Type II JAK Inhibitor AJ1-11095 Under Phase 1 Investigation in Myelofibrosis

A phase 1 study (NCT06343805) will investigate the safety and efficacy of treatment with AJ1-11095 in patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia, according to a poster presented at the 2024 ASH Annual Meeting.1

Primary end points include establishing the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of AJ1-11095; and identifying treatment-emergent adverse effects (AEs), dose-limiting toxicities, and changes in clinical laboratory and electrocardiogram parameters. Key secondary end points include myelofibrosis symptom assessment from total symptom score 4.4 reduction by 50% from baseline to week 24; spleen volume reduction of at least 35% from baseline to week 24 measured by imaging; characterization of the pharmacokinetics of AJ1-11095; and changes in blood counts or hematological improvement. Exploratory end points include changes in variant allele frequency of JAK2 V617F and other clonal markers (somatic mutations); changes in serum levels of pro-inflammatory cytokines influenced by JAK-STAT signaling; and changes in bone marrow fibrosis grade.

“AJ1-11095 is a first-in-class, orally bioavailable small molecule type II JAK2 inhibitor designed to overcome a common mechanism of clonal persistence and drug resistance to Type I JAK2 inhibitors,” the study authors wrote in the poster.

AJ1-11095 Background and Trial Design

AJ1-11095 was designed via structure-based and computational methods to bind directly to the type II conformation of JAK2, which is known to be inactive. The agent is highly selective for JAK2 compared with other related genes, including JAK1, JAK3, and TYK2. The agent has also shown potent activity based on cell line experiments and murine models of myeloproliferative neoplasms (MPN), both as first-line therapy and post-ruxolitinib (Jakafi) treatment, and it induced reduction in the mutant clone in preclinical MPN models.

The phase 1 multicenter, open-label, dose-escalation and -expansion study investigating AJ1-11095 will initially only enroll patients to locations in the United States and then expand enrollment to other regions. Patients are screened a maximum of 28 days before receiving the first dose of AJ1-11095. They then begin treatment in the dose-escalation phase with AJ1-11095 monotherapy in escalating 3 + 3 cohorts. Once an MTD or RP2D has been established, patients are permitted to enter the dose-expansion phase to receive AJ1-1195 at the MTD/RP2D or at 1 dose level below the MTD/RP2D to confirm the RP2D. After the last dose of the study treatment, the follow-up phase will monitor safety and disease progression.

The starting dose of AJ1-11095 is 25 mg once daily, and subsequent doses will be determined by a modified Fibonacci sequence and informed by all available safety/tolerability and pharmacokinetics data. AEs will be graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events 5.0. Of note, the first patient on the trial was enrolled in October 2024.

Trial Eligibility Criteria

The trial is enrolling patients 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. Patients need to be relapsed/refractory after prior treatment with at least 1 type I JAK2 inhibitor as monotherapy or in a combination, as determined by investigator; have a spleen volume of 450 cm3 or greater; and have an ECOG performance status of 0 to 3.

Patients will be ineligible for enrollment in the trial 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; and received erythropoiesis-stimulating agents, unless stable for more than 8 weeks.2

References

1. Mascarenhas JO, Borate U, Bose P, et al. A multicenter, open-label, phase 1 clinical trial of AJ1-11095 administered as oral monotherapy in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia myelofibrosis (PET-MF) who have been failed by a type I JAK2 inhibitor (JAK2i). Blood. 2024:144(suppl 1):3147.1. doi:10.1182/blood-2024-193905
2. A phase 1 study of AJ1-11095 in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia myelofibrosis (PET-MF) who have been failed by a type I JAK2 inhibitor (JAK2i). ClinicalTrials.gov. Updated January 24, 2025. Accessed February 4, 2025. https://clinicaltrials.gov/study/NCT06343805