Experimental drug safely eases resistant myelofibrosis symptoms
Clinical study: Patients' disease had stopped responding to 1st-gen JAK2 inhibitors
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Eli Lilly’s AJ1-11095, an experimental JAK2 inhibitor recently licensed from Ajax Therapeutics, may be safe and effective at easing symptoms of myelofibrosis in patients whose disease has stopped responding to first-generation JAK2 inhibitors.
That’s according to initial results from AJX-101 (NCT06343805), an open-label Phase 1 clinical study that is recruiting up to 76 adults with primary or secondary myelofibrosis who have previously been treated with other JAK2 inhibitors. Its goal is to test how safe AJ1-11095 is and how well it works when taken orally once daily at five different dose levels.
The results show that most patients treated with AJ1-11095 experienced less severe symptoms and a reduction in the proportion of disease-causing genetic mutations, known as variant allele frequency (VAF). Their spleen decreased in volume as early as about three months.
“The depth of response seen across spleen, symptoms, and VAF from these early phase results is in excess of what has been seen historically in this disease setting,” Jacob Van Naarden, executive vice president and president of Lilly Oncology, said in a company press release.
AJ1-11095 designed to inhibit key enzyme
Myelofibrosis is a myeloproliferative neoplasm, a type of blood cancer. In myelofibrosis, the bone marrow starts producing too many abnormal blood cells, leading to inflammation and scarring. This can prevent the bone marrow from producing healthy blood cells. Patients often have an enlarged spleen, fatigue, and easy bruising or bleeding.
AJ1-11095 is designed to inhibit JAK2, an enzyme that helps regulate blood cell production. An overactive JAK2 can drive a blood cancer. Unlike approved type I JAK2 inhibitors, which bind to the enzyme in its active form, AJ1-11095 is a next-generation type II JAK2 inhibitor that binds to the enzyme in its inactive form. This may help overcome resistance that can develop with type I JAK2 inhibitors.
“Patients with myelofibrosis who have been previously treated with an existing type I JAK2 inhibitor face very limited treatment options, highlighting an urgent need for new therapies,” said John Mascarenhas, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City and principal investigator of the AJX-101 clinical study.
Most patients had at least a 35% reduction in spleen volume
Mascarenhas presented the initial results of AJX-101 in an oral presentation at the 2026 European Hematology Association meeting in Stockholm in June. Its abstract was titled “Results of AJX-101, a Phase 1 clinical trial of the type II JAK2 inhibitor AJ1-11095, in patients with myelofibrosis who have been failed by a type I JAK2 inhibitor.”
The dose-escalation part of AJX-101 included 23 patients, ages 47 to 87, who received one of five daily doses ranging from 25 mg to 125 mg. Patients had been diagnosed with myelofibrosis for a median of 6.1 years and had received a median of two different type I JAK2 inhibitors before joining the clinical study.
Of the 20 patients who had reached their three-month treatment evaluation, 13 (65%) had at least a 35% reduction in spleen volume. With dose escalation, two other patients achieved this outcome. Based on changes in the Total Symptom Score (TSS), a measure of symptom severity, 17 (74%) patients achieved at least a 50% reduction in symptom burden.
With an encouraging safety profile, meaningful spleen size reduction, symptom improvement, and decrease in underlying mutant disease burden, these data, while early, point to the potential to meaningfully impact treatment options for people with certain myeloproliferative neoplasms.
Researchers also measured VAF, which estimates the proportion of blood cells that carry disease-causing genetic mutations. Reductions in VAF were observed in 21 (91.3%) patients. Among the 17 patients who completed six months of treatment, more than half (59%) had at least a 20% reduction, while one-third (35%) had at least a 50% reduction. Such reductions are rarely reported with type I JAK2 inhibitors, according to Lilly.
“Selective targeting of the type II conformation of JAK2 may provide a differentiated approach. With an encouraging safety profile, meaningful spleen size reduction, symptom improvement, and decrease in underlying mutant disease burden, these data, while early, point to the potential to meaningfully impact treatment options for people with certain myeloproliferative neoplasms,” Mascarenhas said.
No dose-limiting toxicities were reported, meaning none of the tested doses caused side effects severe enough to prevent further increases. The most common side effects were anemia (low red blood cell counts), changes in taste, low platelet counts, and elevated liver enzymes. According to the researchers, the selected initial dose for expansion was 75 mg.
“With this program now officially part of Lilly’s pipeline, we are committed to rapidly advancing it through clinical development and further exploring its potential to meaningfully improve outcomes for people with myeloproliferative neoplasms across a range of disease settings,” van Naarden said.
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