New CLL Medicines in Clinical Trials: BTK Degraders

What is the BTK Protein and Why is it Important in CLL? 

The BTK (Bruton's tyrosine kinase) protein is found in B-cells. In healthy B-cells, the BTK protein has an essential role in the normal growth and maturation of these white bloods cells, making them capable of fighting against infections. 

CLL cells are dysfunctional B-cells with an over-activation of the BTK protein, which helps them proliferate and survive. In CLL, the overactive BTK protein promotes uncontrolled cell division, leading to the accumulation of malignant B-cells in the bone marrow, blood, and lymph nodes. 

Understanding the role of BTK in CLL is essential for developing targeted therapies that can specifically block the activation of the BTK protein and stop the expansion of CLL cells. CLL patients may be familiar with BTK inhibitors that bind to the BTK protein, stopping its activity. These medicines include acalabrutinib (Calquence), zanubrutinib (Brukinsa), ibrutinib (Imbruvica), and pirtobrutinib (Jaypirca).  

After several years of BTK inhibitor exposure, the CLL cell often finds a way to mutate its BTK proteins, causing BTK inhibitors to stop working. When this happens, patients would be considered as BTK inhibitor-resistant, and therefore not eligible to continue on treatment with these agents.

Why Create a BTK Degrader? 

Instead of trying to inhibit the BTK protein, what if it was removed entirely? This hypothesis encouraged scientists to develop BTK degraders, which are medicines that bind to and eliminate the BTK protein, helping stop the replication of CLL cells even if they are resistant to BTK inhibition. 

Data has shown that removing the BTK protein helps overcome CLL resistance previously caused by BTK inhibitors. This may allow BTK degraders to work even longer than BTK inhibitors. 

What are the Available BTK Degraders? 

The two BTK degraders are currently being studied for relapsed/refractory CLL patients: BGB-16673, created by BeiGene (maker of CLL medicine zanubrutinib), and NX-2127 created by Nurix. The clinical trial administering NX-2127 is no longer recruiting; however, the study administering BGB-16673 is still actively recruiting patients. Both medications are pills, taken by mouth.

If you would like to know if you are eligible to receive the BTK degrader BGB-16673, click here to find a location near you. The study has many locations in the United States, Australia, Canada, France, Georgia, Germany, Italy, Moldova, Spain, and Sweden.

If you need help enrolling in the study to receive BGB-16673, click “Begin Now,” and HealthTree Foundation’s Patient Navigators will assist you. Joining a clinical trial can be a great way to access innovative therapies that are not yet openly available to the public. If you would like to learn more about the benefits of joining a CLL clinical trial, click here. 

How Effective are BTK Degraders? 

Early-stage data with NX-2127 showed that all 29 heavily pre-treated CLL patients experienced BTK degradation regardless of their resistance to BTK inhibitors. At the check-in point of 9.5 months, 9 patients had reduced CLL signs/symptoms, and 11 had stable disease (CLL was not increasing nor decreasing). More time will help provide further data on how potent BTK degraders are for CLL patients. 

Common side effects of the BTK degrader NX-2127 included fatigue, decreased neutrophils (neutropenia), and high blood pressure (hypertension). 

Conclusion 

In summary, BTK degraders are a new category of CLL medicines that can help overcome disease resistance caused by BTK inhibitor treatment. There are open clinical trials recruiting patients at the moment, if you think this medicine could be helpful for you, check the locations of the aforementioned clinical trial. The CLL patient community looks forward to more data that will help reveal the efficacy of BTK degraders as a treatment option. 

Join the HealthTree CLL Chapter to Learn More About CLL and Its Treatments

We invite you to join the HealthTree CLL Chapter by clicking on the button below to gain the benefit of participating in virtual events that cover various CLL topics with experts. 

Click Here to Join the CLL Chapter

Upcoming HealthTree for CLL events include: 

• How Can CLL Clinical Trials Help Me? Learn from Dr. Danielle Brander of Duke Cancer Institute on May 6th at 2:00 PM ET 
• Tracking Your CLL Labs in HealthTree Cure Hub on May 7th at 1:00 PM ET
• A Personalized CLL Vaccine: NeoVax with Inhye Ahn, MD Dana-Farber Cancer Institute on May 10th at 2:30 PM ET 
• All About Bispecific Antibodies for CLL with Dr. Adam Kittai on May 13th at 1:00 PM ET
• Relapsed/Refractory CLL Treatment Options with Dr. Kerry Rogers on Jun 25 at 1:00 PM ET

Sources

• A First-in-Human Phase 1 Trial of NX-2127, a First-in-Class Bruton's Tyrosine Kinase (BTK) Dual-Targeted Protein Degrader with Immunomodulatory Activity, in Patients with Relapsed/Refractory B Cell Malignancies
• Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127