Medically reviewed by Dr. Brian Koffman
The Bottom Line:
NX-2127 is a new type of drug that degrades BTK. Phase 1 clinical trial data shows that it has a manageable safety profile in patients with CLL / SLL.
Who Performed the Research and Where Was it Presented:
Dr. Alexey Danilov from the City of Hope National Medical Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2023.
Background:
Bruton tyrosine kinase (BTK) inhibitors are very effective drugs for managing chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), and they can work for many years. However, because patients must take BTK inhibitors continuously for an indefinite period of time, many patients eventually develop resistance to them. Over time, the BTK protein mutates, which reduces the ability of BTK inhibitors to bind, and this means that they can no longer reliably block the function of BTK.
NX-2127 is a new experimental type of drug known as a protein degrader. It binds to BTK and tags it for degradation by the proteasome, which acts as the garbage disposal of the cell. The proteasome takes in unwanted cellular garbage and destroys it by chopping it into tiny pieces. Because NX-2127 is removing BTK rather than inhibiting its function, it can target both the original and mutated forms. NX-2127 also causes the degradation of two other proteins (Ikaros and Aiolos) that regulate T-cell function. This increases the activation of T cells, thereby increasing T-cell-mediated anti-tumor effects. More in-depth information can be found in our previous coverage of the initial results of this clinical trial from ASH 2022. This current report provides updated information as more patients have enrolled in the trial.
Methods and Participants:
This is a first-in-human phase 1 clinical trial to evaluate the safety and preliminary efficacy of NX-2127 in treating relapsed / refractory B cell malignancies, including CLL / SLL.
Results:
- The trial is ongoing, and 47 patients have been enrolled thus far, including 29 patients with CLL / SLL.
- Patients were heavily pretreated with a median of four prior lines of therapy in non-Hodgkin lymphoma patients and five prior lines of therapy in CLL patients.
- All CLL patients had previously been treated with a BTK inhibitor, and 76% had been treated with a BCL2 inhibitor.
- The median follow-up at the time of analysis was 9.5 months.
- Thus far, NX-2127 appears to be well-tolerated.
- Some side effects typical of BTK inhibitors have been observed, including bruising, hypertension, and low white blood cell counts.
- Most side effects have been manageable and have not required discontinuation of the drug.
- Atrial fibrillation (abnormal heart rhythm) occurred in 13% of patients.
- The most common reasons for treatment discontinuation were progressive disease (26%) and adverse events (21%).
- Among the efficacy evaluable patients with CLL, there were nine partial responses; additionally, eleven patients had stable disease at the time of data cut-off, and four had progressive disease.
Conclusions:
The results from this ongoing trial show that NX-2127 appears to have a manageable safety profile thus far with side effects typical of BTK inhibitors. It is still early in the trial, so we look forward to learning more about the efficacy outcomes as the trial progresses. Protein degraders are a promising new class of drugs, and BTK degraders may be an important option in the future for patients who have developed resistance to BTK inhibitors such as ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib.
Update:
There is a partial hold on NX-2127 trials at the time of publication. This is not due to any safety issues but due to manufacturing concerns. We will update this review once the hold is lifted. In the meantime, trials are open with other BTK degraders, including NX- 5948.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: 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.
Take care of yourself first.
Ann Liu, PhD
