BTK Degraders

[DaveCll]

will BTK degraders help people with CLL and MDS?

[CLLerinOz Administrator]

Dave, I'll limit my discussion here to CLL/SLL as I've not followed the literature relating to MDS.

Although they've been on our radar for CLL for a few years now, we're still only in the early days with this new class of drug, the BTK degrader.

The idea is that these degraders, which use a different mechanism to existing BTK inhibitors, will work even if a patient has developed mutations that make them resistant to those more traditional BTK inhibitors.

It's worth noting that not everyone who takes a BTK inhibitor will develop a mutation that makes them resistant to ongoing treatment. However, for those who do, this new class of drug potentially offers another therapy should they need one.

There are still very few trials underway for them, the main ones being a Phase I trial for NX-5948 (which has superseded NX-2127), a Phase I/II trial for BGB-16673, a Phase I trial for ABBV-101 and a Phase I trial for AC-676, all of which are for patients with relapsed/refractory disease.

clinicaltrials.gov/search?c...

Nevertheless, we have some encouraging and promising early data for BTK degraders, including some which appeared in abstracts at last December's ASH conference.

NX-2127: ash.confex.com/ash/2023/web...

NX-5948: ash.confex.com/ash/2023/web...

BGB-16673: ash.confex.com/ash/2023/web...

ABV-101: ash.confex.com/ash/2023/web...

More recently, the journal Science published a research article about the NX-2127 trial and the authors of that article concluded:

"We identified that BTK inhibitor resistance mutations fall into two distinct functional categories. Kinase-impaired BTK mutants disable BTK kinase activity while promoting physical interactions with other kinases to sustain downstream BCR signaling. This scaffold function of BTK was disrupted by NX-2127, a potent BTK degrader, which showed promising responses for patients with relapsed and refractory CLL, independently of mutant BTK functional category."

science.org/doi/abs/10.1126... (unfortunately, the full article is paywalled)

On 6 Feb 2024, The ASCO Post published an article about the NX-2127 study. It explains the background to BTK degraders - their role and function - and noted that:

"The recent findings suggested that BTK degraders may have the potential to treat other B-cell malignancies or autoimmune conditions such as multiple sclerosis. The researchers are currently enrolling patients in another study evaluating a more potent and selective BTK degrader, NX-5948.

“CLL is an incurable disease, but with treatments like BTK inhibitors and these promising new BTK degraders, we have more ways to alleviate symptoms and get patients back to their normal everyday routines,” underscored lead study author, Skye Montoya, BS, a graduate student in the Taylor Lab at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. “The future looks brighter for them,” she concluded.

ascopost.com/news/february-...

Here's a link to some of the previous discussions here about BTK degraders:

healthunlocked.com/cllsuppo...

There's also information in AussieNeil 's excellent post that keeps track of current and developing BTK inhibitors: healthunlocked.com/cllsuppo...

What I've shared here isn't meant to be a complete list of information - it's just a summary of some of the recent highlights, I guess. I expect we'll be seeing more about this class of drug.

CLLerinOz

[DaveCll in reply to CLLerinOz]

Thanks for giving me a little better insight. I was diagnosed back in 2010 with CLL unfortunately the only treatment back then was FCR and BR. I started with one treatment of FCR but lymph nodes returned to enlarged size again so the next 4 treatments were BR. After a one year of remission my lymph nodes started to get larger again lucky for me imbrutinib was fda approved so I was on that for 4 year but then developed some medical issues and had to stop. I went back to remission for another 2.5 years. Last March my doctor put me on Pirtobrutinib which I am still on. Unfortunately my last bone marrow biopsy showed that I had MDS from the original treatment of BR. Now I’m dealing with both.

Best

Dave

[gardening-girl in reply to DaveCll]

Dave, I'm so sorry that you are now dealing with both CLL and MDS.

CLLerinOz has provided a wealth of information on PROTACs focusing on their use in CLL. In my answer to your question "Will BTK degraders help people with CLL and MDS?' will focus not on BTK degraders for CLL, but how they just might have a beneficial effect on some cases of MDS.

If a BTK PROTAC has an effect on MDS, I don’t think that it would be because of the degradation of BTK. I found two clinical trials of the BTK inhibitor ibrutinib in treatment of MDS and neither reported positive results. A trial titled “Ibrutinib added to 10-day decitabine” reported the following:

“In conclusion, the addition of ibrutinib does not improve the therapeutic efficacy of decitabine.” Blood Adv 2020 Sep 22;4(18):4267-4277. pubmed.ncbi.nlm.nih.gov/329...

I could find no report from the second trial, “Ibrutinib and Lenalidomide in Treating Patients with Myelodysplastic Syndrome” even after checking for publications by the PI. NCT03359460

Here are my thoughts about how it might just be possible that the BTK PROTAC NX-2127 could have a beneficial effect on some cases of MDS.

The literature on NX-2127 touts its immunomodulatory activity in addition to it's BTK degradation. The immunomodulatory activity which involves degradation of the transcription factors IKZF1 & IKZF3 as described below might also hold for the anti-apoptotic casein kinase 1α (CK1α), all three being targets of lenalidomide, an accepted treatment for del(5q) MDS. In the case of lenalidomide treatment, all three of these proteins are degraded by E3 ubiquitination and subsequent proteasomal degradation which is the same pathway that NX-2127 uses.

Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton’s Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies

Journal of Medicinal Chemistry February, 2024

“In addition to degrading BTK, NX-2127 was designed to incorporate the immunomodulatory activity of drugs such as pomalidomide and lenalidomide. Through binding to CRBN, these drugs alter the substrate repertoire of the CRBN ligase complex, which leads to the degradation of nonphysiologic substrates, or neosubstrates such as the transcriptions factors IKZF1 (Ikaros) and IKZF3 (Aiolos).”

pubs.acs.org/doi/10.1021/ac...

This publication does not mention CK1α, but it may well be a target of NX-2127 and if so, it could possibly work as a treatment for del(5q) MDS. Time will tell.

Best Wishes going forward.

[CLLerinOz Administrator in reply to DaveCll]

Dave, I'm really sorry you're dealing with both CLL and MDS.

The journal Blood published an article in Dec 2022 which indicated that the incidence of secondary MDS (sMDS) "following CLL (including treatment-naïve CLL) has been reported as high as 3.5%", noting that "chemoimmunotherapy (CIT) treatment for CLL likely contributes to the occurrence of MDS".

That retrospective study involved a chart review of a cohort of 27 patients at The Ohio State University between 01/01/2016 and 02/10/2021 who were diagnosed with CLL and who "subsequently or concurrently were diagnosed with MDS".

It found that the:

"Median number of therapies for CLL prior to sMDS was 1 (range 0-10), with 4 pts diagnosed with CLL at the same time as MDS. CLL treatments, as any line of therapy, included CT/CIT in 21 pts (77.8%) and ibrutinib in 10 pts (37.0%). Of the pts that received CLL therapy, only 1 pt did not receive CT/CIT. 5 pts (18.5%) were not treated for CLL.

ashpublications.org/blood/a...

gardening-girl , thanks for adding so much information that's more specific to Dave's particular circumstances and question. Much appreciated.

CLLerinOz