The new INCB160058 targeting Jak2 V617f

[EPguy]

This Incyte drug is in ph1 for MF as well posted previously. As I've noted, a key advance is the ability to find and target something specific to the Jak2 mutation. This has not been possible before. Curious I checked out an early study (2017) and another (2009)

This is quite technical for any of us but this is my effort to figure some. But I've tried to make some sense of it and it gives some "Incyte" into the guys behind the curtain that are helping us while hoping to make money.

There are too many J's in the names, this requires extra attention.

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Info here is from:

ncbi.nlm.nih.gov/pmc/articl...

and

ncbi.nlm.nih.gov/pmc/articl...

There are four Jaks: Jak1, Jak2, Jak3, and Tyk2(Jak4). Each of these has domains JH1 to JH7, see image here (blueish boxes). We know about Jak2 and its v617f mutation, which occurs on the JH2 domain of Jak2 as noted in this report (some of the other Jaks are targets for new autoimmune drugs)

"The JAK pseudokinase domain (JH2) is autoinhibitory of the protein’s kinase domain (JH1) activity, likely by direct interaction with the JH1 domain." This means in non Jak2 mutated people JH2 keeps a lid on JH1. But "mutations within the JAK JH2 domain release autoinhibition" So in us Jak2 MPN pts, JH2 can't do its job and JH1 is not properly controlled.

"Recent evidence shows that displacing ATP from the JAK2 JH2 domain alters the hyperactivation state of the oncogenic JAK2 V617F protein while sparing the wild type JAK2 protein". This is the big advance, finding where and what to modify, see color detail box in the image Fig. A. ATP is a high school biology thing about storing energy that is everywhere in the body.

So "we sought to identify small molecules that bound selectively to the JH2 domain of the JAK2 protein" and keep out the ATP. "The JH2 protein was screened against...kinase inhibitor libraries." They found that the two molecules in the chemistry looking image worked best.

The color image: "Shown is the overall JH2 domain structure and magnified view of the ATP-binding pocket". Hit this newly discovered pocket, keep out the ATP and our mutation is deactivated. The Jak2's with wild type (non-mutated) JH2 are unaffected.

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They did not fully solve best selectivity for JH2 (where the mutation resides) over JH1. But this more recent report (2023) covers the improvements since the 2017 report above. Likely much of the advance was from within Incyte.

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ashpublications.org/blood/a...

" Ruxolitinib acts by directly inhibiting activity of the kinase domain (JH1) of JAK2". We now know from above that we really want to inhibit JH1 indirectly, via JH2, and in a very specific way.

But there is one inaccuracy in this report: " they (current Jaki-s) do not address JAK2V617F allelic burden or achieve molecular remission of disease." While Rux in theory should not have this effect we know from this forum and recent reports that Rux can and does exactly that for many. So the new agent should really knock it out.

"Using structure- and function-guided molecular design, INCB160058 was designed to bind with picomolar (extraordinary small amounts) affinity to the JH2 domain of JAK2V617F at the canonical ATP-binding site, with high specificity (>2500-fold) relative to binding at the active kinase domain (JH1) targeted by currently approved JAK inhibitors". INCB160058 works with the tiniest bit of the drug to occupy the JK2 site, keep out the ATP, and deactivate the mutation. And it leaves JH1 alone to function normally. Rux by contrast targets the JH1 presumably of both Jak1 and Jak2 which would expect to see side effects.

Conclusion: " INCB160058,(is) a high-affinity pseudokinase (JH2) binding inhibitor of JAK2V617F" From the above, this tech sentence can make sense, '0058 hits the sweet spot that was recently discovered. "Extended treatment with INCB160058 at low therapeutic doses results in the specific elimination of mutant JAK2V617F-harboring cells in mouse models and human cancer cells with minimal impact on WT counterparts" This adds a so far unexplained element, the cells with mutated JH2 aren't just deactivated, but are eliminated.

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This is now in phase 1 trial. If you have lost response to Rux with MF you may qualify. But trial sites are few.

clinicaltrials.gov/study/NC...

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From what I've seen, IFN is not understood anywhere near this level, but it's known empirically to work. If the experts could get there, maybe they could make an IFN without the FDA black box.

[Loooonglife]

Thanks for the detailed post. If this new drug shows no or limited toxicity in Phase 1, I predict that it will move quickly through Phase 2 and 3 clinical trials. It may get FDA approval within 4-5 years, perhaps even sooner.

[EPguy in reply to Loooonglife]

I've read that drug development is going smoother as the drugs under study are better designed. This review of three reports over time is a sample of this process. eg in 2017 they didn't know how to avoid selection of JH1, while by 2023 they had solved it. Approval could be as you say, we can hope.

I don't think it will much help CALR or MPL since it is so specific to Jak2. But CALR can look fwd to cell therapies, MPL is less understood. But maybe this new agent will be active beyond just Jak2 thru indirect effects.

[ETinNYC in reply to EPguy]

Not so sure it's fair to say MPL is less understood...but it's certainly more rare than JAK or CALR. My MPN specialist told me there's a group in California and another in Israel working on some therapies specifically targeting MPL mutation. Here's hoping there will be many more drugs available for all of us in the near future....not just for treatment but for cure.

[EPguy in reply to ETinNYC]

Good point it's getting good attention even as there are fewer pts to study. I think if Mpl gets those therapies it will add much to understanding all MPNs. Similar with triple negative, gaining understanding of that in particular should require very deep learning that could uncover much for all MPNs

[ETinNYC in reply to EPguy]

I'm interested to see if there will be any AI applications for advancing knowledge in this area of medicine.

[EPguy in reply to ETinNYC]

It's already happening. AI is not a single thing of course but a continuum of methods that include rational drug design. But AI for now would likely be focused in the early experimental phases that we don't hear about.

In its most advanced form AI would predict biological mechanisms and propose manipulations that are otherwise unknown. I think this is the leading edge.

[RoundTheWorld]

Thanks EPguy. It's always good to know the 'guys behind the curtain' are making strides and improving understanding and options (and thanks for the translation notes!).

[Spanelmad]

Let's hope it passes through the next phases as it could be a game changer for us all of it does eliminate the mutation

[Lena70]

This sounds promising. Thank you for brining it to our attention.

[Aldebaran25]

Thank you EPguy, a very good explanation. Now we await the outcome of real world vs theoretical and keep our fingers crossed. I always wonder about the specificity of these molecules in a massive system that is so complex. But overall it is good news.

[EPguy in reply to Aldebaran25]

I think one reason these molecules can be specific is by being "small molecule" drugs. In basic form these are created, or built, by ordinary chemistry of the elements. There are relatively few locations that interact with our cells. They can be thus studied via not too many parameters. So the drug is simple while the system it's in is complex.

In contrast biologics, like IFN and many new drugs, are " isolated from a variety of natural sources - human, animal, or microorganism" as FDA describes it. These groups of proteins can assume varying shapes and activities in response to what is around them. So predicting their effects is much harder. So the drug and the system are both complex. But as with all, progress here is going fast, modern computing is becoming able to model these 3D happenings. (My take on "complex" in biology is anything that is not well understood)

I might try to learn more here and post what I find if it seems interesting.

[william-Indo]

Thanks for the information👍

[RedCardRob]

Great work by the white coats and of course yourself in producing a technically readable report. I've learnt something new today so that's a box ticked👍Thank you.

[EPguy in reply to RedCardRob]

Same here, I learnt a lot by doing it. I now can imagine all those J's getting fixed within me.

[DiveGoddess]

EPguy,

Thank you for sharing and patience with the advanced jargon. I really appreciate your breakdown. We continue to live each day and hope for our futures. Thanks again from the heart for your perseverance. Christy

[EPguy in reply to DiveGoddess]

I live in a world of the future as the only agents to fix my Sjo are there.

A Jak-i that doesn't make so many pts plumper would be an advance in itself. If it's not immune suppressive that is one the biggest deals.

[EssThro]

Wow! Thanks, EP Guy, for all your work to interpret the reports and to keep us all informed!

[hsdale3]

Did you research show if Incyte also be effective with Polycythemia Vera (PV) MPN as well?

Thanks,

Poppy

[EPguy in reply to hsdale3]

This new drug if it works out should be especially good for PV since it is specific for Jak2. But not discussed is other mutations, ASXL for example. Those likely still need better solutions I think.

Note that Jakafi is also made by Incyte so they know these pills