MYF3001: A Randomized Open Label, Phase 3 Study to Evaluate Imetelstat Versus Best Available Therapy in Patients with Intermediate-2 or High-Risk Myelofibrosis Relapsed/Refractory to Janus Kinase Inhibitor

Myelofibrosis (MF) is a life-threatening myeloproliferative neoplasm. Janus Kinase inhibitors (JAKi) ruxolitinib, pacritinib and fedratinib are the FDA-approved treatment options for MF. Despite benefits reported with ruxolitinib in the frontline setting, a high proportion of patients discontinue treatment (Abdelrahman 2015), and the median overall survival (OS) is 11-16 months (Newberry 2017; Kuykendall 2018; Palandri 2019; Schain 2019; Mascarenhas 2020), highlighting a great unmet need for patients whose disease has relapsed or is non-responsive to JAKi treatment.

Imetelstat, a first-in-class telomerase inhibitor, has shown meaningful clinical improvement in IMbark, a Phase 2 study in patients with intermediate-2 (Int2) or high-risk (HR) MF whose disease has relapsed after or was refractory to JAKi (Mascarenhas JCO 2021; NCT02426086). Treatment with 9.4 mg/kg imetelstat resulted in 32.2% symptom response (total symptom score [TSS] reduction ≥50%) at Week 24 and median OS of 29.9 months with median overall study follow-up of 27.4 months (Figure 1). Dose-dependent inhibition of telomerase with imetelstat resulted in on-target activity that correlated with clinical benefits; including dose-dependent reduction in variant allele frequency (VAF) of MF driver mutations and improvement of bone marrow (BM) fibrosis. Furthermore, VAF reduction and BM fibrosis improvement correlated with OS. Imetelstat has an acceptable safety profile, with the most common Grade 3 or higher treatment-emergent adverse events being thrombocytopenia and neutropenia that were manageable and reversible, with minimal clinical consequences. These Phase 2 efficacy and safety results support continued study of imetelstat 9.4 mg/kg in a Phase 3 randomized controlled study.

Study MYF3001 (IMpactMF; NCT04576156) is a Phase 3, randomized (2:1), open label, multicenter study of imetelstat compared with best available therapy (BAT) in ~320 adult patients with Int2 or HR MF whose disease has relapsed after or is refractory to JAKi treatment, who are not candidates for further JAKi treatment, and who are not eligible for allogeneic stem cell transplantation. Relapsed and refractory disease will be determined by predefined increases in spleen volume after a period of response and a lack of spleen and/or symptom responses after at least 3 months of JAKi therapy, respectively. Patients will be randomized to receive intravenous imetelstat 9.4 mg/kg every 21 days or investigator-selected BAT that may include hydroxyurea, thalidomide, interferon, danazol, hypomethylating agents, chemotherapy, or other non-JAKi-containing therapy as appropriate (Figure 2). Hematopoietic stem cell transplant and splenectomy are not permitted as BATs. Eligible patients will have an Eastern Cooperative Oncology Group Performance Status score of 0-2 and peripheral blood and marrow blast counts <10%. Patients cannot have clinically significant cardiovascular disease, active systemic hepatitis infection, or chronic liver disease unrelated to underlying MF. At randomization, patients will be stratified based on a) Int2 or HR per Dynamic International Prognostic Scoring System; and b) platelet count at entry (platelets ≥75 and <150 x 10⁹/L vs ≥150 x 10⁹/L). Patients who meet progressive disease criteria and discontinue BAT may be eligible to crossover to imetelstat if they exhibit a ≥25% increase in spleen volume from pretreatment baseline at any time during the study or a palpable increase in splenomegaly following 6 months of BAT, as described in the protocol.

The primary endpoint of Study MYF3001 is OS and an interim analysis of safety and efficacy is planned when ~35% of patients planned to be enrolled have died. Secondary endpoints include symptom and spleen response rates at Week 24, progression-free survival, clinical response assessments per modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment criteria, time to and duration of response, reduction in degree of bone marrow fibrosis, safety, pharmacokinetics and patient-reported outcomes. Biomarkers and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones.

Approximately 180 sites are planned in North and South America, Europe, Middle East, Australia and Asia. The study is actively enrolling.

Mascarenhas:GSK: Consultancy; AbbVie: Consultancy, Research Funding; Prelude Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forbius: Research Funding; Merck: Research Funding; Janseen: Research Funding; Merus: Research Funding; PharmaEssentia: Consultancy, Research Funding; Galecto: Consultancy; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos: Consultancy, Research Funding; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Imago: Consultancy; Roche: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Shire: Membership on an entity's Board of Directors or advisory committees; MPN voice: Other: Leadership role; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galecto: Consultancy, Membership on an entity's Board of Directors or advisory committees; Keros: Consultancy; Promedior: Membership on an entity's Board of Directors or advisory committees; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sierra: Honoraria; AOP Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Galacteo: Membership on an entity's Board of Directors or advisory committees; EHA: Other: Leadership role; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings, Research Funding. Kiladjian:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Komrokji:Servier: Consultancy, Honoraria, Speakers Bureau; Taiho Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma, Innovent: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Speakers Bureau; PharmaEssentia, Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Acceleron Pharma: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Geron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; AOP Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; CTI Biopharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; PharmaEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Alexion: Other: Travel support; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Karthos: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; RWTH Aachen University: Patents & Royalties: BET Inhibitor. Vannucchi:Abbvie: Membership on an entity's Board of Directors or advisory committees; AOP Orphans Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; BluePrint: Membership on an entity's Board of Directors or advisory committees, Other: NA; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Other: NA; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Berry:Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Redding:Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Sherman:Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Peng:Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Sun:Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Incyte: Consultancy, Research Funding; NS Pharma: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; ItalPharma: Research Funding; CTI BioPharma Corp.: Research Funding; PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Roche: Research Funding; Genentech: Research Funding; Protagonist Therapeutics: Research Funding; Constellation Pharmaceuticals: Consultancy; Blueprints Medicines Corp.: Research Funding; AstraZeneca: Research Funding; Pragmatist: Consultancy.