Video
Novel Therapies Under Investigation for Myelofibrosis
Author(s):
Focused discussion on emerging trial data surrounding novel, investigational therapies for myelofibrosis.
Transcript:
Aaron Gerds, MD: Momelotinib is the latest JAK inhibitor on the scene. It’s being developed primarily in patients who have anemia due to myelofibrosis [MF]. This is because, in earlier studies, we’ve noticed that patients who were transfusion dependent or anemic had improvement in their transfusion dependency or anemia. The MOMENTUM study focused on patients who were previously treated with a JAK inhibitor who had symptomatic myelofibrosis and were anemic. We presented the updated results at the ASH [American Society of Hematology] Annual Meeting in 2022. These were the results through week 48 of the MOMENTUM study. MOMENTUM is a prospective, randomized trial comparing momelotinib vs danazol. Danazol was selected as a comparator because it’s an active agent in treating anemia and patients with mild fibrosis. This study is serving on a regulatory basis for approval in the United States. We have a PDUFA [Prescription Drug User Fee Act] date from the FDA of June 16, so we hope to hear about this medication soon.
With the updated results, through week 48, patients continue to have excellent responses in terms of anemia response as well as spleen and symptom responses. In fact, 1 of the more surprising findings from this analysis was that patients who weren’t initially responding to momelotinib through week 24 did have late symptom responses through week 48. Perhaps extended treatment with momelotinib can lead to better outcomes over time. Certainly, the end point of interest was the continued durability of the safety signals that we saw from the week 24 analysis. There were no new safety signals seen during week 48 of treatment, which is a key point.
Early in the development of momelotinib, there was concern over peripheral neuropathies. Peripheral neuropathy rates remained very low across the MOMENTUM study, and rates were quite similar to those seen with danazol. Less than a couple of percentage points. The long-term safety data were also presented by Dr Srdan Verstovsek at the ASH Annual Meeting in 2022, and they showed great long-term safety. No new safety signals are emerging with long-term treatment. The long-term treatment is important because data for other JAK inhibitors were interrupted by clinical trial holds. Momelotinib was interrupted by a long and convoluted development course due to some clinical trials being less than positive in the past.
Pankit Vachhani, MD: Imetelstat is 1 of the promising drugs in the field of myeloid neoplasms, in both MDS [myeloproliferative neoplasm] and myelofibrosis. We know that telomerase is upregulated in malignant hematopoietic stem cells. Telomerase allows for the continuous maintenance of telomere in malignant stem cells, which allows for more proliferation of malignant cells without apoptosis. Imetelstat is a small, 13-mer oligonucleotide. It’s a competitive inhibitor for telomerase. In doing so, what it leads to is apoptosis of malignant cells, and that allows for the recovery of normal red blood cells, white blood cells, and platelets. This was previously studied in patients with myelofibrosis in a small phase 1 study. The overall response rate was a 21% response, with a median duration of response of 18 months over 4 complete responses. This subsequently led to the IMbark study.
IMbark was a randomized, dose-finding study of imetelstat, in which imetelstat was administered over 2 hours, once every 3 weeks, to 2 separate cohorts of patients. Both cohorts had myelofibrosis. One got 4.7mg/kg of imetelstat, and the other got 9.4mg/kg of imetelstat, which is double the dose. The first thing that one notices, when they look at the results of imetelstat from the IMbark study, is the symptom and spleen volume reduction data. The results from imetelstat weren’t that impressive. However, a dose effect was seen in favor of the 9.4mg/kg dose. What was very impressive was that the 9.4mg/kg dose of imetelstat had a median overall survival in the relapsed/refractory setting of 28.1 months. That’s very impressive when one keeps in mind the context that such patients, in historical studies, have a median survival of 15 to 18 months. All of a sudden, the 28.1-month data look nice.
That’s the basis of the phase 3 IMpactMF study, which is a registration study taking in relapsed/refractory patients with myelofibrosis. These patients are randomized to imetelstat 9.4mg/kg every 3 weeks, our best available therapy. The primary end point, which is the first trend we’re seeing in a relapsed/refractory setting, is overall survival. We’re waiting to see what results come out of this, and we’re excited that it may bring a change and another option for patients with MF. Imetelstat is also being studied in a separate phase 1/1b study in combination with ruxolitinib in intermediate 1, intermediate 2, or high-risk myelofibrosis. In some ways, it’s a dose-finding study for combination therapy. It will provide benefits, but we have to wait and watch for the results.
Parsaclisib is a novel therapy under investigation for myelofibrosis. It’s a next-generation, potent, and highly selective PI3K-Δ inhibitor. It’s favorable for once-daily dosing. Why is this important, and what’s the rationale for this study in the field of MF? Some patients with myelofibrosis who were getting ruxolitinib therapy have suboptimal responses, and the rationale is that maybe some of those suboptimal responses are happening because of the continuous signaling through the PI3K pathway, which bypasses the JAK-STAT inhibition. By blocking the PI3K pathway, one may be able to get an additional advantage on top of JAK-STAT inhibition using a JAK inhibitor. That’s the rationale for using parsaclisib PI3K-Δ inhibitor.
This was previously studied in an early phase study of the addition of parsaclisib to patients with myelofibrosis with suboptimal responses to ruxolitinib alone, and a 25% reduction of spleen volume or more was noted in 28.6% of patients. Keep in mind that these are on top of responses from ruxolitinib. These are impressive given that these are additional responses. The same patient population also had a nearly 50% rate of 50% or more reduction in symptoms on top of the responses from ruxolitinib alone. These are additional responses of both spleen volume and symptoms by the addition of parsaclisib on top of ruxolitinib.
These impressive results have led to the 2 phase 3 studies, LIMBER-304 and LIMBER-313. LIMBER-304 is a study of patients with myelofibrosis who have a suboptimal response to ruxolitinib. Parsaclisib is added in the experimental group. In the standard-of-care group, it’s ruxolitinib in continuation with the placebo, with crossover at 24 weeks. In the other study, LIMBER-313, the population of interest is patients in the front line with intermediate or high-risk myelofibrosis. The 2 arms are ruxolitinib plus parsaclisib vs ruxolitinib plus placebo. The results are being rated. The primary end point for both studies is spleen volume reduction at 24 weeks.
Transcript edited for clarity.
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