Clinical Summary: 

• Design/Population: The phase 2 RESTORE-PV trial evaluated DISC-3405, a first-in-class monoclonal antibody targeting TMPRSS6, in patients with polycythemia vera requiring therapeutic phlebotomy. The open-label study included 2 dosing cohorts and enrolled patients with or without concomitant cytoreductive therapy.
• Key Outcomes: DISC-3405 substantially reduced or eliminated phlebotomy requirements, with responses observed regardless of concomitant cytoreductive therapy. Reduced phlebotomy burden was accompanied by improvements in fatigue and myeloproliferative neoplasm-related symptoms, with treatment demonstrating a favorable safety profile. 
• Clinical Relevance: These findings support endogenous hepcidin induction through TMPRSS6 inhibition as a novel strategy to maintain hemocrit control, reduce phlebotomy burden, and address iron deficiency-related symptoms in polycythemia vera.

Naseema Gangat, MBBS, Mayo Clinic, Rochester, Minnesota, discusses results from the phase 2 RESTORE-PV trial evaluating DISC-3405, a first-in-class monoclonal antibody targeting TMPRSS6, in patients with polycythemia vera who require therapeutic phlebotomy. 

Dr Gangat reviews early findings demonstrating substantial reductions in phlebotomy requirements, including achievement of phlebotomy independence in a majority of evaluable patients, regardless of concomitant cytoreductive therapy. She also discusses improvements in patient-reported fatigue and disease-related symptoms, the favorability of DISC-3405, and how increasing endogenous hepcidin through TMPRSS6 inhibition may provide a novel approach to hematocrit control while reducing the burden and iron depletion associated with repeated phlebotomy.

Transcript: 

My name is Naseema Gangat, and I'm a professor of medicine with the division of hematology at the Mayo Clinic in Rochester, Minnesota. Today I'm here to discuss the RESTORE-PV clinical trial. This is a phase 2 trial with an anti-TMPRSS6 monoclonal antibody in patients with polycythemia vera.

Just to give you a background on polycythemia vera, polycythemia vera is a myeloproliferative neoplasm. Hallmark of the disease is presence of a JAK2 mutation, and the major complications patients with polycythemia vera experience are thrombosis. The goals of treatment are really focused towards reducing the risk of thrombosis in these patients, and that is accomplished by keeping a hematocrit below 45 in all instances. Typically, that is done through phlebotomy or the use of cytoreductive therapies, and phlebotomies tend to be cumbersome for patients. Some patients are intolerant of phlebotomies, or the frequency of the phlebotomies adds to a lot of burden for the patients, and it depletes iron stores and leads to symptomatic iron deficiency.

Hence, there is considerable interest in trying to manipulate the hepcidin production axis in order to be able to eliminate phlebotomy needs for patients with polycythemia vera.

DISC-3405 is a monoclonal antibody directed against TMPRSS6, also known as matriptase. Looking at the hepcidin production pathway, hemojuvelin is a key protein which increases hepcidin production. Essentially TMPRSS6 negatively regulates hemojuvelin and this medication is inhibiting TMPRSS6. In essence, the negative regulation on the hemojuvelin is being eliminated leading to increased hepcidin production. The increase in hepcidin production restricts the iron availability for erythropoiesis.

The study design, this is a phase 2 study, open label study with 2 dosing cohorts, cohort A and cohort B with 2 different dosing strategies. Cohort A included patients receiving 300 milligrams every 2 weeks of treatment and cohort B is 300 milligrams subq every 4 weeks. There's a dose escalation phase of 12 weeks followed by Maintenance 1 of 20 weeks and Maintenance 2 of 20 weeks. Essentially a 52-week design. All 40 patients have been recruited thus far with 25 of the patients having been recruited at the Mayo Clinic sites and 18 out of the 20 in cohort B have been dosed, whereas all 20 in cohort A have been dosed since cohort A recruited before the starting of cohort B. The patient demographics were typical of a PV patient population. Half of the patients were receiving concomitant cytoreductive therapy and ferritin levels at baseline were low as expected for patients with polycythemia vera.

Moving on to the topline study results, we have efficacy analysis for patients in cohort A, and looking at the baseline phlebotomy needs and the phlebotomy needs post-treatment, there is a marked reduction or elimination of phlebotomy that was seen. This was regardless of whether the patients were receiving cytoreductive therapy or not. In particular, 9 patients have completed Maintenance 1 of treatment. Amongst those 9, 7 were rendered phlebotomy free, which is 77.8%. Out of the 13 patients that have completed 26 weeks of treatment, 8 were rendered phlebotomy free and the mean reduction in phlebotomies was about 3.4 for this patient population. Importantly, the reduction or elimination of phlebotomy needs correlated with the improved patient related outcomes. There were improved fatigue scores as well as the MPN-SAF scores in these patients. Last but not least, the drug was found to be extremely well tolerated. The rate of injection site reactions was fairly low at 13%. There was only 1 anemia event which resolved after dose reduction of the drug.

In conclusion, we did not find any anti-drug antibodies and there was stabilization of the hematocrit noticed in the pharmacodynamic and pharmacokinetic studies. Overall, DISC-3405 is the first in class monoclonal antibody against TMPRSS6 for the treatment of polycythemia vera, which has demonstrated early efficacy with reduction in elimination and phlebotomy needs in a substantial proportion of patients. The drug is found to be relatively safe and in comparison, to other drugs with the same similar mechanisms, the injection site reactions were found to be minimal. Based on these results, it sets the stage for further testing in a randomized placebo-controlled setting.

We expect changes in the management of polycythemia vera with the approval of drugs such as rusfertide, which was recently FDA approved, which is a hepcidin mimetic. DISC-3405 is a hepcidin inducing agent, so you're increasing your endogenous hepcidin levels. In comparison, I think these drugs have made a place in the treatment landscape of polycythemia vera more as an adjunctive agent to cytoreductive therapy, not necessary to replace cytoreductive therapy, but in younger patients who wish to not receive any chemotherapy agents, it could be a consideration as a standalone therapy, but there is a significant proportion of patients who are still requiring frequent phlebotomies despite being on cytoreductive therapy. Medications in this class would definitely fill the void and would help stabilize hematocrit relief patients of symptoms related to iron deficiency. Thank you for your time.

Source:

Gangat N, Tefferi A, Gerds AT, et al. Restore-PV: A phase 2 open-label study evaluating the safety and efficacy of the anti-TMPRSS6 monoclonal antibody DISC-3405 in participants with polycythemia vera. Presented at the SOHO Annual Meeting; September 9-12, 2026; Houston, Texas. Abstract MPN-099.