INCB160058 - new selective JAK2i

[Coffeeglass]

Has anyone been following this drug from incyte? It was presented at last years ASH conference, and they’re already lining up a safety trial on healthy subjects in Australia, followed by a 3-year trial for MF patients who have unsuccessfully tried a JAK2 inhibitor.

My hope is a phase 3 trial around 2027 for folks with ET and PV.

The presentation PDF is a bit out of my league, but it sounds like it could be definitively disease modifying, and maybe even eliminate the mutation.

Page 7 shows how it reduces mutated JAK2, without touching the normal (wild type).

incytemi.com/document/Poste...

clinicaltrials.gov/study/NC...

clinicaltrials.gov/study/NC...

[hunter5582]

This is a promising development in the treatment of JAK2 positive MPNs. It will take some time and study to see if this potential breakthrough can deliver in the way it is hoped that it will. The only way this or any other new treatment can move forward is if people are willing to sign up for clinical trials. Hopefully, there will be plenty of volunteers.

[ainslie]

thanks for posting , great info 👍

[EPguy]

This a good find. Most the authors are from the Co that makes Rux, so they should know well what needs improving in Rux. This image is from page 7 you refer and is the best visual. This plot is from in-vitro results I think so it's very theoretical. But it shows Rux strongly suppresses a marker of of both normal (wild type) Jak2 and mutated Jak2. INCB160058 suppresses only the Jak2 cells that have mutation markers.

They tested up to very high equiv doses (4μM) where even the new agent suppressed wild type markers. This should help them to better understand its action.

We can appreciate that in vitro often does not predict clinical results; we know Rux can reduce allele % which would resemble the new agent in the lower right plot, green line. So if this works out we should expect even better results vs already decent allele reduction on Rux.

In the images page 5 I think they show the purple circle TPO being recovered to its proper position where it can act as the switch it is supposed to thru the action shown in the right plot.

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It could be the most important discovery is actually left image page 4. It binds esp well to the v617f site. If so this solves a critical step in an ability to identify and target mutated Jak2. This could be of much interest for other therapies too. For example CALR is easily identified for the new maybe curative cell therapies while Jak2 allele currently is cloaked. Maybe this will help uncloak it.

INCB160058 vs Rx

[EPguy]

Here is a more detailed report from the authors

sciencedirect.com/science/a...

"Using structure- and function-guided molecular design, INCB160058 was designed..."

We're seeing more of this "rational design" for new drugs. It may be leading to higher success rates.

They state: "...theoretically lead to functional cure of MPNs. " It's a long way to show this, but to consider it a goal is refreshing. It doesn't directly address the non-Jak2 MPNs or various other mutations.

"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"

Low doses is always a good thing. We know from my earlier note re page 7 that they found reduced benefit at a highest dose.

This is a pill in the trials, like Rux. Not sure if they will go for the 1/day goal here. They apparently gave up the 1/day trials with Rux.

[Loooonglife]

Preclinically, this new strategy of selectively inhibiting the mutant JAK2 V617F protein leads to disappearance of the disease causing clone. Incredible data that hopefully will translate in the clinic for MF, PV, and ET, caused by this mutation. If the preclinical data translate this approach could be curative. Very exciting and definitely something to be closely watched!

[EPguy in reply to Loooonglife]

No mutation would be a great accomplishment. But it may not be the full deal for some. One member has reached "undetectable" Jak2 on IFN, but he still has PV symptoms. He may have known or unknown non-driver mutations, unresolved marrow pathologies or something else. This new therapy may provide clearer answers to these questions.