<div id="readability-page-1"><div id="article-body-row"> <div> BeOne Medicines has entered the BCL-2 arena, securing an FDA green light for Beqalzi that carves out a unique piece of territory ahead of a potential broader clash with market leader Venclexta. The FDA has granted an accelerated approval to BeOne’s Beqalzi (sonrotoclax) for the treatment of patients with relapsed or refractory mantle cell lymphoma after at least two prior lines of therapy, including a BTK inhibitor, the company said Wednesday. The go-ahead makes Beqalzi the first BCL-2 inhibitor specifically approved for MCL in the U.S., as AbbVie and Roche’s first-to-market Venclexta has only been used off label for this type of blood cancer. Before the FDA, Chinese regulators had already cleared the BeOne drug in January. Even so, MCL is BeOne’s stepping stone to potentially reshape the broader BCL-2 landscape, which is currently dominated by Venclexta. In preclinical assays, Beqalzi has shown to be 14 times more potent than Venclexta and 6 times more selective for BCL-2, Amit Agarwal, M.D., Ph.D., BeOne’s chief medical officer for hematology, noted during an interview with Fierce Pharma ahead of the FDA approval. Besides a potential efficacy edge over Venclexta, Agarwal highlighted Beqalzi’s shorter half-life as an important advantage from a safety and convenience perspective. One of the most dangerous risks with BCL-2 inhibitors is tumor lysis syndrome (TLS), where cancer cells die so rapidly that they overwhelm the kidneys. Venclexta’s long half-life makes monitoring for TLS a burden on physicians and patients as the drug’s doses are being adjusted. By comparison, Beqalzi clears the body much faster, making dose escalation easier. Patients may undergo a blood test before taking the drug and then re-measure 4 or 6 hours after dosing, Agarwal noted. By comparison, Venclexta requires TLS monitoring 6-to-8 hours and 24 hours after each new dose increase during the ramp-up phase, sometimes with the need for hospitalization. Even though Beqalzi is the first BCL-2 agent to enter MCL, it still has to compete with Eli Lilly’s non-covalent BTK inhibitor Jaypirca, which got its own third-line, post-BTK nod in early 2023. Jaypirca’s initial nod was based on tumor shrinkage data from the phase 1/2 Bruin trial. In a group of MCL patients that had previously received a covalent BTK inhibitor, Jaypirca recorded an overall response rate (ORR) of 50%, with the responses lasting for a median 8.3 months, according to the drug’s label. The complete response rate (CRR) was 13%. In a separate phase 1/2 trial by BeOne, Beqalzi showed an ORR of 52%, with a longer median duration of response of 15.8 months. The CRR was 16%. The two data sets are from similar treatment settings, but cross-trial comparisons should be made with caution due to different patient characteristics and follow-up time. Arguing that physicians “prefer to switch mechanism of action,” Agarwal suggested that transitioning to BCL-2 inhibition with Beqalzi might be more appealing than sticking with BTK and Jaypirca for some doctors. Beqalzi’s MCL trial did record 42 deaths, including 13 that were not pinned on disease progression. Agarwal suggested some patients may not be documented as related to disease progression due to timing. Overall, with just one infection-related death in the study, the BeOne exec said the company hasn’t seen any major safety concerns for Beqalzi and that it’s “very encouraged” by the drug’s safety profile as shown in more than 2,000 patients that have been treated so far across its clinical trials. With the accelerated approval, BeOne is on the hook to provide confirmatory evidence of Beqalzi’s benefit from the Celestial-RRMCL trial. The phase 3 study is enrolling patients with previously treated MCL to be randomized to either BeOne’s BTK drug Brukinsa or a combination of Brukinsa and Beqalzi. While MCL gives Beqalzi an entry ticket, the real battle with Venclexta lies in chronic lymphocytic leukemia (CLL). Because MCL is a generally aggressive non-Hodgkin lymphoma, Beqalzi’s TSL monitoring advantage doesn’t matter that much. “Our ultimate goal is for CLL to actually have probably one—or two at most—monitoring visits throughout the ramp-up,” BeOne’s Agarwal said. Phase 1 data from the BGB-11417-101 trial showed that 91% of a group of frontline CLL patients who received Brukinsa and a 320-mg dose of Beqalzi achieved undetectable measurable residual disease (uMRD), a type of deep response, at 48 weeks of treatment, according to a poster presented in December at the American Society of Hematology annual meeting. By 96 weeks, the uMRD rate climbed to 98% among 56 evaluable patients. “No other data set has even come close to those kinds of numbers” with Venclexta, Agarwal noted. In AstraZeneca’s Amplify trial, a combination of the British pharma’s BTK inhibitor Calquence and Venclexta reported an uMRD rate of 45% at about 56 weeks. BeOne is trying to prove Beqalzi’s worth in previously untreated CLL through two phase 3 studies. The first trial, Celestial-TNCLL, is pitting Brukinsa-Beqalzi against Roche’s Gazyva and Venclexta, with MRD data expected later this year that might be able to support a regulatory filing. As BTK inhibitors are increasingly used in the first-line setting, BeOne recently started a second phase 3 trial that’s instead using Calquence-Venclexta as the comparator. The company needs just one positive study to seek the FDA’s approval, Agarwal said. BeOne is advancing the Beqalzi combo as investors have recently become concerned about first-line CLL competition from AZ’s fixed-duration Calquence-Venclexta combo against Brukinsa, which is currently used indefinitely until disease progression or intolerable toxicity. For the two phase 3 trials, Brukinsa and Beqalzi are given for a fixed period of time. </div> </div></div>

RHHVF

ABBV

BeOne Medicines has received FDA approval for Beqalzi (sonrotoclax), the first BCL-2 inhibitor specifically approved for relapsed or refractory mantle cell lymphoma (MCL) in the U.S. This approval positions Beqalzi as a competitor to AbbVie and Roche's Venclexta. Beqalzi has shown to be 14 times more potent than Venclexta in preclinical assays and offers advantages in safety and convenience due to its shorter half-life. BeOne aims to expand Beqalzi's use in chronic lymphocytic leukemia (CLL), where it has demonstrated promising efficacy in trials.

BeOne's Venclexta challenger Beqalzi nets FDA approval