Myelofibrosis is a disease where patients are afflicted by splenomegaly symptoms, the potential of anaemia and, sadly, risk of premature death. We currently have three FDA approved therapies – ruxolitinib, fedratinib and pacritinib – that improve splenomegaly and symptoms; pacritinib also is safe for patients with a low platelet count. But we truly don’t have anything yet that helps improve all aspects of the disease including anaemia.
Momelotinib is a JAK1/JAK2 inhibitor that also inhibits ACVR1, that decreases hepcidin, that we found helps to improve anaemia. So it’s a drug in earlier trials, SIMPLIFY-1 and SIMPLIFY-2, that can improve splenomegaly symptoms and anaemia.
The MOMENTUM study was a phase III study that specifically outlined its benefit for individuals in the second line setting. 195 patients were randomised between momelotinib and danazol, an androgen active, as best alternative therapy for anaemia. Randomised in a 2:1 fashion with endpoints of trying to improve symptoms, splenomegaly and anaemia in individuals that previously had failed JAK inhibition.
We found in this study that momelotinib was very effective as second line therapy for this group of individuals, that it met all of its endpoints. So what does that mean? First it was clearly superior to danazol for improvement in symptoms, that was the primary goal of the study and it was rewarding to see that. Secondly, it was non-inferior for danazol as related to improvement in anaemia; we knew going in that danazol was active for anaemia. We saw a trend for superiority, so a13-31% transfusion independence for momelotinib versus just 15-20% with danazol. It didn’t quite reach the threshold of statistical significance for superiority but the trial really was aimed as a non-inferiority study. We did notice that if we looked at just individuals that were transfusion independent or became transfusion independent with zero transfusions momelotinib was clearly superior to danazol.
Third, and importantly, there was clear superiority of improvement in splenomegaly, a difficult feature of myelofibrosis. Whether we looked at two different thresholds, a 35% volume reduction or a 25% volume reduction, probably more realistic for individuals in the second line setting, a full 40% of patients had that response.
So our takeaway is that the drug was very active and clearly was superior to the best alternative therapy for improving splenomegaly symptoms and anaemia.
Will momelotinib be a new standard of care for anaemic myelofibrosis patients?
First the therapy will need to be approved, which will be a critical step, but if it is approved it clearly will have a significant role in the therapy of myelofibrosis. It remains a heterogeneous disease but in individuals in the front line setting that have significant anaemia I suspect momelotinib will be a very important consideration.
As with all of these things there are individualised considerations in terms of choice of therapy. We’re working on the correlatives as well to best understand are there specific molecular subgroups or other markers that help best predict response. But it will be a strong consideration for front line for patients with anaemia.
Second, as second line therapy very much aligned with the data that we have here from the MOMENTUM study, it really makes a very strong case for patients with anaemia to be considered for therapy with momelotinib. So it definitely will make an important impact on really fleshing out the options that patients with myelofibrosis will have for care of their disease.