Regulatory Decision Summary for Onakta

The purpose of this New Drug Submission (NDS) was for AVIR Pharma Inc. to obtain market authorization for Onakta (tirbanibulin 1% w/w ointment) topical ointment. The final approved indication was for the topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (AK) (Olsen grade 1) on the face or scalp in adults.

In support of the proposed indication for use of Onakta as “the topical treatment of actinic keratosis (AK) on the face or scalp in adults”, two (2) double-blind, vehicle-controlled clinical trials (KX01-AK-003 and KX01-AK-004) were conducted with 702 adult subjects with actinic keratosis (AK) on the face or scalp. Subjects were randomized 1:1 to Onakta (tirbanibulin 1 % w/w ointment) or vehicle (353 patients treated with tirbanibulin and 349 patients treated with vehicle). Subjects received five consecutive days of once daily treatment with either Onakta or vehicle control. The primary efficacy endpoint was complete (100%) clearance of AK lesions in the treatment area at Day 57. The secondary endpoint was partial response (75%) clearance rate. Patients were assessed for recurrence up to 12 months (assessments every 3 months) post-Day 57 visit.

Onakta demonstrated complete clearance in 49.3% of subjects as compared to 8.6% in the vehicle arm. Onakta has been studied only for the AK lesions with Olsen grade I on the face/scalp. Efficacy of Onakta in Olsen grades II/III AK lesions is not known. The majority of subjects with 100% clearance who continued to the follow up period dropped out during the open observation period due to AK recurrence. Efficacy of Onakta for more than 1 treatment course of 5 consecutive days is not known. New lesions can occur over time with or without prior treatment. Efficacy of Onakta in immunocompromised patient population is not evaluated.

Given the above-mentioned results, the following restricted indication was recommended:

• Onakta is indicated for the topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (AK) (Olsen grade I) on the face or scalp in adults.

The limited use of Onakta was therefore labelled (under “Dosing Consideration” section) to indicate that the efficacy for more than 1 treatment course of 5 consecutive days has not been studied. If recurrences occur, or new lesions develop within the treatment area, other therapeutic options may be considered.

Local skin adverse reactions (LSARs) were observed in over 50% of subjects with Onakta more often than vehicle. LSARs in the treated area, including erythema, flaking/scaling, crusting, swelling, erosion/ulceration, and vesiculation/pustulation, may occur. Erythema, scaling and flaking, peaked on Day 8 or Day 15. The LSARs were tolerable and diminished by Day 57. Clinical studies in healthy subjects demonstrated Onakta caused skin irritation under open patch, semi occlusive and occlusive patches. Onakta is not recommended under semi/occlusive conditions and until the skin is healed or on open wounds or broken skin. Tirbanibulin was genotoxic and induced chromosomal damage in in vitro studies and induced micronuclei in rats. Tirbanibulin was not mutagenic in Ames test. Considering minimal systemic exposure, the potential of genotoxicity with topical use of Onakta is considered low. In rats and rabbits, oral administration of tirbanibulin was associated with maternal toxicity and embryo-fetal toxicity including implantation loss and teratogenicity. Onakta is not recommended during pregnancy and in women of childbearing potential not using contraception. The risk of progression to skin cancer was also labelled.

The potential of development of risk of skin cancer in long-term use of Onakta is not known. Onakta has been restricted for one time (5-day course of once daily dose) use only.

The Risk Management Plan was reviewed and found acceptable. Based on the above results, the benefits-risks profile of Onakta is deemed to be favorable.