Phase 1 Clinical Trial of AJ1-11095 Administered As Oral Monotherapy in Patients with post ET or PV myelofibrosis

[Manouche]

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.

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.

ash.confex.com/ash/2024/web...

[Bluetop]

Thanks for posting.

[EPguy]

Your link has some fresh info from:

pubmed.ncbi.nlm.nih.gov/228...

Undesired "reactivation of JAK–STAT signalling" occurs with Rux via Jak1 and Tyk2 while : (AJ1-11095) "prevents heterodimerization with JAK1 and TYK2". Means there is no "biophysical interaction " with Jak1 or TYK2 and thus implication of a more durable effect.

According to this citation actions on Jak1 and Tyk2 are a reason for Rux losing effectiveness.

Rux targets only the active state of Jak2 (thus is a Type 1 Jak-i) while AJ1-11095 targets "both the active and inactive conformations of JAK2". Targeting only the active state is another source of loss of effect for Rux. (most of the early info on Rux is re MF)

"bind(ing) the active conformation leads to JAK2 becoming resistant to degradation "

haematologica.org/article/v...

Interesting that the citation here is from 2012, so they knew what need to happen, but getting a type 2 Jak-i to work has been a long effort.

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Here is some other info on AJ1-11095:

"AJ1-11095 has been shown in preclinical studies to reverse marrow fibrosis, reduce mutant allele burden and maintain efficacy against MPN cells that become resistant to chronic Type I JAK2 inhibition"

healthunlocked.com/mpnvoice...