New Type II JAK2 Inhibitor AJ1-11095 for Myelofibrosis is Under Development

For people living with myelofibrosis (MF), JAK inhibitors are commonly used to manage symptoms and reduce an enlarged spleen. This is a condition called splenomegaly. These therapies function by targeting signaling pathways within stem cells.

However, long-term care remains a challenge. Many patients stop taking current type I JAK2 inhibitors within  3 years. This is because they stop working to treat the myelofibrosis symptoms or because of side effects.  To address this problem, researchers are evaluating new  medications.

Type II JAK2 inhibitors 

Early data from  phase 1 AJX-101 clinical trial (NCT06343805) was presented during the annual European Hematology Association (EHA) meeting. The study tested the safety profile and early results for people treated with a type II JAK2 inhibitor called AJ1-11095,. 

AJ1-11095 shows it can avoid common resistance mechanisms that cause standard treatment to fail 

Standard type I inhibitors target the active state of the JAK2 enzyme. Over time, the mutated cells can adapt, leading to drug resistance.

AJ1-11095 has a different mechanism. It blocks the pairing of JAK2 enzymes. It also prevents them from pairing with other enzymes like JAK1 and TYK2. In early lab studies, this action has been shown to bypass common resistance mechanisms that cause standard type I therapies to lose their effectiveness. 

The study revealed promising results, and is moving to phase 2  

This trial included people with primary or secondary myelofibrosis. The participants had recurrent or persistent spleen enlargement and systemic symptoms and prior treatment with at least one type I inhibitor.

There were 23 patients who participated in the study. All of them had prior exposure to ruxolitinib (Jakafi), and 8 had also received momelotinib (Ojjaara). They were given AJ1-11095 in increasing doses to monitor safety. The five daily oral dose levels ranged from 25 mg to 125 mg once daily. After 17 months, 19 out of the 23 remained on the therapy. None discontinued due to side effects. 

The most common side effects were mild, and included anemia and low platelet counts. Many  patients had anemia when they started the trial. An encouraging result was the reduction in spleen size. Thirteen patients (65%)experienced a 35% or greater reduction in spleen volume.

Overall 74% of patients reported symptom relief. Two people reported it as early as after the second cycle of therapy. By week 24, 4 out of 7 patients treated with doses above 25 mg experienced a 50% or greater reduction in their mutant clone size.

What’s next for AJ1-11095? 

The initial results of the AJX-101 trial indicate that it can safely manage symptoms, reduce spleen enlargement, and lower mutant clone sizes in individuals who did not find the desired results with standard type I JAK2 inhibitors. Based on these safety and efficacy trends, researchers have selected the 75 mg once-daily dose to initiate the next phase of dose expansion. 

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Source: 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