FDA Again Delays Liso-cel Approval, Jeopardizing BMS’s $74 Billion Celgene Acquisition Milestones

Compiled by Keke

On November 16, BMS announced that the U.S. FDA had notified the company that the review of its Biologics License Application (BLA) for lisocabtagene maraluel (liso-cel) for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma would not be completed by the Prescription Drug User Fee Act (PDUFA) goal date of November 16, 2020.

Earlier this month, BMS disclosed that the U.S. FDA must inspect two manufacturing facilities before making an approval decision on the liso-cel application. At the time, the company noted that one site had already been inspected, while the other had not yet been scheduled. However, “we believe the scheduling of the second on-site inspection is not contingent upon the outcome of the first inspection, as they are independent facilities.”

However, on Monday, Bristol-Myers Squibb (BMS) stated that due to travel restrictions associated with the COVID-19 pandemic, the U.S. Food and Drug Administration (FDA) was unable to inspect the third-party manufacturing facility located in Texas, USA, within the current review cycle. Consequently, the agency has decided to postpone its approval decision on the application until the inspection is completed. Currently, the application for liso-cel remains under review, and the FDA has not provided a new expected decision date.

The BLA for liso-cel is based on the safety and efficacy data from the TRANSCEND NHL 001 trial, a Phase 1 clinical study that evaluated liso-cel treatment in 268 patients with relapsed or refractory (R/R) large B-cell lymphoma, including diffuse large B-cell lymphoma, high-grade lymphoma, primary mediastinal B-cell lymphoma, and Grade 3B follicular lymphoma. TRANSCEND NHL 001 is the largest study to date supporting a BLA for anti-CD19 CAR T-cell therapy.

However, with the approval delayed, BMS faces another challenge: fulfilling the contingent value rights (CVRs), traded under the ticker symbol BMY-RT, issued during its acquisition of Celgene. CVRs are a type of option granted by the acquirer to the target company’s shareholders in merger and acquisition deals, allowing them to purchase additional shares of the acquiring company upon the occurrence of specific events. Specifically, CVRs can tie a portion of the total transaction value to whether the target company’s pipeline products successfully achieve predefined milestones, such as obtaining regulatory approval, commercial launch, or reaching certain sales targets within specified timeframes.

The U.S. FDA’s approval, within the specified timeframe, of indications for three Celgene therapies constitutes a milestone set by the contingent value rights (CVRs) issued by Bristol-Myers Squibb (BMS) when it acquired Celgene for $74 billion in the fourth quarter of 2019. Under the agreement, the CVRs entitle Celgene shareholders to a one-time payment of $9 per share; however, if the milestones are not met within the prescribed period, the CVRs will become worthless. One of these therapies, the S1P receptor modulator Zeposia (ozanimod), was approved in March of this year for the treatment of adult patients with relapsing forms of multiple sclerosis.

Approval of the CD19-targeted CAR T-cell therapy liso-cel by December 31, 2020, remains one of the outstanding milestones for CVR, with fewer than 45 days remaining until that deadline. Liso-cel was once a frontrunner in cell therapy development, on par with competing CAR T products from Novartis and Kite Pharma (now part of Gilead). Novartis’s Kymriah (tisagenlecleucel) became the first to market in 2017, and Kite’s Yescarta (axicabtagene ciloleucel) received approval in the same year, whereas liso-cel’s regulatory review has faced multiple setbacks. Although the timing of the final regulatory decision remains uncertain, Salim Syed, an analyst at Mizuho Financial Group in Japan, stated, “If the U.S. FDA can promptly inspect the Texas manufacturing facility, BMS could still secure approval for liso-cel before year-end, as completing all required product testing typically takes only three weeks.”

Another milestone event was the U.S. FDA’s approval of the BCMA-targeted CAR T-cell therapy Idecabtagene Vicleucel (ide-cel) by March 31, 2021. Also known as bb2121, this therapy has been granted Priority Review by the U.S. FDA for adult patients with multiple myeloma (MM) who have previously received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. A regulatory decision is expected by March 27 of the following year. However, whether this cell therapy will reach the market as scheduled remains uncertain. In May of this year, the U.S. FDA issued a Refuse-to-File letter for the ide-cel Biologics License Application (BLA), stating: “After preliminary review, the Agency determined that the Chemistry, Manufacturing, and Controls (CMC) module of the BLA requires additional detail to facilitate completion of the review.” As the first CAR-T cell therapy targeting BCMA for the treatment of MM to submit a regulatory application, ide-cel positions Bristol-Myers Squibb (BMS) to strive for early market entry.

References:

1. Wikipedia

2.Bris­tol My­er­s' $9 Cel­gene CVR is tee­ter­ing on the brink of dis­as­ter as the FDA de­lays the liso-cel ap­pli­ca­tion yet again

3..Bristol Myers Squibb Provides Regulatory Update on Lisocabtagene Maraleucel (liso-cel)

4.CVR tied to BMS's Celgene takeover dealt blow as FDA again delays liso-cel review