In this video, Dr. Adrian Wiestner, M.D., PhD, a Senior Investigator in the Laboratory of Lymphoid Malignancies within the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) in Bethesda, Maryland, is interviewed by CLL Society founder and Chief Medical Officer, Dr. Brian Koffman, M.D., a retired family physician and a CLL patient. This video was recorded at the 61st Annual Meeting of the American Society of Hematology in 2019, in Orlando, Florida.
In this interview, Dr. Wiestner discusses a new way to address Bruton’s Tyrosine Kinase (BTK), the protein that is over expressed in CLL cells that leads to proliferation of the malignant cells. The title of the abstract that Dr. Wiestner presented is: Highly Potent BTK Degradation Induced By NRX0492 As a Therapeutic Strategy for CLL.
BTK, which is part of the B-cell receptor pathway, plays an essential role in normal B-cell development and is a major driver of proliferation and survival of chronic lymphocytic leukemia (CLL) B-cells. BTK is over-expressed in CLL cells. Ibrutinib (Imbruvica®) and acalabrutinib (Calquence®) are the first and second drugs approved that covalently bind to BTK, inhibiting its proliferation signaling to the CLL cell. Unfortunately, progressive disease or resistance has been noted with ibrutinib and acalabrutinib after continuous therapy as a result of mutations in BTK and 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 (PLCG2). The most common of these mutations affects the cysteine amino acid at position 481 on the BTK molecule, which is the binding site for ibrutinib/acalabrutinib and is known as a C481S mutation. Because of the re-emergence of CLL following this mutation, we have further validation of the importance of BTK as a therapeutic target. Agents that can target C481 mutant BTK are of great interest. The non-covalently bound BTK inhibitor (BTKi) drugs vecabrutinib and LOXO 405 are currently in clinical trial, as are other candidates.
NRX042, a chimeric targeting molecule, works by a different mechanism that unites two molecules, a “hook” that binds to BTK and a “harness” that recruits ligases (enzymes). These mediate proteasome-dependent degradation of BTK, rendering it ineffective in signaling pathways. This effect is found both with C481 mutated BTK as well as “wild” or untreated BTK. In animal studies, NRX042 is both efficient and specific to BTK.
- This drug, which has only been studied in animals at this point, shows potential promise as another means of treating CLL either after mutation on ibrutinib or potentially as a first line therapy.
- Unlike the BTKi drugs, NRX042 does not bind to the cysteine at position 481 that is replaced by a serine amino acid in the mutated form.
- NRX042 potentially could have lower side effects. The side effects associated with BTKi treatments generally are caused by the fact that in addition to targeting BTK, the BTKi drugs also target other kinases.
- First human clinical trials may come as soon as late 2020.
Although it is still early in the process of drug discovery to drug availability, preclinical data on NRX042 is promising. NRX042 has the potential to become the first of an entirely new class of targeted agents available to treat CLL.
Thank you for reading this summary and viewing this interview.
Stay strong! We are all in this together!
Thomas. E. Henry III, MBA, RPh, CPh