On November 16, Gilead announced the results from its two Phase III trials SIMPLIFY-1 and SIMPLIFY-2. The two trials tested Gilead’s Janus kinase 1 and 2 (JAK1/2) inhibitor, momelotinib, in myelofibrosis (MF) patients. In the SIMPLIFY-1 trial, momelotinib met the primary endpoint of non-inferiority to Jakafi, Incyte/Novartis’ JAK1/2 inhibitor, in terms of spleen response, but failed to meet a key secondary endpoint of non-inferiority in terms of total symptom score (TSS) response rate. In the SIMPLIFY-2 trial, momelotinib failed to meet its primary endpoint for superior spleen response compared with best available therapy (BAT) in patients previously treated with Jakafi. These results raise doubts over whether momelotinib will obtain regulatory approval for use in MF patients.

The enlargement of the spleen, splenomegaly, is one of the main complications associated with MF. Jakafi, the only approved drug in MF, was approved on the basis of its ability to treat splenomegaly. The results from the SIMPLIFY-1 trial showed that momelotinib produced a 35% or more reduction in spleen volume over 24 weeks in 26.5% of patients, which was similar to that of Jakafi at 29% of patients(95% confidence interval [CI]: -11.2% to +5.6%; P = 0.011).

These results mean that momelotinib is statistically non-inferior to Jakafi, which confirms similar results from Phase II data comparing momelotinib and Jakafi. Momelotinib also showed greater improvement in all three pre-specified, anemia-related secondary endpoints, namely the proportion of patients who are transfusion independent or transfusion dependent, as well as the transfusion rate. However, as non-inferiority was not demonstrated for the key secondary endpoint of TSS response rate, formal statistical analyses were not performed for the anemia-related endpoints. GlobalData considers this to greatly undermine the potential benefits of momelotinib in MF patients, who require treatment for both splenomegaly and anemia at the same time.

In the SIMPLIFY-2 trial, momelotinib failed to show statistically significant superiority in spleen response compared with BAT; 6.7% of patients on momelotinib achieved a 35% or more reduction in spleen volume over 24 weeks compared to 5.8% of patients on BAT (95% CI: -8.9% to +10.2%; P = 0.90).

GlobalData believes that one of the main reasons momelotinib failed to show superiority is that, as reported, 88% of patients receiving BAT actually remained on Jakafi. This is also a worrying sign for Gilead, as it suggests that hematologists are likely to prescribe Jakafi even in patients who have anemia-related adverse events, and that hematologists may consider the anemia associated with Jakafi to be manageable, as they have gained considerable experience in using Jakafi since its approval in 2011.

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These unfavorable Phase III results represent a major setback for Gilead’s momelotinib in the treatment of MF. Gilead says it will discuss the next steps for momelotinib in MF with the FDA. However, the non-inferiority to Jakafi in spleen response in the front-line setting and some therapeutic benefit on anemia-related endpoints, as demonstrated in the SIMPLIFY-1 trial, may not be enough for momelotinib’s approval. Even if approval is received due to the fact that there are very limited treatment options currently available for MF patients, based on the overall data from the two SIMPLIFY trials, GlobalData expects Gilead to struggle to convince hematologists to switch from the current standard-of-care therapy to momelotinib in either the first line or following treatment with Jakafi.

According to GlobalData’s recently published report on MF, sales of momelotinib across the seven major markets (7MM: US, France, Germany, Italy, Spain, UK, and Japan) were forecast to reach $362m in 2025, with approximately 57% from the second-line setting following Jakafi treatment. Following the release of the SIMPLIFY trials’ results, GlobalData expects the sales potential of momelotinib to be greatly reduced, as it is likely to garner only a small patient share in MF patients who experience dose-limiting anemia while receiving Jakafi.

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OpportunityAnalyzer: Myelofibrosis – Opportunity Analysis and Forecasts to 2025
Myelofibrosis (MF) is a rare blood disorder, which is characterized by bone marrow fibrosis. Currently, there is only one approved drug, Incyte/Novartis’ Jakafi (ruxolitinib), for the treatment of MF, and other conventional therapies used in MF are off-label. However, none of these drugs are curative, and the only potentially curative intervention is allogeneic stem cell transplant (allo-SCT), which is available to a very small percentage of eligible patients because of the high risk of morbidity and mortality. Therefore, there is a huge unmet need for the treatment of MF.