Robert E. Richard, MD
There are several new therapies on the horizon for polycythemia vera. What is the potential impact of these treatments coming to market?
Dr. Richard: There are a number of emerging therapies for polycythemia vera (PV), such as PTG-300, idasanutlin, and givinostat. PTG-300, or rusfertide, is a hepcidin mimetic that works by regulating iron metabolism and potentially controlling erythropoiesis, limiting the need for phlebotomy. Idasanutlin, a selective MDM2 inhibitor, targets p53 activity. Even though this drug is early in its development, everyone who treats patients with cancer has been hoping for a drug that works through p53. If it is effective here, who knows where else it could be effective across various other conditions.
Givinostat is well along the development pathway in advanced trials. This drug shows promise in modulating gene expression and reducing the inflammation and fibrosis associated with PV, potentially improving patient outcomes and quality of life. Everyone is hopeful that givinostat could show some effect on disease control and potentially an effect on the myeloproliferative clone. However, rigorous clinical trials and further research are necessary to validate their efficacy, safety profiles, and long-term impacts on patients with PV.
Now, with the approval of peginterferon, the next step is going to be to see how effective it will be and what the adverse events might be. I think we will be getting more data as it starts to be used more. My prediction is that there will be a slow uptake, largely because many older physicians such as myself remember the significant side effects from interferon in the past. Despite being an FDA-approved treatment, it remains an emerging therapy, particularly in the United States. Its adoption and efficacy will become clearer as time progresses.
Another promising drug early in its development is bomedemstat, which functions through a different mechanism as a deacetylase. While the potential effect of histone deacetylase drugs on patient treatment outcomes remains uncertain this year, there might be significant data—either positive or negative—that accelerate the progress of these drugs in their developmental trajectory.
We know that ruxolitinib can be used effectively for patients once they fail hydroxyurea. And now there has been the development of other JAK2 inhibitors that are approved for myelofibrosis. I am not quite sure how they can be evaluated in PV, since we are talking about relatively small numbers of patients, but they do seem to have some slight differences that may be significant and could be used in this space.
Those are the main therapies that I will have my eye on this year.
What is the potential significance of an accelerated dosing schedule for BESREMi (ropeginterferon-alfa-2b-njft), which is being investigated in the ECLIPSE PV phase 3b clinical trial ?
Dr. Richard: The potential significance of an accelerated dosing schedule for BESREMi, as investigated in the ECLIPSE PV phase 3b clinical trial, lies in its capacity to enhance treatment efficacy and outcomes for patients with PV. I am incredibly pleased that it is being done as a trial, partly because a lot of people assume that once a phase 3 study is complete and a drug receives FDA approval, everything is finished and done, and we will move on to the next thing. I really appreciate it when phase 3b or 4 studies are performed, and the data get collected and published.
This study is going to follow a group of patients closely for adverse events and for the JAK2 signal. By administering BESREMi at an accelerated pace, researchers can evaluate its ability to better control hematocrit levels and symptoms associated with PV. In addition, an accelerated dosing schedule could potentially offer patients more efficient symptom management and disease control, leading to improved quality of life and reduced complications associated with PV. I believe that findings from this trial could thus pave the way for optimized treatment strategies and better outcomes for individuals living with PV.
What should future trials focus on to help improve prognosis and survival for patients with PV?
Dr. Richard: We are starting to move increasingly into finding better therapies for patients with PV, and I’ll add in essential thrombocytosis, which are based on informed prognostication. I would love to see studies that just pull out the patients at the highest risk, where the survival is down around 5 years—those are small numbers of patients. To conduct a study like that is exceedingly difficult to do. We are seeing increased consortiums of myeloproliferative neoplasm physicians. Europe has always been particularly good at this. The United States is getting better at it, so it is possible that a trial like that could be pulled together, where centers put in 1 or 2 patients at a time.
Future trials aimed at improving prognosis and survival for PV should prioritize several critical areas. First, there is a need for comprehensive studies to better understand the molecular mechanisms underlying PV pathogenesis, including the JAK2 mutation and its downstream effects. Exploring new therapeutic i mplications and improve long-term outcomes. Additionally, identifying reliable biomarkers for disease progression and treatment response can facilitate early intervention and personalized treatment approaches. Finally, trials should focus on assessing the impact of treatment on quality of life and addressing the unique needs of patients with PV to optimize overall prognosis and survival.
I have always held hope that the Veterans Administration could serve as a platform for conducting some of these studies, given that we possess the largest healthcare system in the country. Whether we participate in larger studies or conduct our research internally, this is something I have long envisioned.