Novel hepcidin mimetic shows remarkable potential for polycythemia vera

In the three-part, phase II REVIVE study, the investigational, first-in-class hepcidin mimetic rusfertide was highly effective in regulating haematocrit levels in individuals with polycythemia vera (PV) who had a high phlebotomy burden.

 

“The study met all efficacy endpoints of proportion of responders, absence of phlebotomy eligibility, and haematocrit control,” said Dr Marina Kremyanskaya from the Icahn School of Medicine at Mount Sinai, New York City, New York, US, at EHA 2023.

 

In part 1, 70 patients (median age 57 years, 70 percent male) were initiated on rusfertide 10–120 mg once weekly. The dose was uptitrated to achieve the goal haematocrit (<45 percent) and was maintained until week 28. Following which, part 2 ensued, wherein 53 patients were randomized 1:1 to maintain their last active rusfertide dose or to placebo. After 12 weeks, nonresponders entered the 3-year open-label extension phase (part 3). [EHA 2023, abstract LB2710]

 

Part 1: Meaningful reduction in phlebotomy frequency

“Upon initiation of treatment, the number of phlebotomy events is drastically reduced,” said Kremyanskaya. This was seen in both phlebotomy only and phlebotomy + cytoreductive cohorts.

 

The patients’ phlebotomy requirements however returned when they were off treatment for 2–3 months, she noted. “But once they restarted, the need for phlebotomy was eliminated. Majority of patients (92 percent) returned and continued on study.”

 

By week 29, there were marked reductions (denoting improvement) in baseline symptom scores for problems with concentration (from 6.1 to 3.0; p=0.0018), itching (from 6.2 to 3.3; p=0.0054), fatigue (from 6.0 to 4.2; p=0.0074), and inactivity (from 5.8 to 3.0; p=0.0005). “These are some of the most debilitating symptoms that patients with PV can have, which can have a significant impact on their quality of life,” Kremyanskaya said.

 

Moreover, patients with PV are often significantly iron deficient, especially those who are heavily phlebotomy-dependent. Ferritin level was very low at study initiation, but this normalized while on study and was sustained at normal levels.

 

Part 2: Proportion of responders

There were more responders in the rusfertide vs the placebo arm (69 percent vs 18 percent; p=0.0003), translating to a highly significant efficacy favouring the former. This effect was similarly seen in the phlebotomy alone (p=0.0209) and phlebotomy + cytoreductive subgroups (p=0.0215).

 

“Responders are patients who did not receive any phlebotomy during the 12 weeks of treatment,” Kremyanskaya said. Phlebotomy-free rate in the rusfertide arm was 92 percent.

 

“Responders also had their haematocrit control maintained without becoming phlebotomy eligible,” she added. Elevated haematocrit is a hallmark of the disease, and uncontrolled haematocrit is tied to higher rates of death from cardiovascular causes and thrombotic events. “Maintaining haematocrit <45 percent is critical in PV to decrease the risk of thromboembolic complications.”

 

There were also significant improvements in terms of maintenance of response, absence of the need for phlebotomy, and persistent haematocrit control <45 percent with rusfertide vs placebo (p<0.0001 for all).

 

Safety

Treatment emergent adverse events (TEAEs) were mostly grade 1/2, with no grade 4/5 TEAEs. The most common TEAEs were injection site reactions, which were mild and did not lead to treatment discontinuation. Continued treatment led to reductions in severity and incidence.

 

“Rusfertide was generally well tolerated. Patients remained on study for a long period, with three subjects being on study for ≥2.5 years, indicating the long-term tolerability of the drug,” Kremyanskaya noted.

 

Limited treatment alternatives

Patients with PV have limited therapeutic options that can effectively control haematocrit levels and reduce the need for phlebotomy and the occurrence of thrombosis. Moreover, the current standard of care does not consistently maintain haematocrit at 45 percent, thus potentially increasing the risk of thromboembolic events.

 

The findings suggest that rusfertide has the potential to consistently maintain haematocrit at <45 percent in PV patients receiving phlebotomy with or without cytoreductive therapy, said Kremyanskaya.

 

The phase III VERIFY study on rusfertide vs placebo is underway. “A separate follow-on 2-year extension trial will open this year for patients who have completed participation in the 3-year REVIVE study,” she added.