Regulatory Decision Summary for Doptelet

This New Drug Submission – New Active Substance (NDS-NAS) was filed to obtain market authorization pursuant to section C.08.004 of the Food and Drugs Regulations for Doptelet (avatrombopag) for the treatment of severe thrombocytopenia in adult patients with chronic liver disease (CLD) who are scheduled to undergo an invasive procedure, and for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

The effect of Doptelet in the treatment of severe thrombocytopenia in patients with CLD was evaluated in two pivotal, identically designed,  randomized, double-blind, placebo-controlled trials (ADAPT-1 and ADAPT-2). In each trial, adult patients were assigned to the Low (less than 40 × 10⁹/litre [L]) or the High Baseline Platelet Count Cohort (greater than or equal to 40 to less than 50 × 10⁹/L) based on their platelet count at baseline. Patients were then randomized in a 2:1 ratio to receive either Doptelet (60 milligram [mg] in the Low- or 40 mg in the High-Baseline Platelet Count Cohort) or placebo once daily for 5 days. In ADAPT-1, a total of 231 patients were randomized, 149 patients were treated with Doptelet and 82 patients were treated with placebo. In ADAPT-2, a total of 204 patients were randomized, 128 patients were treated with Doptelet and 76 patients were treated with placebo. The primary efficacy endpoint for both trials was the proportion of responders, defined as subjects who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure (including but not limited to; endoscopy, colonoscopy, chemoembolization, biopsy, dental procedures, radiofrequency ablation).

The efficacy results showed that the proportion of patients not requiring a platelet transfusion or rescue procedure for bleeding 7 days after the procedures was greater for Doptelet versus (vs) placebo in both baseline platelet count cohorts (66% vs 23% and 88% vs 38% in ADAPT-1; 69% vs 35% and 88% vs 33% in APAPT-2, for the Low- and the High-Baseline Platelet Count Cohort, respectively). Across cohorts, the platelet response in the Doptelet groups was clinically meaningful and statistically significant. The positive treatment effect of Doptelet on the primary endpoint was consistent across the two pivotal studies, and across key subgroups of; age, sex, race, geographic region, bleeding risk, and aetiology of liver disease.

The pooled safety data from ADAPT-1 and ADAPT-2 included a total of 430 randomised patients who received at least 1 dose of study drug and had at least 1 post-dose assessment, with 274 patients in the combined Doptelet treatment group, and 156 patients in the combined placebo group across the 2 baseline platelet count cohorts. The safety of Doptelet was generally comparable to that of placebo. The frequency, severity, and types of adverse events (AEs) reported were consistent with those expected in patients with CLD, and no unexpected safety signals were identified. The most common treatment-emergent adverse events (TEAEs) in the Doptelet-treated groups (60 mg or 40 mg) versus placebo were pyrexia (10% vs 9%), abdominal pain (7% vs 6%), nausea (7% vs 7%), headache (6% vs 6%), fatigue (4% vs 3%) and edema peripheral (3% vs 2%). The incidence of serious TEAEs was 7% in the 60 mg Doptelet treatment group vs 13% in placebo, and 8% in the 40 mg Doptelet treatment group vs 3% in placebo. The most common serious TEAE reported with Doptelet was hyponatremia (0.7%). Thromboembolic events (portal vein thrombosis) occurred in 0.4% of patients receiving Doptelet. TEAEs resulting in discontinuation of Doptelet occurred in two patients in the Doptelet (60 mg) treatment group. Anemia and myalgia were reported in a single patient (0.4%) and pyrexia was reported in another patient (0.4%). The reported anemia and myalgia were considered to be treatment-related serious adverse events.

The efficacy of Doptelet in the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) was evaluated in a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial in patients who have had an insufficient response to a previous treatment (including but not limited to corticosteroids, immunoglobulins, azathioprine, danazol, cyclophosphamide, and/or rituximab). Patients were centrally stratified by splenectomy status, baseline platelet count (less than or equal to 15 × 10⁹/L or greater than 15 × 10⁹/L to less than 30 × 10⁹/L), and use of concomitant chronic ITP medication, and then were randomized (2:1) to receive either Doptelet or placebo for 6 months. Patients received a starting dose of 20 mg once daily, with doses subsequently titrated based on platelet response. The primary efficacy endpoint was the cumulative number of weeks of platelet response (platelet count greater than or equal to 50 × 10⁹/L) during 6 months of treatment in the absence of rescue therapy.

The efficacy results showed that Doptelet-treated patients had a longer duration of platelet counts greater than or equal to 50 × 10⁹/L in the absence of rescue therapy than those who received placebo (median 12.4 [range 0 to 25] vs 0 [range 0 to 2] weeks, respectively, p<0.0001).

The safety of Doptelet in patients with chronic ITP was based on pooled data from four clinical trials: two randomized, double-blind placebo- or active-controlled Phase 3 trials (Study 302, Study 305) and two Phase 2 trials (one randomized, double-blind, placebo-controlled, dose-ranging trial, Study CL-003, and one open-label extension trial, Study CL-004) in both the double-blind and the open-label extension phases. The pooled safety data from these four clinical trials included 128 patients who received 2.5 to 40 mg of Doptelet once daily for a median duration of exposure of 29 weeks and had one post-dose safety assessment.

The most common TEAEs in the Doptelet treatment group versus placebo were headache (31% vs 14%), fatigue (28% vs 9%), contusion (26% vs 18%), epistaxis (19% vs 18%), upper respiratory tract infection (15% vs 5%), arthralgia (13% vs 0%), gingival bleeding (13% vs 0%), petechiae (11% vs 9%), and nasopharyngitis (10% vs 0%). A higher percentage of patients experienced TEAEs leading to discontinuation of study drug in the Doptelet treatment group (13.3%) compared to placebo group (0%). The system organ class (SOCs) with the highest incidence of TEAEs leading to discontinuation of Doptelet were Nervous System Disorders and Investigations (3.9% patients each) followed by Blood and Lymphatic System Disorders and Gastrointestinal Disorders (1.6% patients each). The most common serious TEAEs were thrombocytopenia (6.3%), vomiting (3.1%), platelet count decreased (2.3%), followed by cerebrovascular accident, gastritis hemorrhagic, headache, immune thrombocytopenic purpura, and nausea (1.6% each). Bleeding events occurred in 14% ITP patients receiving Doptelet compared to 4.5% patients receiving placebo. Other TEAEs of special interest included recurrence of thrombocytopenia occurring in 9%, thromboembolic events (arterial or venous) in 7%, and neoplastic event in 5% of patients receiving Doptelet, compared to 0% in placebo groups.

The Sponsor provided a nitrosamine risk assessment as part of the initial submission that was found to be deficient because they did not consider potential nitrite impurities in excipients, and a Notice of Non-Compliance (NON) was issued.

A Risk Management Plan was submitted and reviewed by the Marketed Health Products Directorate and was considered acceptable.

Overall, the benefit-harm-uncertainty profile is favourable for Doptelet for the recommended indications, therefore a Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations was recommended.

For further details about Doptelet, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.