Treatment and prevention of basal cell cancer using topical compositions comprising paltidegi

Abstract

Disclosed herein is a method of treating and / or preventing basal cell carcinoma lesions, the method comprising topically administering to a subject in need thereof a pharmaceutical composition comprising patinigib, or a pharmaceutically acceptable salt thereof, where (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a genetically mutated PTCH; or (iii) the subject must have at least 6 BCC lesions and a genetically mutated PTCH.

Description

Technical Field

[0001] In some embodiments of the present invention, the present invention relates to a method for treating and / or preventing basal cell carcinoma (BCC) lesions, comprising topically administering a pharmaceutical composition comprising patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject in need thereof, wherein (i) the subject has at least 6 facial BCC lesions; or (ii) the subject has a PTCH gene mutation; or (iii) the subject has at least 6 BCC lesions and a PTCH gene mutation. Background Art

[0002] Basal cell carcinoma (BCC) is a common form of skin cancer and a subtype of non-melanoma skin cancer (NMSC). BCC arises from abnormal, uncontrolled growth of basal cells and is driven by the Hedgehog (HH) signaling pathway, which is considered the primary signaling pathway during embryonic development but is typically shut down after birth. Activated Hedgehog (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 the growth of BCC. Mutations in human patched 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 nonsurgical therapies are available for treating BCC. Nonsurgical therapies include radiation therapy, chemotherapy, and immunotherapy. These therapies can be useful for definitive treatment of primary tumors and some recurrent BCC tumors, as well as for relieving symptoms associated with inoperable tumors. However, some of these therapies can also have significant and uncomfortable side effects. The side effects of radiation therapy and certain chemotherapy treatments are well documented. One form of immunotherapy involves intralesional injections of interferon. While interferon therapy can be effective for BCC, multiple intralesional injections can require several weekly clinic visits for several weeks and can be painful.

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

[0005] Some genetic conditions are associated with an increased risk and incidence of BCC at a young age. These conditions 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 cases (but not all) by germline mutations in the human patched gene-1 (PTCH1) and, more rarely, by mutations in SMO, SUFU (SUFU negative regulator of hedgehog signaling), and / or PTCH2. 1,2a, 2b Affected patients present with developmental dysplasia and postnatal tumors, including multiple BCCs, with a mean age of 20 to 21 years, odontogenic keratocysts, and medulloblastomas.[ 3 Individuals affected by Gorlin syndrome develop multiple (tens to thousands) microscopic and macroscopic BCCs, various benign follicular hamartomas, and palmar and plantar pitting, in addition to skeletal defects (rib bifurcation and syndactyly), central nervous system abnormalities (calcification of the falx cerebri and agenesis of the corpus callosum), craniofacial features (cranial enlargement, organ hypertelorism, and frontal bossing), and benign odontogenic keratocysts of the jaw.

[0007] Rombo syndrome - Rombo syndrome was first described in a family with verminous atrophic dermatoses and peripheral vasodilation, accompanied by cyanosis, milia, trichoepithelioma in childhood, hypotrichosis in adulthood, and BCC developing in the third and fourth decades. 4 Romberg syndrome appears to be transmitted in a dominant manner; however, the causative mutation has not been identified.

[0008] Bazex-Dupré-Christol syndrome - Bazex-Dupré-Christol syndrome (also known as Bazex syndrome or follicular atrophic dermatosis and basal cell carcinoma) is an X-linked dominant disorder characterized by congenital hypotrichosis, follicular atrophic dermatosis, 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 repairing UV-induced DNA damage. 6 Clinical findings include early-onset pigmentary skin changes and early development of skin cancer. The average age of onset for both SCC and BCC is nine 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. Affected individuals suffer from 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 melanin biosynthesis disorders that present with a range of visual impairments and decreased skin and hair pigmentation. Individuals with OCA are at increased risk for early-onset skin cancer, possibly during adolescence. SCC is the most common type of cancer that occurs in patients with OCA, but BCC and melanoma can also occur. 7 ].

[0012] In the general population, BCCs are commonly observed on sun-exposed areas of the skin.

[0013] Furthermore, immunosuppressed subjects or subjects exposed to radiation, asbestos, sunlight, or tanning salons are at increased risk for developing BCC.Thus, there remains a need for a non-surgical treatment for BCC that provides better therapy.

[0014] Patideji

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

[0016]

[0017] Patidegi is covered by US 8,785,635 (US'635), entitled "Cyclopamine analogs." Patidegi is a member of a class of anticancer compounds known as Hedgehog (HH) pathway inhibitors. Patidegi exerts its pharmacological effects by inhibiting the G protein-coupled receptor smoothened, a component of the Hedgehog (HH) signaling pathway.

[0018] References

[0019] [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

[0020] [2a] Farndon PA, Del Mastro RG, Evans DG, Kilpatrick MW. Location of gene for Gorlin syndrome. Lancet 1992;339:581.

[0021] [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.

[0022] [4] Schierbeck J, Vestergaard T, Bygum A. Skin Cancer Associated Genodermatoses: A Literature Review. Acta Derm Venereol 2019;99:360.

[0023] [5] Torrelo A, Sprecher E, Mediero IG, et al. What syndrome is this? Bazex-Dupre-Christol syndrome. Pediatr Dermatol 2006;23:286.

[0024] [6] DiGiovanna JJ, Kraemer KH. Shining a light onxeroderma pigmentosum. J Invest Dermatol 2012;132:785.

[0025] [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

[0026] The present invention relates to a method for treating and / or preventing basal cell carcinoma lesions, comprising topically administering a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the subject eligible for said treatment and / or said prevention is selected according to any one of the following criteria: (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The subject matter which is regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. However, the invention both as to its organization and method of operation, together with objects, features, and advantages thereof, may be best understood from the following detailed description when read with the accompanying drawings in which:

[0028] Figure 1 : Graphical representation of the number of new basal cell carcinoma (BCC) lesions observed for subjects with PTCH1 mutations that exclude BCC no longer suspected. Based on the study described in Example 2.

[0029] Figure 2 : Graphical illustration of the number of new BCCs observed after exclusion of no longer suspicious BCCs for subjects with a PTCH1 mutation and at least 6 facial BCC lesions at baseline. Based on the study described in Example 2.

[0030] Figure 3 : Graphical illustration of the number of new BCCs observed after exclusion of no longer suspicious BCCs for subjects with a PTCH1 mutation and at least 8 facial BCC lesions at baseline. Based on the study described in Example 2.

[0031] Figure 4 : Graphical illustration of the number of new BCCs observed after exclusion of no longer suspicious BCCs for subjects with a PTCH1 mutation and at least 10 facial BCC lesions at baseline. Based on the study described in Example 2.

[0032] Figure 5 : 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.

[0033] Figure 6 : Graphical illustration of the number of qualified nSEBs observed for subjects with a PTCH1 mutation and at least 6 facial BCC lesions at baseline. Based on the study described in Example 2.

[0034] Figure 7 : Graphical illustration of the number of qualified nSEBs observed for subjects with a PTCH1 mutation and at least 8 facial BCC lesions at baseline. Based on the study described in Example 2.

[0035] Figure 8 : Graphical illustration of the number of qualified 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.

[0036] Figure 9: Graphical representation of the proportion of clinically resolved SEB observed in subjects with PTCH1 mutations. Based on the studies described in Example 2.

[0037] Figure 10 : Graphical illustration of the proportion of clinically resolved SEB observed in subjects with PTCH1 mutations and at least 6 facial BCC lesions at baseline. Based on the study described in Example 2.

[0038] Figure 11 : Graphical illustration of the proportion of clinically resolved SEB observed in subjects with PTCH1 mutations and at least 8 facial BCC lesions at baseline. Based on the study described in Example 2.

[0039] Figure 12 : Graphical illustration of the proportion of clinically resolved SEB observed in subjects with PTCH1 mutations and at least 10 facial BCC lesions at baseline. Based on the study described in Example 2.

[0040] Figure 13 : Graphical representation of the observed proportion of clinically resolved SEB in the intent-to-treat population (ITT). Based on the study described in Example 3.

[0041] It should be understood that for simplicity and clarity of illustration, the elements shown in the figures are not necessarily drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. In addition, where deemed appropriate, reference numerals may be repeated in the drawings to indicate corresponding or similar elements. DETAILED DESCRIPTION

[0042] 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 cases, well-known methods, procedures, and components are not described in detail in order to avoid obscuring the present invention.

[0043] In some embodiments, the present invention provides a method for treating and / or preventing basal cell carcinoma (BCC) lesions, comprising topically administering a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject in need thereof, wherein (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a genetic mutation; or (iii) the subject must have at least 6 BCC lesions and a genetic mutation. In another embodiment, the genetic mutation comprises PATCH, PATCH1, PATCH2, SMO, SUFU, or any combination thereof.

[0044] In some embodiments, the present invention provides a method for treating and / or preventing basal cell carcinoma (BCC) lesions, comprising topically administering a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the subject eligible for said treatment and / or said prevention is selected based on any of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. 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 8 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 4 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions. 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.

[0045] In some embodiments, provided herein is 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 patilide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject eligible for said treatment and / or said prevention is selected according to any one of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation, and wherein the composition comprises patilide in an amount of about 0.1% w / w to about 6% w / w. In another embodiment, the composition comprises an amount of Patidegib 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 an amount of Patidegib 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 an amount of Patidegib of about 2% w / w, 3% w / w or 4% w / w. In another embodiment, the composition comprises an amount of Patidegib of about 2%.

[0046] 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 Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject eligible for said treatment and / or said prevention is selected according to any one of the following criteria: (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation.

[0047] In another embodiment, the PTCH is PTCH 1. In another embodiment, the PTCH is PTCH 2. In another embodiment, the PTCH is PTCH 1 and / or PTCH 2.

[0048] 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 PTCH mutation. In another embodiment, the subject must have at least 10 BCC lesions and a PTCH mutation. In another embodiment, the subject must have at least 12 BCC lesions and a PTCH mutation.

[0049] In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH mutation. In another embodiment, the subject must have at least 8 facial BCC lesions and a PTCH mutation. In another embodiment, the subject must have at least 10 facial BCC lesions and a PTCH mutation. In another embodiment, the subject must have at least 12 facial BCC lesions and a PTCH mutation.

[0050] In some embodiments, provided herein is 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 patidegid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation, and wherein the composition comprises patidegid in an amount of about 0.1% w / w to about 6% w / w. In another embodiment, the composition comprises an amount of Patidegib 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 an amount of Patidegib 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 an amount of Patidegib of about 2% w / w, 3% w / w or 4% w / w. In another embodiment, the composition comprises an amount of Patidegib of about 2%.

[0051] In some embodiments, provided herein is 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 patidegid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject eligible for said treatment and / or said prevention is selected according to any one of the following criteria: (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 facial BCC lesions and a PTCH gene mutation, and wherein the composition comprises patidegid in an amount of about 0.1% w / w to about 6% w / w. In another embodiment, the composition comprises an amount of Patidegib 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 an amount of Patidegib 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 an amount of Patidegib of about 2% w / w, 3% w / w or 4% w / w. In another embodiment, the composition comprises an amount of Patidegib of about 2%.

[0052] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising patidegid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject eligible for said treatment and / or said prevention is selected according to any one of the following criteria: (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation, and wherein the composition comprises patidegid in an amount of about 2% w / w.

[0053] In some embodiments, the topical composition of Patidegib of the present invention is selected from a cream, an ointment, a gel, a lotion, a spray, a patch, or a foam. In some embodiments, the topical composition of Patidegib of the present invention is a gel.

[0054] In another embodiment, the patilide is formulated as a gel formulation.

[0055] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject eligible for said treatment and / or said prevention is selected according to any one of the following criteria: (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation, and wherein the amount of Patidegib is about 0.1% w / w to about 6% w / w, and wherein said Patidegib is formulated into a gel formulation. In another embodiment, said Patidegib is formulated as described in Example 1.

[0056] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least 6 BCC lesions.

[0057] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least 6 facial BCC lesions.

[0058] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the subject must have a PTCH gene mutation.

[0059] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the subject must have at least 6 BCC lesions and a gene mutation PTCH.

[0060] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0061] In some embodiments, provided herein is a method for treating basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject eligible for treatment is selected according to any one of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation.

[0062] In some embodiments, provided herein is a method for treating basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject eligible for treatment is selected according to any one of the following criteria: (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. In some embodiments, provided herein is a method for treating basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject eligible for treatment is selected according to any one of the following criteria: (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0063] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject eligible for treatment is selected based on any of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation, and wherein the subject has Gorlin syndrome. In another embodiment, the subject must have at least 6 facial lesions. In another embodiment, the subject must have a PTCH gene mutation. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0064] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least 6 BCC lesions, and wherein the subject suffers from Gorlin syndrome.

[0065] In some embodiments, provided herein is a method of treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least 6 facial BCC lesions, and wherein the subject suffers from Gorlin syndrome.

[0066] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the subject must have a gene mutation PTCH, and wherein the subject suffers from Gorlin syndrome.

[0067] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the subject must have at least 6 BCC lesions and a gene mutation PTCH, and wherein the subject suffers from Gorlin syndrome.

[0068] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the subject must have at least 6 facial BCC lesions and a gene mutation PTCH, and wherein the subject suffers from Gorlin syndrome.

[0069] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the subject must have at least 6 BCC lesions, and wherein the subject is immunosuppressed, or the subject is exposed to radiation, asbestos, sunlight, or a tanning salon. In another embodiment, the subject must have at least 8 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 6 facial BCC lesions. 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.

[0070] In some embodiments, provided herein is a method of treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least 6 facial BCC lesions, and wherein the subject is immunosuppressed, or the subject has been exposed to radiation, asbestos, sunlight, or a tanning salon.

[0071] In some embodiments, provided herein is a method of treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least 6 BCC lesions, and wherein the subject has a condition comprising: non-melanoma skin cancer, Romberg syndrome, Barzet-du-Pre-Christopher syndrome, xeroderma pigmentosum, Miehl-Dorie syndrome, oculocutaneous albinism, or Gorlin syndrome.

[0072] In some embodiments, provided herein is a method of treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least 6 facial BCC lesions, and wherein the subject has a condition comprising: non-melanoma skin cancer, Romberg syndrome, Barzet-du-Pre-Christopher syndrome, xeroderma pigmentosum, Miehl-Dorie syndrome, oculocutaneous albinism, or Gorlin syndrome.

[0073] In some embodiments, provided herein is a method of treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least 6 BCC lesions, and wherein the subject has Romberg syndrome, Barzet-du-Pre-Christopher syndrome, xeroderma pigmentosum, Miehl-Dorie syndrome, or oculocutaneous albinism.

[0074] In some embodiments, provided herein is a method of treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject must have at least 6 facial BCC lesions, and wherein the subject has Romberg syndrome, Barzet-du-Pre-Christopher syndrome, xeroderma pigmentosum, Miehl-Dorie syndrome, or oculocutaneous albinism.

[0075] In some embodiments, the methods of treating BCC of the present invention result in a reduction in BCC lesion size or clinical regression over time. In another embodiment, the methods of treating BCC of the present invention result in a reduction in BCC lesion size. In another embodiment, the BCC lesion size is reduced by approximately 1-100%. In another embodiment, the lesion size is reduced by approximately 5%. In another embodiment, the BCC lesion size is reduced by approximately 10%. In another embodiment, the BCC lesion size is reduced by approximately 20%. In another embodiment, the lesion size is reduced by approximately 30%. In another embodiment, the lesion size is reduced by approximately 40%. In another embodiment, the lesion size is reduced by approximately 50%. In another embodiment, the BCC lesion size is reduced by approximately 60%. In another embodiment, the BCC lesion size is reduced by approximately 70%. In another embodiment, the lesion size is reduced by approximately 75%. In another embodiment, the BCC lesion size is reduced by approximately 80%. In another embodiment, the BCC lesion size is reduced by approximately 85%. In another embodiment, the BCC lesion size is reduced by approximately 90%. In another embodiment, the BCC lesion size is reduced by approximately 95%. In another embodiment, the BCC lesion size is reduced by approximately 100%.

[0076] In another embodiment, the treatment of BCC results in clinical regression of the BCC, in particular complete disappearance of the BCC. In another embodiment, the treatment of a BCC lesion results in clinical regression of the BCC, wherein the lesion is no longer suspected to be a BCC.

[0077] In some embodiments, the methods of the present invention prevent the formation of new BCCs, wherein subjects eligible for treatment and / or prevention are selected based on any of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH mutation. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH mutation.

[0078] In some embodiments, the methods of the present invention prevent the development of nSEB, wherein subjects eligible for treatment and / or prevention are selected based on any of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH mutation. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH mutation. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH mutation.

[0079] In some embodiments, the methods of the present invention reduce the number of nSEBs, wherein the subject is selected based on any of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH mutation. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH mutation.

[0080] In some embodiments, the present invention provides a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject eligible for said treatment and / or said prevention is selected according to any one of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a gene mutation PTCH; or (iii) the subject must have at least 6 BCC lesions and a gene mutation PTCH; wherein the composition is topically administered once a day, twice a day, three times a day, once every other day, or three times a week.

[0081] In some embodiments, the present invention provides a method for treating and / or preventing basal cell carcinoma (BCC), comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject eligible for said treatment and / or said prevention is selected according to any of the following criteria: (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation; wherein the composition is topically administered once a day, twice a day, three times a day, once every other day, or three times a week. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0082] In some embodiments, provided herein is a method of treatment and / or prevention comprising topically applying a therapeutically effective amount of a composition comprising Patidegib or a pharmaceutically acceptable salt thereof once a day, twice a day, three times a day, every other day, or three times a week.

[0083] In some embodiments, provided herein is a method for treating and / or preventing BCC, comprising topically applying a therapeutically effective amount of a composition comprising Patidegib or a pharmaceutically acceptable salt thereof to the facial skin of a subject in need thereof once a day, twice a day, three times a day, once every other day, or three times a week until the BCC is cured, prevented, or alleviated or as directed by a physician, and wherein the subject eligible for said treatment and / or said prevention is selected according to any one of the following criteria: (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0084] In some embodiments, provided herein is a method for treating and / or preventing BCC, comprising topically applying a therapeutically effective amount of a composition described herein to the 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, and wherein the subject eligible for said treatment and / or said prevention is selected based on one of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0085] In some embodiments, provided herein is a method for treating and / or preventing BCC, comprising topically applying a therapeutically effective amount of a composition described herein to the 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, and wherein the subject eligible for said treatment and / or said prevention is selected based on one of the following criteria: (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0086] In some embodiments, provided herein is a method for treating and / or preventing BCC, comprising topically applying a therapeutically effective amount of a composition described herein to any area of ​​the 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 alleviated, or as directed by a physician, and wherein the subject eligible for said treatment and / or said prevention is selected based on one of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0087] In some embodiments, provided herein is a method 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 alleviated, or as directed by a physician, and wherein the subject eligible for the treatment and / or prevention is selected based on one of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0088] In some embodiments, provided herein is a method for treating BCC lesions, comprising topically applying a therapeutically effective amount of the composition to the BCC lesions of a subject in need thereof once a day, twice a day, three times a day, once every other day, three times a day, once every other day, or three times a week until the BCC is cured, prevented, or alleviated, or as directed by a physician, and wherein (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation.

[0089] In some embodiments, provided herein is a method for treating and / or preventing BCC lesions, comprising topically applying a therapeutically effective amount of the composition to the BCC lesions and the skin surrounding the BCC lesions of a subject in need thereof once a day, twice a day, three times a day, once every other day, three times a day, once every other day, or three times a week until the BCC is cured, prevented, or alleviated or as directed by a physician, and wherein (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0090] In some embodiments, provided herein is a method of treating BCC lesions, comprising topically applying a therapeutically effective amount of the composition to the BCC lesions of a subject in need thereof once a day, twice a day, three times a day, once every other day, three times a day, once every other day, or three times a week until the BCC is cured, prevented, or alleviated, or as directed by a physician, and wherein the subject has (i) at least 6 facial BCC lesions; or (ii) a mutated PTCH gene; or (iii) at least 6 facial BCC lesions and a mutated PTCH gene.

[0091] In some embodiments, provided herein is a method for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is topically administered for a period of about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, about 24 months, about 36 months, chronically, or for life; and wherein (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. Each represents a separate embodiment of the present invention. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0092] 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 lifetime. In another embodiment, the composition is topically administered chronically.

[0093] In some embodiments, provided herein is a method for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is administered for a period of 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 chronic administration, or for life; and wherein the subject eligible for said treatment and / or said prevention is selected based on one of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. Each represents a separate embodiment of the present invention. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation. In another embodiment, the subject does not develop drug resistance. In another embodiment, the subject does not develop drug resistance after a period of discontinuation of administration during the treatment.

[0094] In some embodiments, the subject of the methods provided herein does not develop drug resistance. In another embodiment, the subject of the methods provided herein does not develop drug resistance after a period of discontinuation of administration during the treatment period.

[0095] In some embodiments, provided herein is a method for treating and / or preventing BCC, comprising topically administering a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the composition is topically administered for a period of greater than 12 months; wherein the subject eligible for treatment and / or prevention is selected based on one of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH mutation; and wherein the subject has not developed drug resistance. Each represents a separate embodiment of the present 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 lifetime. In another embodiment, the composition is administered chronically. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH mutation. In another embodiment, said subject does not develop drug resistance during said treatment following a period of discontinuation of administration.

[0096] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma, the method comprising topically administering to a subject a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject eligible for said treatment and / or said prevention is selected according to any one of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a gene mutation PTCH; or (iii) the subject must have at least 6 BCC lesions and a gene mutation PTCH, wherein the subject has not developed drug resistance. In another embodiment, wherein the subject does not develop drug resistance after a certain period of discontinuation of administration during the treatment. In some embodiments, the administration period of the method of the present invention does not affect the efficacy of the drug. In another embodiment, the efficacy of the drug is not affected after a certain period of discontinuation of administration during the treatment.

[0097] In some embodiments, provided herein is a method for treating and / or preventing basal cell carcinoma, comprising topically administering to a subject a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation, and wherein during the treatment period, after a certain period of discontinuation of administration, the efficacy of the drug is not affected.

[0098] In some embodiments, the methods provided herein, the administration period comprises at least 12 consecutive months of administration.

[0099] In some embodiments, the methods provided herein, the administration period comprises (i) 12 consecutive months of administration, (ii) followed by a suspension period, and (iii) followed by continued administration, wherein the efficacy of the drug is not affected after a certain suspension period of administration during the treatment period. In another embodiment, the suspension period is 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months or 1-3 months, 1-24 months, 2-12 months, 3-12 months, 3-8 months, 3-10 months.

[0100] In some embodiments, provided herein is a method for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib 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, wherein after 9 months of administration, the efficacy of treating and / or preventing BCC is improved compared to administration of a vehicle, and wherein (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0101] In some embodiments, provided herein is a method for treating clinically resolved SEB, the method comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib 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, wherein after 9 months of administration, the efficacy of treating and / or preventing BCC is improved compared to administration of a vehicle, and wherein the subject eligible for treatment and / or prevention is selected based on one of the following criteria: (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0102] In some embodiments, provided herein is a method for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is topically administered for a period of more than 12 months, wherein after 12 months of administration, the efficacy of treating and / or preventing BCC is improved compared to administration of a vehicle, and wherein (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0103] In some embodiments, provided herein is a method for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising Patidegib 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, wherein after 12 months of administration, the efficacy of treating and / or preventing BCC is not affected compared to the efficacy of treating / preventing within the first 12 months of topical administration of the pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and wherein (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

[0104] In some embodiments, provided herein is a method for treating and / or preventing BCC, the method comprising topically administering a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the composition is topically administered for a period of at least 18 months, wherein after 18 months of administration, the efficacy of treating and / or preventing BCC is not affected, and wherein (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation.

[0105] In another embodiment, the subject must have at least 6 facial BCC lesions. In another embodiment, the subject must have at least 6 facial BCC lesions and a mutation in the gene PTCH.

[0106] In some embodiments, provided herein is a method for treating and / or preventing BCC, comprising topically administering to a subject in need thereof a pharmaceutical composition comprising patilide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the composition is topically administered for a period of about 3 months, about 6 months, about 9 months, about 12 months, chronically, or for life; and wherein (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation.

[0107] In some embodiments, provided herein is a method for treating and / or preventing BCC, comprising topically administering a pharmaceutical composition comprising Patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the number of BCC surgeries is reduced; and wherein (i) the subject must have at least 6 BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation. In another embodiment, BCC surgeries were reduced after 12 months of treatment (Example 2, Table 14).

[0108] In some embodiments, the pharmaceutically acceptable carrier of the composition 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 composition of the present invention encompasses carriers, excipients, and diluents, meaning materials, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, that are involved in carrying or transporting the drug across the stratum corneum.

[0109] 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.

[0110] In another embodiment, Patidegib or its pharmaceutically acceptable salt compound can be formulated with any pharmaceutically acceptable carrier and can be a liquid, semisolid or solid composition. Pharmaceutical and cosmetic carriers or vehicles suitable for topical application of the composition to the skin or mucous membranes are known to those skilled in the art, and the Patidegib compound can 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 comprising Patidegib or its pharmaceutically acceptable salt is a liquid. Liquid dosage forms for topical administration include emulsions, solutions and suspensions containing diluents commonly used in the art, such as alcohols, glycols, oils, water, etc. The composition may also include a wetting agent, an emulsifier and a suspending agent.

[0111] The composition can be in the form of a solution, suspension, emulsion, ointment, lotion, gel, etc. Emulsions in oil-in-water or water-in-oil forms are contemplated. Gels are formed by embedding a large amount of aqueous or aqueous alcoholic liquid in a network of polymeric or colloidal solid particles. Such polymers or colloids are typically present in a concentration of less than 10% w / w and are also referred to as gelling agents or thickening agents. Examples of suitable gelling agents include carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, sodium alginate, alginic acid, pectin, tragacanth gum, carrageenan, agar, clay, aluminum silicate, carbomer, etc.

[0112] Creams and ointments can also be used. They are emulsions of oily substances and water (i.e., carriers). Creams can be water-in-oil (w / o) in which the aqueous phase is dispersed in the oil phase, or oil-in-water (o / w) in which the oil is dispersed in a water base. Ointments are also contemplated, and ointments are generally more viscous than oil-in-water creams. Traditional ointment bases (i.e., carriers) include hydrocarbons (vaseline, beeswax, etc.), vegetable oils, fatty alcohols (cholesterol, lanolin, lanolin alcohol, stearyl alcohol, etc.), or silicones. Pastes are a type of ointment in which a high percentage of insoluble particulate solids, up to 50% by weight, is added. Insoluble solids, such as starch, zinc oxide, calcium carbonate, or talc, can be used.

[0113] Aerosols can also be used. The compound can be dissolved in a propellant and a cosolvent, such as ethanol, acetone, hexadecanol, etc. A foaming agent can be incorporated to produce a mousse.

[0114] A moisturizer or lubricating vehicle may also be used to help moisturize the skin. Examples of suitable bases or vehicles for preparing moisturizing compositions for use on human skin are petrolatum, petrolatum plus volatile silicones, lanolin, cold cream (USP), and hydrophilic ointment (USP).

[0115] A variety of methods can be used to prepare the formulations described above. Broadly speaking, the formulations can be prepared by combining the components of the formulations as described herein at a temperature and time sufficient to provide a pharmaceutically acceptable composition. As used herein, the term "combined together" means that all components of the composition can be combined and mixed together at about the same time. The term "combined together" also means that the various components can be combined in one or more sequences to provide the desired product. Depending on the form of the final dosage form, the formulation can be prepared on a weight / weight (w / w) or weight / volume (w / v) basis.

[0116] The composition comprises a certain weight fraction of Patidegi or a pharmaceutically acceptable salt thereof, which can be dissolved, suspended, dispersed or otherwise mixed in a selected carrier or vehicle at an effective concentration, thereby alleviating or improving the pruritus condition. A composition in the form of a solution and intended for topical application can contain Patidegi or a pharmaceutically acceptable salt thereof in an amount of about 0.1% w / w to about 6% w / w, the remainder of the solution being water, a suitable organic solvent or other suitable solvent or buffer. Compositions formulated into solutions, emulsions or suspensions can be applied to the skin, or can be formulated into aerosols or foams and applied to the skin in the form of a spray. Aerosol compositions typically contain 25% to 80% w / w, preferably 30% to 50% w / w of a suitable propellant.

[0117] Solid forms of compositions intended for topical application can be formulated as stick 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 Patidegib compound is typically from about 0.1% w / w to about 6% w / w. The solid form of the composition may also contain from about 40% to 98% w / w, preferably from about 50% to 90% w / w, of a carrier.

[0118] As used herein, the term "pharmaceutically acceptable salt" refers to alkali metal salts of free acids and conventional salts of addition salts of free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. The term "pharmaceutically acceptable salt" also includes solvates of addition salts, such as hydrates, and polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic acids or from organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic and heterocyclic carboxylic acids 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, methanesulfonic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, p-aminobenzenesulfonic acid, cyclohexylaminobenzenesulfonic acid, alginic acid, 3-hydroxybutyric acid, galactaric acid and galacturonic acid.

[0119] The term "mutated PTCH gene" refers to mutated PTCH1 and / or mutated PTCH2 gene.

[0120] The term "treatment of BCC" refers to treating BCC, including BCC that is amenable to surgery, until the BCC disappears completely or the lesion growth is reduced (e.g., the size of the lesion / tumor is reduced). In addition, "treatment of BCC" refers to treating BCC found on the entire body of a subject. In another embodiment, the term "treatment of BCC" refers to treating BCC, including BCC that is amenable to surgery, until the BCC disappears completely or the lesion growth is reduced (e.g., the size of the lesion / tumor is reduced), wherein the subject (i) must have at least 6 facial BCC lesions at baseline prior to treatment; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions at baseline (as a baseline prior to treatment) and a PTCH gene mutation. In another embodiment, the term "treatment of BCC" refers to treating BCC, including BCC that is eligible for surgery, until the BCC disappears completely or the lesion growth is reduced (e.g., the size of the lesion / tumor is reduced), wherein the subject (i) must have at least 6 facial BCC lesions at baseline prior to treatment; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 facial BCC lesions and a PTCH gene mutation at baseline prior to treatment.

[0121] The term "prevention of BCC" refers to the prevention of the development of new BCCs and new surgically eligible BCCs. Additionally, "prevention of BCC" refers to the prevention of the development of new BCCs and / or n-SEBs throughout the body. In another embodiment, the term "prevention" refers to the prevention of the development of new BCCs and / or n-SEBs throughout the body, wherein the subject (i) must have at least 6 facial BCC lesions at baseline prior to treatment; or (ii) the subject must have a PTCH mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH mutation at baseline prior to treatment. In another embodiment, the term "prevention" refers to the prevention of the development of new BCCs and / or n-SEBs on the face, wherein the subject (i) must have at least 6 facial BCC lesions at baseline prior to treatment; or (ii) the subject must have a PTCH mutation; or (iii) the subject must have at least 6 facial BCC lesions and a PTCH mutation at baseline prior to treatment.

[0122] The term "long-term" means more than 5, 10 years or longer, lasting a lifetime.

[0123] The term "drug resistance" refers to a drug that is no longer effective.

[0124] The term "efficacy of a drug" refers to the effectiveness of a drug, including preventing the recurrence of BCC and / or reducing the size / dimension of BCC lesions over time.

[0125] In some embodiments, the treatment and / or prevention described herein refers to the treatment and / or prevention of BCC, wherein the subject must have at least 6 BCC lesions anywhere in the entire body at baseline prior to treatment. "Whole body" refers to any specific part of the body (i.e., face, back, legs, hands, stomach, etc.). Thus, treatment comprises applying a composition comprising an effective amount of Patidegib or a pharmaceutically acceptable salt thereof to the specific part of the body to be treated.

[0126] The term "facial BCC lesions" refers to BCC lesions on the face.

[0127] The term "BCC lesions" refers to BBC lesions throughout the body.

[0128] The term "clinically resolved BCC" means that there is no longer any visible evidence of a lesion consistent with BCC at the treated site, i.e., a previously defined BBC lesion is no longer a BCC. In another embodiment, the term clinically resolved BCC refers to a BCC that has completely disappeared clinically.

[0129] The term "nSEB" refers to BCCs with a longest diameter ≥5 mm:

[0130] a. Not a surgically eligible BCC (SEB) at baseline;

[0131] b. The longest diameter has grown by ≥2 mm relative to baseline; and

[0132] c. has been confirmed by histology.

[0133] Additionally, nSEB refers to a histologically confirmed new BCC that should be surgically removed due to possible functional facial / health impairment as determined by the investigator.

[0134] The term "SEB" refers to surgically eligible BCCs with a longest diameter ≥5 mm.

[0135] The term "regressed SEB lesion" refers to a BCC lesion that no longer requires surgical removal. In another embodiment, the term "regressed SEB lesion" refers to a BCC lesion with a diameter of <5 mm or a complete disappearance of the BCC lesion.

[0136] Whenever a numerical range is indicated herein, this is meant to include any cited numeral (fractional or integer) within the indicated range. The phrases "range / range between" a first indicated numeral and a second indicated numeral and "range / range from" a first indicated numeral to a second indicated numeral are used interchangeably herein and are meant to include the first and second indicated numerals and all fractions and integers therebetween.

[0137] The dimensions and values ​​disclosed herein should not be understood as being strictly limited to the exact numerical values ​​recited. Indeed, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as "10 μm" is intended to mean "about 10 μm."

[0138] As used herein, the numerical ranges preceding the term "about" should not be considered to be limited to the recited range. Instead, the numerical ranges preceding the term "about" should be understood to include the ranges accepted by those skilled in the art for any given element in the microcapsules or formulations according to the present invention.

[0139] As used herein, the term "about" means within an acceptable error range for 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 still more preferably up to 1% of a given value. When describing a particular value in this application and the claims, unless otherwise indicated, the term "about" means within an acceptable error range for that particular value.

[0140] The terms "comprise," "comprising," "includes," "including," "having" and their cognates mean "including but not limited to."

[0141] The term "consisting of" means "including and limited to."

[0142] As used herein, the singular forms "a / an" and "the" include plural referents unless the content clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0143] As used herein, the term "method" refers to manners, means, techniques and procedures for accomplishing a given task, including but not limited to those manners, means, techniques and procedures known to practitioners in the fields of chemistry, pharmacology, biology, biochemistry and medicine or readily developed based on known manners, means, techniques and procedures.

[0144] It should be understood that, for the sake of clarity, certain features of the present invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for the sake of simplicity, various features of the present invention described in the context of a single embodiment may also be provided in any other described embodiment of the present invention, alone or in any suitable subcombination or where appropriate. Certain features described in the context of individual embodiments should not be considered essential features of those embodiments, unless the embodiment would be ineffective without those elements.

[0145] Examples

[0146] Example 1 - Gel Formulation

[0147] The Patidegi composition is the gel formulation presented in the table below.

[0148] Composition of Patidegi Topical Gel

[0149]

[0150] Example 2

[0151] A randomized, double-blind, stratified, vehicle-controlled study was conducted to measure the efficacy and safety of Patidegi Topical Gel 2% applied twice daily to the face in adult participants with Gorlin syndrome. Participants were asked to apply the study product for 12 months. The primary endpoint was a comparison of the number of new BCCs that developed over a 12-month period with the two treatments (Patidegi Topical Gel 2% versus vehicle).

[0152] Experimental: Patidegi Topical Gel 2%

[0153] Participants will be randomly assigned to receive Patidegi Topical Gel 2%. Patidegi Topical Gel 2% will be dispensed to participants at each study visit and applied topically to the face twice daily.

[0154] Placebo comparator: Patidegi topical gel vehicle

[0155] Participants will be randomly assigned to receive vehicle. Patidegib topical gel vehicle will be dispensed to participants at each study visit and applied topically to the face twice daily.

[0156] Criteria for participants

[0157] Inclusion criteria:

[0158] 1. Participants must be at least 18 years of age at the screening visit.

[0159] 2. Participants must provide written informed consent before any research procedures.

[0160] 3. Participants must meet the diagnostic criteria for basal cell nevus (Gorlin) syndrome, including a PTCH1 gene mutation, or at least six histologically confirmed facial BCC lesions and a PTCH1 gene mutation at baseline.

[0161] 4. Participant is willing to undergo blood collection for measurement of circulating drug levels.

[0162] 5. Participants are willing to avoid the use of non-study topical medications (prescription or over-the-counter) on their facial skin during the trial unless otherwise prescribed by the investigator. Moisturizers and emollients are permitted. Participants will be encouraged to use their preferred sunscreen with a sun protection factor (SPF) of at least 30 daily on all exposed skin areas.

[0163] 6. If the participant is a woman of childbearing potential (WOCBP), she must be willing to abstain from sexual intercourse completely, and / or she and her partner must be willing to use at least 2 highly effective forms of birth control starting before baseline, throughout the study period, and for 12 months after the last application of IP.

[0164] 7. If the participant is a male whose female sexual partner is a WOCBP, the participant must be willing to use condoms starting before baseline, throughout the study period, and for at least 8 months after the last application of IP, even after vasectomy.

[0165] 8. Participants are willing to have all facial BCCs evaluated and treated by researchers only.

[0166] 9. The participant is willing to forgo any medications other than the study IP for facial BCC treatment, unless the investigator determines that delaying treatment of facial BCC could potentially harm the participant's health. During the trial, the only permitted form of treatment is surgical resection. Non-facial BCCs may be removed at the discretion of the investigator or primary care skin physician (PSCP).

[0167] Exclusion criteria:

[0168] 1. The subject has previously participated in a clinical trial evaluating Patidegi topical gel.

[0169] 2. Participants have used topical facial treatments or systemic therapies that may interfere with the evaluation of the study IP. This includes the use of the following:

[0170] a. Systemic or topical application of 5-fluorouracil, imiquimod, diclofenac, or ingenol mebutate (except as topical treatment for discrete non-facial BCC) to the skin within 2 months prior to the screening visit.

[0171] b. Systemic chemotherapy within 1 year prior to the screening visit.

[0172] c. Topical or systemic use of known Hedgehog signaling pathway inhibitors (such as vismodegib, sonidegib, itraconazole) within 3 months prior to the screening visit.

[0173] d. Photodynamic therapy (PDT), except for localized non-facial individual BCC within 2 months prior to the screening visit.

[0174] 3. Participants are known to have hypersensitivity to any of the ingredients in the study drug formulation.

[0175] 4. The participant is unable or unwilling to make a good faith effort to return to the study site for all study visits and testing.

[0176] 5. Participants suffer from uncontrolled systemic diseases.

[0177] 6. Participants have received treatment for invasive cancer within the past 5 years, excluding non-melanoma skin cancer, stage I cervical cancer, ductal carcinoma in situ of the breast, or chronic lymphocytic leukemia (CLL) stage 0.

[0178] 7. Participant is currently participating in, has recently participated (within five half-lives of the investigational drug, or if half-life is unknown, within the past 6 months prior to the screening visit), or plans to participate in an investigational drug study in this study.

[0179] 8. The participant is a WOCBP who is unwilling or unable to comply with contraceptive measures.

[0180] 9. The participant is pregnant or breastfeeding.

[0181] 10. The investigator believes that the participant has any condition or circumstance that may place the participant at significant risk, may confound the study results, or may seriously interfere with the participant's participation in the study. This may include other skin conditions (such as severe facial eczema) or a medical history, metabolic dysfunction, physical examination results, or clinical laboratory results that reasonably suspect that the use of the study drug is contraindicated or that may affect the interpretation of the study results or place the participant at high risk of treatment complications.

[0182] result:

[0183] like Figure 1 As shown in Table 1 , the number of new BCCs observed in subjects with PTCH1 mutations that excluded BCCs that were no longer suspicious is as follows:

[0184] Table 1

[0185]

[0186] *N = number of patients.

[0187] *Nobs = number of patients with clinical data.

[0188] As shown in Table 1 and Figure 1 As shown, after 6 months of treatment with Patidegi Gel 2%, the number of new BCCs that excluded no longer suspected BCCs was approximately 1.59, while for patients treated with vehicle, this number was approximately 2.6. After 12 months of treatment with Patidegi Gel 2%, the number of new BCCs that excluded no longer suspected BCCs was approximately 2.61, while for patients treated with vehicle, this number was approximately 4.29. Therefore, administration of Patidegi Gel 2% prevents the appearance of new BCCs in subjects with PTCH1 mutations.

[0189] Figure 2 Table 2 shows the number of new BCCs observed in subjects with PTCH1 mutations and a baseline total facial BCC lesion count of at least 6, excluding BCCs that were no longer suspicious, as follows:

[0190] Table 2

[0191]

[0192] *N = number of patients.

[0193] *Nobs = number of patients with clinical data.

[0194] As shown in Table 2 and Figure 2 As shown, after 6 months of treatment with Patidegi Gel 2%, the number of new BCCs that were no longer suspected BCCs was approximately 1.68, while for patients treated with vehicle, this number was approximately 3.15. After 12 months of treatment with Patidegi Gel 2%, the number of new BCCs that were no longer suspected BCCs was approximately 2.78, while for patients treated with vehicle, this number was approximately 5.18. Therefore, administration of Patidegi Gel 2% prevented the appearance of new BCCs in subjects with PTCH1 mutations and a baseline total facial BCC lesion count of at least 6.

[0195] Figure 3 Table 3 shows the number of new BCCs observed after exclusion of no longer suspicious BCCs in subjects with PTCH1 mutations and a baseline total facial BCC lesion count of at least 8, as follows:

[0196] Table 3

[0197]

[0198] *N = number of patients.

[0199] *Nobs = number of patients with clinical data.

[0200] As shown in Table 3 and Figure 3 As shown, after 6 months of treatment with Patidegi Gel 2%, the number of new BCCs that were no longer suspected BCCs was approximately 1.96, while for patients treated with vehicle, this number was approximately 3.57. After 12 months of treatment with Patidegi Gel 2%, the number of new BCCs that were no longer suspected BCCs was approximately 2.96, while for patients treated with vehicle, this number was approximately 5.80. Therefore, administration of Patidegi Gel 2% prevented the appearance of new BCCs in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 8.

[0201] Figure 4 Table 4 shows the number of new BCCs observed after exclusion of no longer suspicious BCCs in subjects with PTCH1 mutations and a baseline total facial BCC lesion count of at least 10, as follows:

[0202] Table 4

[0203]

[0204] *N = number of patients.

[0205] *Nobs = number of patients with clinical data.

[0206] As shown in Table 4 and Figure 4 As shown, after 6 months of treatment with Patidegi Gel 2%, the number of new BCCs that were no longer suspected BCCs was approximately 1.93, while for patients treated with vehicle, this number was approximately 4.18. After 12 months of treatment with Patidegi Gel 2%, the number of new BCCs that were no longer suspected BCCs was approximately 2.88, while for patients treated with vehicle, this number was approximately 6.38. Thus, administration of Patidegi Gel 2% prevented the appearance of new BCCs in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 10.

[0207] Figure 5 and Table 5 shows the number of qualified nSEBs observed in subjects with PTCH1 mutations, as follows:

[0208] Table 5

[0209]

[0210]

[0211] *N = number of patients.

[0212] *Nobs = number of patients with clinical data.

[0213] As shown in Table 5 and Figure 5 As shown, after 6 months of treatment with Patidegi Gel 2%, the number of qualified nSEBs was approximately 0.38, while for patients treated with vehicle, this number was approximately 0.56. After 12 months of treatment with Patidegi Gel 2%, the number of qualified nSEBs was approximately 0.5, while for patients treated with vehicle, this number was approximately 1.04. Therefore, administration of Patidegi Gel 2% reduces the number of qualified nSEBs in subjects with PTCH1 mutations.

[0214] Figure 6 Table 6 shows the number of qualified nSEBs observed in subjects with a PTCH1 mutation and a baseline total BCC facial lesion count of at least 6, as follows:

[0215] Table 6

[0216]

[0217] *N = number of patients.

[0218] *Nobs = number of patients with clinical data.

[0219] As shown in Table 6 and Figure 6 As shown, after 6 months of treatment with Patidegi Gel 2%, the number of qualified nSEBs was approximately 0.42, while for patients treated with vehicle, this number was approximately 0.68. After 12 months of treatment with Patidegi Gel 2%, the number of qualified nSEBs was approximately 0.47, while for patients treated with vehicle, this number was approximately 1.23. Thus, administration of Patidegi Gel 2% reduced the number of qualified nSEBs in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 6.

[0220] Figure 7 Table 7 shows the number of qualified nSEBs observed in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 8, as follows:

[0221] Table 7

[0222]

[0223] *N = number of patients.

[0224] *Nobs = number of patients with clinical data.

[0225] As shown in Table 7 and Figure 7As shown, after 6 months of treatment with Patidegi Gel 2%, the number of qualified nSEBs was approximately 0.52, while for patients treated with vehicle, this number was approximately 0.77. After 12 months of treatment with Patidegi Gel 2%, the number of qualified nSEBs was approximately 0.52, while for patients treated with vehicle, this number was approximately 1.40. Thus, administration of Patidegi Gel 2% reduced the number of qualified nSEBs in subjects with PTCH1 mutations and a baseline total facial BCC lesion count of at least 8.

[0226] Figure 8 Table 8 shows the number of qualified nSEBs observed in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 10, as follows:

[0227] Table 8

[0228]

[0229] *N = number of patients.

[0230] *Nobs = number of patients with clinical data.

[0231] As shown in Table 8 and Figure 8 As shown, after 6 months of treatment with Patidegi Gel 2%, the number of qualified nSEBs was approximately 0.64, while for patients treated with vehicle, this number was approximately 0.82. After 12 months of treatment with Patidegi Gel 2%, the number of qualified nSEBs was approximately 0.56, while for patients treated with vehicle, this number was approximately 1.69. Thus, administration of Patidegi Gel 2% reduced the number of qualified nSEBs in subjects with PTCH1 mutations and a baseline total facial BCC lesion count of at least 10.

[0232] Figure 9 Table 9 shows the proportion of clinically resolved SEB observed in subjects with PTCH1 mutations, as follows:

[0233] Table 9

[0234]

[0235] *N = number of patients.

[0236] *Nobs = number of patients with clinical data.

[0237] As shown in Table 9 and Figure 9As shown, after 9 months of treatment with Patidegi Gel 2%, the proportion of clinically resolved SEB was approximately 8.11, while for patients treated with vehicle, this proportion was approximately 9.55. After 12 months of treatment with Patidegi Gel 2%, the proportion of clinically resolved SEB was approximately 14.68, while for patients treated with vehicle, this proportion was approximately 12.62. Thus, administration of Patidegi Gel 2% increased the proportion of clinically resolved SEB in subjects with PTCH1 mutations compared to administration of vehicle.

[0238] Figure 10 Table 10 shows the proportion of clinically resolved SEB observed in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 6, as follows:

[0239] Table 10

[0240]

[0241]

[0242] *N = number of patients.

[0243] *Nobs = number of patients with clinical data.

[0244] As shown in Table 10 and Figure 10 As shown, after 9 months of treatment with Patidegi Gel 2%, the proportion of SEB that resolved clinically was approximately 10.22, while for patients treated with vehicle, this proportion was approximately 8.30. After 12 months of treatment with Patidegi Gel 2%, the proportion of SEB that resolved clinically was approximately 18.79, while for patients treated with vehicle, this proportion was approximately 11.33. Thus, compared to administration of vehicle, administration of Patidegi Gel 2% increased the proportion of SEB that resolved clinically in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 6.

[0245] Figure 11 Table 11 shows the proportion of clinically resolved SEB observed in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 8, as follows:

[0246] Table 11

[0247]

[0248] *N = number of patients.

[0249] *Nobs = number of patients with clinical data.

[0250] As shown in Table 11 and Figure 11As shown, after 9 months of treatment with Patidegi Gel 2%, the proportion of SEB that resolved clinically was approximately 8.73, while for patients treated with vehicle, this proportion was approximately 6.89. After 12 months of treatment with Patidegi Gel 2%, the proportion of SEB that resolved clinically was approximately 12.84, while for patients treated with vehicle, this proportion was approximately 10.38. Thus, compared to administration of vehicle, administration of Patidegi Gel 2% increased the proportion of SEB that resolved clinically in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 8.

[0251] Figure 12 Table 12 shows the proportion of clinically resolved SEB observed in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 10, as follows:

[0252] Table 12

[0253]

[0254] *N = number of patients.

[0255] *Nobs = number of patients with clinical data.

[0256] As shown in Table 12 and Figure 12 As shown, after 9 months of treatment with Patidegi Gel 2%, the proportion of clinically resolved SEB was approximately 13.39, while for patients treated with vehicle, this proportion was approximately 6.07. After 12 months of treatment with Patidegi Gel 2%, the proportion of clinically resolved SEB was approximately 16.89, while for patients treated with vehicle, this proportion was approximately 9.01. Thus, compared to administration of vehicle, administration of Patidegi Gel 2% increased the proportion of clinically resolved SEB in subjects with a PTCH1 mutation and a baseline total facial BCC lesion count of at least 8.

[0257] Table 13 shows the number of new BCCs per subject observed by Month 12 in subjects with PTCH1 mutations as follows:

[0258] Table 13

[0259]

[0260]

[0261] As shown in Table 13, after 12 months of treatment with Patidegi Gel 2%, the number of new BCCs per subject was approximately 3.08, while for patients treated with vehicle, this number was approximately 4.19. Thus, administration of Patidegi Gel 2% prevented the formation of new BCCs in subjects with PTCH1 mutations compared to administration of vehicle.

[0262] Table 14 below shows the number of BCC surgical procedures per subject by Month 12 for subjects with more than 6 BCC lesions at Baseline:

[0263] Table 14

[0264]

[0265] As shown in Table 14, after 12 months of treatment with Patidegi Gel 2%, the number of BCC surgeries per subject was approximately 0.6, while for patients treated with vehicle, this number was approximately 1.3. Thus, administration of Patidegi Gel 2% reduced BCC surgeries in subjects with at least 6 facial BCC lesions compared to administration of vehicle.

[0266] Example 3

[0267] A randomized, double-blind, stratified, vehicle-controlled study was conducted to measure the efficacy and safety of Patidegi Topical Gel 2% applied twice daily to the face in adult participants with Gorlin syndrome. Participants were required to apply the study product for 12 months. The primary endpoint was a comparison of the number of new BCCs that developed over a 12-month period between the two treatment groups.

[0268] Experimental: Patidegi Topical Gel 2%

[0269] Participants will be randomly assigned to receive Patidegi Topical Gel 2%. Patidegi Topical Gel 2% will be dispensed to participants at each study visit and applied topically to the face twice daily.

[0270] Placebo comparator: Patidegi topical gel vehicle

[0271] Participants will be randomly assigned to receive vehicle. Patidegib topical gel vehicle will be dispensed to participants at each study visit and applied topically to the face twice daily.

[0272] Criteria for participants

[0273] Inclusion criteria:

[0274] 1. Participants must be at least 18 years of age at the screening visit.

[0275] 2. Participants must provide written informed consent before any research procedures.

[0276] 3. Participants must meet the diagnostic criteria for basal cell nevus (Gorlin) syndrome, including major criterion #3a plus 1 additional major criterion or 2 additional minor criteria listed below.

[0277] Main criteria:

[0278] a. >2 histologically confirmed BCCs, or for participants younger than 20 years, 1 histologically confirmed BCC.

[0279] b. Histologically confirmed odontogenic keratocyst of the jaw.

[0280] c. ≥3 palmar and / or plantar indentations seen at the screening visit.

[0281] d. Double-layer calcification of the falx cerebri occurs before the age of 20.

[0282] e. The ribs are fused, bifurcated, or significantly flared.

[0283] f. First-degree relative with Gorlin syndrome.

[0284] g. Patched protein 1 (PTCH1) mutations are predicted to have functional significance in normal tissues.

[0285] Secondary criteria:

[0286] h. Macrocephaly.

[0287] i. Congenital anomalies, including frontal bossing, cleft lip and palate, "coarse face," and moderate to severe organ hypertelorism.

[0288] j. Clinically detectable skeletal abnormalities: Sprengel deformity, marked pectoral deformity, or marked syndactyly of the fingers.

[0289] k. Radiographically detectable skeletal abnormalities: sella turcica bridging; spinal anomalies such as hemivertebrae, fusions, or elongations of the vertebrae; malformations of the hands and feet; flare-like radiolucencies of the hands or feet.

[0290] l. Ovarian fibroma.

[0291] m. Medulloblastoma (Modification of criteria of V Kimonis et al., Am J Med Genet, 69:299-308, 1997).

[0292] 4. Participants must have had 10 clinically typical BCCs (of which at least 3 were on the face) within 24 months prior to randomization (baseline / day 1). Additionally, subjects must have had at least 2 BCCs on the face with a longest diameter of <5 mm before randomization (baseline / day 1).

[0293] 5. Participant is willing to undergo blood collection for measurement of circulating drug levels.

[0294] 6. Participants are willing to avoid the use of non-study topical medications (prescription or over-the-counter) on their facial skin during the trial unless otherwise prescribed by the investigator. Moisturizers and emollients are permitted. Participants will be encouraged to use their preferred sunscreen with a sun protection factor (SPF) of at least 30 daily on all exposed skin areas.

[0295] 7. If the participant is a woman of childbearing potential (WOCBP), she must be willing to abstain from sexual intercourse completely, and / or she and her partner must be willing to use at least 2 highly effective forms of birth control starting before baseline, throughout the study period, and for 12 months after the last application of IP.

[0296] 8. If the participant is a male whose female sexual partner is a WOCBP, the participant must be willing to use condoms starting before baseline, throughout the study period, and for at least 8 months after the last application of IP, even after vasectomy.

[0297] 9. Participants are willing to have all facial BCCs evaluated and treated by researchers only.

[0298] 10. The participant is willing to forgo any medications other than the study IP for facial BCC treatment, unless the investigator determines that delaying treatment of the facial BCC could potentially harm the participant's health. During the trial, the only permitted form of treatment is surgical resection. Non-facial BCCs may be removed at the discretion of the investigator or primary care skin physician (PSCP).

[0299] Exclusion criteria:

[0300] 1. The subject has previously participated in a clinical trial evaluating Patidegi topical gel.

[0301] 2. Participants have used topical facial treatments or systemic therapies that may interfere with the evaluation of the study IP. This includes the use of the following:

[0302] a. Systemic or topical application of 5-fluorouracil, imiquimod, diclofenac, or ingenol mebutate (except as topical treatment for discrete non-facial BCC) to the skin within 2 months prior to the screening visit.

[0303] b. Systemic chemotherapy within 1 year prior to the screening visit.

[0304] c. Topical or systemic use of known Hedgehog signaling pathway inhibitors (e.g., vismodegib, sonidegi, itraconazole) within 3 months prior to the screening visit.

[0305] d. Photodynamic therapy (PDT), except for localized non-facial individual BCC within 2 months prior to the screening visit.

[0306] 3. Participants are known to have hypersensitivity to any of the ingredients in the study drug formulation.

[0307] 4. The participant is unable or unwilling to make a good faith effort to return to the study site for all study visits and testing.

[0308] 5. Participants suffer from uncontrolled systemic diseases.

[0309] 6. Participants have received treatment for invasive cancer within the past 5 years, excluding non-melanoma skin cancer, stage I cervical cancer, ductal carcinoma in situ of the breast, or chronic lymphocytic leukemia (CLL) stage 0.

[0310] 7. Participant is currently participating in, has recently participated (within five half-lives of the investigational drug, or if half-life is unknown, within the past 6 months prior to the screening visit), or plans to participate in an investigational drug study in this study.

[0311] 8. The participant is a WOCBP who is unwilling or unable to comply with contraceptive measures.

[0312] 9. The participant is pregnant or breastfeeding.

[0313] 10. The investigator believes that the participant has any condition or circumstance that may put the participant at significant risk, may confound the study results, or may seriously interfere with the participant's participation in the study. This may include other skin conditions (such as severe facial eczema) or a medical history, metabolic dysfunction, physical examination results, or clinical laboratory results that reasonably suspect that the use of the study drug is contraindicated or that may affect the interpretation of the study results or put the participant at high risk of treatment complications.

[0314] result:

[0315] Figure 13 Table 15 shows the results of the proportion of clinically resolved SEB observed in all types of subjects in Example 3, as follows:

[0316] Table 15

[0317]

[0318] *N = number of patients

[0319] *Nobs = number of patients with clinical data

[0320] As shown in Table 15 and Figure 13As shown, after 9 months of treatment with Patidegi Gel 2%, the proportion of clinically resolved SEB was approximately 9.13, while for patients treated with vehicle, this proportion was approximately 12.66. After 12 months of treatment with Patidegi Gel 2%, the number of qualified SEB was approximately 15.03, while for patients treated with vehicle, this number was approximately 16.75. Therefore, the administration of Patidegi Gel 2% did not affect the proportion of clinically resolved SEB in all types of subjects in the study of Example 3 compared to the administration of vehicle.

[0321] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now 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. A method for treating and / or preventing basal cell carcinoma lesions, the method comprising topically administering to a subject a pharmaceutical composition comprising patidegib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject eligible for said treatment and / or said prevention is selected according to any one of the following criteria: (i) the subject must have at least 6 facial BCC lesions; or (ii) the subject must have a PTCH gene mutation; or (iii) the subject must have at least 6 BCC lesions and a PTCH gene mutation.

2. The method according to claim 1, wherein the subject must have at least 6 facial BCC lesions and a PTCH gene mutation.

3. The method of claim 1 or 2, wherein the amount of patiidegid is from about 0.1% w / w to about 6% w / w.

4. The method of claim 3, wherein the amount of patidegi is 2%, 3% or 4% w / w.

5. The method according to claim 4, wherein the amount of Patidegib is 2% w / w.

6. The method according to any one of claims 1 to 5, wherein the patilide is formulated into a gel formulation.

7. The method according to any one of claims 1 to 6, wherein the subject must have at least 6 facial BCC lesions and suffer from a condition comprising: non-melanoma skin cancer, Rombo syndrome, Bazex-Dupré-Christol syndrome, xeroderma pigmentosum, Muir-Torre syndrome, oculocutaneous albinism, Gorlin syndrome, or any combination thereof.

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

9. The method of any one of claims 7, wherein the subject must have at least 6 BCC facial lesions; and wherein the subject has Gorlin syndrome.

10. The method of any one of claims 1 to 9, wherein the method of treating basal cell carcinoma results in a reduction in size of BBC lesions or clinical regression of BBC lesions over time.

11. The method according to any one of claims 1 to 9, wherein the method of preventing basal cell carcinoma lesions is to prevent the formation of new BCCs or new surgically suitable BCCs.

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

13. The method of claim 12, wherein the pharmaceutical composition is topically administered for a period of about 6 months, about 9 months, about 12 months, greater than 12 months, or for life.

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

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

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

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