By Dark Horse Principal Kevin Whittlesey, Ph.D.
In the field of cell and gene therapy we’re seeing more excitement and growth each year, and the recent ZYNTEGLO® approval adds to that. The significance of the new approval is due to a variety of reasons, including that…
- to date there are only a few FDA-approved gene therapies.
- new therapies being made available to patients is the end-goal of nearly everyone in cell and gene.
- it’s one of the two bluebird bio therapies that received unanimous FDA Advisory Committee (AdComm) recommendation earlier this summer, suggesting that another approval may be on the near horizon.
These two recommendations came as a result of a shared AdComm session at which two different products were considered, which we have not seen before in cell and gene therapy. The FDA’s opening comments to the AdComm addressed this directly by stating that it is highly irregular to have two different therapies considered at the same AdComm review. This unexpected pairing could have been at least partially due to the fact that a single sponsor (bluebird bio) had two therapies with BLAs pending so as to even allow for near-simultaneous consideration by the FDA.
The therapy that was approved earlier this month, ZYNTEGLO® (beti-cel), is for the treatment of beta-thalassemia. The BLA was filed in September of 2021, it was unanimously recommended for approval by the FDA AdComm on June 10th of this year, and the FDA approved it two days before its official PDUFA target date of August 19, 2022.
The other therapy that was considered in the shared AdComm was eli-cel, for the treatment of early cerebral adrenoleukodystrophy (CALD). That BLA was accepted by the FDA in December of 2021, it was unanimously recommended for approval by the same AdComm on the day before beti-cel (on June 9th), and the updated PDUFA target date for a review decision is Sept 16, 2022.
ZYNTEGLO®’s approval was widely anticipated. Beti-cel (ZYNTEGLO®)’s clinical trial data demonstrated good efficacy, durability, and a favorable safety profile.
On the other hand, though, we have the other bluebird bio product awaiting a final decision: eli-cel. To someone unfamiliar with the world of regulatory approvals or CMC consideration, they may have appeared to be somehow related…but it’s important to note that they are not. They have the same parent company/sponsor and are both lentivirus-modified hematopoietic stem cells, but they are different products to treat different diseases utilizing different vector components. Importantly, they also exhibit different safety and risk:benefit profiles.
Eli-cel has a more complicated safety profile and thus a very different risk:benefit assessment. I don’t anticipate that the first bluebird bio approval necessarily signals an increased likelihood of eli-cel also being approved. If eli-cel is approved next month, though, it is likely to come with caveats.
The Serious Adverse Events (SAEs) seen with eli-cel—cases of myelodysplastic syndrome, a disease that is not typically coincident with CALD—are severe enough that in a different risk:benefit analysis (for example, if the disease being treated were less dangerous and/or treatment options were already in place) approval would be less likely. The SAEs appear to be related to the strong ubiquitous promoter used in eli-cel, which is called MND and comes from a myeloproliferative virus. It appears likely that the promoter may have activated cancer-related genes in the neighborhood of the vector integration sites.
Bluebird addressed the safety concerns head-on to the AdComm. Their explanation was that a strong ubiquitous promoter was necessary in this case because it wasn’t known which cells in the hematopoietic lineage might be necessary for engraftment to the brain to be able to effectively treat CALD, meaning that a ubiquitous promoter would maximize this therapy’s chance for success.
Factoring in these safety issues as well as the severity of CALD and lack of treatment options for a significant segment of the patient population means that the nuances of this patient population will likely influence the FDA’s decision. In considering what treatment options are currently available, there are essentially three patient population pools discussed by the AdComm:
a) patients with a matched sibling bone marrow donor,
b) patients with a matched but unrelated bone-marrow donor, and
c) patients for whom there are no matched bone marrow donors at all.
The first pool (a) would experience the lowest risk and greatest chance for benefit by receiving the current gold standard of care treatment: a bone marrow transplant from that matched sibling donor (for whom the risks of GVHD would be minimized due to the degree of overlap in the gene pool of a sibling). For them, the AdComm agreed that eli-cel would not make sense.
However, CALD is a devastating disease and the options for children in pool (c) with no donor match at all are so limited that these patients and their families may well be willing to tolerate a higher degree of risk and try eli-cel. For that middle pool (b), the decision could be even more difficult but eli-cel could still offer a previously unavailable hope and provide a new treatment option for patients and their physicians to consider. It is this middle population for whom the AdComm’s views were mixed, making it more difficult to anticipate what the FDA will do with their final decision on the BLA.
Interestingly, the AdComm brought into the discussion a third bluebird bio product in the pipeline, although that product is arguably even less related than the other two. The third product is currently known as bb1111 (or by its brand name, LentiGlobinTM) and is an investigational therapy to treat sickle cell disease (SCD). This product has experienced some safety concerns and is not on a similar timeline as the first two: the BLA hasn’t even been filed yet. The FDA posed the question to the AdComm whether safety concerns seen with LentiGlobin should be considered in evaluating eli-cel. It was surprising to see the FDA try to once again link the safety profiles of two different products, but the AdComm agreed on this point: LentiGlobin data should not be considered in the evaluation of eli-cel.
In wondering how connections between these two therapies could have been drawn to merit this highly unusual AdComm structure, it is worth considering whether the concept of “the process is the product” came into play. If someone looking at these therapies is a strong proponent of this concept, in which the process that is used to develop the therapy is overwhelmingly indicative of the end product, then it follows that one could consider the robustness of the sponsor’s CMC program to be a factor. If that’s the case, eli-cel could well be in a stronger position than it would otherwise have been, given ZYNTEGLO®’s robust CMC characterization and subsequent approval.
The approval of ZYNTEGLO® is great news for patients and it’s also excellent for the field to have more marketed products available. But there is reason for sponsors to look at the process the FDA has taken here and wonder whether this is foreshadowing a shift in regulatory thinking. Typically products are considered independently from one another and evaluated based on the data collected with that particular product. Is FDA now signaling that it might in the future also look at data and any potential safety concerns seen with other similar products? Or was this an exceptional case due to the number of products at a mature stage of development utilizing a similar approach by the same sponsor? Time will tell, and the entire cell and gene therapy field will be watching.
* Briefing documents are publicly available. We’ve linked to them here: