FDA Breakthrough Designation Signals New Therapeutic Avenue in R/R MCL

The FDA has granted breakthrough therapy designation (BTD) to the investigational B-cell lymphoma 2 (BCL2) inhibitor sonrotoclax (BGB-11417) for the treatment of adult patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) following therapy with a Bruton tyrosine kinase inhibitor (BTKi) and an anti-CD20 agent.¹

This BTD, granted to BeOne Medicines, is supported by positive topline data from the phase 1/2 BGB-11417-201 study (NCT05471843),² which successfully met its primary end point of overall response rate (ORR). The designation is a pivotal regulatory milestone, signaling the potential for sonrotoclax to address a critical unmet clinical need in a disease state characterized by limited effective treatment options after progression on established standards of care.

What is Sonrotoclax’s Significance in BTKi-Refractory MCL?

BTD is reserved for drug candidates that demonstrate preliminary clinical evidence of substantial improvement over available therapies for serious or life-threatening conditions.¹ MCL is an aggressive subtype of B-cell non-Hodgkin lymphoma that frequently relapses. While the introduction of BTKis and anti-CD20 agents has significantly improved outcomes, nearly all patients will eventually develop R/R disease, particularly those who fail a BTKi regimen. The 5-year survival rate for MCL is approximately 50%, underscoring the necessity for novel modalities that can induce deep and durable responses in highly pretreated cohorts.

“Breakthrough therapy designation is reserved for medicines with the potential to transform outcomes for patients with serious diseases. This recognition affirms the strength of the emerging data for sonrotoclax and its potential to become a new standard of care for people with relapsed or refractory mantle cell lymphoma,” said Julie Lepin, senior vice president, chief regulatory affairs officer at BeOne, in a press release. “Additionally, by participating in Project Orbis, we may be able to accelerate access to sonrotoclax, potentially helping patients faster than previously imagined.”

What is the Data Supporting This Designation?

The data that served as the foundation for the BTD originate from the global, multicenter, open-label, single-arm BGB-11417-201 study. The trial was specifically designed to evaluate the safety, tolerability, and preliminary efficacy of sonrotoclax monotherapy in a heavily pretreated R/R MCL population.

The study enrolled 125 adult patients who had received prior treatment with at least one BTKi (covalent or noncovalent) and an anti-CD20 antibody. The trial was conducted in 2 parts:

• Part 1 (n = 22): Focused on dose-finding, evaluating daily doses of sonrotoclax at 160 mg and 320 mg to establish a recommended dose.
• Part 2 (n = 103): Enrolled patients who received the recommended daily dose of 320 mg following a defined dose ramp-up schedule designed to mitigate the risk of tumor lysis syndrome (TLS).

The primary end point was the ORR as assessed by an independent review committee. Secondary end points included complete response rate, duration of response, and progression-free survival. The full, detailed clinical data from this study are currently being prepared for presentation at an upcoming major medical meeting, which will provide comprehensive insight into the agent's efficacy and safety profile in this refractory setting.

What is Sonrotoclax’s Pharmacological Profile and Clinical Rationale?

Sonrotoclax is classified as a next-generation BCL2 inhibitor. The BCL2 protein acts as a critical antiapoptotic regulator that is frequently overexpressed in B-cell malignancies, preventing the programmed cell death of cancer cells. Sonrotoclax, a BH3 mimetic, acts by binding to BCL2, thereby displacing proapoptotic proteins and restoring the cell's capacity for apoptosis.

Preclinical and early clinical data position sonrotoclax as a highly potent and specific inhibitor of BCL2. Furthermore, its distinctive pharmacological properties, including a shorter half-life and a lack of systemic drug accumulation, may confer clinical benefits, particularly concerning the management of adverse events such as TLS, a known complication associated with BCL2 inhibition therapy. By maintaining high potency while potentially offering a more manageable safety profile, sonrotoclax may offer a differentiated therapeutic option.

What is the Ongoing Development of Sonrotoclax?

The BTD further accelerates the agent’s ongoing broad clinical development program. Sonrotoclax is currently being evaluated in the randomized, double-blind, pivotal phase 3 CELESTIAL-RRMCL study (NCT06742996).³ This trial is comparing the combination of sonrotoclax plus zanubrutinib (Brukinsa), a next-generation BTKi, vs placebo plus zanubrutinib in patients with R/R MCL who have not been previously treated with a BCL2 inhibitor.

REFERENCES:

1. BeOne Medicines’ Sonrotoclax Granted Breakthrough Therapy Designation by U.S. FDA. News release. BeOne Medicines. October 14, 2025. Accessed October 14, 2025. https://tinyurl.com/3anvcduu

2. Study of BGB-11417 Monotherapy in Participants With Relapsed or Refractory Mantle Cell Lymphoma. ClinicalTrials.gov. Updated September 9, 2025. Accessed October 14, 2025. https://clinicaltrials.gov/study/NCT05471843

3. A Study to Investigate the Efficacy and Safety of Sonrotoclax Plus Zanubrutinib Compared With Placebo Plus Zanubrutinib in Adults With Relapsed/​Refractory Mantle Cell Lymphoma. ClinicalTrials.gov. Updated September 22, 2025. Accessed October 14, 2025. https://www.clinicaltrials.gov/study/NCT06742996