Regulatory Decision Summary for Ojjaara

This New Drug Submission (NDS) was filed by GlaxoSmithKline Inc. to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Ojjaara (momelotinib), an oral inhibitor of Janus-associated kinases 1 and 2 (JAK1/JAK2) and activin A receptor type 1 (ACVR1).

The sponsor proposed Ojjaara for the treatment of disease-related splenomegaly or symptoms, and anaemia in adult patients with primary myelofibrosis (MF), post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis who are Janus-associated kinase (JAK) inhibitor naïve or have been treated with a JAK inhibitor.

Upon review, Ojjaara (momelotinib) was authorized for the treatment of splenomegaly and/or disease-related symptoms in adult patients with intermediate or high-risk primary myelofibrosis (MF), post-polycythemia vera MF, or post-essential thrombocythemia MF, who have moderate to severe anaemia.

The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

In this submission, the sponsor proposed Ojjaara (momelotinib or MMB) for the treatment of disease-related splenomegaly or symptoms, and anaemia in adult patients with primary myelofibrosis (MF), post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis who are Janus-associated kinase (JAK) inhibitor naïve or have been treated with a JAK inhibitor.

Evidence to support the proposed indication was provided by two pivotal Phase 3, randomized, double-blind, active-controlled trials, SIMPLIFY-1 and MOMENTUM. The efficacy endpoints used by both studies included: splenic response rate (SRR, for assessment of splenomegaly), reduction in total symptom score (TSS, to measure improvements in constitutional symptoms), and transfusion independence (TI, used to evaluate anaemia).

SIMPLIFY-1 enrolled JAK inhibitor-naïve patients with myelofibrosis with varying levels of haemoglobin (Hgb), ranging from non-anaemic (Hgb > 12 g/dL) to severely anaemic (Hgb < 8 g/dL), and prognostic risks (intermediate-1, intermediate-2, and high risk). The anaemia subgroup represents the target population of the proposed indication for MMB and aligns with the population recruited in MOMENTUM.

In SIMPLIFY-1, patients were randomized 1:1 to receive MMB 200 mg (n = 215) once daily or ruxolitinib (RUX) adjusted dose, twice daily (n = 217) for 24 weeks, followed by an open-label phase where cross-over to MMB was allowed.

SIMPLIFY-1 met its primary endpoint, demonstrating non-inferiority of MMB versus RUX in SRR, with 26.5% of subjects in the MMB group achieving a ≥ 35% reduction from baseline in spleen volume at Week 24 compared to 29.5% in the RUX group (p = 0.014). The first secondary endpoint of non-inferiority in TSS reduction ≥ 50% was not met, as the response rate in the MMB group was 28.4% compared to 42.2% in the RUX group (p = 0.98). MMB showed improvements in TI over the 24-week period, with 66.5% of patients treated with MMB achieving transfusion independence compared to 49.3% of patients treated with RUX (nominal p-value < 0.001). Overall, the MMB treatment effect on SRR, TSS response, and TI rates in the anaemic subgroup was consistent with those in the overall intent-to-treat population.

In MOMENTUM, 195 symptomatic, anaemic adults (Hgb < 10 g/dL) with MF who had been previously treated with an approved JAK inhibitor were randomized 2:1 to receive MMB 200 mg once daily or danazol (DAN) 300 mg twice daily for 24 weeks, after a washout period of at least 2 weeks. This study also included an open-label phase. DAN is a synthetic attenuated androgen used to ameliorate anaemia associated with various haematological conditions, but it is not expected to improve organomegaly or constitutional symptoms. After 24 weeks of treatment, MMB proved to be superior to DAN in reducing TSS by at least 50% (25% MMB vs 9% DAN, p = 0.009), and non-inferior in improving TI rate (30% MMB vs 20% DAN, p = 0.012). MMB was also superior to DAN in SRR, with 39% of MMB-treated patients showing a ≥ 25% reduction in spleen volume compared to 6% of DAN-treated patients (p < 0.0001).

The safety profile of MMB is based on pooled data from 488 patients with MF treated with MMB during the randomized treatment period of the Phase 3 clinical trials MOMENTUM, SIMPLIFY-1, and the supportive study SIMPLIFY-2. Across these three studies, the median duration of MMB exposure was 23.9 weeks, and the median dose was 187.5 mg (93.8% dose intensity).

Several of the adverse reactions reported in the MMB safety population overlap with signs and symptoms observed in patients with MF. The most frequently reported adverse reactions were fatigue (25%), diarrhoea (23%), thrombocytopenia (21%), haemorrhage (21%), abdominal pain (17%), bacterial infection (17%), dizziness (17%), and nausea (17%).

Gastrointestinal toxicities (diarrhoea, nausea, vomiting) were more common in the MMB group compared to DAN or RUX treatment groups, but were manageable with supportive care. Cases of peripheral neuropathy, mostly grade 1 or 2, were also reported more frequently in the MMB group compared to RUX or DAN, and were described in the Adverse Reactions section.

Thrombocytopenia, although reported at a lower proportion than in the RUX group, was the main adverse reaction leading to treatment modification or discontinuation among patients treated with MMB, and was the most common Grade ≥ 3 adverse event. The risks of thrombocytopenia, neutropenia, and hepatotoxicity (mostly in the form of elevations in liver enzymes) were included in the label, along with monitoring and dose reduction recommendations. Overall, the frequency of most adverse reactions of clinical relevance in patients treated with MMB decreased or remained largely constant over time.

Serious and fatal events were reported in 29.2% and 6.5% of subjects treated with MMB during the randomized treatment period of the studies, and these events were mostly attributed to bacterial or viral infections. A Serious Warnings and Precautions box was included in the label to highlight the increased risk of infections with MMB and precautionary measures.

A dedicated hepatic impairment study showed a significant increase in momelotinib exposure in patients with severe hepatic impairment; therefore, dose adjustments are recommended for this patient population.

Reproductive toxicity animal studies suggest that a potential risk to the fetus from exposure to momelotinib during pregnancy cannot be excluded, and it is unknown if momelotinib is excreted in human milk. According to non-clinical toxicology data, momelotinib impaired fertility in male and female rats at exposures much higher than those anticipated in humans at the clinically recommended dose. Drug-drug interactions have been adequately investigated, and appropriate risk mitigation measures are included in the Product Monograph. Momelotinib was not mutagenic, clastogenic, or carcinogenic, based on in vitro and in vivo studies.

Comparative bioavailability data were reviewed and demonstrated that co-administration with food does not have a clinically significant impact on the rate and extent of momelotinib absorption from the commercial formulation of Ojjaara.

The chemistry and manufacturing information submitted for Ojjaara demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

A Risk Management Plan (RMP) was submitted by GlaxoSmithKline Inc. to Health Canada. Upon review, the RMP was considered acceptable. Routine pharmacovigilance activities and risk minimization measures were proposed for all safety concerns in the RMP.

Upon review, Health Canada and the sponsor agreed to the following approved indication: Ojjaara (momelotinib) is indicated for the treatment of splenomegaly and/or disease-related symptoms in adult patients with intermediate or high-risk primary myelofibrosis (MF), post-polycythemia vera MF, or post-essential thrombocythemia MF, who have moderate to severe anaemia.

Overall, the benefit-harm-uncertainty profile was favourable for Ojjaara (tablets 100 mg, 150 mg, and 200 mg) for the approved indication when used under the conditions of use recommended in the approved Product Monograph. The final labelling and Product Monograph dated November 7, 2024, in Sequence 0035 were deemed acceptable. A Notice of Compliance (NOC) is recommended.

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