Lilly’s first-in-class type II JAK2 inhibitor AJ1-11095 achieved 70% spleen and symptom response rates in Phase 1 myelofibrosis patients previously treated with JAK inhibitors.
Written By: Sana Khan, BPharm
Fact-Checked By: Dr. Nevetha Natraj, PharmD
Reviewed By: Pharmacally Editorial Team
Eli Lilly has reported encouraging Phase 1 results for AJ1-11095, an investigational type II JAK2 inhibitor, in patients with myelofibrosis previously treated with a type I JAK2 inhibitor. The first-in-class therapy delivered high rates of spleen reduction and symptom improvement while also demonstrating molecular responses rarely observed with currently available JAK inhibitors.
Lilly presented the findings from the ongoing AJX-101 study during an oral session at the European Hematology Association (EHA) 2026 Congress in Stockholm. The program entered Lilly’s oncology pipeline following its acquisition of Ajax Therapeutics.
Targeting a New Form of JAK2 Inhibition
Myelofibrosis is a chronic myeloproliferative neoplasm characterized by bone marrow scarring, splenomegaly, debilitating symptoms, and progressive disease burden. Although type I JAK2 inhibitors have become a standard treatment option, many patients eventually lose response or develop resistance, leaving limited therapeutic alternatives.
AJ1-11095 takes a different approach by binding the inactive, or type II, conformation of JAK2. Existing approved JAK2 inhibitors primarily target the active form of the kinase. By selectively inhibiting inactive JAK2, the therapy may provide deeper pathway suppression and overcome resistance mechanisms associated with current treatments.
Preclinical studies previously showed superior activity compared with ruxolitinib, supporting advancement into clinical development.
Phase 1 Trial Demonstrates Promising Clinical Responses
The dose-escalation portion of the AJX-101 Phase 1 study enrolled 23 patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis. All participants had previously received a type I JAK2 inhibitor and had undergone a median of two prior therapies.
Patients received once-daily AJ1-11095 across five dose levels ranging from 25 mg to 125 mg.
The therapy demonstrated meaningful activity across key efficacy endpoints. Investigators reported a best-response spleen volume reduction of at least 35% (SVR35) in 70% of patients. A 50% or greater improvement in total symptom score (TSS50) at Week 12 was also observed in 70% of patients.
The study additionally showed evidence of disease-modifying activity. Reductions in driver mutation variant allele frequency (VAF) occurred in 21 of 23 patients. Among 17 patients who reached Week 24, 59% achieved at least a 20% VAF reduction and 35% achieved reductions of 50% or greater. Responses were observed across JAK2, MPL, and CALR mutations.
Such molecular responses are uncommon with currently available type I JAK2 inhibitors, making the findings particularly noteworthy.
Manageable Safety Profile Supports Further Development
AJ1-11095 demonstrated a generally manageable safety profile across all dose levels. Investigators reported no dose-limiting toxicities, and 78% of patients remained on treatment at the time of analysis.
The most common treatment-emergent adverse events included anemia, dysgeusia, decreased platelet count, and elevated alanine aminotransferase levels.
According to principal investigator Dr. John Mascarenhas of the Icahn School of Medicine at Mount Sinai, the combination of spleen reduction, symptom improvement, and molecular responses suggests that selective type II JAK2 inhibition may offer a differentiated therapeutic strategy for patients whose disease progresses after existing JAK inhibitor therapy.
Expansion Studies Underway
Lilly views the results as an early proof of concept for a new class of JAK2-targeted therapies. The company has already opened an expansion cohort in second-line myelofibrosis and plans to evaluate AJ1-11095 in patients with high-risk polycythemia vera and in treatment-naïve myelofibrosis.
The ongoing AJX-101 trial (NCT06343805) represents the first clinical evaluation of a selective type II JAK2 inhibitor and could help redefine treatment options for patients with myeloproliferative neoplasms who have limited choices after JAK inhibitor failure.
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About the Writer
Sana Jamil Khan (LinkedIn) is a B. Pharm graduate with a strong interest in medical writing and scientific communication. Her work focuses on interpreting clinical research, exploring developments in pharmaceutical science, and presenting complex medical information in a clear and accessible manner. She is particularly interested in topics related to human clinical studies, drug safety observations, and emerging therapeutic research.