A Randomized Open-Label, Phase 3 Study to Evaluate Imetelstat Versus Best Available Therapy (BAT) in Patients with Intermediate-2 or High-Risk Myelofibrosis (MF) Refractory to Janus Kinase (JAK) Inhibitor

Background: Myelofibrosis (MF) is a life-threatening myeloproliferative neoplasm. Ruxolitinib, a Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor and fedratinib, a JAK2/FLT3 inhibitor, are the only approved treatment options for MF. Despite the benefits reported with ruxolitinib in the front‑line setting, a high proportion of patients discontinue treatment, the 1-, 2-, and 3-year discontinuation rates are 49%, 71%, and 86%, respectively (Abdelrahman et al, 2015). For patients who discontinue treatment with ruxolitinib, the median overall survival (OS) is dismal and ranges from 13 to 16 months (Kuykendall et al, 2018; Newberry et al, 2017; Schain et al, 2019; Palandri et al, 2019; Mcnamara et al, 2019). There remains a great unmet need for patients who are non-responsive to and have discontinued treatment with a JAK inhibitor.

Imetelstat, a first-in-class telomerase inhibitor, has shown meaningful clinical improvement in symptom response and improved OS in IMbark, a Phase 2 study in patients with intermediate-2 or high-risk MF who have relapsed after or are refractory to JAK inhibitors (Mascarenhas et al, ASH 2018 #685; Mascarenhas et al, EHA 2020 #EP1107). Nineteen (32.2%) patients in the 9.4 mg/kg arm and 3 (6.3%) patients in the 4.7 mg/kg arm achieved symptom response (total symptom score [TSS] reduction ≥50%) at Week 24. As of clinical cutoff (7 February 2020), with an overall study follow up of 42 months, median OS was 28.1 months for the 9.4 mg/kg arm (95% confidence interval [CI]: 22.8, 31.6) and 19.9 months for the 4.7 mg/kg arm (95% CI: 17.1, 33.9). The improvement in OS for patients treated with 9.4mg/kg imetelstat was further supported by analyses of IMbark patients with closely matched real world controls (Kuykendall et al, EHA 2019 #PS1456). Taken together, these findings support continued study of imetelstat 9.4 mg/kg dose in a well-designed Phase 3 randomized controlled study in patients with refractory MF.

Methods: Study MYF3001 is an open label, randomized (2:1), multicenter, Phase 3 study of imetelstat compared with best available therapy (BAT) in approximately 320 patients with intermediate-2 or high-risk MF (primary MF, post-essential thrombocythemia-MF, or post-polycythemia vera-MF) who are refractory to JAK inhibitor treatment. Approximately 214 patients will be randomized to Arm A to receive imetelstat, and approximately 106 patients will be randomized to Arm B to receive BAT. Eligible patients will be stratified based on: a) intermediate-2 or high-risk per Dynamic International Prognostic Scoring System (DIPSS); and b) platelet count at study entry (platelets ≥75 x 10⁹/L and <150 x 10⁹/L versus ≥150 x 10⁹/L). Patients randomized to Arm A will receive imetelstat at the dose of 9.4 mg/kg intravenous (IV) every 21 days. Patients randomized to BAT will receive investigator-selected therapy, which may include hydroxyurea, thalidomide, interferon, danazol, hypomethylating agents, chemotherapy, or other non-JAK inhibitor containing therapy as appropriate in this setting.

The primary endpoint of the study is OS. Secondary endpoints include symptom response rate at week 24, progression-free survival, spleen response rate at week 24, clinical response assessment per modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG MRT) criteria, time to and duration of response, reduction in the degree of bone marrow fibrosis, safety, pharmacokinetics, and patient-reported outcomes. One interim analysis based on OS is planned.

Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with OS and clinical responses. Mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification.

The study will be conducted at approximately 150 centers in North and South America, Europe, Asia, and Middle East.