Rusfertide reduces blood draws, maintains hematocrit, eases symptoms in polycythemia vera

Rusfertide reduces blood draws, maintains hematocrit, eases symptoms in polycythemia vera

Key takeaways:

• Rusfertide reduced need for phlebotomies and offered better hematocrit control than placebo.
• Results showed reduced fatigue and improvement in other symptoms among patients assigned rusfertide.

CHICAGO — Rusfertide significantly reduced the need for therapeutic phlebotomies compared with placebo for patients with polycythemia vera, according to results of the randomized phase 3 VERIFY study presented at ASCO Annual Meeting.

Rusfertide (Protagonist Therapeutics/Takeda Pharmaceuticals) — administered as a once-weekly subcutaneous injection — also helped maintain red blood cell levels at goal levels, reduced patient-reported fatigue and improved other disease-related symptoms.

“The data are very reassuring,” lead author Andrew T. Kuykendall, MD, associate member at Moffitt Cancer Center in the department of malignant hematology, told Healio. “We saw substantial activity in the phase 2 study with this agent that we felt optimistic about the phase 3 data. To see the phase 2 data translate to phase 3, in addition to achieving key secondary endpoints that assessed patient-reported outcomes, is very exciting for us and for patients.”

‘A better way’

Polycythemia vera is a myeloproliferative neoplasm in which the bone marrow produces too many red blood cells.

The blood cancer is associated with elevated risk for cardiovascular events. Antiplatelet therapy, hematocrit control and cytoreductive therapy can reduce thrombotic risk. Phlebotomy often is used for hematocrit control; however, frequent phlebotomy can become a burden for patients and remove iron stores in red blood cells, exacerbating symptoms — and this approach still may be inadequate to maintain hematocrit below 45%.

“We historically have offered a very archaic form of therapy for patients with polycythemia vera,” Kuykendall said. “Phlebotomies keep blood counts at a safe level and that reduces risk for cardiovascular events, but it is a challenging and uncomfortable procedure that ties patients to the health care system and exacerbates iron deficiency.

“We call that ‘a win’ but, for many patients, it doesn’t feel like a win,” he added. “They actually often feel quite poorly, so we wanted to investigate whether we could do this in a better way.”

Rusfertide is an investigational hepcidin mimetic peptide therapeutic. It binds to ferroportin, and downstream blockade results in reduced iron availability in the bone marrow, helping to prevent excessive red blood cell production.

The phase 2 REVIVE trial showed the addition of rusfertide to phlebotomy and/or cytoreductive therapy reduced the need for phlebotomies and offered long-term hematocrit control.

In the phase 3 VERIFY trial, Kuykendall and colleagues aimed to confirm rusfertide’s benefit vs. placebo for patients who had uncontrolled hematocrit levels and required frequent phlebotomies despite receiving standard therapy. All participants had received at least three phlebotomies in the prior 28 weeks or at least five in the prior year.

Researchers randomly assigned patients 1:1 to ongoing therapy plus either rusfertide (n = 147) — at a starting dose of 20 mg weekly — or placebo (n = 146). Assigned treatment continued for 32 weeks, at which point all participants could receive open-label rusfertide for an additional 124 weeks.

Clinical response between weeks 20 and 32 — defined as absence of phlebotomy eligibility, which meant either confirmed hematocrit of 48% or higher, or 45% or higher and at least 3 percentage points higher than baseline — served as the primary endpoint.

Key secondary endpoints included mean number of phlebotomies, proportion of patients with hematocrit less than 45%, and mean changes from baseline in PROMIS Fatigue SF-8a score and Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score.

The intention-to-treat population included 147 patients assigned rusfertide (median age, 58 years; range, 28-86; 72.1% men; 44.9% high risk) and 146 assigned placebo (median age, 57 years; range, 27-82; 74% men, 47.9% high risk).

A comparable percentage of patients in the rusfertide and placebo groups received concurrent cytoreductive medication (56.5% vs. 55.5%), including hydroxyurea (40.1% vs. 39.7%).

‘Very noticeable improvements’

A higher percentage of patients assigned rusfertide than placebo achieved clinical response (76.9% vs. 32.9%; P < .0001).

Rusfertide reduced the mean number of phlebotomies from baseline to week 32 (mean, 0.5 vs. 1.8; P < .0001).

Four times as many patients assigned rusfertide maintained hematocrit below 45% (62.6% vs. 14.4%; P < .0001).

“The results show this agent should add to the current standard care,” Kuykendall said. “I do think this obviates the need for phlebotomies. I don’t think this obviates the need for cytoreductive therapy, but I do think it allows for more optimal dosing of cytoreductive therapy. We won’t have to use higher doses to control hematocrit if we have another agent that can do that.”

Results also showed statistically significant improvements in the PROMIS Fatigue SF-8a total T-score (– 1.76 vs. 0.17; difference, 1.93; P = .0281) and MFSAF total symptom score (–2.43 vs. –0.52; difference, –1.91; P = .0212) at week 32 in the rusfertide group.

“Statistical significance does not always mean clinical significance, but I think that is something we’re moving toward with these patient-reported outcomes,” Kuykendall said. “I had patients on this trial who reported very noticeable improvements in quality of life. We knew we could reduce the number of phlebotomies. To see across-the-board improvement in fatigue and other symptoms, I think it shows there is at least a subset of patients for whom this is clinically meaningful.”

A comparable percentage of patients assigned rusfertide and placebo experienced at least one treatment-emergent adverse event (89% vs. 86.3%). The most common events in the rusfertide group included injection site reactions (55.9%), anemia (15.9%), fatigue (15.2%) and headache (10.3%).

Serious adverse events occurred among 3.4% of those assigned rusfertide — though none were deemed related to treatment — and 4.8% of those assigned placebo. One patient assigned rusfertide experienced acute myocardial infarction that occurred about 2 weeks after treatment initiation.

“Fatigue, which was equal between the rusfertide and placebo groups, is inherent in the disease itself,” Kuykendall said. “Anemia is essentially the mechanism of action of rusfertide — to decrease red blood cells. To me, injection site reactions are the main events we need to address. Fortunately, they tend to be local and manageable, and they decrease over time.”

Patients treated with rusfertide also can see early platelet count increases of 20% to 25%.

“That is consistent with the mechanism of a hepcidin emetic but, as this agent is moved into the community, I think it will require counseling for patients,” Kuykendall said. “They’re often starting treatment with high platelet counts, so knowing that seeing them tick up a little early in treatment is an expected consequence can alleviate any concerns.”

Follow-up will continue for up to 3 years to allow for more complete assessments of rusfertide’s long-term efficacy and safety profile.

Data from VERIFY also will serve as the basis of applications seeking marketing authorization for rusfertide for treatment of polycythemia vera in the United States, Europe, Japan and elsewhere.

“Hopefully this becomes an option for patients in the clinic,” Kuykendall said. “Survival for people with polycythemia vera is less — but not too much different — than age-matched controls, so a normal lifespan should be the goal. When we face the reality of a disease people will live with for a long time, they shouldn’t have to always feel like they are struggling with a chronic disease. We need to make sure we’re thinking about how well they can live with that disease, and that has been our focus from the outset.”

For more information:

Andrew T. Kuykendall, MD, can be reached at [email protected].