Regulatory Decision Summary for Jakavi

The purpose of this Supplemental New Drug Submission (SNDS) was to obtain market authorization for Ruxolitinib for the treatment of patients aged 12 years and older with graft-versus-host disease who had an inadequate response to corticosteroids or other systemic therapies.

The submission was separated into reviews for acute and chronic graft-versus-host disease. Separate indications were granted for acute graft-versus-host disease and chronic graft-versus-host disease.

Clinical pharmacology data supported the same starting dose of Jakavi in adolescent patients as in adult patients with graft-versus-host disease. Key clinical pharmacology findings, relevant risks, and uncertainties were addressed in the approved Product Monograph.

Acute graft-versus-host disease is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation, occurring in approximately 30% to 50% of recipients. Corticosteroids are the standard first-line therapy; however, approximately 50% of patients do not respond adequately and may become steroid refractory or fail to taper corticosteroids, increasing the risk of nonrelapse mortality. No therapy is currently approved in Canada for the treatment of steroid refractory or dependent acute graft-versus-host disease.

The pivotal, open-label, multicentre, Phase 2 REACH1 study supported the market authorization of Jakavi (ruxolitinib) for the treatment of adults and pediatric patients 12 years and older with steroid refractory or dependent acute graft-versus-host disease. Efficacy was established by the overall response rate and duration of response in 49 patients with moderate-to-severe acute graft-versus-host disease who failed first-line corticosteroid therapy. Ruxolitinib was administered at a starting dose of 5 mg twice daily, with escalation to 10 mg twice daily after 3 days in the absence of toxicity. On treatment Day 28, the overall response rate was 57.1% (95% confidence interval [CI]: 42.2, 71.2), with complete response in 14 patients (28.6%). The median duration of response calculated from Day 28 to progression, new salvage therapy, or death was 16 days (95% confidence interval: 9, 83). An alternate measure of duration of response calculated from Day 28 to death or treatment failure was 173.0 days (95% confidence interval: 77.0, 304.0), which is considered clinically meaningful.

No adolescent patients were enrolled in REACH1; however, based on similar disease biology and mechanism of action, efficacy in adolescents was extrapolated from adult data. Clinical safety data from five adolescent patients and population pharmacokinetic analyses indicated comparable safety and pharmacokinetic profiles between adolescent and adult patients.

Safety was evaluated in all 71 patients enrolled in REACH1 who had received corticosteroids alone or in combination with other immunosuppressive agents as first-line therapy. Following a median exposure to ruxolitinib of 46 days (range: 4 to 811), the most common adverse drug reactions (≥ 20%) were anemia, thrombocytopenia, neutropenia, nausea, sepsis, and hypertension. Serious adverse events occurred in 83% of patients. The most frequently reported serious adverse events (in at least five patients) were sepsis, pyrexia, respiratory failure, lung infection, and pneumonia. Four cases of sepsis resulted in death. These findings are consistent with the study population and known safety profile of ruxolitinib.

Additional safety data were obtained from the Phase 3 REACH2 study, which compared ruxolitinib to Best Available Therapy added to the patient’s immunosuppressive regimen in adults and adolescents (≥ 12 years of age) with moderate-to-severe steroid refractory acute graft-versus-host disease. Higher incidences of adverse events leading to dose adjustment, interruption, or discontinuation were observed in the ruxolitinib arm, mainly due to cytopenias, consistent with known risks.

Chronic graft-versus-host disease is defined as any graft-versus-host disease present beyond 100 days. Systemic corticosteroids are the standard first-line treatment for moderate-to-severe chronic graft-versus-host disease. For patients who do not respond or cannot taper steroids, prognosis remains poor and additional agents are required. No standard second-line therapy is defined.

The pivotal, open-label, active-controlled, Phase 3 crossover REACH3 study supported the market authorization of Jakavi for the treatment of adults and pediatric patients 12 years and older with moderate-to-severe steroid refractory chronic graft-versus-host disease. REACH3 randomized patients 1:1 to receive Jakavi (10 mg twice daily) or Best Available Therapy for up to 39 treatment cycles or until additional systemic therapy was required due to unchanged or mixed response, disease progression, or intolerable toxicity. Patients continued their systemic immunosuppressive regimen per standard of care. After evaluation of the primary efficacy endpoint, patients randomized to Best Available Therapy were permitted to cross over to ruxolitinib.

REACH3 randomized 329 patients, including 12 adolescents. Patients treated with ruxolitinib demonstrated statistically significant improvement in the primary efficacy endpoint of overall response rate at interim analysis (N = 196), with an overall response rate of 50.5% (95% confidence interval: 40.2, 60.8) compared with 26.3% (95% confidence interval: 17.9, 36.1) in the Best Available Therapy arm (p < 0.0001). Ruxolitinib also demonstrated statistically significant improvement in failure-free survival at interim analysis, with 34.0% reporting an event compared with 67.7% in the Best Available Therapy arm (p < 0.0001). The second key secondary endpoint met statistical significance at primary analysis. The rate of responders with ≥ 7-point improvement in total symptom score from baseline of the modified Lee Symptom Scale was 24.2% (95% confidence interval: 17.9, 31.5) in the ruxolitinib arm and 11.0% (95% confidence interval: 6.6, 16.8) in the Best Available Therapy arm (p = 0.0011). REACH3 data were used to validate the modified Lee Symptom Scale.

Sixty-one patients crossed over from Best Available Therapy to ruxolitinib after evaluation of the primary efficacy endpoint. At data cut-off, the best overall response was 78.7%, supporting ruxolitinib treatment after an additional line of systemic therapy.

Safety data from REACH3, based on median treatment durations of 25.6 weeks and 24.0 weeks for ruxolitinib and Best Available Therapy arms respectively, were consistent with the known safety profile of ruxolitinib. No new or unexpected toxicities were observed. The most common adverse event (≥ 20%) was anemia. Serious adverse events were reported in 33.3% of patients. The most common serious adverse events were pneumonia (7.9%), pyrexia (4.8%), and lower respiratory tract infection (2.4%). More deaths were reported in the ruxolitinib arm (13 patients, 7.9%) than in the Best Available Therapy arm (nine patients, 5.7%) up to Cycle 7 Day 1. Twelve of the 13 deaths in the ruxolitinib arm were attributed to the study indication, most of which were pneumonia. No deaths occurred in the adolescent subgroup.

The Risk Management Plan submitted by the sponsor included the required information to characterize the safety profile of ruxolitinib for the new indication. Routine pharmacovigilance and risk minimization measures were proposed for all safety concerns listed in the Risk Management Plan and relevant to the new indication. The Risk Management Plan was considered acceptable.

Labelling documents were reviewed and found to conform to regulatory requirements and guidance documents.

Overall, the clinical data support a favourable benefit-risk-uncertainty profile for Jakavi for the treatment of steroid refractory or dependent acute graft-versus-host disease in adult and pediatric patients 12 years and older, and for the treatment of moderate-to-severe steroid refractory chronic graft-versus-host disease in adult and pediatric patients 12 years and older who have inadequate response to corticosteroids or other systemic therapies.

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