Treatment with the novel TMPRSS6-targeting monoclonal antibody DISC-3405 reduced the rate of phlebotomies and maintained hematocrit levels below 45% in patients with polycythemia vera (PV) requiring regular phlebotomy, according to initial data from the ongoing phase 2 RESTORE-PV trial (NCT06985147) presented at the
Among evaluable patients in Cohort A who completed 26 weeks of therapy (n = 13), the mean total number of phlebotomies per 26 weeks decreased from 4.0 (standard error [SE], 0.4) in the 26 weeks before day 1 of treatment to 0.6 (SE, 0.3) in the 26 weeks after treatment initiation (mean difference, −3.4; SE, 0.5; 95% CI, −4.5 to −2.3; P < .0001). In this group, 61.5% of patients remained phlebotomy-free after baseline through 26 weeks. Among the patients in cohort A who completed the first maintenance period (n = 9), 77.8% remained phlebotomy-free during that period.
“This class of [hepcidin-increasing] drugs is thought to be an adjunct to PV therapy. All patients with PV take aspirin daily, and a significant proportion of patients—particularly the high-risk patients, patients who are older, and [those] who have a thrombosis history—are on cytoreductive therapy,” Naseema Gangat, MBBS, of the Mayo Clinic in Rochester, Minnesota, said in an interview with OncLive®. “Despite the use of cytoreductive therapy, if [patients] have phlebotomy needs, this class of drugs would have a role, [including] in those who are intolerant to phlebotomies.”
PV is a JAK2-driven myeloproliferative neoplasm, in which maintaining hematocrit levels below 45% is central to reducing thromboembolic complications; phlebotomy and cytoreductive therapy remain standard of care but can be burdensome and can drive iron deficiency, contributing to fatigue and other symptoms. TMPRSS6 negatively regulates hepcidin, the master regulator of iron, and inhibiting TMPRSS6 raises endogenous hepcidin, restricts iron availability, and can lower hematocrit.
The open-label RESTORE-PV trial enrolled patients at least 18 years of age with PV based on 2022 World Health Organization criteria who required phlebotomy to maintain hematocrit levels below 45%, defined as at least 3 phlebotomies in 26 weeks or at least 5 in 52 weeks. An ECOG performance status of 0 or 1 was also required. Cytoreductive therapy was not required but, when used, had to be stable for at least 2 months.
The study included 2 cohorts. In cohort A (n = 20), patients received subcutaneous DISC-3405 during a 12-week dose-escalation period, followed by a pair of 20-week maintenance periods. During dose escalation, 4 patients in cohort A received DISC-3405 at an initial dose of 150 mg, followed by 300 mg 4 weeks later, then 300 mg every 2 weeks for 2 doses; the other 16 patients received DISC-3405 at 2 initial doses of 300 mg every 4 weeks, then 2 doses at 300 mg every 2 weeks. During both maintenance phases, patients in cohort A were treated at 300 mg every 2 weeks.
In cohort B (n = 20), patients received the agent at 300 mg every 4 weeks throughout dose escalation, and this schdule was continued in both maintenance phases. Patients in both cohorts could continue treatment in an optional phase lasting 2 years beyond the initial 52 weeks. Efficacy data from cohort B were not presented during SOHO.
The primary end point was safety and tolerability; secondary end points included the proportion of participants achieving a therapeutic response, defined as absence of phlebotomy or phlebotomy eligibility, and pharmacokinetic (PK) and pharmacodynamic (PD) changes. Exploratory end points included anti-drug antibody (ADA) emergence and changes in quality-of-life measures. The data cutoff was July 13, 2026.
In cohort A, the mean age was 58.6 years (standard deviation [SD], 13.3), 80.0% of participants were male, and 95% were White. Patients had a mean disease duration of 5.8 years (SD, 5.7), and 65% had high-risk disease. Additionally, 95% of patients harbored a JAK2 V617F mutation, and 5% had a JAK2 exon 12 mutation. Forty-five percent of patients were not receiving cytoreductive therapy, 40% were receiving hydroxyurea, and 15% were receiving interferon. The mean baseline phlebotomy rate in the 26 weeks prior to dose was 3.7 (SD, 1.4; 0.14 per week [SD, 0.05]), and the mean baseline ferritin level was 14.2 ng/mL (SD, 7.9). The mean time on study was 205.5 days (SD, 62.2).
DISC-3405 administration increased hepcidin, reduced serum iron, and stabilized hematocrit in patients in cohort A, with mean hematocrit level maintained below the 45% threshold through week 26. The agent demonstrated a predictable PK and hepcidin response, and no ADAs were detected in cohort A to date. Among the 13 patients who completed 26 weeks of therapy, symptom scores improved on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) in 11 of 13 participants and on the Patient-Reported Outcomes Measurement Information System–Fatigue Short Form (PROMIS-F-SF) 7a in 12 of 13 participants.
Across both cohorts (n = 38), treatment-emergent adverse effects (TEAEs) occurred in 71.1% of patients, including 80.0% in cohort A and 61.1% in cohort B. Treatment-related TEAEs occurred in 26.3% of patients between the 2 cohorts. The majority of AEs (82.4%) were grade 1, and DISC-3405 was administered without dose-limiting toxicities.
Two serious AEs (5.3%), one in each cohort, were reported; neither was considered treatment-related, and no treatment-related serious AEs occurred. TEAEs did not lead to any instances of treatment discontinuation.
The most common TEAEs included abdominal pain (18.4%) and injection site reactions (13.2%), all of which were grade 1. One instance of grade 2 anemia occurred in cohort B, which resolved with dose reduction.
