Pelabresib May Represent Optimal Partner for JAK Inhibition in Myelofibrosis

The benefits yielded with the BET inhibitor pelabresib (formerly CPI-0610) in patients with myelofibrosis are multifold, and the agent’s potential to improve disease biology and overcome shortcomings faced with JAK inhibitors make it a strong partner for combinations and a stand-out option vs other agents under exploration in the paradigm, according to Prithviraj Bose, MD.

“With the amount of data available with pelabresib, and the different types of benefits we are seeing, [such as improvements in] spleen, symptoms, anemia, and bone marrow fibrosis, accompanied by some translational work and solid synergism data from the lab, this disease-modifying agent is probably the best partner for JAK inhibitors, which are the cornerstone of treatment for myelofibrosis,” Bose said.

In an interview with OncLive®, Bose, an associate professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed data with pelabresib from the MANIFEST trial, and future research directions for BET inhibition in patients with myelofibrosis.

OncLive®: How is BET inhibition being leveraged in the treatment of patients with myelofibrosis?

Bose: Several BET inhibitors have been developed by many companies, and many of them have [made their way] into the clinic. However, as far as I know, I am not aware of clinical data [regarding their use] in myelofibrosis [beyond what has been seen with] pelabresib, [which is an agent] from Constellation Pharmaceuticals. Some other [inhibitors] are in trials. For example, AbbVie Pharmaceuticals has 2 BET inhibitors that are [under investigation] and Incyte Corporation also has a BET inhibitor [that is in development for myelofibrosis, referred to as INCB57643]. However, I am not aware of any clinical results [with these agents] yet.

What are some of the data that have been reported thus far with pelabresib?

Pelabresib has been studied in the MANIFEST trial [NCT04603495]. This is a 3-arm study in patients with myelofibrosis who have intermediate-1-, intermediate-2-, and high-risk disease. It is a very cleverly designed study in that it looks at the 3 broad segments of patients. In arm 1, we have patients who are no longer on ruxolitinib [Jakafi] or who are ineligible for ruxolitinib; in arm 2, we have patients who are on a stable dose of ruxolitinib and are experiencing a suboptimal response; and in arm 3, we have patients who are JAK inhibitor naïve and who are receiving ruxolitinib plus pelabresib from the start.

In arm 1, it is pelabresib alone, because those patients are not eligible for ruxolitinib or have stopped the agent for whatever reason, and arm 2 is an add on to ruxolitinib. Arms 1 and 2 are divided into 2 cohorts: transfusion dependent and transfusion independent. The primary end point in patients who are transfusion dependent, is of course, the achievement of transfusion independence. In patients who are not transfusion dependent, the primary end point is a 35% reduction in spleen volume. In arm 3, which is the JAK inhibitor–naïve group, the primary end points include a 35% spleen volume reduction and a 50% or greater reduction in total symptom score. It is a little complicated, but it is a very comprehensive approach to look at all the main unmet needs or questions in the field in just one [effort]. This is a large study [that included] more than 200 patients across the 3 arms.

To quickly go over the results, we can go to arm 3 first, as that is the subject of the pivotal trial that this drug is now going into. Again, arm 3 is [looking at] JAK inhibitor–naïve patients who are receiving the combination regimen. Here, patients experienced a 67% spleen response rate, and a 57% symptom response rate at week 24. This is using the usual benchmarks of 35% or greater spleen volume reduction and 50% or greater symptom reduction. These findings compare very favorably with what we have seen in the phase 3 trials of ruxolitinib alone. [This suggests] synergism, which has been seen in the lab and nicely shown in mouse models and patient-derived cells between [BET] bromodomain and JAK inhibition.

Pivoting to arms 1 and 2, if we look at the transfusion responses or anemia responses—because this drug is unique in the sense that it also improves anemia beyond spleen and symptoms—pelabresib alone led to a 59% improvement in hemoglobin in non-transfusion–dependent patients, and by that I mean a 1.5-gm/dL increase in hemoglobin that was sustained over 12 weeks. In arm 2, when we look at the transfusion-dependent patients, [we saw a] 36% rate of transfusion independence in this cohort. [These were] striking results.

What are some of the clinical differentiators between pelabresib and other options on the market for patients with myelofibrosis?

Right now, all we have approved for myelofibrosis are the JAK inhibitors ruxolitinib and fedratinib [Inrebic]. We do not have a non–JAK inhibitor approved yet, although many of these agents are being investigated and are of interest. What excites me about pelabresib is that beyond spleen and symptoms, which tend to be the usual end points in myelofibrosis trials, we are seeing a nice anemia signal, whether it is in transfusion-dependent patients, or patients who are not transfusion-dependent but anemic. This is a major unmet need in the field.

What I did not mention earlier is that pelabresib lead to bone marrow fibrosis improvement of 1 grade or higher in 20% to 40% of patients if we [consider] all the arms of the MANIFEST trial. What is quite striking is that this [improvement] happened within 6 months; it happened very quickly. We consider bone marrow fibrosis improvement to be something that takes a lot of time, so one could imagine that with longer exposure, we are going to see even better bone marrow fibrosis improvement, hopefully of 2 grades or more.

[Pelabresib] has got quite a few unique aspects. It seems to be a drug that can really improve the disease biology, which has been shown in the lab. BET inhibition essentially shuts down transcription of several important oncoproteins, so we really hope that this will modify the underlying disease process beyond just suppressing inflammation, which primarily is what JAK inhibitors do. [The latter agents] suppress cytokines, and inflammation; they are great for patients, but as far as the underlying biology is concerned, the effects may be limited.

Of the other agents that are being looked at in this space as a partner for JAK inhibitors, such as navitoclax [previously ABT-263], parsaclisib [INCB050465], an MDM2 inhibitor called KRT-232 [AMG 232], the data, as it stands now, is most impressive for pelabresib. Part of that is because we just have the most data on [this agent compared with the others]. We have more than 200 patients for whom we have data with pelabresib. Also, the 3 arms of the MANIFEST study look at different clinical scenarios, so we have data everywhere we need it. As such, for all those reasons, pelabresib appears to be the most promising of these partner drugs.

Are any efforts underway to examine different partners for pelabresib beyond ruxolitinib? What are the next steps for the agent?

Several BET inhibitors are in development. However, again, we do not have clinical data [with those agents] in the myelofibrosis space yet, [beyond pelabresib]. As far as combinations with pelabresib beyond ruxolitinib, I have not seen that. Obviously, we could combine [pelabresib] with fedratinib, as well, as any other good JAK inhibitor. The only combination data that we have is from the MANIFEST trial.

The MANIFEST-2 trial is the direction in which the development of this drug is headed. This pivotal phase 3 trial is looking at ruxolitinib plus pelabresib vs ruxolitinib with placebo in another JAK inhibitor–naïve population. Spleen and symptoms will serve as the traditional end points [for the research].