2nd generation Jak-i's, what's up?

[EPguy]

I posted last year on a 2nd gen Jak inhibitor. This is different from the various recently approved ones for MF (Vonjo etc) that are more related to Gen 1 Jak-i's.

The concept is Gen 2 catches Jak2 while it's sleeping while Gen 1s are limited to acting on the awake (active) config of Jak2. This was supposed to provide a better action.

There are two publicly known ones, AJ1-10502 from Ajax Therapeutics, and CHZ868 by Abcam. CHZ868 seems to be dormant, searches bring to dates ~2015. It seems to have run into resistance as reported here just recently (2024):

"We report on a novel mechanism of AXL/MAPK-driven escape from type II JAK2 inhibition". They propose a solution to the problem. But this is likely why CHZ868 is not in the MPN news lately.

aacrjournals.org/clincancer...

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The old post is about AJ1-10502 which claims to be superior to CHZ868 (and of course they say, to Rux) :

healthunlocked.com/mpnvoice...

"AJ1-10502 revealed potent JAK2 selectivity with minimal kinase cross-reactivity compared to CHZ868,"

Above we can assume is true, but:

Ajax Co states that for Rux "mutant allele burden remains essentially unchanged, and efficacy wanes over time."

We have various threads discussing this very topic. We now know that at least for PV, their statement is out of date. There has been no public progress on AJ1-10502 since the preclinical report of 2022, while if it were hot there would be at least ph 1 clinical results by now and their site would have a pipeline. ajaxtherapeutics.com/

It still may be a big thing for one or both of PV and MF, but the Co is not telling.

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My conclusion is, for PV they may have been after a non-problem, but they may be after MF. If there are any updates I'll post on it.

[Walshman]

The Ajax trial should be recruiting soon and looks like a start date of July:

classic.clinicaltrials.gov/...

[EPguy in reply to Walshman]

Good catch. This trial posted just a few weeks ago.

I see they are using a new formula, AJ1-11095, vs original 10502, an increase of 593 in totally arbitrary units. This explains the delay, they absorbed the new research below and used the "template" identified in that.

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Here is a specific of what goes wrong with resistance in Rux (G993A):

"Ajax is going into a post-Jakafi phase 1 trial with AJ1-11095, which specifically hits type II of the protein; this approach is intended to overcome G993A, a resistance mutation acquired in response to treatment with typical JAK1/2 inhibitors like Jakafi."

oncologypipeline.com/apexon...

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But it seems G993A makes trouble for both Gen 1 (ie Rux) and 1st round of Gen 2's (likely Ajax-10502 failed this criteria):

" Finally, we identify a JAK2 G993A mutation that confers resistance to the type II JAK2 inhibitor CHZ868 but not to our analogs. These data provide a template for identifying novel type II kinase inhibitors and inform further development of agents targeting JAK2 that overcome resistance. "

pubmed.ncbi.nlm.nih.gov/372...

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One possibly actionable item above, for those on Rux, (esp for MF) get checked for G993A if such a test exists.

[Pogm]

Hello,

Saw my MPN specialist a few days ago and discussed the intolerable itching problem. She has recommended adding a low dose of Jakafi(5m in morning and 5mg in evening). I am pleased with going this direction and she and the pharmacist at the institution say that jakafi is tolerated well and no interaction between Jakafi and Besremi. I take 75mcg of Besremi biweekly. She is more inclined to this addition rather than others I had mentioned.(alanine, etc) She also wants me to increase Besremi to 100mcg, but we are going to wait and see how Jakafi works first. I believe there may be a few members on this site who are doing this combination. I would love to hear how it has worked out. The one thing I do have to keep an "eye out" for is any bleeding or bruising since I am also on Xarelto and Jakafi, as the pharmacist said, has blooding thinning qualities. I do see my cardio-oncologist next week and will be going over everything with him as well. Thanks for all the support from this wonderful community.