used herein, means that all of the components of the composition may be combined and mixed together at approximately the same time. The term "combining together" also means that the various components may be combined in one or more sequences to provide the desired product. The formulations may be prepared on a weight / weight (w / w) or weight / volume (w / v) basis, depending on the form of the final dosage form.

[0097] The compositions comprise a weight percentage of patidegib or a pharmaceutically acceptable salt thereof, which may be dissolved, suspended, dispersed, or otherwise mixed in a selected carrier or vehicle at an effective concentration to relieve or ameliorate the pruritic condition. Compositions in solution form and intended for topical administration may contain about 0.1% w / w to about 6% w / w of patidegib or a pharmaceutically acceptable salt thereof, with the remainder of the solution being water, a suitable organic solvent, or other suitable solvent or buffer. Compositions formulated as solutions, emulsions, or suspensions may be applied to the skin, or they may be formulated as aerosols or foams and applied to the skin as a spray-on. Aerosol compositions typically contain 25% to 80% w / w, preferably 30% to 50% w / w, of a suitable propellant.

[0098] Solid compositions intended for topical application can be formulated as stick-type compositions intended for application to the lips or other parts of the body. Such compositions contain an effective amount of patidegib or a pharmaceutically acceptable salt thereof. The amount of the patidegib compound is typically about 0.1% w / w to about 6% w / w. The solid form of the composition may also contain about 40% to 98% w / w, preferably about 50% to 90% w / w, of a carrier.

[0099] As used herein, the term "pharmaceutically acceptable salts" refers to salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. The term "pharmaceutically acceptable salts" also includes solvates of addition salts, such as hydrates, as well as polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of such inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from aliphatic, alicyclic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic and sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesyl, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, alginic acid, 3-hydroxybutyric acid, galactaric acid, and galacturonic acid.

[0100] The term "mutated PTCH" refers to mutant PTCH1 and / or mutant PTCH2.

[0101] The term "treating BCC" refers to treating BCC, including surgically eligible BCC, until the BCC has completely disappeared or until the growth of the lesion has decreased (e.g., the size of the lesion / tumor has decreased). Furthermore, "treating BCC" refers to treating BCC found throughout the subject's body. In other embodiments, the term "treating BCC" refers to treating BCC, including surgically eligible BCC, until the BCC has completely disappeared or until the growth of the lesion has decreased (e.g., the size of the lesion / tumor has decreased), and the subject must (i) have at least six facial BCC lesions at baseline before treatment, or (ii) have genetically mutated PTCH, or (iii) have at least six BCC lesions and genetically mutated PTCH at baseline before treatment. In other embodiments, the term "treating BCC" refers to treating BCC, including surgically eligible BCC, until the BCC disappears completely or until the growth of the lesion is reduced (e.g., the size of the lesion / tumor is reduced), and the subject must (i) have at least six facial BCC lesions at baseline before treatment, or (ii) have genetically mutated PTCH, or (iii) have at least six facial BCC lesions and genetically mutated PTCH at baseline before treatment.

[0102] The term "prevention of BCC" refers to preventing the development of new BCCs and new surgically eligible BCCs. Furthermore, "prevention of BCC" refers to preventing the development of new BCCs and / or n-SEB throughout the body. In another embodiment, the term "prevention" refers to preventing the development of new BCCs and / or n-SEB throughout the body, and the subject must (i) have at least six facial BCC lesions at baseline before treatment, or (ii) have genetically mutated PTCH, or (iii) have at least six BCC lesions and genetically mutated PTCH at baseline before treatment. In another embodiment, the term "prevention" refers to preventing the development of new BCCs and / or n-SEB on the face, and the subject must (i) have at least six facial BCC lesions at baseline before treatment, or (ii) have genetically mutated PTCH, or (iii) have at least six facial BCC lesions and genetically mutated PTCH at baseline before treatment.

[0103] The term "chronically" refers to more than 5 years, 10 years or more, or lifelong.

[0104] The term "drug resistance" refers to a drug that is no longer effective.

[0105] The term "drug efficacy" refers to the effectiveness of a drug, including prevention of BCC recurrence and / or reduction in the size / dimensions of BCC lesions over time.

[0106] In some embodiments, the treatment and / or prevention described herein refers to treatment and / or prevention of BCC, and the subject must have at least six BCC lesions at baseline prior to treatment anywhere in the body. "The whole body" refers to a specific part of the body (such as the face, back, legs, hands, stomach, etc.). Thus, treatment involves applying a composition comprising an effective amount of pasidegib or a pharmaceutically acceptable salt thereof to the specific body part to be treated.

[0107] The term "facial BCC lesions" refers to BCC lesions on the face.

[0108] The term "BCC lesions" refers to BCC lesions throughout the body.

[0109] The term "clinically resolved BCC" refers to lesions consistent with BCC at the treatment site that are no longer visible evidence of previously defined BCC lesions that are no longer BCC. In another embodiment, the term clinically resolved BCC refers to a BCC that has completely disappeared clinically.

[0110] The term "nSEB" refers to a BCC with a longest diameter of 5 mm or greater that: a.Not a surgically eligible BCC (SEB) at baseline; b. The longest diameter has grown by 2 mm or more since baseline; and c. Histologically verified.

[0111] Furthermore, nSEB refers to a histologically verified new BCC that, as determined by the investigator, should be surgically removed due to the potential for functional facial / health impairment.

[0112] The term "SEB" refers to a surgically eligible BCC with a longest diameter of 5 mm or greater.

[0113] The term "resolved SEB lesion" refers to a BCC lesion that no longer requires surgical removal. In another embodiment, the term "resolved SEB lesion" refers to a BCC lesion that is less than 5 mm in diameter or that has completely disappeared.

[0114] Whenever a numerical range is given herein, it is meant to include any recited numbers (fractional or integer) within the range given. The expressions "ranging between" a first recited number and a second recited number, and "ranging from" a first recited number to a second recited number, are used interchangeably herein and are meant to include the first recited number and the second recited number, and all fractional and integer numbers therebetween.

[0115] The dimensions and values ​​disclosed herein should not be understood as being strictly limited to the exact numerical values ​​recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a potentially equivalent range surrounding that value. For example, a dimension disclosed as "10 μm" is intended to mean "about 10 μm."

[0116] As used herein, numerical ranges preceded by the term "about" should not be considered limiting to the recited range. Rather, numerical ranges preceded by the term "about" should be understood to include the range accepted by one of ordinary skill in the art for any given element in the microcapsules or formulations according to the present invention.

[0117] As used herein, the term "about" means within an acceptable error range of a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean a range of up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. When a particular value is described in this application and claims, unless otherwise specified, the meaning of the term "about" is within an acceptable error range of that particular value.

[0118] The words "comprise," "comprising," "includes," "including," "having," and their conjugations mean "including but not limited to."

[0119] The term "consisting of" means "including and limited to."

[0120] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0121] As used herein, the term "method" refers to methods, means, techniques, and procedures for accomplishing a given task, including, but not limited to, methods, means, techniques, and procedures known to, or readily developed from, methods, means, techniques, and procedures known to, practitioners of chemistry, pharmacology, biology, biochemistry, and medicine.

[0122] It should be understood that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination, or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments should not be considered essential features of those embodiments, unless the embodiment is inoperable without those elements. [Example]

[0123] Example 1 - Gel Formulation

[0124] The patidegib composition is a gel formulation as shown in the table below.

[0125] [Table 1]

[0126] Example 2

[0127] A randomized, double-blind, stratified, vehicle-controlled study was conducted to measure the efficacy and safety of pachydegib topical gel, 2%, applied topically twice daily to the face in adult participants with Gorlin syndrome. Participants were required to apply the study drug for 12 months. The primary endpoint was a comparison between the two treatments, pachydegib topical gel, 2%, and vehicle, and the number of new BCCs that developed over 12 months.

[0128] Experiment: Patidegib topical gel, 2%,

[0129] Participants will be randomized to receive pacydegib topical gel, 2%, which will be dispensed to participants at each study visit and applied topically to the face twice daily.

[0130] Placebo comparator: pacydegib topical gel, vehicle

[0131] Participants will be randomized to receive vehicle: pacydegib topical gel, which will be dispensed to participants at each study visit and applied topically to the face twice daily.

[0132] Participant Criteria Inclusion Criteria: 1. Participants must be at least 18 years of age at the time of the screening visit. 2. Participants must provide written informed consent prior to any study procedures. 3. Participants must meet diagnostic criteria for Basal Cell Nevus (Gorlin) Syndrome, including a PTCH1 gene mutation or at least six histologically confirmed facial BCC lesions at baseline and a PTCH1 gene mutation. 4. Participant is willing to have blood drawn to measure circulating drug levels. 5. Participants are willing to refrain from applying non-investigational topical medications (prescription or over-the-counter) to facial skin during the study, unless prescribed by the investigator. Moisturizers and emollients are permitted. Participants are encouraged to use a preferred sunscreen with a sun protection factor (SPF) of at least 30 daily on all exposed skin areas. 6. If the participant is a woman of childbearing potential (WOCBP), she must be willing to completely abstain from sexual intercourse and / or she and her partner must be willing to use at least two highly effective forms of contraception starting before baseline, throughout the study, and for 12 months after the last application of IP. 7. If the participant is a man with a female sex partner who is a WOCBP, the participant must be willing to use condoms, even after a vasectomy, starting before baseline, throughout the study, and for at least 8 months after the last application of IP. 8. Participant is willing to be evaluated for all facial BCCs and have treatment recommendations made only by the investigator. 9. Participant is willing to forgo treatment of facial BCCs with anything other than study IP, unless the investigator believes that delaying treatment of facial BCCs may compromise the subject's health. During the study, the only form of treatment permitted is surgery. Non-facial BCCs may be removed at the discretion of the investigator or primary skin care physician (PSCP). Exclusion criteria: 1. Subject has previously participated in a clinical trial evaluating pacydegib topical gel. 2. Participant uses topical treatments on the face or systemic therapy that may interfere with the evaluation of study IP. Among these are the use of: a. Systemic or topical 5-fluorouracil, imiquimod, diclofenac, or ingenol mebutate to the skin (except as topical treatment for an individual non-facial BCC) within 2 months prior to the screening visit. b. Systemic chemotherapy within 1 year prior to the screening visit. c. Known local or systemic inhibitors of the hedgehog signaling pathway (e.g., vismodegib, sonidegib, itraconazole) within 3 months prior to the screening visit. d. Photodynamic therapy (PDT) for any localized, non-facial, individual BCC within 2 months prior to the screening visit. 3. Participant has known hypersensitivity to any of the ingredients in the investigational drug formulation. 4. Participant is unable or unwilling to make a good faith effort to return to the study site for all study visits and testing. 5. Participant has an uncontrolled systemic disease. 6. Participant has been treated for invasive cancer within the past 5 years, except for non-melanoma skin cancer, stage I cervical cancer, ductal carcinoma in situ, or stage 0 chronic lymphocytic leukemia (CLL). 7. Participant is currently, recently (within 5 half-lives of the experimental drug, or if the half-life is unknown, within the past 6 months prior to the screening visit), or planning to participate in an experimental drug study while enrolled in this study. 8. Participants are WOCBP who are unwilling or unable to comply with pregnancy prevention measures. 9. Participant is pregnant or breastfeeding. 10. The participant has any condition or situation that, in the opinion of the investigator, could place the subject at significant risk, confound the study results, or significantly prevent the subject from participating in the study. This could include a history of other skin conditions (e.g., severe facial eczema) or diseases, metabolic dysfunction, physical examination findings, or clinical laboratory findings that raise reasonable suspicion of a disease or condition that contraindicates the use of the investigational drug or that could affect the interpretation of the study results or place the participant at increased risk for treatment complications.

[0133] result

[0134] As shown below in Figure 1 and Table 1, the number of new BCCs, excluding BCCs that were no longer suspicious, was observed in subjects with PTCH1 mutations.

[0135] [Table 2]

[0136] As shown in Table 1 and Figure 1, after 6 months of treatment with patidegib gel 2%, the number of new BCCs, excluding BCCs no longer suspected, was approximately 1.59 compared to approximately 2.6 in vehicle-treated patients. After 12 months of treatment with patidegib gel 2%, the number of new BCCs, excluding BCCs no longer suspected, was approximately 2.61 compared to approximately 4.29 in vehicle-treated patients. Thus, administration of patidegib gel 2% prevents new BCCs in subjects with PTCH1 mutations.

[0137] The number of new BCCs, excluding BCCs no longer suspicious, observed in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 6 is shown in Figure 2 and Table 2 below.

[0138] [Table 3]

[0139] As shown in Table 2 and Figure 2, after 6 months of treatment with Patidegib Gel 2%, the number of new BCCs, excluding those no longer suspected, was approximately 1.68 compared to approximately 3.15 in vehicle-treated patients. After 12 months of treatment with Patidegib Gel 2%, the number of new BCCs, excluding those no longer suspected, was approximately 2.78 compared to approximately 5.18 in vehicle-treated patients. Thus, administration of Patidegib Gel 2% prevented new BCCs in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 6.

[0140] The number of new BCCs, excluding BCCs no longer suspicious, observed in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 8 is shown in Figure 3 and Table 3 below.

[0141] [Table 4]

[0142] As shown in Table 3 and Figure 3, after 6 months of treatment with Patidegib Gel 2%, the number of new BCCs, excluding BCCs no longer suspected, was approximately 1.96 compared to approximately 3.57 in vehicle-treated patients. After 12 months of treatment with Patidegib Gel 2%, the number of new BCCs, excluding BCCs no longer suspected, was approximately 2.96 compared to approximately 5.80 in vehicle-treated patients. Thus, administration of Patidegib Gel 2% prevented new BCCs in subjects with a PTCH1 mutation and at least 8 total facial BCC lesions at baseline.

[0143] The number of new BCCs, excluding BCCs no longer suspicious, observed in subjects with a PTCH1 mutation and a baseline total of at least 10 facial BCC lesions is shown in Figure 4 and Table 4 below.

[0144] [Table 5]

[0145] As shown in Table 4 and Figure 4, after 6 months of treatment with Patidegib Gel 2%, the number of new BCCs, excluding BCCs no longer suspected, was approximately 1.93 compared to approximately 4.18 in vehicle-treated patients. After 12 months of treatment with Patidegib Gel 2%, the number of new BCCs, excluding BCCs no longer suspected, was approximately 2.88 compared to approximately 6.38 in vehicle-treated patients. Thus, administration of Patidegib Gel 2% prevented new BCCs in subjects with a PTCH1 mutation and at least 10 total facial BCC lesions at baseline.

[0146] The number of qualifying nSEBs observed in subjects with PTCH1 mutations is shown in Figure 5 and Table 5 below.

[0147] [Table 6]

[0148] As shown in Table 5 and Figure 5, after 6 months of treatment with Patidegib Gel 2%, the number of qualifying nSEBs is approximately 0.38 compared to approximately 0.56 in vehicle-treated patients. After 12 months of treatment with Patidegib Gel 2%, the number of qualifying nSEBs is approximately 0.5 compared to approximately 1.04 in vehicle-treated patients. Thus, administration of Patidegib Gel 2% reduces the number of qualifying nSEBs in subjects with PTCH1 mutations.

[0149] The number of qualifying nSEBs observed in subjects with a PTCH1 mutation and a baseline total of at least 6 facial BCC lesions is shown in Figure 6 and Table 6 below.

[0150] [Table 7]

[0151] As shown in Table 6 and Figure 6, after 6 months of treatment with Patidegib Gel 2%, the number of qualifying nSEBs is approximately 0.42 compared to approximately 0.68 in vehicle-treated patients. After 12 months of treatment with Patidegib Gel 2%, the number of qualifying nSEBs is approximately 0.47 compared to approximately 1.23 in vehicle-treated patients. Thus, administration of Patidegib Gel 2% reduces the number of qualifying nSEBs in subjects with PTCH1 mutations and at least 6 total facial BCC lesions at baseline.

[0152] The number of qualifying nSEBs observed in subjects with PTCH1 mutations and a baseline total of at least 8 facial BCC lesions is shown in Figure 7 and Table 7 below.

[0153] [Table 8]

[0154] As shown in Table 7 and Figure 7, after 6 months of treatment with Patidegib Gel 2%, the number of qualifying nSEBs is approximately 0.52 compared to approximately 0.77 in vehicle-treated patients. After 12 months of treatment with Patidegib Gel 2%, the number of qualifying nSEBs is approximately 0.52 compared to approximately 1.40 in vehicle-treated patients. Thus, administration of Patidegib Gel 2% reduces the number of qualifying nSEBs in subjects with PTCH1 mutations and at least 8 total facial BCC lesions at baseline.

[0155] The number of qualifying nSEBs observed in subjects with a PTCH1 mutation and a baseline total of at least 10 facial BCC lesions is shown in Figure 8 and Table 8 below.

[0156] [Table 9]

[0157] As shown in Table 8 and Figure 8, after 6 months of treatment with Patidegib Gel 2%, the number of qualifying nSEBs is approximately 0.64 compared to approximately 0.82 in vehicle-treated patients. After 12 months of treatment with Patidegib Gel 2%, the number of qualifying nSEBs is approximately 0.56 compared to approximately 1.69 in vehicle-treated patients. Thus, administration of Patidegib Gel 2% reduces the number of qualifying nSEBs in subjects with PTCH1 mutations and at least 10 total facial BCC lesions at baseline.

[0158] The rates of clinically resolved SEB observed in subjects with PTCH1 mutations are shown in Figure 9 and Table 9 below.

[0159] [Table 10]

[0160] As shown in Table 9 and Figure 9, after 9 months of treatment with Patidegib Gel 2%, the rate of clinically resolved SEB was approximately 8.11 compared to approximately 9.55 in vehicle-treated patients. After 12 months of treatment with Patidegib Gel 2%, the rate of clinically resolved SEB was approximately 14.68 compared to approximately 12.62 in vehicle-treated patients. Thus, administration of Patidegib Gel 2% increases the rate of clinically resolved SEB in subjects with PTCH1 mutations compared to administration of vehicle.

[0161] The rate of clinically resolved SEB observed in subjects with PTCH1 mutations and a baseline total of at least 6 facial BCC lesions is shown in Figure 10 and Table 10 below.

[0162] [Table 11]

[0163] As shown in Table 10 and Figure 10, after 9 months of treatment with Patidegib Gel 2%, the proportion of clinically resolved SEB was approximately 10.22, compared to approximately 8.30 for vehicle-treated patients. After 12 months of treatment with Patidegib Gel 2%, the proportion of clinically resolved SEB was approximately 18.79, compared to approximately 11.33 for vehicle-treated patients. Thus, administration of Patidegib Gel 2% increased the proportion of clinically resolved SEB in subjects with PTCH1 mutations and baseline total facial BCC lesions of at least 6, compared to vehicle administration.

[0164] The rate of clinically resolved SEB observed in subjects with PTCH1 mutations and at least 8 total facial BCC lesions at baseline is shown in Figure 11 and Table 11 below.

[0165] [Table 12]

[0166] As shown in Table 11 and Figure 11, after 9 months of treatment with Patidegib Gel 2%, the proportion of clinically resolved SEB was approximately 8.73, compared to approximately 6.89 in patients treated with vehicle. After 12 months of treatment with Patidegib Gel 2%, the proportion of clinically resolved SEB was approximately 12.84, compared to approximately 10.38 in patients treated with vehicle. Thus, administration of Patidegib Gel 2% increased the proportion of clinically resolved SEB in subjects with PTCH1 mutations and baseline total facial BCC lesions of at least 8, compared to administration of vehicle.

[0167] The rate of clinically resolved SEB observed in subjects with PTCH1 mutations and at least 10 total facial BCC lesions at baseline is shown in Figure 12 and Table 12 below.

[0168] [Table 13]

[0169] As shown in Table 12 and Figure 12, after 9 months of treatment with Patidegib Gel 2%, the rate of clinically resolved SEB was approximately 13.39 compared to approximately 6.07 for vehicle-treated patients. After 12 months of treatment with Patidegib Gel 2%, the rate of clinically resolved SEB was approximately 16.89 compared to approximately 9.01 for vehicle-treated patients. Thus, administration of Patidegib Gel 2% increased the rate of clinically resolved SEB in subjects with PTCH1 mutations and baseline total facial BCC lesions of at least 8 compared to vehicle administration.

[0170] The number of new BCCs per subject by 12 months observed in subjects with PTCH1 mutations is shown in Table 13, shown below.

[0171] [Table 14]

[0172] As shown in Table 13, after 12 months of treatment with patidegib gel 2%, the number of new BCCs per subject was approximately 3.08, compared with approximately 4.19 for vehicle-treated patients. Thus, administration of patidegib gel 2% prevents the formation of new BCCs in subjects with PTCH1 mutations compared with administration of vehicle.

[0173] The number of BCC surgeries per subject up to 12 months in subjects with more than six BCC lesions at baseline is shown in Table 14 below.

[0174] [Table 15]

[0175] As shown in Table 14, after 12 months of treatment with Patidegib Gel 2%, the number of BCC surgeries per subject was approximately 0.6 compared to approximately 1.3 in vehicle-treated patients. Thus, administration of Patidegib Gel 2% reduces BCC surgeries in subjects with at least six facial BCC lesions compared to administration of vehicle.

[0176] Example 3

[0177] A randomized, double-blind, stratified, vehicle-controlled study was conducted to measure the efficacy and safety of patidegib topical gel, 2%, applied topically twice daily to the face of adult participants with Gorlin syndrome. Participants were required to apply the study drug for 12 months. The primary endpoint was a comparison between the two treatment arms of the number of new BCCs that developed over 12 months.

[0178] Experiment: Patidegib topical gel, 2%,

[0179] Participants will be randomized to receive pacydegib topical gel, 2%, which will be dispensed to participants at each study visit and applied topically to the face twice daily.

[0180] Placebo comparator: pacydegib topical gel, vehicle

[0181] Participants will be randomized to receive vehicle: pacydegib topical gel, which will be dispensed to participants at each study visit and applied topically to the face twice daily.

[0182] Participant Criteria Inclusion Criteria: 1. Participants must be at least 18 years of age at the time of the screening visit. 2. Participants must provide written informed consent prior to any study procedures. 3. Participants must meet diagnostic criteria for Basal Cell Nevus (Gorlin) Syndrome, including major criterion #3a plus one additional major criterion or two additional minor criteria listed below. Main criteria: a. More than two histologically confirmed BCCs, or one for participants under 20 years of age. b. Histologically confirmed odontogenic horn cyst of the jaw. c. 3 or more palmar and / or plantar pits present at the screening visit. d. Bilaminar calcification of the falx cerebri present in a patient under 20 years of age. e. Fused, bisected, or noticeably splayed ribs. f. First-degree relative with Gorlin syndrome. g. Patch protein 1 (PTCH1) mutations predicted to be functionally significant in normal tissues. Minor Criteria: h. Macrocephaly. i. Congenital malformations including frontal bossing, cleft lip or palate, "coarse face," and moderate to severe hypersensitivity. j. Clinically detectable skeletal abnormalities: Sprengel deformity, prominent thoracic deformity, or prominent syndactyly of the fingers. k. Radiographically detectable skeletal abnormalities: bridging of the sella turcica; vertebral abnormalities such as hemivertebrae, vertebral fusion or elongation; modeling defects of the hands and feet; flaring brightness of the hands or feet. l. Ovarian fibroma. m. Medulloblastoma (modification of the criteria of V Kimonis et al Am J Med Genet 69:299-308,1997). 4. Participants must have had 10 clinically typical BCCs (at least 3 on the face) within the 24 months prior to randomization (Baseline / Day 1). In addition, subjects must have had at least 2 BCCs on the face with a longest diameter less than 5 mm prior to randomization (Baseline / Day 1). 5. Participant is willing to have blood drawn to measure circulating drug levels. 6. Participants are willing to refrain from applying non-investigational topical medications (prescription or over-the-counter) to facial skin during the study period, unless prescribed by the investigator. Moisturizers and emollients are permitted. Participants are encouraged to use a preferred sunscreen with a sun protection factor (SPF) of at least 30 daily on all exposed skin areas. 7. If the participant is a woman of childbearing potential (WOCBP), she must be willing to completely abstain from sexual intercourse and / or she and her partner must be willing to use at least two highly effective forms of contraception starting before baseline, throughout the study, and for 12 months after the last application of IP. 8. If the participant is a man with a female sex partner who is a WOCBP, the participant must be willing to use condoms, even after a vasectomy, starting before baseline, throughout the study, and for at least 8 months after the last application of IP. 9. Participant is willing to be evaluated for all facial BCCs and have treatment recommendations made only by the investigator. 10. Participant is willing to forgo treatment of facial BCCs with anything other than study IP, unless the investigator believes that delaying treatment of facial BCCs may compromise the subject's health. During the study, the only form of treatment permitted is surgery. Non-facial BCCs may be removed at the discretion of the investigator or primary skin care physician (PSCP). Exclusion criteria: 1. Subject has previously participated in a clinical trial evaluating pacydegib topical gel. 2. Participant uses topical treatments on the face or systemic therapy that may interfere with the evaluation of study IP. Among these are the use of: a. Systemic or topical 5-fluorouracil, imiquimod, diclofenac, or ingenol mebutate to the skin (except as topical treatment for an individual non-facial BCC) within 2 months prior to the screening visit. b. Systemic chemotherapy within 1 year prior to the screening visit. c. Known local or systemic inhibitors of the hedgehog signaling pathway (e.g., vismodegib, sonidegib, itraconazole) within 3 months prior to the screening visit. d. Photodynamic therapy (PDT) for any localized, non-facial, individual BCC within 2 months prior to the screening visit. 3. Participant has known hypersensitivity to any of the ingredients in the investigational drug formulation. 4. Participant is unable or unwilling to make a good faith effort to return to the study site for all study visits and testing. 5. Participant has an uncontrolled systemic disease. 6. Participant has been treated for invasive cancer within the past 5 years, except for non-melanoma skin cancer, stage I cervical cancer, ductal carcinoma in situ, or stage 0 chronic lymphocytic leukemia (CLL). 7. Participant is currently, recently (within 5 half-lives of the experimental drug, or if the half-life is unknown, within the past 6 months prior to the screening visit), or planning to participate in an experimental drug study while enrolled in this study. 8. Participants are WOCBP who are unwilling or unable to comply with pregnancy prevention measures. 9. Participant is pregnant or breastfeeding. 10. The participant has any condition or situation that, in the opinion of the investigator, could place the subject at significant risk, confound the study results, or significantly prevent the subject from participating in the study. This could include a history of other skin conditions (e.g., severe facial eczema) or diseases, metabolic dysfunction, physical examination findings, or clinical laboratory findings that raise reasonable suspicion of a disease or condition that contraindicates the use of the investigational drug or that could affect the interpretation of the study results or place the participant at increased risk for treatment complications.

[0183] result

[0184] The results of the proportion of clinically resolved SEB observed in all types of subjects in Example 3 are shown in Figure 13 and Table 15 below.

[0185] [Table 16]

[0186] As shown in Table 15 and Figure 13, after 9 months of treatment with Patidegib Gel 2%, the rate of clinically resolved SEB was approximately 9.13, compared to approximately 12.66 for vehicle-treated patients. After 12 months of treatment with Patidegib Gel 2%, the number of eligible SEB was approximately 15.03, compared to approximately 16.75 for vehicle-treated patients. Thus, administration of Patidegib Gel 2% did not affect the rate of clinically resolved SEB in all types of subjects in the study of Example 3, compared to administration of vehicle.

[0187] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

1. 1. A method for treating and / or preventing basal cell carcinoma (BCC) lesions, comprising: topically administering to a subject a pharmaceutical composition comprising patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; The subject eligible for treatment and / or prevention of BCC lesions is (i) the subject has at least six facial BCC lesions; (ii) the subject has a genetically mutated PTCH; and (iii) the subject is selected according to any one of the following criteria: having at least six BCC lesions and a genetically mutated PTCH.

2. 10. The method of claim 1, wherein the subject has at least six facial BCC lesions and a genetically mutated PTCH.

3. 3. The method of claim 1 or 2, wherein the patidegib is present in an amount of about 0.1% w / w to about 6% w / w.

4. 4. The method of claim 3, wherein the patidegib is present in an amount of 2%, 3%, or 4% w / w.

5. 5. The method of claim 4, wherein the patidegib is present in an amount of 2% w / w.

6. The method of any one of claims 1 to 5, wherein the patidegib is formulated as a gel formulation.

7. The subject has at least six facial BCC lesions, and 7. The method of any one of claims 1-6, wherein the subject is afflicted with non-melanoma skin cancer, Rombo syndrome, Bazex-Dupre-Christol syndrome, xeroderma pigmentosum, Muir-Torre syndrome, oculocutaneous albinism, Gorlin syndrome, or any combination thereof.

8. The subject eligible for treatment and / or prevention of BCC lesions is (i) the subject has at least six facial BCC lesions; (ii) the subject has a genetically mutated PTCH; and (iii) the subject is selected according to any one of the following criteria: the subject has at least six BCC lesions and a genetically mutated PTCH; and The method of any one of claims 1 to 6, wherein the subject is suffering from Gorlin syndrome.

9. The subject has at least six facial BCC lesions, and 8. The method of claim 7, wherein the subject is suffering from Gorlin syndrome.

10. Treatment of BCC lesions using this method results in:

10. The method of any one of claims 1 to 9, which results in a reduction in size of the BCC lesions or clinical resolution of the BCC lesions over time.

11. Prevention of BCC lesions using this method:

10. The method of any one of claims 1 to 9, wherein the formation of new BCC or new surgically eligible BCC is prevented.

12. 12. The method of any one of claims 1 to 11, wherein the pharmaceutical composition is administered topically once daily, twice daily, three times daily, every other day, or three times weekly.

13. 13. The method of claim 12, wherein the pharmaceutical composition is administered topically for about 6 months, about 9 months, about 12 months, more than 12 months, or lifelong.

14. The method of any one of claims 1 to 13, wherein the subject does not develop drug resistance.

15. The method of any one of claims 1 to 13, wherein the subject does not develop drug resistance after a period of cessation of administration during treatment of a BCC lesion.

16. The method of any one of claims 1 to 15, wherein the efficacy of the pharmaceutical composition is not affected after a period of discontinuation of administration during the treatment of BCC lesions.

Images