Summary Basis of Decision for Onakta

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Onakta is located below.

The SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle. At this time, no PAAT is available for Onakta. When the PAAT for Onakta becomes available, it will be incorporated into this SBD.

Date SBD issued: 2023-07-20

The following information relates to the New Drug Submission for Onakta.

Tirbanibulin

Drug Identification Number (DIN): DIN 02537818 – 1% w/w tirbanibulin, ointment, topical administration

Avir Pharma Inc.

New Drug Submission Control Number: 262080

Submission Type: New Drug Submission (New Active Substance)

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): D06 Antibiotics and chemotherapeutics for dermatological use

Date Filed: 2022-04-08

Authorization Date: 2023-05-12

On May 12, 2023, Health Canada issued a Notice of Compliance to Avir Pharma Inc. for the drug product Onakta.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit‑harm-uncertainty profile of Onakta is favourable for the topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (Olsen grade 1) on the face or scalp in adults.

Onakta, a chemotherapeutic for topical use, was authorized for the topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (Olsen grade 1) on the face or scalp in adults.

Health Canada has not authorized an indication for pediatric use. Actinic keratosis is not a condition generally seen within the pediatric population (younger than 18 years of age).

Evidence from clinical studies suggests that the use of Onakta in the geriatric population (65 years of age or older) is not associated with differences in safety or effectiveness compared to patients younger than 65 years of age.

Onakta (1% w/w tirbanibulin, i.e., 10 mg of tirbanibulin per gram of Onakta [10 mg/g]) is presented as an ointment. In addition to the medicinal ingredient, the ointment contains glycerol monostearate 40-55 Type I and propylene glycol.

The use of Onakta is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Onakta Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Health Canada considers that the benefit-harm-uncertainty profile of Onakta is favourable for the topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (Olsen grade 1) on the face or scalp in adults.

Actinic keratosis is an ultraviolet light-induced precancerous lesion of the skin that represents the initial intraepidermal manifestation of abnormal keratinocyte proliferation. The lesion has the potential to progress to invasive squamous cell carcinoma. Cutaneous squamous cell carcinoma represents 20% to 50% of skin cancers and poses a significant threat due to its ability to metastasize to any organ in the body. Actinic keratoses present as erythematous, scaly patches located on sun-exposed areas such as the face, scalp, and extremities and can occur as a single lesion or multiple lesions or as an entire field (known as “field cancerization”). The prevalence of actinic keratoses is high and increases with age. Actinic keratoses that do not progress to squamous cell carcinoma may regress or persist as actinic keratoses. Lesions that regress may subsequently recur.

The treatment of actinic keratosis is based on the number of lesions present, and it may be broadly categorized as lesion-directed (e.g., cryosurgery) or field-directed therapy (e.g., topical drug products). In Canada, available topical drug products for the treatment of actinic keratosis include 5-fluorouracil (an antineoplastic agent) and imiquimod (an immune response modifier).

Onakta (tirbanibulin 1% w/w ointment) was developed for the field-directed treatment of actinic keratosis. Tirbanibulin is a new synthetic chemical entity that has shown potent antiproliferative and antitumour activities in vitro and in vivo by inducing cell cycle arrest and apoptotic cell death. In vitro studies have shown that tirbanibulin binds to tubulin, inhibiting its polymerization and promoting microtubule disruption, as well as indirectly altering Src tyrosine kinase signalling.

Onakta has been shown to be efficacious in the treatment of multiple actinic keratoses of the face or scalp. The market authorization of Onakta was primarily based on efficacy and safety data derived from two randomized, double-blind, vehicle-controlled Phase III studies (KX01-AK-003 and KX01-AK-004) conducted in 702 adult patients with actinic keratosis on the face or scalp. Patients were randomized 1:1 to topical treatment with Onakta (353 patients) or vehicle ointment (349 patients) applied to a treatment area of 25 cm² once daily for 5 consecutive days. The primary efficacy endpoint of the studies was the complete (100%) clearance rate of actinic keratosis lesions, defined as the proportion of patients on Day 57 with no clinically visible actinic keratosis lesions in the treatment area. The key secondary endpoint was the partial clearance rate of actinic keratosis lesions, i.e., the proportion of subjects on Day 57 with a reduction of at least 75% in the number of actinic lesions identified at baseline (Day 1 before the first dose) in the treatment area. Patients who achieved complete clearance of the actinic keratosis lesions in the treatment area were assessed for recurrence every 3 months up to 12 months after the Day 57 visit.

In the pooled data from both studies, the Onakta group had statistically significantly higher complete and partial clearance rates than the vehicle group. A complete clearance rate of 49% was achieved among the Onakta-treated patients versus 9% among the vehicle-treated patients (p<0.0001). The partial clearance rate was 72% in the Onakta group compared to 18% in the vehicle group (p<0.0001).

Actinic keratosis recurrence (that was defined as appearance of any actinic keratosis lesions in the treatment area, including recurred lesions and newly developed lesions) was observed in the majority (73%) of patients who had complete clearance of lesions after the 5-day treatment with Onakta and who were followed up for 12 months after Day 57.

Notably, the efficacy of re-treatment with Onakta in patients who have recurrence of the actinic keratosis lesions, or in those who develop new actinic keratosis lesions has not been studied. Accordingly, if recurrences occur, or new lesions develop within the treatment area, other therapeutic options may be considered. This information has been included in the Dosage and Administration section of the Onakta Product Monograph. Furthermore, given that the efficacy of Onakta has only been studied in adult patients with non-hyperkeratotic, non-hypertrophic actinic keratosis (Olsen grade 1) located on the face or scalp, the use of a single 5-day treatment course with Onakta is restricted to this patient population, as stated in the approved indication.

Based on the pooled analysis of the Phase III studies (up to the Day 57 visit), the most commonly reported adverse reactions were application site pruritus (9.1%) and pain (9.9%) in the treatment area. These adverse reactions were transient (mostly occurring during the first 10 days after the start of treatment) and mild to moderate in severity. No patient withdrew from the studies due to adverse reactions.

Local skin reactions at the application site (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration) occurred more frequently in patients treated with Onakta than in patients treated with vehicle. The local skin reactions reached a peak 8 days after starting the treatment with Onakta and typically resolved within 2 to 3 weeks after the completion of treatment. Severe local skin reactions occurred in 13% of the Onakta-treated patients. The highest incidence of severe local skin reactions was observed for flaking/scaling (9% of patients). Severe erythema was reported in 6% of patients. The other local skin reactions were reported as severe in 2% or in less than 1% of patients.

One isolated squamous cell carcinoma in the treatment field was reported in one Onakta-treated patient following the Day 57 assessment; this event was considered by the investigator not to be related to treatment with Onakta. However, to further evaluate the risk of progression of actinic keratosis to squamous cell carcinoma in adult patients with non-hyperkeratotic, non-hypertrophic actinic keratosis after administration of topical tirbanibulin 10 mg/g ointment and to assess the long-term safety and efficacy of tirbanibulin 10 mg/g ointment over a 3-year study period, the sponsor will conduct a post-authorization safety study (M-14789-41), as a post-authorization measure imposed by the European Medicines Agency. The study will include an active-comparator treatment arm. The sponsor is expected to provide Health Canada with the study interim and final reports.

A Risk Management Plan (RMP) for Onakta was submitted by Avir Pharma Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Onakta Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Onakta was accepted.

Overall, the data reviewed support the efficacy of Onakta when used as a single 5-day topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (Olsen grade 1) on the face or scalp in adults and applied over a surface area of up to 25 cm². The safety profile of Onakta is considered acceptable for the intended patient population. Long-term safety and efficacy data will be provided from the post-authorization safety study (M-14789-41). Appropriate warnings and precautions are in place in the Onakta Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

The review of the quality, non-clinical, and clinical components of the New Drug Submission (NDS) for Onakta was based on a critical assessment of the data package submitted to Health Canada. In addition, the foreign reviews completed by the European Medicines Agency and the United States Food and Drug Administration were used as added references, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision regarding the Onakta NDS was made independently based on the Canadian review.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

Submission Milestones: Onakta

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

At this time, no PAAT is available for Onakta. When available, the PAAT will be incorporated into this SBD.

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