AJ1-11095 Shows Spleen Responses and Symptom Improvement in Post–Type I JAK Inhibitor Myelofibrosis

AJ1-11095, a first-in-class type II selective JAK2 inhibitor, produced high rates of spleen volume reduction (SVR) and symptom improvement with a manageable safety profile in patients with myelofibrosis who had previously received a type I JAK2 inhibitor, according to dose-escalation data from the phase 1 AJX-101 trial (NCT06343805) presented at the 2026 EHA Congress.¹

Among patients enrolled in the dose-escalation phase across 5 dose levels (25 mg, 50 mg, 75 mg, 100 mg, and 125 mg orally once daily), an SVR of at least 35% (SVR35) was achieved as a best response at any time in 70%, and an SVR of at least 25% (SVR25) was achieved in 83%. At a median follow-up of 8.1 months, 78% of patients remained on study therapy, with the longest-followed patients treated for more than 18 months. A 50% or greater reduction in Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) total symptom score (TSS) was observed at any time in 96% of patients, at week 12 in 70% of patients, and at week 24 in 65% of patients.

“AJ1-11095 is the first type II JAK2 inhibitor to enter the clinic,” John Mascarenhas, MD, said in a presentation of the data. “We see very significant spleen and symptom improvement volume after prior type I JAK inhibitor exposure. We see evidence of disease modification with reduction in VAF [of] CALR, JAK2, and MPL. These responses have so far been durable.”

Mascarenhas is a professor of medicine at the Icahn School of Medicine at Mount Sinai; as well as director of the Center of Excellence for Blood Cancers and Myeloid Disorders, director of the Adult Leukemia Program, leader of clinical investigation within the Myeloproliferative Disorders Program, and a member of the Mount Sinai Tisch Cancer Center in New York, New York.

What is the rationale for investigating type II JAK2 inhibition in post–type I JAK inhibitor myelofibrosis?

FDA-approved type I JAK2 inhibitors, including ruxolitinib (Jakafi), have been shown to generate improvements in symptoms and spleen size in myelofibrosis but do not meaningfully reduce clonal burden or prevent disease progression, Mascarenhas noted. In a real-world European cohort, loss/lack of response and disease progression accounted for 34.8% and 23.4% of ruxolitinib discontinuations, respectively.² The absence of acquired resistance mutations at progression indicates that incomplete pathway inhibition, rather than strong selective pressure, drives resistance to type I agents, according to Mascarenhas.¹

JAK2 exists in 2 conformations: a type I (active, DFG-in) conformation to which all currently approved JAK2 inhibitors bind, and a type II (inactive, DFG-out) conformation. Binding the active conformation allows JAK2 heterodimerization with JAK1 and TYK2, enabling clonal persistence and resistance. Type II inhibition functions by stabilizing JAK2 in its inactive state and preventing heterodimerization. It has also shown disease modification capabilities in preclinical models. AJ1-11095 was designed using computational chemistry and a structure-based design to bind the type II conformation selectively, and showed superior efficacy and disease modification compared with ruxolitinib in head-to-head preclinical studies across validated myelofibrosis/myeloproliferative neoplasm (MPN) models.

What patients were enrolled in the AJX-101 dose-escalation phase?

AJX-101 enrolled adult patients with primary myelofibrosis, post-polycythemia vera (PV) myelofibrosis, or post-essential thrombocythemia (ET) myelofibrosis who had Dynamic International Prognostic Scoring System (DIPSS) intermediate-2 or high-risk disease with blast levels of 10% or lower, a spleen volume of at least 450 cm³, an MFSAF v4.0 TSS of at least 10 or with at least 2 of 7 symptoms rated 3 or higher, an ECOG performance status of 0 to 3, a platelet count of at least 75 × 10⁹/L, an eGFR level of at least 45 mL/min/1.73 m², and prior therapy with at least 1 type I JAK2 inhibitor.

Of the patients enrolled across the dose-escalation cohorts, the median age was 69 years (range, 47-87), and 30% were female. The median time from initial diagnosis was 6.1 years (range, 0.6-20.7). By DIPSS status at screening, 74% of patients had intermediate-2–risk disease, and 13% of patients had high-risk disease. Myelofibrosis subtypes included primary (43%), post-ET (35%), and post-PV (22%). Driver mutations were JAK2 V617F (n = 16), CALR type 1 (n = 5), CALR type 2 (n = 1), and MPL W515 (n = 1). The median number of prior therapies was 2 (range, 1-6); all 23 patients had received prior ruxolitinib, 6 patients had received momelotinib (Ojjaara), and 2 patients each had received pacritinib (Vonjo) and fedratinib (Inrebic). The mean spleen volume at baseline was 2389 cm³ (range, 610-4511), and the mean MPN-SAF TSS was 22 points (range, 6-55).

Pharmacokinetic data showed dose-proportional increases in C_max and area under the curve from the 25-mg dose level to the 125-mg dose level. The time to T_max was 1 to 4 hours across patients and cohorts, and the mean terminal half-life was estimated at 8 hours to 11 hours across all dose levels. Coverage above the SET2 IC⁵⁰ increased with higher doses.

What molecular activity did AJ1-11095 demonstrate in AJX-101?

Post-baseline driver mutation VAF reductions were observed in 21 of 23 patients. Among the 17 patients who reached cycle 7 (week 24), 10 (59%) had achieved a 20% or greater relative VAF reduction, and 6 (35%) had achieved at least a 50% relative VAF reduction to date. VAF reductions were observed across driver mutation types, including JAK2 V617F, MPL W515, and CALR type 1 and type 2 mutations.

AJ1-11095 also reduced levels of key pro-inflammatory cytokines, including TNFα, IL-6, MCP-1 (CCL2), and TGFβ, as measured by Meso Scale Discovery Proinflammatory V-PLEX assay. Mascarenhas noted that symptom improvement was observed across all 7 domains of MFSAF v4.0, including fatigue, and was observed regardless of the duration since discontinuing prior therapy.

What was the safety profile of AJ1-11095 in the AJX-101 trial?

No dose-limiting toxicities were observed across any dose level, and no treatment-related discontinuations due to adverse effects (AEs) were reported. Dose reductions due to AEs occurred in 13 patients (57%). Five patients discontinued treatment: 1 due to transplant, 1 due to logistics, 2 due to non-response, and 1 due to an unrelated AE; no discontinuations were due to drug-related toxicity.

Any-grade and grade 3 or higher treatment-emergent AEs (TEAEs) occurring in at least 20% of patients included anemia (65%, 52%), dysgeusia (48%, 0%), decreased platelet count (39%, 30%), increased alanine aminotransferase levels (35%, 4%), increased amylase levels (30%, 0%), constipation (30% 0%), diarrhea (30%, 0%), dizziness (30%, 0%), increasd aspartate aminotransferase levels (26%, 0%), headache (26%, 0%), hyperkalemia (26%, 4%), cough (22%, 0%), and muscle spasms (22%, 0%). At doses of 100 mg or lower, the only grade 3/4 AEs observed were cytopenias. Amylase and transaminase elevations were transient, occurred primarily at the 125-mg dose level, and resolved on treatment.

“I would say this drug is well tolerated,” Mascarenhas concluded. “The most common on-target [AE] was anemia, [as] anticipated, and is manageable with dose adjustments. We saw both clinical and molecular responses across the genotypes driving this disease.”

AJ1-11095 is under further investigation in an expansion-phase study in patients with myelofibrosis who have previously received a JAK2 inhibitor. This trial plans to enroll patients with high-risk PV, as well as patients with myelofibrosis who are naive to JAK2 inhibition.

Overall, the AJX-101 findings add to an evolving body of myelofibrosis research presented at EHA 2026 and the 2026 ASCO Annual Meeting; separately, luspatercept-aamt (Reblozyl) produced clinically meaningful improvements in red blood cell transfusion independence in patients with myelofibrosis-associated anemia in the phase 3 INDEPENDENCE trial (NCT04717414), although the trial did not meet the prespecified threshold for statistical significance for this end point.³ Additionally, selinexor (Xpovio) plus ruxolitinib demonstrated superior SVR35 rates over ruxolitinib alone in patients with JAK inhibitor–naive myelofibrosis, meeting a co-primary end point of the phase 3 SENTRY trial (NCT04562389).⁴

Disclosures: Mascarenhas reported receiving consulting fees/honoraria from Incyte, Novartis, Geron, AbbVie, Sobi, Disc Medicine, Karyopharm, PharmaEssentia, Italfarmaco, Sumitomo, Merck, GSK, Takeda, Galecto, Blueprint Medicines, and Cogent; and research funding paid to his institution from Novartis, Incyte, Ajax, Geron, Kartos, Karyopharm, AbbVie, Disc Medicine, PharmaEssentia, Italfarmaco, and Dompé.

References

1. Mascarenhas J, Borate U, Bose P, et al. 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. Presented at: 2026 EHA Congress. June 11-14, 2026; Stockholm, Sweden. Abstract S218.
2. Palandri F, Breccia M, Bonifacio M, et al. Life after ruxolitinib: reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. Cancer. 2020;126(6):1243-1252. doi:10.1002/cncr.32664
3. OncLive Staff. Luspatercept misses primary RBC-TI end point but shows clinically meaningful improvement for anemia in myelofibrosis. OncLive.com. June 13, 2026. Accessed June 13, 2026. https://www.onclive.com/view/luspatercept-misses-primary-rbc-ti-end-point-but-shows-clinically-meaningful-improvement-for-anemia-in-myelofibrosis
4. Kandel R. Selinexor plus ruxolitinib yields superior spleen responses, OS signal in JAK inhibitor–naive myelofibrosis. OncLive.com. June 2, 2026. Accessed June 13, 2026. https://www.onclive.com/view/selinexor-plus-ruxolitinib-yields-superior-spleen-responses-os-signal-in-jak-inhibitor-na-ve-myelofibrosis