Interpharma Praha a.s.

Transcription

1 C C 2 C 2 C C C C C C C PhC Eucapil : a topical 2% fluridil solution in rubbing alcohol for androgenetic alopecia Ph Ac Bz Ac 2 F 3 C 2

2 Androgens and hair loss Androgens play a pivotal role in first promoting and then suppressing scalp hair growth n genetically predisposed individuals binding of androgens to the androgen receptors of the hair follicle initiates a cascade of cellular events, resulting in thinning hair and eventual loss Site specific interference of androgen receptor binding in the hair follicle should be useful in AGA treatment 3 on-steroidal anti-androgens androgens (AA) Closely mimic steroid binding to the androgen receptor (AR) ndiscriminately block all androgens from binding AR Steroidal Androgen AR AA AR Flutamide, bicalutamide and other analogs are administered orally for AA blockage in prostate cancer These products are systemically absorbed when applied topically, suppressing the effects of male hormones and thus sexual function 4

3 Design of a topical AA for treatment of AGA Minimal or no systemic absorption Locally metabolized Minimal or no effects on target tissues, sex organs and gonadotropin levels! Degradation to non-toxic excretable fragments devoid of anti- androgenic activity upon encountering the milieu of circulation oming ead ydrolyzable Linker ydrophobic Tail fluridil 2 F 3 C W A topical antiandrogen for hairloss and other hyperandrogenic conditions. Sovak, Seligson, Campion, Brown US 6,184,249 Androgen receptor suppressors in the therapy and diagnosis of prostate cancer, alopecia and other hyperandrogenic syndromes. Sovak, Seligson, Douglass, Campion, Brown 5 Pre-clinical safety assessment of fluridil Suppresses (down regulates) expression of AR in LCaP cells t 1/2 in human serum ~6 h (in( vitro) Degrades into two bi-products devoid of anti-androgenicity androgenicity 2 Both fluridil and its degradation products had oral and i.p. MTD s in mice and rats well in excess of any intended topical dose either fluridil nor its degradation product (BP-34) was detected in the serum of rabbits after daily topical application (detection limit of 5 ng/ml) 2 BP F 3 C 6

4 Pre-clinical safety assessment of fluridil (continued) Displayed no skin sensitization potential in guinea pigs and was non-irritating when applied to rabbits Showed no cutaneous phototoxic or photoallergic potential in guinea pigs nduced only slight and reversible eye irritancy in rabbits and was not cytotoxic to rabbit corneal fibroblasts Displayed no mutagenic potential Production scale batches readily synthesized in >99% purity 2% solution of fluridil in anhydrous isopropanol (Eucapil( Eucapil ) >2 yr stability 7 Cumulative irritancy assay of fluridil in humans 2, 4 and 6% fluridil in isopropanol was applied to the forearm skin of human volunteers using an occlusive patch Fluridil proved both non-irritating and devoid of sensitization potential in both induction and challenge phases Response to formulated fluridil was equivalent to neat isopropanol (rubbing alcohol) and less irritating than Vaseline control (The study was conducted by the Dermatology laboratories of Professor. Maibach,, M.D., University f California, San Francisco) 8

5 Safety and efficacy of Eucapil in male AGA Daily application of 2 ml of Eucapil or anhydrous isopropanol as placebo 43 male patients phototype -V, V, AGA degree -Va Double-blinded blinded (23 Eucapil /20 placebo) % anagen (growth phase) and % telogen (resting phase) determined by phototrichogram and observation at 0, 3, 9 and 12 months ematology, blood and urine chemistries at 0, 3 and 12 months 9 Safety and efficacy of Eucapil in male AGA (Results) o change in hematology, blood or urine biochemistry parameters nly traces of fluridil (<3 ng/ml) and none of its degradation product (BP-34) were detected in serum. either was detected in urine Testosterone levels varied only seasonally within normal limits o effects on libido or sexual functions were reported Patients generally observed cessation of hair loss Some observed strengthening of hair and re-growth After 3 months no significant change was observed in placebo group while a significant increase in the % anagens (growth phase) was observed in Eucapil patients, persisting throughout the 12 month study (76 to 89%) 10

6 Statistical analysis of % anagen and % telogen hair count derived from phototrichogram 11 Global scalp view of a Eucapil patient Before Eucapil treatment After 6 months daily topical Eucapil use 12

7 Abstract Dermatol Surg 13 Abstract - DDR 14

8 ther publications and presentations Efficacy and Safety Clinical Assessment of Fluridil: Results of a 12 Month Study. Kucerova R, Bienova M, ajduch M, Seligson AL, Bucek M, Sovak M. Presented at the 11 th Congress of the European Academy of Dermatology and Venereology. Prague, Czech Republic, ctober 2-6, Eucapil Approved and sold in the Czech and Slovak Republics Approval pending in other countries 16