Rusfertide Improves Efficacy Vs Placebo in Phlebotomy-Dependent Polycythemia Vera

The efficacy and safety demonstrated by rusfertide (PTG-300) in the phase 2 REVIVE trial (NCT04057040) could make the novel hepcidin mimetic an additional therapeutic option for patients with polycythemia vera (PV) who require regular phlebotomies or cannot tolerate them, according to Marina Kremyanskaya, MD, PhD.

Data from part 2 REVIVE presented at the 2023 EHA Congress showed that the study met its primary end point. For patients in the rusfertide arm (n = 26), 69.2% experienced sustained hematocrit control, freedom from phlebotomy, and 12-week treatment completion vs 18.5% of patients (n = 27) in the placebo arm.

“In the future, we could see the use of rusfertide as an additional agent for those patients who are benefiting from cytoreductive therapy but still not completely responding, or in those patients who are not tolerating phlebotomies well,” Kremyanskaya explained.

In an interview with OncLive®, Kremyanskaya detailed the outcomes of the phase 2 trial, expanded on the potential implications for rusfertide in the treatment of patients with PV, and detailed the next steps for investigating the agent in this patient population. Kremyanskaya is an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai in New York, New York.

OncLive: Could you provide background on the hepcidin mimetic rusfertide? What is the rationale for investigating this agent in patients with PV?

Kremyanskaya: What's interesting about PV is that the standard of care for this disease where [patients] have uncontrolled erythrocytosis has been therapeutic phlebotomy to maintain a hematocrit [level] of less than 45%. Historically, this has been done for many years. For those patients who are considered to have high-risk disease, in addition to therapeutic phlebotomy, they are also treated with cytoreductive therapies. Some patients who are low risk are also treated with cytoreductive therapy if they are symptomatic from their disease or if they can't tolerate phlebotomies.

What is interesting about the development of rusfertide is that we're using a hepcidin mimetic, which is basically a hormone peptide that is naturally produced by the liver to control erythrocytosis and the manifestation of hematologic malignancies. What led to the development [of rusfertide] is the idea that if you are use hepcidin as a controller of erythrocytosis, it could be looked at as a chemical phlebotomy or as a replacement for phlebotomy in patients with PV.

Some patients with PV become very iron deficient because of a phlebotomy. Potentially, some of the symptoms of PV are related to iron deficiency, as well as the inflammatory nature of a myeloproliferative neoplasm such as PV. When these patients are treated with a hepcidin such as rusfertide, what was shown in earlier phases of the study was that as the dose was up-titrated to get them to the goal of a hematocrit [level] of less than 45%, these patients were able to maintain that dose. A majority of these patients do not need a therapeutic phlebotomy anymore. Some of these patients reported feeling better, and we saw some improvements in their systemic symptoms.

Could you explain the goal of REVIVE and what patients were enrolled?

REVIVE is a phase 2 study of rusfertide in patients with PV who have heavy phlebotomy requirements. Patients had to have PV per revised 2016 World Health Organization criteria, and they had to have required 3 or more phlebotomies in the 28 weeks prior to enrollment. These were heavy phlebotomy requirements. That included patients who were treated with phlebotomies alone, or those patients that were treated with phlebotomies and cytoreductive therapies.

The trial consists of 3 parts. The first part consisted of dose finding, where for each individual patient, the dose was titrated to get them to the therapeutic hematocrit [level] of less than 45%. Patients then entered part 2 of the study, where patients were randomly assigned to either placebo or to their last therapeutic dose [of rusfertide]. It was a double-blinded, randomized study. Once patients were on part 2 of the study, they stayed on this until they needed a phlebotomy.

Once a patient required a phlebotomy, they stopped part 2 of the study and entered part 3, which is the open-label extension where they could continue on the therapeutic dose of rusfertide. Data [presented at the 2023 EHA Congress] focused on the randomized part 2 of the study.

What key efficacy data from part 2 were presented at the 2023 EHA Congress?

We summarized some of the data that were presented earlier from part 1, where it showed nicely that [among] patients who were heavily phlebotomy dependent, once they started on rusfertide, phlebotomy requirements were basically eliminated.

For part 2, which was the primary end point of the study, there was a significant difference between those patients who were randomly assigned to rusfertide vs placebo. In the primary efficacy analysis, [69.2%] of patients on rusfertide vs 18.5% of patients on placebo were considered to be responders. The definition of a responder was [a patient who] completed part 2 of the study and did not meet eligibility for phlebotomy as defined in the protocol. There was a very significant difference between these 2 patient populations.

When we go back to part 1 of this study and look at the symptoms, there was a statistically significant improvement in certain symptoms for those patients who had baseline moderate or severe symptoms. That was specifically looking at things such as pruritus, difficulties in concentration, and fatigue, which are some of the more devastating but difficult-to-describe [symptoms] for patients. The reason why we looked at this data from part 1 is because in part 2, most patients in the placebo arm did not last long enough to be evaluated at 12 weeks. Therefore, these data were from part 1 of this study.

Notably, we also looked at iron parameters, and if we look at ferritin as a marker for systemic iron, most patients at baseline were iron deficient with low ferritin levels. When they started on study, ferritin levels normalized and were maintained in the normal range, showing that systemic iron deficiency was improved.

What was found regarding safety for patients treated with rusfertide?

Rusfertide was very well tolerated, and a majority of patients were able to remain on study with some patients remaining on study for over 2.5 years. The major adverse effects [AEs] were grade 1 and 2, and the most common AE was injection-site reaction. Rusfertide was given as a subcutaneous injection once weekly that patients self-administer. Patients experienced a low-grade injection-site reaction, that for majority of patients, was self-limited and improved over time. Patients did not really have to come off study because of this AE. There were no grade 4/5 AEs.

What are the implications of these results? How could this agent potentially affect the treatment paradigm for patients with PV?

The potential advantage that rusfertide could offer to patients with PV is that it could eliminate phlebotomy requirements for those patients who are heavily dependent on phlebotomy, and for some patients, this could make a big difference if they don't tolerate phlebotomies well or if they're symptomatic from multiple phlebotomies.

An additional benefit is that [rusfertide] can be and is often given as an additional agent to another PV-directed therapy. Often, the dose of a cytoreductive agent, such as hydroxyurea or interferon, cannot be increased because patients are not tolerating the higher dose, but they're still requiring phlebotomies and perhaps are still symptomatic. Therefore, a combination also works very well.

This could free them from being dependent on visiting an institution and worrying about their blood counts, which could lead to some independence and significant improvement in their quality of life.

What the next steps for investigating rusfertide in patients with PV?

This was a phase 2 trial, and there is the worldwide phase 3 [VERIFY trial (NCT05210790)] , which is a randomized, placebo-controlled trial [that is currently] enrolling patients. That phase 3 study will allow us to get more information on the effectiveness of a rusfertide in controlling hematocrit levels and improving patient symptoms. We're looking forward to completing enrollment and analyzing the data from phase 3.

Reference

Kremyanskaya M, Kuykendall A, Pemmaraju N, et al. Targeted therapy of uncontrolled erythrocytosis in polycythemia vera with the hepcidin mimetic, rusfertide: - blinded randomized withdrawal results of the REVIVE study. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LBA2710.