Emerging Research in Myelofibrosis Treatment
A thorough review of promising therapies currently under investigation for the treatment of myelofibrosis.
Transcript:
Aaron Gerds, MD, MS: We now have 3 JAK inhibitors approved for the treatment of myelofibrosis and potentially a fourth coming in 2023. We are, of course, looking to other ways of targeting this disease. Again, myelofibrosis is not a 1-hit wonder. It’s not like we target the JAK-STAT pathway and get long-term disease-free remissions out of a single agent, similar to what we see in CML [chronic myelocytic leukemia]. We have to think about new and creative ways of targeting this disease through other pathways. There are a lot of therapies looking at that. There’s a prospective randomized trial with imetelstat, which is a telomerase inhibitor. That trial is ongoing. Earlier trials suggested that telomerase inhibition with imetelstat could lead to improved survival and the potential reversal of fibrosis in the marrow. We’re all interested in those markers because we are in desperate need of a biomarker for survival. So if we can find a drug that can change fibrosis and then translate that into improved survival, I think that would be a huge win for the field.
There’s a lot of interest in targeting calreticulin. Calreticulin is kind of the oddball mutation in terms of the driver mutations. Again, JAK2 and MPLmutations lead to the JAK-STAT pathway being turned on internally, but calreticulin is this protein that kind of floats around, if you will, and then activates the TPO receptor. It works in a very different way, so we can be more creative in targeting calreticulin. There are certainly calreticulin antagonists being developed. As well, the plenary session at the ASH [American Society of Hematology] annual meeting this year was on an antibody that targets calreticulin mutant protein, which is very exciting. Because antibody therapies work through a whole different mechanism than what we normally use in terms of small molecule inhibitors, and also antibody therapies in other diseases have been an augment to other treatment. As oncologists, we like to combine things. If one thing works and another thing works, boy, if we stick them together, they’re probably going to work more. I think there’s a keen interest in developing antibody therapy as well, to target calreticulin.
Then on top of that, you could propose that we could develop bispecific antibodies also known as BiTEs [bispecific T-cell engagers] to harness the power of the immune system to tackle these diseases, or even CAR [chimeric antigen receptor] T-cell [therapy] going forward, an engineered cellular therapy. You can see that as the start of this whole other line of therapies. More immediately, we are developing combination therapies in myelofibrosis, and there’s a lot of interest in the combination of ruxolitinib plus navitoclax. Navitoclax is a BCL2family inhibitor. Early phase 2 data have shown that navitoclax can act, particularly in high-risk disease, which I find the most interesting part of that. For patients who you say they’re not going to do very well or not have long-term responses on JAK inhibitors alone, navitoclax seems to be getting in there and affecting the disease in a very deep way.
Pelabresib is a BET inhibitor. In the phase 2 trial, combinations in the upfront setting of pelabresib plus ruxolitinib doubled response rates over what we would expect with ruxolitinib alone. There is the ongoing MANIFEST-2 trial looking at ruxolitinib plus or minus pelabresib or placebo in a randomized prospective manner. That trial is anticipated to finish accrual here in the first quarter of 2023. At the ASH annual meeting, Joseph M. Scandura, [MD, PhD,] presented some interesting data looking at megakaryocyte clustering in patients treated with pelabresib, showing that it could have also a deeper effect on disease in potentially this kind of holy grail of disease modification we’re always looking for. MDM2 is upregulated in MPN [myeloproliferative neoplasm] cells, and that’s been targeted in a number of different ways. MDM2 is an inhibitor of TP53, so by inhibiting MDM2, we can hopefully turn on apoptosis in these cells and kill off MPN cells, particularly myelofibrosis cells in this case. There’s a drug called navtemadlin, also known as KRT-232, that is being developed. There is an ongoing study combining ruxolitinib with KRT-232, or navtemadlin, in patients with myelofibrosis. In prior studies that targeted MDM2, we definitely see deep responses, molecular responses and the like, so there’s a keen interest in that.
In addition to pelabresib, there are a number of other BET inhibitors being developed by other companies, but I would say right now, pelabresib is the lead compound within the BET inhibitor cohort. Certainly, there are other trials ongoing. There’s also a drug called parsaclisib, which is a PI3 kinase delta inhibitor specifically, that’s being tested in a prospective trial in combination with ruxolitinib based on promising earlier phase 2 results. Other drugs like siremadlin are being tested as well. Other drugs like luspatercept have already completed phase 2 trials and are in ongoing phase 3 trials to specifically address anemia. I could go on and on for probably hours talking about therapies in development for myelofibrosis. But I think key themes here are attacking pathways outside of JAK-STAT, other key pathways in myelofibrosis, and combining JAK inhibitors plus these new therapies to improve outcomes even more than JAK inhibitors have already.
Transcript edited for clarity.
