- Email: [email protected]
Efinaconazole 10% solution: Nonclinical safety supports topical use in onychomycosis
P6552
P6327
Efinaconazole 10% solution: Nonclinical safety supports topical use in onychomycosis Marian Glynn, PhD, Dow Pharmaceutical Sciences (a division of Valeant Pharmaceuticals International), Petaluma, CA, United States; Hiroaki Nejishima, MS, PhD, Kaken Pharmaceutical Co Ltd, Shizuoka, Japan; Hiroyuki Sanada, MS, PhD, Kaken Pharmaceutical Co Ltd, Shizuoka, Japan; William Jo, PhD, Dow Pharmaceutical Sciences (a division of Valeant Pharmaceuticals International), Petaluma, CA, United States Background: Efinaconazole is a new triazole antifungal in development as a 10% solution for the topical treatment of onychomycosis. Objective: To evaluate toxicity potential of efinaconazole and efinaconazole 10% solution in nonclinical models of general toxicity, developmental and reproductive toxicity, genotoxicity and carcinogenicity in accordance with current FDA/ICH guidances, and to conduct a safety assessment of efinaconazole 10% solution clinical use in onychomycosis. Methods: Efinaconazole and efinaconazole 10% solution were assessed for chronic toxicity potential in rats (via subcutaneous injection) and minipigs (via dermal application) using standard endpoints of clinical observations, body weight, ophthalmology, cardiology (minipigs), toxicokinetics, and clinical, macroscopic, and microscopic pathology. Efinaconazole was assessed for potential to affect fertility and early embryonic development in rats, embryo-fetal development in rats and rabbits, and prenatal/postnatal development in rats via daily subcutaneous administration using standard endpoints. Efinaconazole was assessed for genotoxicity potential using in vitro (mutagenicity and clastogenicity) and in vivo (clastogenicity) assays. Efinaconazole 10% solution was assessed for carcinogenicity potential via daily dermal application to mice for 2 years using standard endpoints. Results: Efinaconazole and efinaconazole 10% solution were well tolerated with chronic dosing; no target organs of systemic toxicity were identified, and only minor vehicle-related dermal toxicity (transient erythema, modest hyperkeratosis) was elicited at maximum feasible doses. Consistent with the azole class, efinaconazole elicited embryo-fetal and early post-natal effects at high, maternally-toxic doses; it was not teratogenic and did not affect fertility. Efinaconazole was not genotoxic and efinaconazole 10% solution was not a carcinogen. High margins of safety were established based on plasma toxicokinetics. Mean efinaconazole systemic exposures (AUC) at nonclinical no-observed-effect-levels ranged from 10- to 250-fold the highest individual human systemic exposure.
Facial lichen planopilaris: An atypical presentation and review of a new variant Israel Andrews, MD, Roger Williams Medical Center, Department of Dermatology and Skin Surgery, Providence, RI, United States; Catherine Breen, MD, Roger William Medical Center, Departments of Pathology and Laboratory Medicine, Providence, RI, United States; Linda Zhou, MD, Roger Williams Medical Center, Department of Dermatology and Skin Surgery, Providence, RI, United States Lichen planopilaris (LPP) is a cicatricial alopecia of unknown etiology that results from an inflammatory process. It typically presents on the scalp with hyperkeratotic plugs at follicular ostia and perifollicular violaceous erythema at the perimeter of the alopecia. Variations of LPP, including frontal fibrosing alopecia (FFA), involve the scalp and nonscalp hair bearing areas including the extremities, eyebrows, axillae, and groin. We describe a 46-year-old man presenting with a 1-month history of an asymptomatic eruption of umbillicated papules distributed symmetrically over the temples, preauricular, infraorbital and buccal aspects of the cheeks, sparing the face medial to the nasolabial folds and the hair bearing areas of the preauricular cheeks. His presentation was initially thought to be molluscum contagiosum. Histology revealed lymphocytic perifollicular lichenoid interface dermatitis with necrotic keratinocytes involving the follicular infundibulum and vacuolar degeneration of the basement membrane. This confirmed the diagnosis of lichen planopilaris. He was prescribed tretinoin 0.05% cream nightly and clindamycin lotion daily for preexisting acne of the beard. At follow-up, the papular lesions had resolved. Facial LPP without involvement of the scalp or other hair bearing areas is an extremely rare variant of LPP with unknown incidence. It is a disorder affecting the pilosebaceous unit of facial vellus and terminal hairs. A review of the literature found 10 cases of facial linear LPP presenting with asymptomatic follicular papules in a linear configuration. Each of the cases described a limited distribution of linear LPP lacking the bilateral and symmetric involvement observed in our patient. Two case series have reported hyperkeratotic facial papules associated with FFA in perimenopausal women, however, one series lacked biopsies, and a correlation to LPP was not established. A review of the literature found variable success in the treatment of facial linear LPP and hyperkeratotic papules associated with FFA. To our knowledge, we are the first to describe a case of facial LPP lacking the features of classic LPP or its variants; including FFA and facial linear LPP. Additionally, we are the first to report successful treatment of facial LPP with topical retinoids. With an increasing number of reports in the literature detailing LPP restricted to the face, it may be possible to classify this rare presentation as a new variant of lichen planopilaris.
Conclusion: The toxicity profiles of efinaconazole and efinaconazole 10% solution were comprehensively characterized. Based on low toxicity demonstrated in nonclinical models and very low systemic exposure associated with clinical treatment, efinaconazole 10% solution is safe for chronic topical onychomycosis therapy.
Commercial support: None identified.
100% sponsored by Valeant Dermatology a division of Valeant Pharmaceuticals North America LLC.
P6322 Evaluation of safety profile, pharmacokinetics, and clinical benefit of an innovative terbinafine transungual solution (P-3058): A phase I study in patients with mild-to-moderate distal subungual onychomycosis Ilona Hartmane, MD, Clinical Center of Skin and STD, Riga, Latvia; Andra Dervenice, MD, Clinical Center of Skin and STD, Riga, Latvia; Federico Mailland, MD, Polichem SA, Lugano, Switzerland; Ingmars Mikazans, MD, Clinical Center of Skin and STD, Riga, Latvia; Linda Frisenda, ScD, Polichem SA, Lugano, Switzerland; Maurizio Caserini, MD, Polichem SA, Lugano, Switzerland P-3058 is an innovative transungual solution containing terbinafine HCl as the sole active ingredient and the novel excipient hydroxypropyl chitosan as a film-forming agent. This phase I-IIa, randomized, parallel groups, open label study evaluated the safety profile, plasma and nail concentrations and clinical benefit of three regimens of P-3058, namely 5% o.d., 10% o.d. and 10% o.w. in patients with mild-to-moderate distal subungual onychomycosis due to dermatophytes (confirmed by KOH and culture), having 25% to 60% diseased big toenail area, without lunula involvement. The study consisted in a 24 weeks treatment period and a wash-out period until week 48. Sixty adult patients of both genders signing the informed consent forms and meeting the main inclusion criteria were randomly allocated to 1 treatment group. Overall, 57 patients completed the study: 18 in 5% o.d. group, 19 in the 10% o.d. group, and 20 in the 10% o.w. group. The three study dose regimens were safe and well tolerated. No patients discontinued due to adverse events. No patients experienced any adverse drug reaction. The pooled data of the three P-3058 dose regimens showed a statistically significant decrease of the diseased target nail area at the end of treatment (P \.0001) and at the end of wash-out (P \.0001) versus baseline. The plasma steady state was reached after 12/24 treatment weeks. Data at end of wash out showed that P-3058 was almost cleared. Comparing to PKs oral terbinafine literature data, P-3058 showed a terbinafine plasma concentration three orders of magnitude lower. The nail steady state was reached after 4 weeks in the o.d. group and after 12 weeks in the o.w. group and lasted up to the end of treatment. The drug was detectable up to 48 weeks in all treatment groups. Terbinafine nail concentrations with P-3058 were over 3 orders of magnitude (up to 16- fold) higher than the oral published nail concentrations data. After 24 weeks of treatment, all patients in 5% o.d. had negative culture (100%) and 77.8% had negative KOH. In 10% o.d. group 84, 2% had negative culture and 68, 4% had negative KOH. Finally, in 10% o.w. group 90% had negative culture and 75% had negative KOH. At week 48, in each group the percentages of negative KOH increased and negative culture was quite similar to week 24. The study met its primary objectives: all the investigated dosage regimens were safe and well tolerated. Mycologic and clinical results appear promising considering the relative short treatment course. 100% is sponsored by POLICHEM SA.
APRIL 2013
P6318 Follicular red dots in areas with an anatomic colocalization of alopecia areata and vitiligo Nayra Merino de Paz, MD, Hospital Universitario de Canarias, La Laguna, Spain; Abian Vega Falcon, MD, Hospital Universitario de Canarias, La Laguna, Spain; Marina Rodriguez-Martin, MD, PhD, Hospital Universitario de Canarias, La Laguna, Spain; Miguel Saez Rodriguez, MD, Hospital Universitario de Canarias, La Laguna, Spain; Patricia Contreras-Ferrer, MD, Hospital Universitario de Canarias, La Laguna, Spain; Sonia Garcıa-Hernandez, MD, Hospital Universitario de Canarias, La Laguna, Spain Background: The follicular red dot pattern is a specific feature of scalp lesions of active discoid lupus erythematosus. This entity shows loss of follicular ostia, follicular keratotic plugs, arborizing vessels, honeycomb pigmented network, dyschromia and variable scaling. Alopecia areata trichoscopy is characterized by black dots, yellow dots, dystrophic hairs, tapering and exclamation mark hairs, cadaverized hairs and short vellus hairs. Case report: We report two patients with clinical criteria of alopecia areta and vitiligo. They showed multiple well-marginated alopecic plaques with normal skin located on scalp. The hair loss areas were colocalizated with achromic skin areas. The trichoscopy was consistent with alopecia areata and it showed black dots, broken hairs and exclamation mark hairs. However, a high number of red dots were observed too. Discussion: Red dots are not one of the typical dermatoscopy features of alopecia areata. They have been described in active discoid lupus erythematosus. Both red dots and yellow dots correspond pathologically to dilated infundibula with keratotic material. The presence of dilated vessels and red blood cell extravasation around the isthmus explains the red color of this dermatoscopic pattern in discoid lupus. Our hypothesis for this case is that the lack of pigmentation in vitiligo areas could explain the red appearance of these dots. Commercial support: None identified.
J AM ACAD DERMATOL
AB105
P6327
Efinaconazole 10% solution: Nonclinical safety supports topical use in onychomycosis Marian Glynn, PhD, Dow Pharmaceutical Sciences (a division of Valeant Pharmaceuticals International), Petaluma, CA, United States; Hiroaki Nejishima, MS, PhD, Kaken Pharmaceutical Co Ltd, Shizuoka, Japan; Hiroyuki Sanada, MS, PhD, Kaken Pharmaceutical Co Ltd, Shizuoka, Japan; William Jo, PhD, Dow Pharmaceutical Sciences (a division of Valeant Pharmaceuticals International), Petaluma, CA, United States Background: Efinaconazole is a new triazole antifungal in development as a 10% solution for the topical treatment of onychomycosis. Objective: To evaluate toxicity potential of efinaconazole and efinaconazole 10% solution in nonclinical models of general toxicity, developmental and reproductive toxicity, genotoxicity and carcinogenicity in accordance with current FDA/ICH guidances, and to conduct a safety assessment of efinaconazole 10% solution clinical use in onychomycosis. Methods: Efinaconazole and efinaconazole 10% solution were assessed for chronic toxicity potential in rats (via subcutaneous injection) and minipigs (via dermal application) using standard endpoints of clinical observations, body weight, ophthalmology, cardiology (minipigs), toxicokinetics, and clinical, macroscopic, and microscopic pathology. Efinaconazole was assessed for potential to affect fertility and early embryonic development in rats, embryo-fetal development in rats and rabbits, and prenatal/postnatal development in rats via daily subcutaneous administration using standard endpoints. Efinaconazole was assessed for genotoxicity potential using in vitro (mutagenicity and clastogenicity) and in vivo (clastogenicity) assays. Efinaconazole 10% solution was assessed for carcinogenicity potential via daily dermal application to mice for 2 years using standard endpoints. Results: Efinaconazole and efinaconazole 10% solution were well tolerated with chronic dosing; no target organs of systemic toxicity were identified, and only minor vehicle-related dermal toxicity (transient erythema, modest hyperkeratosis) was elicited at maximum feasible doses. Consistent with the azole class, efinaconazole elicited embryo-fetal and early post-natal effects at high, maternally-toxic doses; it was not teratogenic and did not affect fertility. Efinaconazole was not genotoxic and efinaconazole 10% solution was not a carcinogen. High margins of safety were established based on plasma toxicokinetics. Mean efinaconazole systemic exposures (AUC) at nonclinical no-observed-effect-levels ranged from 10- to 250-fold the highest individual human systemic exposure.
Facial lichen planopilaris: An atypical presentation and review of a new variant Israel Andrews, MD, Roger Williams Medical Center, Department of Dermatology and Skin Surgery, Providence, RI, United States; Catherine Breen, MD, Roger William Medical Center, Departments of Pathology and Laboratory Medicine, Providence, RI, United States; Linda Zhou, MD, Roger Williams Medical Center, Department of Dermatology and Skin Surgery, Providence, RI, United States Lichen planopilaris (LPP) is a cicatricial alopecia of unknown etiology that results from an inflammatory process. It typically presents on the scalp with hyperkeratotic plugs at follicular ostia and perifollicular violaceous erythema at the perimeter of the alopecia. Variations of LPP, including frontal fibrosing alopecia (FFA), involve the scalp and nonscalp hair bearing areas including the extremities, eyebrows, axillae, and groin. We describe a 46-year-old man presenting with a 1-month history of an asymptomatic eruption of umbillicated papules distributed symmetrically over the temples, preauricular, infraorbital and buccal aspects of the cheeks, sparing the face medial to the nasolabial folds and the hair bearing areas of the preauricular cheeks. His presentation was initially thought to be molluscum contagiosum. Histology revealed lymphocytic perifollicular lichenoid interface dermatitis with necrotic keratinocytes involving the follicular infundibulum and vacuolar degeneration of the basement membrane. This confirmed the diagnosis of lichen planopilaris. He was prescribed tretinoin 0.05% cream nightly and clindamycin lotion daily for preexisting acne of the beard. At follow-up, the papular lesions had resolved. Facial LPP without involvement of the scalp or other hair bearing areas is an extremely rare variant of LPP with unknown incidence. It is a disorder affecting the pilosebaceous unit of facial vellus and terminal hairs. A review of the literature found 10 cases of facial linear LPP presenting with asymptomatic follicular papules in a linear configuration. Each of the cases described a limited distribution of linear LPP lacking the bilateral and symmetric involvement observed in our patient. Two case series have reported hyperkeratotic facial papules associated with FFA in perimenopausal women, however, one series lacked biopsies, and a correlation to LPP was not established. A review of the literature found variable success in the treatment of facial linear LPP and hyperkeratotic papules associated with FFA. To our knowledge, we are the first to describe a case of facial LPP lacking the features of classic LPP or its variants; including FFA and facial linear LPP. Additionally, we are the first to report successful treatment of facial LPP with topical retinoids. With an increasing number of reports in the literature detailing LPP restricted to the face, it may be possible to classify this rare presentation as a new variant of lichen planopilaris.
Conclusion: The toxicity profiles of efinaconazole and efinaconazole 10% solution were comprehensively characterized. Based on low toxicity demonstrated in nonclinical models and very low systemic exposure associated with clinical treatment, efinaconazole 10% solution is safe for chronic topical onychomycosis therapy.
Commercial support: None identified.
100% sponsored by Valeant Dermatology a division of Valeant Pharmaceuticals North America LLC.
P6322 Evaluation of safety profile, pharmacokinetics, and clinical benefit of an innovative terbinafine transungual solution (P-3058): A phase I study in patients with mild-to-moderate distal subungual onychomycosis Ilona Hartmane, MD, Clinical Center of Skin and STD, Riga, Latvia; Andra Dervenice, MD, Clinical Center of Skin and STD, Riga, Latvia; Federico Mailland, MD, Polichem SA, Lugano, Switzerland; Ingmars Mikazans, MD, Clinical Center of Skin and STD, Riga, Latvia; Linda Frisenda, ScD, Polichem SA, Lugano, Switzerland; Maurizio Caserini, MD, Polichem SA, Lugano, Switzerland P-3058 is an innovative transungual solution containing terbinafine HCl as the sole active ingredient and the novel excipient hydroxypropyl chitosan as a film-forming agent. This phase I-IIa, randomized, parallel groups, open label study evaluated the safety profile, plasma and nail concentrations and clinical benefit of three regimens of P-3058, namely 5% o.d., 10% o.d. and 10% o.w. in patients with mild-to-moderate distal subungual onychomycosis due to dermatophytes (confirmed by KOH and culture), having 25% to 60% diseased big toenail area, without lunula involvement. The study consisted in a 24 weeks treatment period and a wash-out period until week 48. Sixty adult patients of both genders signing the informed consent forms and meeting the main inclusion criteria were randomly allocated to 1 treatment group. Overall, 57 patients completed the study: 18 in 5% o.d. group, 19 in the 10% o.d. group, and 20 in the 10% o.w. group. The three study dose regimens were safe and well tolerated. No patients discontinued due to adverse events. No patients experienced any adverse drug reaction. The pooled data of the three P-3058 dose regimens showed a statistically significant decrease of the diseased target nail area at the end of treatment (P \.0001) and at the end of wash-out (P \.0001) versus baseline. The plasma steady state was reached after 12/24 treatment weeks. Data at end of wash out showed that P-3058 was almost cleared. Comparing to PKs oral terbinafine literature data, P-3058 showed a terbinafine plasma concentration three orders of magnitude lower. The nail steady state was reached after 4 weeks in the o.d. group and after 12 weeks in the o.w. group and lasted up to the end of treatment. The drug was detectable up to 48 weeks in all treatment groups. Terbinafine nail concentrations with P-3058 were over 3 orders of magnitude (up to 16- fold) higher than the oral published nail concentrations data. After 24 weeks of treatment, all patients in 5% o.d. had negative culture (100%) and 77.8% had negative KOH. In 10% o.d. group 84, 2% had negative culture and 68, 4% had negative KOH. Finally, in 10% o.w. group 90% had negative culture and 75% had negative KOH. At week 48, in each group the percentages of negative KOH increased and negative culture was quite similar to week 24. The study met its primary objectives: all the investigated dosage regimens were safe and well tolerated. Mycologic and clinical results appear promising considering the relative short treatment course. 100% is sponsored by POLICHEM SA.
APRIL 2013
P6318 Follicular red dots in areas with an anatomic colocalization of alopecia areata and vitiligo Nayra Merino de Paz, MD, Hospital Universitario de Canarias, La Laguna, Spain; Abian Vega Falcon, MD, Hospital Universitario de Canarias, La Laguna, Spain; Marina Rodriguez-Martin, MD, PhD, Hospital Universitario de Canarias, La Laguna, Spain; Miguel Saez Rodriguez, MD, Hospital Universitario de Canarias, La Laguna, Spain; Patricia Contreras-Ferrer, MD, Hospital Universitario de Canarias, La Laguna, Spain; Sonia Garcıa-Hernandez, MD, Hospital Universitario de Canarias, La Laguna, Spain Background: The follicular red dot pattern is a specific feature of scalp lesions of active discoid lupus erythematosus. This entity shows loss of follicular ostia, follicular keratotic plugs, arborizing vessels, honeycomb pigmented network, dyschromia and variable scaling. Alopecia areata trichoscopy is characterized by black dots, yellow dots, dystrophic hairs, tapering and exclamation mark hairs, cadaverized hairs and short vellus hairs. Case report: We report two patients with clinical criteria of alopecia areta and vitiligo. They showed multiple well-marginated alopecic plaques with normal skin located on scalp. The hair loss areas were colocalizated with achromic skin areas. The trichoscopy was consistent with alopecia areata and it showed black dots, broken hairs and exclamation mark hairs. However, a high number of red dots were observed too. Discussion: Red dots are not one of the typical dermatoscopy features of alopecia areata. They have been described in active discoid lupus erythematosus. Both red dots and yellow dots correspond pathologically to dilated infundibula with keratotic material. The presence of dilated vessels and red blood cell extravasation around the isthmus explains the red color of this dermatoscopic pattern in discoid lupus. Our hypothesis for this case is that the lack of pigmentation in vitiligo areas could explain the red appearance of these dots. Commercial support: None identified.
J AM ACAD DERMATOL
AB105