When Bristol-Myers Squibb issued Celgene holders with a contingent value right as part of its takeout of the latter company, the approval of ide-cel was not seen as one of its riskier conditions. The shock of a US refusal-to-file letter, issued today, suddenly throws ide-cel’s approval into the spotlight.
For now, of course, Bristol and its partner Bluebird are putting on brave faces, saying the filing will be resubmitted by the end of July – a four-month setback. But this is the second delay to one of the CVR’s three elements in a week, raising serious questions over the documentation that Bristol took over from Celgene.
After all, a refusal-to-file (RTF) letter is not a sign of a mere administrative slip, or a missing piece of trifling data. It generally signifies that a filing is incomplete, or submitted in the wrong format, to such an extent that it is not capable of even being reviewed.
On the other hand, the FDA has also said that an RTF allows a sponsor to be informed of filing deficiencies as soon as possible, allowing such issues to be corrected sooner than would be the case were they to wait for a complete response letter.
Bristol and Bluebird say the problem with the ide-cel filing is that it lacks “further detail” primarily on chemistry, manufacturing and control processes used in the lentiviral vector and manufacturing processes. However, on an analyst call Bristol said there were no issues with its “ability to manufacture” the product.
Filing is the responsibility of Bristol, and the original submission had been made on March 31, at the time putting approval by the CVR-specified deadline well within reach. No additional clinical or non-clinical data have been requested, allowing for the quick resubmission plan.
|More uncertainty for holders of Bristol's CVR|
|Ozanimod||Approval by Dec 31 2020||Approved|
|Liso-cel||Approval by Dec 31 2020||BLA filed; Pdufa date initially 17 Aug, delayed to 16 Nov 2020|
|Ide-cel||Approval by Mar 31 2021||BLA filed, RTF letter received; refiling due by end Jul 2020|
|*Each CVR pays out $9 only if all three events are met.|
However, it will not go unnoticed that just a week ago the second of the CVR’s three events, an approval decision on the Juno-derived liso-cel by the end of this year, slipped by three months owing to Bristol’s submission of new data, which the FDA deemed a major amendment.
Both assets came to Bristol via the Celgene takeover, and liso-cel had been acquired by Celgene from Juno, so an obvious question is whether the problems now emerging are a result of the numerous handovers of data and possible personnel changes.
Curiously, Bluebird held a separate analyst call today, on which it threw into the mix the issue of Covid-19 as a consideration in a timely review process. However, it also stressed that it did not expect a “second shoe to drop”.
It was the approval not of ide-cel but of liso-cel that was seen as the CVR’s riskiest element, and this is probably still the case. If everything goes without a hitch now liso-cel approval is still just about possible by the December 2020 deadline, but today’s RTF adds ide-cel to the uncertainties.
If ide-cel is refiled in July, and if no new issues arise and the filing is accepted within 45 days, approval under six-month priority review could happen in February – with a month to spare. Clearly the CVR is still in play, but its holders are having to contend with a growing list of “ifs”.