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)

Background: Myelofibrosis (MF) is a chronic hematologic malignancy characterized by substantial symptom burden, splenomegaly, anemia, and reduced overall survival. Aberrant JAK-STAT signaling in clonal hematopoietic stem and progenitor cells is a fundamental biologic driver of MF, and this pathway is the therapeutic target for 4 currently approved type 1 JAK2 inhibitors. Although these drugs provide patients with important spleen, symptom, and sometimes anemia improvement, they do not induce major molecular remission or reliably alter disease course, and most patients discontinue therapy within 2-3 years of treatment initiation due to lack of clinical response, relapse after an initial response, disease progression, or adverse events.

AJ1-11095 is a novel orally bioavailable small molecule type II non-covalent tyrosine kinase inhibitor that binds both the active and inactive conformations of JAK2 and prevents heterodimerization with JAK1 and TYK2, overcoming a common mechanism of clonal persistence and drug resistance to type I inhibitors (Koppikar P et al Nature 2012; Meyer SC et al Cancer Cell 2015) in vitro and in pre-clinical models of MPN.

Design and Methods: The primary objective of this first-in-human study (NCT06343805) is to evaluate the safety and tolerability and establish the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of AJ1-11095 in patients with MF. Key secondary endpoints include clinical benefit as assessed by the Myelofibrosis Symptom Assessment Form Total Symptom Score (TSS) version 4.0 (MFSAF v4.0) and spleen volume reduction (SVR) of ≥35% from baseline to Week 24 measured by imaging, and characterization of the pharmacokinetics of AJ1-11095. Exploratory endpoints include assessment of changes in variant allele frequency (VAF) of JAK2 V617F and other clonal markers (somatic mutations), serum levels of pro-inflammatory cytokines influenced by JAK-STAT signaling, and bone marrow fibrosis grade change.

Key eligibility criteria include a confirmed diagnosis of primary MF or post-PV/ET MF with ≤10% marrow blasts; intermediate-2/high-risk disease by Dynamic International Prognostic Scoring System (DIPSS); spleen volume of ≥450cm³; MFSAF TSS ≥10 or at least 2 of 7 MFSAF-assessed symptoms with scores ≥3; relapsed/refractory after prior therapy with at least one type I JAK2 inhibitor, either as monotherapy or in combination; baseline platelet count ≥75 x 10⁹ /L, baseline neutrophil count ≥1.0 x 10⁹ /L, AST/ALT ≤ 3 x upper limit of normal (ULN), estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73m, and QTcF ≤ 480ms. MF-directed therapy must be stopped at least 5 half-lives (5 days for hydroxyurea) before start of AJ1-11095. Erythropoiesis-stimulating agents (ESAs) are permitted if on a stable dose for >8 weeks or >5 half-lives.

Based on repeated dose testing in animals and ICH S9 guidelines, the starting dose for this Phase 1, multicenter, open-label dose escalation and expansion study will be 25 mg once daily; dose escalation will follow a conventional 3+3 design, with subsequent doses determined by a modified Fibonacci sequence and informed by all available safety/tolerability and pharmacokinetics data. Dose limiting toxicities (DLTs) are defined within the protocol and will be determined during the first 28-day cycle of treatment. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Evenst (NCI CTCAE) v. 5.0.

A Study May Proceed letter was received from the US Food and Drug Administration in May 2024. We expect to enroll the first patient in this trial September of 2024 and to activate approximately 10 sites in the US, with inclusion of sites outside the US in the dose expansion stage for a total of ~76 subjects across both stages.