Treatment of Myelofibrosis: Emerging Therapies

Transcript:

Harry Erba, MD, PhD: Moshe, how about pacritinib, momelotinib, and all those other ones?

Moshe Talpaz, MD: Those are still experimental. Pacritinib and momelotinib are still experimental drugs. As a general statement, each of them in fairly extensive studies is somewhat less efficient as far as splenic response and perhaps symptom control compared with ruxolitinib. The claim to fame is not on increased activity. When we say claim to fame, it’s an effort to get this drug approved. The claim to fame of pacritinib is activity in patients with low platelets, and the drug has substantial positive effect on patients with less than 50,000 platelets. I think that that’s the approach the company is taking to further explore this option. If they have a chance to develop the drug, that’s the area. I cannot quote you numbers how much the patients improved and to what extent, but we have seen some platelet responses.

Harry Erba, MD, PhD: I’m going to turn to Mary Frances.

Mary Frances McMullin, MD: Momelotinib trials have been done. Unfortunately, I think they picked the wrong end point for the trial, because this was a drug that showed promise in patients who were anemic, which is obviously a huge unmet need. My experience is small, but certainly for the patients I have in the trial it was quite exciting that they seemed to get good responses to their anemia. That was not the primary end point of the trial. I understand that they’re now going back and there’s another trial about to enroll. I think momelotinib probably has something to offer in the future, because a drug that improved the anemia would be very helpful.

Harry Erba, MD, PhD: John, anything else coming down the pike? Anything you’re interested in?

John Mascarenhas, MD: I just want to add to that. I can envision a world where you have multiple JAK inhibitors at your disposal. Our patients with low platelets with pacritinib could fill that unmet niche in a patient population that does terribly and has a dismal prognosis, with no real therapeutic options to patients with significant anemia. Mary Frances said that the momelotinib may be an option where you’re guaranteed to get anemia with ruxolitinib. Beyond that, we’re really looking at second-line therapies in a patient group that has a median survival that’s about 12 to 14 months. There are no approved therapies and very few effective therapies. I think that’s where a lot of the clinical trial focus is right now: adding drugs to ruxolitinib to synergize hopefully with preclinical rationale to inform those early phase studies.

Moshe Talpaz, MD: Can you comment on the BET inhibitor and the LSD1 inhibitors?

John Mascarenhas, MD: CPI-0601 is a pan-BET inhibitor. It’s an oral drug that’s given 2 weeks on, 1 week off. It has really been not impressive in other myeloid malignancies. In myelofibrosis it does have activity. If you go back to papers that Ross Levine and his colleagues have published, it seemed to converge on the NF—kappa B [nuclear factor–kappa B] pathway, which is upregulated and promotes a proinflammatory cytokine signaling. The combination of those 2 drugs in the MANIFEST study, which is a phase II study that will present results at this meeting American Society of Hematology Annual Meeting & Exposition, was impressive. For a patient population that was destined to not do well, we saw spleen responses, symptom responses, and even anemia responses and regression in bone marrow fibrosis. This is still in a growing patient population. This study is ongoing but at least gives us some confidence that that may be an active agent and a pretty well-tolerated agent too.

Moshe Talpaz, MD: LSD1 is another epigenetic regulator. BET inhibitor is an epigenetic regulator by interfering with the activity of bromodomains, whereas LSD1 interferes with chromatin methylation. This one, the LSD1, also has activity as far as symptom control and some minor activity on spleen size and some splenic regression. Because they both may work on the NF—kappa B pathway, which is kind of complementary to the JAK/STAT pathway, it seems that these drugs or these agents offer some promise as far as additional control of the inflammatory process in this disease.

Robyn Scherber, MD: There are a few other quick drugs: luspatercept, either in combination or alone in patients with anemia in myelofibrosis being investigated.

Moshe Talpaz, MD: You think it will come back?

Robyn Scherber, MD: Maybe.

Moshe Talpaz, MD: It was sold to another company. It’s in the hands of Hoffman—LaRoche AG. We hope it will come back, but meanwhile it’s active in pulmonary fibrosis.

Transcript Edited for Clarity