As part of its $74 billion Celgene pickup, Bristol Myers Squibb offered future payouts based on FDA approval for three key pipeline assets. Already in jeopardy after one delay, that payoff looks even more tenuous now that the FDA has made a rare—and embarrassing—refusal to even consider one of those approval filings.

Bristol on Wednesday revealed the FDA had refused to review its submission for ide-cel (bb2121), a CAR-T cell therapy for multiple myeloma co-developed with bluebird bio and acquired in the drugmaker's buyout of Celgene in late 2019. 

Bristol said the FDA highlighted concerns about the manufacturing portion of ide-cel's filing rather than clinical or non-clinical data. The drugmaker expects to refile by July. 

Ide-cel was one of five key pipeline assets Bristol picked up in its Celgene deal, and its approval by March 2021 was one of three regulatory milestones for investors holding contingent value rights in the $74 billion transaction. 

In a call with analysts Wednesday morning, Bristol CEO Giovanni Caforio said the FDA's pushback on scanty documentation—specifically in the application's chemistry, manufacturing and control section—was usually reserved for the preliminary review process. An expedited approval could still be accomplished when the submission is refiled, Caforio contended. 

"We believe we submitted a completed dossier to the FDA, so what we are really discussing here is the level of detail the FDA has requested," Carforio said. 

Bluebird CEO Nick Leschly mirrored Carforio's comments on a separate analyst call, calling the FDA's letter "unusual" and stressing that no new data were requested. 

RELATED: BMS investors bet big on 3 newly acquired Celgene drugs for cancer and MS

Despite both companies' optimism that ide-cel will eventually pass FDA muster, investors may read the FDA's pushback as a possible nail in the coffin for related payments offered as part of the Bristol-Celgene pact.

The contingent value rights granted to Celgene shareholders—but tradeable on the open market—pay out after regulatory approvals for three assets: multiple sclerosis drug Zeposia (ozanimod), ide-cel and another CAR-T therapy, liso-cel.

Zeposia's FDA approval in March was a positive sign, but Bristol set a tight deadline of March 2021 for the ide-cel approval and an even tighter timeline for liso-cel, which needs the FDA's OK by the end of 2020.

That deadline didn't look so tight last month; the agency had granted liso-cel a priority review, setting it up for a potential approval in August. But last week, the FDA delayed that decision by three months. That puts the agency's new deadline at mid-November, leaving not much margin for error.

RELATED: Biogen, Novartis, Sanofi catch a break with holdup to Celgene MS prospect

An FDA refusal to review a submission is a rare move at a late stage in the approval process but one that Bristol is uniquely familiar with. 

In February 2018, the FDA refused to review Celgene's submission for ozanimod, citing “incomplete” pharmacology information. Because of that and other stumbles on the R&D side, Celgene shares slid, making it a more affordable buy when Bristol came calling in early 2019.

Celgene took more than a year to amend the complaints cited in the FDA's letter, but the agency eventually accepted the revised application in June 2019 and approval followed this March. Because of the COVID-19 pandemic, Bristol is waiting to launch the med, and it's already set to face rivals that might not have been a factor had ozanimod been reviewed on time. 

RELATED: Bluebird Bio delays Zynteglo launch as manufacturing trips up another gene therapy

For bluebird, ide-cel's latest manufacturing hiccup isn't the first for one of its advanced therapies. 

After nabbing a conditional European approval for gene therapy Zynteglo in 2019, the drugmaker announced it would delay the pricey and complex therapy's launch to this year to "tighten up" its manufacturing processes. 

That delay has carried all the way through the first half of 2020, in part due to manufacturing concerns and partly due to complications from the novel coronavirus pandemic, which have also pushed an FDA filing for Zynteglo. 

Earlier this week, Bristol agreed to hand over $200 million upfront to buy out its obligations to pay bluebird ex-U.S. milestones and royalties on ide-cel and its follow-up, bb21217. The cash will help bluebird build its lentiviral vector manufacturing site in North Carolina “to support the U.S. commercial market for ide-cel and for bluebird bio’s pipeline,” while BMS will pick up vector manufacturing outside the U.S.