A phase 1 clinical trial is currently investigating the safety and efficacy of AJ1-11095, a novel type II JAK2 inhibitor, in patients with myelofibrosis (MF). The study (NCT06343805) is enrolling patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia who have relapsed or are refractory to prior type I JAK2 inhibitor therapy. The trial aims to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AJ1-11095, while also evaluating its impact on myelofibrosis symptoms and spleen volume.
Novel Type II JAK2 Inhibitor
AJ1-11095 is a first-in-class, orally bioavailable small molecule designed to selectively bind to the type II conformation of JAK2, which is the inactive form of the kinase. This mechanism of action differs from currently approved JAK2 inhibitors like ruxolitinib (Jakafi), which bind to the type I conformation. The rationale behind targeting type II JAK2 is to overcome common resistance mechanisms observed with type I inhibitors and potentially achieve greater disease modification.
According to a poster presented at the 2024 ASH Annual Meeting, preclinical studies have demonstrated that AJ1-11095 can reverse marrow fibrosis, reduce mutant allele burden, and maintain efficacy against MPN cells that have developed resistance to type I JAK2 inhibitors. These findings suggest that AJ1-11095 may offer a new treatment option for patients who have failed or become resistant to existing therapies.
Trial Design and Endpoints
The phase 1 trial is a multicenter, open-label, dose-escalation and -expansion study. The dose-escalation phase will use a 3 + 3 cohort design to determine the MTD and RP2D of AJ1-11095. Once the MTD/RP2D is established, the study will enter the dose-expansion phase to confirm the RP2D.
Key secondary endpoints include a 50% reduction in total symptom score 4.4 from baseline to week 24 and a spleen volume reduction of at least 35% from baseline to week 24, measured by imaging. The trial will also assess the pharmacokinetics of AJ1-11095 and changes in blood counts. Exploratory endpoints include changes in variant allele frequency of JAK2 V617F and other clonal markers, changes in serum levels of pro-inflammatory cytokines, and changes in bone marrow fibrosis grade.
Eligibility Criteria
Patients eligible for the trial must be at least 18 years of age with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis; marrow with up to 10% blasts with or without a JAK2 mutation; and intermediate-2 or high-risk disease established via the Dynamic International Prognostic Scoring System. They must also be relapsed/refractory after prior treatment with at least one type I JAK2 inhibitor, have a spleen volume of 450 cm3 or greater, and have an ECOG performance status of 0 to 3.
Patients are ineligible if they have had prior splenectomies, splenic irradiation within 3 months before the first dose of AJ1-11095, ongoing use of systemic corticosteroids at a dose equivalent to greater than 10 mg per day of prednisone, received chemotherapy within 4 weeks leading up to the first dose of AJ1-11095, received a JAK2 inhibitor within 10 days leading up to treatment of AJ1-11095, or received erythropoiesis-stimulating agents, unless stable for more than 8 weeks.
Myelofibrosis and Unmet Needs
Myelofibrosis is a rare blood cancer affecting approximately 20,000 patients in the United States. It is characterized by spleen enlargement, bone marrow scarring (fibrosis), progressive anemia, and debilitating symptoms. While type I JAK2 inhibitors can reduce spleen size and improve symptoms, they often have limited impact on the underlying disease and patients may eventually discontinue treatment due to lack of benefit, adverse events, or disease progression. The development of AJ1-11095 represents a potential advancement in the treatment of myelofibrosis, particularly for patients who have failed prior JAK2 inhibitor therapy. Ajax Therapeutics, the developer of AJ1-11095, designed the drug to selectively bind the Type II conformation of the JAK2 kinase, potentially offering greater efficacy with disease modification compared to currently approved JAK2 inhibitors.
