Blog | June 27, 2022

Bluebird Bio AdCom: Risk Vs. Benefit A "Living" Measurement For Commercialized CGTs

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By Anna Rose Welch, Director, Cell & Gene Collaborative
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Editor’s Note: This is the first in a three-part series discussing several main takeaways from bluebird bio’s recent FDA AdCom evaluating its two ex-vivo gene therapies: eli-cel in cerebral adrenoleukodystrophy (CALD) and beti-cel in β-thalassemia.

Over the past few years, the advanced therapies industry has become intimately familiar with the phrase “risk vs. benefit.” This “golden” ratio has become increasingly top of mind as companies, regulators, and the healthcare system weigh the clinical and economic profiles of these complex therapies. However, I’d argue that, so far in this nascent space, we often only think of risk vs. benefit in the context of the FDA review. If the totality of the evidence demonstrates at the time of review that the treatment’s benefits outweigh its overall risks, we can breathe a sigh of relief. But the recent bluebird bio AdCom nicely reminded us that, much like the structure of a biologic drug, the risk vs. benefit analysis can shift over the course of a CGT’s life.

There were a lot of factors muddying the overall clinical risk vs. benefit equation for bluebird bio’s eli-cel and beti-cel. Of course, the giant elephant in the room was the FDA’s concern that the lentiviral vectors — Lenti-D LVV for eli-cel and BB305 LVV for beti-cel — could cause blood cancers. In part, these concerns were based on a handful of serious adverse events (SAEs) observed in the eli-cel trial, as well as in bluebird’s lovo-cel trial, which has encountered myeloid malignancies in the past. (Please note that lovo-cel was not up for review during this AdCom, however it was often brought up in comparison to eli-cel and beti-cel because it shares the same BB305 LVV/promoter with beti-cel.) There is also a marked lack of historical knowledge around LVV vector integration in humans and/or primates, which no doubt added to the FDA’s uncertainty around LVV-mediated insertional oncogenesis. In fact, there was an entire presentation during this AdCom on the potential consequences of HIV provirus integration because of the dearth of LVV-specific information in the literature.

In addition to these hefty vector-specific concerns, we can’t forget that small patient populations, limited natural history data, and disease heterogeneity also made it infinitely more challenging to design clinical trials for these two gene therapies and to interpret their data.

By now, we already know how the penultimate chapters of these therapies’ stories end: in light of both therapies’ primarily positive clinical impacts and the fact that both CALD and β-thalassemia are in great need of alternative treatment options, the advisory committees voted in favor of approving both eli- and beti-cel. The final chapter — the FDA approval — has yet to be written.

Though clinical risks and benefits were discussed extensively throughout both days, the most meaningful discussion occurred during the advisory committee’s review of eli-cel on day one. Of the two treatments being evaluated, eli-cel had a greater number of clinical questions given that 8 of 67 patients exhibited adverse reactions. Five patients’ adverse events (AEs) were classified as serious (SAEs), which included 3 cases of myelodysplastic syndrome (caused by LVV insertion). One of these cases developed more than 7 years after treatment. There are also four patients currently being monitored because they are high-risk for developing MDS.

However, given the high rates and nefarious nature of graft vs. host disease (GVHD) when treating CALD with the current standard of care (matched or unmatched donor allogeneic hematopoietic stem-cell transplantation), several of the AdCom members pointed to the importance of having multiple treatment options to promote a better quality of life and offer physicians and patients a choice. As one AdCom member memorably expressed, extending these patients’ lives ultimately gives the patients (and their families) more time which may also grant them the potential opportunity to access even better therapeutics in the future.

Current clinical benefits of both these therapies aside, it’s important to note that novel, new-to-market treatments aren’t necessarily the only “belles of the ball.” As several committee members mentioned, there have been notable advances in recent years in current standards of care (SOC) — particularly in the CALD/eli-cel patient population. In fact, because of these SOC improvements and concerns over gene therapy durability and long-term development of SAEs, there were several requests that the post-marketing of eli-cel not be carried out in a bubble. In addition to monitoring eli-cel, committee members recommended comparing outcomes and quality of life between patients receiving eli-cel and those who receive allogeneic transplants and develop GVHD.

It was in listening to the AdCom’s risk monitoring recommendations that I started to think more about the risk vs. benefit ratio as a “living” metric for any novel CGT treatment being approved — especially for patient populations with available SOCs. The outcomes for any approved ATMP must (and likely will be required to) be compared to the outcomes of (often improving) standards of care. In turn, we’ll be better able as an industry to establish a clearer framework for determining a therapy’s benefits overtime and the types/levels of risk we and our patients are comfortable with in the long-term.