Cracking the Code: Nemtabrutinib's Success Story in Defeating Treatment-Resistant Blood Cancers

Summary:

Nemtabrutinib, a novel reversible BTK inhibitor, presents a promising breakthrough in combating refractory B-cell malignancies such as chronic lymphocytic leukemia (CLL) and Non-Hodgkin lymphoma (NHL). The first clinical trial showcased an impressive 75% efficacy with minimal severe side effects, marking it as a potential game-changer in treating patients unresponsive to conventional therapies. Its unique resistance profile against BTK mutations, in contrast to other inhibitors like ibrutinib, sets it apart. Additionally, the drug's oral bioavailability, liver metabolism, and non-covalent binding contribute to its favorable safety profile. Ongoing Phase 2 trials continue to underscore Nemtabrutinib's potential as a transformative therapy.

Introduction:

Nemtabrutinib, a groundbreaking treatment, belongs to a new wave of therapies designed to combat blood cancers. This novel targeted drug, has shown remarkable efficacy in patients with chronic lymphocytic leukemia (CLL) and Non-Hodgkin lymphoma (NHL) whose disease has become unresponsive to conventional treatments. It is a reversible, ATP-competitive kinase inhibitor. Normally patients with leukemia are given ATRA (All Trans Retinoic Acid) or Imatinib mesylate but some cases remain unresponsive and classified as refractory or resistant. Typically, resistant cancers may be treated by stem cell transplantation but it is expensive and poorly prognostic. Nemtabrutinib thus comes as a novel strategy that brings new hope to fight resistant B-cell malignancies.

Nemtabrutinib chemical structure

(image is in the public domain)

The results of the first clinical trial of nemtabrutinib in humans, published in the journal Cancer Discovery, reveal that this drug was effective in approximately 75% of the cancer patients tested and caused minimal severe side effects.

It is orally bioavailable. The capsules are swallowed with a glass of water without chewing or breaking them. It exhibits high plasma protein binding, primarily to serum albumin. This binding influences their distribution within the bloodstream. Nemtabrutinib is metabolized in the liver, primarily via CYP3A4, with limited involvement of other hepatic enzymes. Elimination is via a combination of hepatic metabolism and excretion in the feces, with a smaller fraction excreted in urine.

It is a reversible BTK inhibitor unlike other drugs in the same category like ibrutinib which is an irreversible inhibitor. Resistance to therapy in blood cancers is due to mutation in the BTK catalytic domain Cys481. But unlike ibrutinib which is susceptible to this mutation, Nemtabrutinib is unaffected by this mutation and hence its efficacy is not reduced. Nemtabrutinib has inhibitory activities against a range of other TEC family kinases, as well as Src and Trk kinases [1-2]. This non-selective activity is believed to contribute to nemtabrutinib's efficacy against chronic lymphocytic leukemia cells.

Fig-2.B-cell receptor mediated signaling, highlighting BTK and PLCG2 kinases. Resistance causing mutations are mapped on to domains of BTK and PLCG2, showing their location and corresponding covalent (ibrutinib, acalabrutinib and zanubrutinib) and non-covalent (pirtobrutinib, fenebrutinib, nemtabrutinib and vecabrutinib) inhibitor resistances

(Montoya S, Thompson MC. Non-Covalent Bruton’s Tyrosine Kinase Inhibitors in the Treatment of Chronic Lymphocytic Leukemia. Cancers. 2023; 15(14):3648. https://doi.org/10.3390/cancers15143648)

It is currently in Phase 2 of clinical trials. However, initial clinical trials by lead investigator Dr. Jennifer Woyach and by researchers at the Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC—James). The researchers conducted their clinical trial with 47 patients who had undergone at least two previous therapies for their blood cancer. Over half of these patients had relapsed CLL, while the others had NHL. The trial involved administering different doses of nemtabrutinib to the patients and closely monitoring their responses and side effects.

The results were highly encouraging, with more than 75% of patients with relapsed CLL responding positively to the drug, particularly at an optimal dose of 65mg. This response also extended to patients with mutations in BTK. Importantly, most patients remained cancer-free for at least 16 months during the trial. While it is common for chemotherapeutic drugs to cause side effects, the majority of these were mild and manageable, underscoring the safety of nemtabrutinib (3).

Common side effects that were noticed among the study participants include dysgeusia, hypertension, peripheral edema, cough, fatigue , constipation, decreased neutrophil count ,dizziness, nausea , pyrexia, diarrhea (28%; 3%), dyspnea , arthralgia , decreased platelet count, upper respiratory tract infection , chills, pneumonia, and anemia (4).

Certain drug interactions have been observed, specifically with Jak kinase inhibitors and other DMARDs (Disease Modifying Antirheumatic Drugs). Additionally, caution is advised as there are interactions with CYP3A4 microsomal enzyme inhibitors such as vancomycin, ciprofloxacin, cycloserine, isoniazid, among others. It is recommended to avoid these combinations to minimize the risk of drug toxicity.

Conclusion:

Nemtabrutinib emerges as a beacon of hope in the challenging landscape of refractory blood cancers. Its encouraging Phase 1 trial results, with high efficacy and manageable side effects, indicate a promising avenue for patients resistant to standard treatments. The drug's distinctive properties, including reversible BTK inhibition and resistance to key mutations, underscore its potential as a breakthrough therapy. As clinical trials progress, Nemtabrutinib stands poised to revolutionize the treatment paradigm for CLL and NHL, offering renewed optimism for patients facing limited therapeutic options.

References:

1.Woyach, J. A., Stephens, D. M., Flinn, I. W., Bhat, S. A., Savage, R. E., Chai, F., Eathiraj, S., Reiff, S. D., Muhowski, E. M., Granlund, L., Szuszkiewicz, L., Wang, W., Schwartz, B., Ghori, R., Farooqui, M. Z. H., & Byrd, J. C. (2024). First-in-Human Study of the Reversible BTK Inhibitor Nemtabrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and B-Cell Non-Hodgkin Lymphoma. Cancer discovery, 14(1), 66–75. https://doi.org/10.1158/2159-8290.CD-23-0670

2.Montoya S, Thompson MC. Non-Covalent Bruton’s Tyrosine Kinase Inhibitors in the Treatment of Chronic Lymphocytic Leukemia. Cancers. 2023; 15(14):3648. https://doi.org/10.3390/cancers15143648

3.IUPHAR/BPS Guide to Pharmacology.| IUPHAR/BPS Guide to PHARMACOLOGY. (n.d.). https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology

4.Aasim, M. (2023, November 8). Promising blood cancer treatment: Nemtabrutinib Breakthrough. medtigo.https://medtigo.com/news/nemtabrutinib-shows-promise-in-unresponsive-blood-cancers/?t=eyJ0eXAiOiJKV1QiLCJhbGciOiJIUzI1NiJ9.eyJ1c2VySWQiOiIifQ.sYXDuQ_mmkvrfWpfkzXLZJk1pCjz2k2Sthr15VaQlDQ

Writer: Niragh Sikdar

Editor: Angad Tiwari