Bluebird bio has asked the US FDA to take a flexible and innovative approach to the CMC comparability data review for gene therapy candidate LentiGlobin.

It had been estimated that bluebird bio was aiming to submit a Biologics License Application (BLA) for its gene therapy candidate LentiGlobin (autologous CD34+ cells encoding βA-T87Q-globin gene) in the second half of 2021.

But following US Food and Drug Administration (FDA) concerns, guidance has been put back by a year, management said on a third quarter call this week.

Image: iStock/BrianAJackson

Due to “new CMC requirements from the agency and COVID-19 based CMO [contract manufacturing organization] operational delays, we are adjusting the timing of the BLA submission back to the more conservative initial timing of late 2022,” CEO Nick Leschly told investors.

Agency meetings

First the chemistry, manufacturing, and control (CMC) requirements:

According to Leschly, bluebird recently had a meeting with the FDA and the agency is asking for comparability data between clinical-grade/adherent cells manufactured for trials and commercial-grade/suspension cells that will be used going forward. This was different than the plan bluebird proposed and expected, he said.

“Comparability will now include not only a small number of drug product lots manufactured from healthy donors, but also from patients with sickle cell disease. The lots to be manufactured with patient cells to support this analytical comparability package will be manufactured within the HGB210 [Phase III] study and are in addition to the patients already treated with the drug product manufactured with suspension lentivirus.”

The FDA is also requiring the firm uses commercial vector versus clinical vector to demonstrate the comparability of the commercial drug product.

“As thoughtful as the agency was in their feedback, we believe there is still room for potential flexibility in the plan to close the gap between clinical and CMC timelines. Very concretely we’d like to explore ideas like real-time review of CMC module…or CMC flexibly allowing for the submission of data either during review or post approval,” he said.

“In short, breakthrough and RMAT [regenerative medicine advanced therapy] designation have been successful in accelerating clinical development and it is now critical to resolve the misalignment on what accelerated means when thinking about CMC portions of the BLA. We will continue to work with the agency and are hopeful they will use a flexible and innovative approach to avoid unnecessary delays.”

CMO delays

Leschly highlighted delays driven by the COVID-19 pandemic in its external manufacturing network as adding further pressure to being commercial ready.

“Our CMOs have been operating under stringent COVID protocols and in some cases have experienced significant local outbreaks as the pandemic continues. Specifically, the CMOs ramping up to support both commercial LVV, or lentiviral viral vector, and drug product for sickle cell disease have been affected causing slower operational progress in commercial readiness activities in the order of 4-6 months.”

The CMOS were not named, but bluebird works with several third parties for production of the gene therapy. In Europe, where LentiGlobin is approved as a one-off treatment for beta-thalassaemia under the brand name Zynteglo, bluebird uses apceth Biopharma, part of Minaris Regenerative Medicine (previously Hitachi Chemical Advanced Therapeutics Solutions, or HCATS).

Bluebird also uses CMOs Thermo Fisher, Novasep and MilliporeSigma.

Manufacturing problems have also plagued bluebird since the EU approval, with ‘manufacturing readiness’ delaying initial launch.