Regulatory Decision Summary for REVOLADE

Benefits

The pivotal study supporting the new indication was a single-arm, single-center, phase II study in 43 patients with severe aplastic anemia (SAA) who had an insufficient response to at least one course of antithymocyte globulin (rabbit or horse) plus cyclosporine and who had a platelet count ≤30 x 10⁹/L. The primary endpoint of hematologic response, measured by blood counts (platelets, hemoglobin or neutrophils) or reduction in platelet or red blood cell (RBC) transfusions was achieved in 40% (17/43) of patients in at least one cell lineage after twelve or sixteen weeks of treatment with Revolade following dose escalations up to a maximum dose of 150 mg daily. Twenty-six percent of patients (11/43) had a confirmed response in platelets while 9% (4/43) achieved a response in two or more cell lineages at the primary response assessment which doubled to 19% (8/43) at the last assessment. At any point on study, a tri-lineage response was observed in <10% of patients treated with Revolade.

The longest platelet or RBC transfusion free period for responders was around 200 days (median), and can be considered of clinical benefit to the patient. Further, patients achieving a platelet response did not experience a clinically relevant bleeding event in the pivotal study.

Benefit Uncertainties

Over half the patients enrolled in the study did not have a response to Revolade. Responses in the pivotal study were mainly observed in the platelet lineage, with most of the patients achieving platelet transfusion independence rather than an increase in platelet count in the Primary Response Assessment, followed by smaller subsets of patients with neutrophil or hemoglobin responses. The biology of a tri-lineage effect of the drug, as shown in the results of the non-clinical study, does not establish a persuasive role for Revolade on cells other than those of the megakaryocytic lineage.

The assessment of clinical efficacy in the pivotal study was based on very conservative endpoints. The criteria for hematologic response in the primary endpoint were either improvements in blood counts or a reduction in transfusion requirements. There were no guidelines for transfusion in the pivotal study protocol and it could not be ascertained that transfusion requirements were consistent in patients prior to study entry and during study treatment even though the Sponsor noted the study was performed in a single center.

Risks

The safety profile of Revolade is considered well characterized and overall the drug is well tolerated. In the SAA population, the risk of developing cytogenetic abnormalities and disease evolution to myelodysplastic syndromes (MDS)/acute myelogenous leukemia (AML) has been identified as eight patients (19%) had a new cytogenetic abnormality detected in the pivotal study and three patients (7%) were diagnosed with MDS following treatment with Revolade.

Other adverse events associated with Revolade treatment include thromboembolic events, hepatotoxicity (increases in liver transaminases and bilirubin), hepatobiliary disorders, bone marrow reticulin formation and bone marrow fibrosis, cataracts, and thrombotic microangiopathy. Nonetheless, the risks associated with Revolade are considered manageable for SAA patients with an unmet medical need. Further risk mitigation strategies have been implemented in the Product Monograph.

Risk Uncertainties

A small number of SAA patients (43 in total) were enrolled in the pivotal study. The available safety data in this patient population are considered short-term with a median time on study treatment of 3.6 months (range: 2 to 37 months), with 7 patients having received Revolade for more than 12 months.

Conclusion

Overall, the benefits of Revolade treatment outweigh its risks in the treatment of patients SAA, a rare disease, who have unmet medical need based on prior unresponsiveness to immunosuppressive therapy.