BTK Degrader Shows Potential for Treating Refractory CLL and SLL

[Jm954]

A novel Bruton's tyrosine kinase (BTK) degrader, NX-2127, has shown potential for treating patients with double- and triple-refractory CLL or SLL who have experienced disease progression while on any covalent or non-covalent BTK inhibitor, as well as a BCL2 inhibitor.

NX-2127 a BTK degrader has a novel mechanism which works differently to a BTK inhibitor. Instead of inhibiting BTK, the molecule degrades BTK, producing the same effect and is not affected by BTK mutations that lead to the ineffectiveness of BTKi's.

Dr. Wierda and colleagues reported that the early-phase study showed clinically meaningful results among patients with CLL or SLL, including many who developed resistant mutations to BTK and BCL2 inhibitors.

As of June 2022, the study enrolled a total of 28 patients with B-cell malignancies, including 17 with CLL or SLL. The patients with CLL or SLL had a median age of 76 (range, 61 to 92) and had received a median of six prior lines of therapy (range, 2 to 12). All patients had previously received a BTK inhibitor and just over 75% had also been treated with venetoclax.

Of the 17 patients with CLL/SLL, 23.5% had unmutated IGHV and 17.6% had TP53 mutations/deletions. Among the 14 patients who were assessed for BTK mutations, 29% had C481 mutations, 7% had V416 mutations, and 29% had L528 mutations, all of which are known to result in a loss of BTK kinase function. Patients received NX-2127 orally, once daily, in 28-day cycles starting at 100 mg. Patients also received 200 mg and 300 mg doses. 

Researchers observed an 86% mean BTK degradation by the first cycle on day 22 in all patients. This included a mean degradation of 83% among patients with CLL, which led to a reduction in plasma CCL4 and decreased BCR signaling.

Patients with CLL or SLL who have progressed on both BTK and BCL2 inhibitors represent an unmet medical need with poor survival rates and no proven or effective treatments. Unfortunately, this is a group of patients that will inevitably grow in the future.

obroncology.com/article/btk...

ash.confex.com/ash/2022/web...

Jackie

[DebKat999]

Thank you Jackie, your post was very timely for me. Recently I had read the words of my CLL specialist Dr. Furman, mentioning his optimism for this study. He was answering another patient's question online at the time, and upon reading that I had already written down, "What is a BTK Degrader?" as a question for him for the next time we speak. I hadn't recalled ever hearing about it before.

So again, thank you for sharing this information today. 🙂

Debbie x

[AussieNeil Partner Administrator]

Encouraging results for this hard to treat group with an average of 6 lines of previous therapies. I too read of Dr Furman expressing optimism for BTKi degrader treatment. Given he picked ibrutinib as the new winner therapy over 10 years ago, this certainly is one to watch.

Neil

[CLLerinOz Administrator]

Thanks, Jackie, for the promising update.

This week, an article about a real-world database study of CLL patients who received treatment with a covalent BTK and BCL2 inhibitor in the United States was released and it also highlights the need for new treatment options for those who have progressed on both treatments.

tandfonline.com/doi/full/10...

Toby A. Eyre, Lisa M. Hess, Tomoko Sugihara, Dan He, Manoj Khanal, John M. Pagel, Richard A. Walgren, Paolo B. Abada, Heiko Konig, Lindsey E. Roeker & Anthony Mato (2023) Clinical outcomes among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who received treatment with a covalent BTK and BCL2 inhibitor in the United States: a real-world database study, Leukemia & Lymphoma, DOI: 10.1080/10428194.2023.2190436

[UK-Sparky]

Another greater share Jackie, these new degraders are opening up another line of possibilities for CLL/SLL patients. Thanks for sharing

[Classicaljazz]

See steve5441's good clinical trial experience for more than a year on NX-2127 and comparison with BTKi past use at healthunlocked.com/cllsuppo...

[Packrat]

Thank you for this! Definitely keeping this one on my radar for the future! I'm unmutated, TP53 mutated after 5.5 years on Ibrutinib, now on Ven and will ride that as long as I can. Always looking for the next best thing !

[steve5441]

Great post, good to see some more info on this drug. There has been little published so far on this totally new approach to controlling BTK. I actually had my monthly exam on 3-27-23 at MSK Basking Ridge, everything still going well. It is going so well that my Dr, Megan Thompson, asked me to get a BMB to actually see what is going on with things inside. My abnormal cell population in my peripheral blood is 0.67 as of last Monday. This will be my 7th BMB since 2009, to be honest, I hated every one. I always just bite down on a leather strap for pain, this time I'm going to put the entire shoe in my mouth, it might help. And for your info, I have C-481, L-528 and V-416 mutations. Dr Thompson says that the Nurex chews those up also.

[Jm954 Administrator in reply to steve5441]

I'm so happy to hear that this is working well for you

[CLLerinOz Administrator]

In more good news about this new class of drug, the latest edition of the journal Blood contains an article about another new degrader, NRX-0492 which "induced rapid and sustained degradation of wild-type and C481 mutant BTK at subnanomolar concentrations in primary CLL samples".

The article concludes that "this class of targeted protein degraders [is] uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022)

A related article appears in the same journal and is titled "The cat-and-mouse game of BTK inhibition". It is written by Ana Portelinha and Hans-Guido Wendel who state:

"In summary, the study reports on the sub-nanomolar efficacy and in vivo activity of a new, orally bioavailable BTK degrader with advantages in target occupancy that overcome ibrutinib resistance related to the C481 mutation and that, intriguingly, may even retain activity against BTK forms that are resistant to noncovalent inhibitors. Hence, BTK degraders ring the opening bell for a new round in the cat-and-mouse game of BTK-directed therapeutics."

Deyi Zhang, Hailey M. Harris, Jonathan Chen, Jen Judy, Gabriella James, Aileen Kelly, Joel McIntosh, Austin Tenn-McClellan, Eileen Ambing, Ying Siow Tan, Hao Lu, Stefan Gajewski, Matthew C. Clifton, Stephanie Yung, Daniel W. Robbins, Mehdi Pirooznia, Sigrid S. Skånland, Erika Gaglione, Maissa Mhibik, Chingiz Underbayev, Inhye E. Ahn, Clare Sun, Sarah E. M. Herman, Mark Noviski, Adrian Wiestner; NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts. Blood 2023; 141 (13): 1584–1596. doi: doi.org/10.1182/blood.20220...

Ana Portelinha, Hans-Guido Wendel; The cat-and-mouse game of BTK inhibition. Blood 2023; 141 (13): 1502–1503. doi: doi.org/10.1182/blood.20220...

See also this earlier post about NRX-4092:

healthunlocked.com/cllsuppo...

CLLerinOz

[jonathan7176]

What are the differences between these nx/nrx drugs? Different compounds but same class? Is there enough evidence to compare efficacy or not possible with phase 1 trials?

[lankisterguy Volunteer in reply to jonathan7176]

Hi jonathan7176,

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We had a discussion yesterday on another thread, and I think this may answer your question:

healthunlocked.com/cllsuppo...

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Len

[jonathan7176 in reply to lankisterguy]

Sorry if I'm missing something, Len, but I don't think that answers my specific question, which is about differences within the "degrader" class, e.g. NX 2127, NRX 0492? There seem to be quite a few with different letter/number combinations, and I'm wondering what the significance is. Both 2127 and 0492 seem to be associated with Nurix. But are they the same thing, or variations within the degrader class of drugs? Many thanks. 🙂

[lankisterguy Volunteer in reply to jonathan7176]

Hi jonathan7176,

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My point was that in Phase 1, there is almost no way to compare the way different drugs behave in real human bodies.

Many drugs look promising in bench top testing but then fail or cause unacceptable side effects in "first in human" trials. (Many substances kill CLL cells in a petri dish).

Getting into Phase 2 & 3 costs many 10x millions of dollars in the CLL space today. Those are where the first comparisons are done.

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If you haven't read it already, a well written and interesting insight can be found in For Blood and Money: google.com/books/edition/Fo...

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Len

[jonathan7176 in reply to lankisterguy]

Ah, right. Understood. Thanks.