BeOne Medicines has entered the BCL-2 space, securing FDA green light for Beqalzi, carving out a space of its own ahead of a potential broader clash with market leader Venclexta.
The FDA has granted accelerated approval to BeOne’s Beqalzi (sonrotoclax) for the treatment of patients with relapsed or refractory mantle cell lymphoma after receiving at least two lines of therapy, including a BTK inhibitor, the company announced Wednesday.
This approval makes Becultzi the first BCL-2 inhibitor specifically approved for MCL in the United States, as Venclexta, first brought to market by AbbVie and Roche, has only been used off-label for this type of blood cancer. Prior to the FDA, Chinese regulators had already granted BeOne drug approval in January.
Still, MCL is BeOne’s stepping stone to potentially rebuilding the broader BCL-2 environment currently dominated by Venclexta.
In preclinical assays, Becaldi was shown to be 14 times more potent and six times more selective for BCL-2 than Venclexta, Amit Agarwal, MD, BeOne’s chief medical officer of hematology, said in an interview with Fierce Pharma ahead of FDA approval.
In addition to its potential efficacy advantages over Venclexta, Mr. Agarwal emphasized that Becalzi’s short half-life is 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 rapidly die and overwhelm the kidneys. Venculesta has a long half-life, making it a burden for physicians and patients to monitor TLS when adjusting the drug’s dose.
In comparison, Becardi is cleared from the body much faster, making it easier to titrate the dose. Agarwal noted that patients may undergo a blood test before taking the drug and repeat the test four to six hours after taking the drug. By comparison, Venclexta requires TLS monitoring at 6 to 8 hours and 24 hours after each new dose increase during the escalation phase, and may require hospitalization.
Despite being the first BCL-2 drug to enter MCL, Bekardi still has to compete with Eli Lilly’s non-covalent BTK inhibitor Jypirka, which received its own third-line, post-BTK approval in early 2023.
Jaypirca’s initial consent was based on tumor regression data from the phase 1/2 Bruin trial. According to the drug’s label, in a group of MCL patients who had previously received a covalent BTK inhibitor, Jpiruca recorded an overall response rate (ORR) of 50%, with a median duration of response of 8.3 months. The complete response rate (CRR) was 13%.
In another phase 1/2 trial with BeOne, Beqalzi showed an ORR of 52% and a longer median duration of response at 15.8 months. CRR was 16%.
Although the two datasets are from similar treatment settings, comparisons between trials should be made with caution as patient characteristics and follow-up periods differ.
Agarwal argued that physicians “prefer to switch mechanisms of action,” and suggested that for some physicians, moving to BCL-2 inhibition with Bekardi may be more attractive than continuing to use BTK and Jaypirka.
Becarzi’s MCL trial recorded 42 deaths, including 13 in which disease progression was not identified. Agarwal suggested that depending on the timing, some patients may not have been recorded as being associated with disease progression. Overall, there was only one infection-related death in the study, and BeOne executives said the company has not seen any significant safety concerns for Becalzi and is “very encouraged” by the drug’s safety profile demonstrated in more than 2,000 patients treated across clinical trials to date.
With accelerated approval, BeOne is committed to providing confirmatory evidence of Beqalzi’s benefit from the Celestial-RRMCL trial. The Phase 3 trial will enroll previously treated MCL patients and randomly assign them to either BeOne’s BTK drug Brukinsa or the combination of Brukinsa and Becaldi.
MCL has given Becarzi the right to compete, but the real battle against Benclexta is chronic lymphocytic leukemia (CLL).
Because MCL is generally an aggressive non-Hodgkin’s lymphoma, the benefits of Becalzi’s TSL monitoring are less significant.
“Our ultimate goal is for CLL to actually do perhaps one, or at most two monitoring visits during the ramp-up period,” said BeOne’s Agarwal.
According to a poster presented at the American Society of Hematology annual meeting in December, phase 1 data from the BGB-11417-101 trial showed that 91% of a group of front-line CLL patients who received 320 mg of Burkinsa and Bekardi achieved undetectable measurable residual disease (uMRD), a type of deep response, after 48 weeks of treatment. By week 96, the uMRD rate had increased to 98% in 56 evaluable patients.
“No other dataset even comes close to those numbers” for Venclexta, Agarwal said.
AstraZeneca’s Amplify trial reported a uMRD rate of 45% in about 56 weeks when the British drugmaker’s BTK inhibitor Calquence was combined with Venclexta.
BeOne seeks to prove the value of Beqalzi in previously untreated CLL through two Phase 3 trials. The first case, Celestial-TNCLL, pits Brukinsa-Beqalzi against Roche’s Gazyva and Venclexta, and MRD data that could support a regulatory filing is expected to be released later this year.
Due to the increasing use of first-line BTK inhibitors, BeOne recently initiated a second Phase 3 trial using Calquence-Venclexta as an alternative comparator. Agarwal said the company only needs one positive study to get FDA approval.
BeOne is promoting the Bekarzi combo as investors have recently begun to worry about front-line CLL competition with AZ’s fixed-term Calquence and Venclexta combo against Burkinsa. Brukinsa is currently used indefinitely until disease progression or intolerable toxicity occurs. In two Phase 3 trials, Brukinsa and Becaldi will be administered over a period of time.
