Continued Research on Exa-cel and Lovo-cel Remains Important After FDA Approval

Alexis A. Thompson, MD, MPH

Vertex Pharmaceuticals' and CRISPR Therapeutics’ autologous gene-edited cell therapy exagamglogene autotemcel (exa-cel), marketed under the name Casgevy, and bluebird bio’s lovotibeglogene autotemcel (lovo-cel), marketed as Lyfgenia, were both approved by the FDA for the treatment of sickle cell disease on December 8, 2023. Notably, the indications for both therapies were limited to patients aged 12 years or older.

Shortly after the approval, CGTLive™ spoke to Alexis Thompson, MD, MPH, the chief of hematology at Children’s Hospital of Philadelphia, at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12, in San Diego, California, about her thoughts on the FDA’s decision. Thompson pointed out the importance of the moment, but emphasized the need for further research.

CGTLive: What are your thoughts on the FDA’s approval of exa-cel and lovo-cel?

Alexis Thompson, MD, MPH: That the FDA approval for both products occurred at the beginning of the ASH meeting was amazing. To have over 30,000 folks who are interested in blood disorders convening in one place—the excitement has been palpable—and it's not surprising, there are many investigators who take care of individuals with inherited blood disorders. To be able to imagine the use of genetic approaches for treatment of blood disorders—I think many have hoped that this is where we were going. I don't know that everyone thought that we would have gotten there so quickly with CRISPR. But having said that, the results are impressive. It is undeniable that the vast majority of individuals with sickle cell disease who are having CRISPR-based gene editing have superb responses and that the toxicity profile is one that is generally well-tolerated for patients. It’s really an amazing time.

Is there any high-priority further research you would like to see done with for these therapies?

Both of the agents were approved down to age 12. My hope is that we continue to gather information to determine whether or not one or both of these approaches are safe and effective in children under the age of 12. That remains to be seen, but I think that certainly it will be very important because I think one could make the case that there would likely be benefit, if safe, for children who are younger.

I also want to be sure that we are thinking about access. We already know that these agents will be expensive. We know that these are patient populations sometimes that have limited personal resources. But it is very important that we be sure that we think about equity when we look at offering these new agents, which I concede are fairly expensive.

We're going all in. I mean, I think that it's very important for us to really think this through looking at the science. The clinical trial data is compelling so there really cannot continue to be any questions about the likelihood of benefit. This is a disease that is [financially] devastating, both personally and to the healthcare system, even without gene therapy. With a shortened lifespan and the frequent needs for acute care, hospitalizations, plus the expenses of a lot of their other treatments [it] can't be ignored. As such, when we think about the potential benefit, if one can think about early access to a medication or a treatment that is a one-time treatment, it becomes a bit of a different equation—a different discussion—when we think about the benefits of something like gene therapy.

What else are you excited about at ASH’s 2023 conference?

I learn something every year [at the ASH meeting]. I always come with my list of posters I intend to see and abstract sessions I want to attend. Invariably, there's just so many amazing presentations as part of this meeting that my head is really full of new ideas. The array of presentations, even at the plenary session yesterday—that included 2 sickle cell presentations for the very first time. One [presentation was on] a potential new small molecule; that was incredibly exciting to see research being done in something that at some point may be an actual treatment or moving into clinical trials. And then [we saw] incredible data from Sub-Saharan Africa, with the REACH study [NCT01966731] showing that optimizing hydroxyurea for children across Africa can be done safely and continues to extend our understanding of the benefits of long-term use of hydroxyurea at escalated doses for a patient population that otherwise has been underserved. I was extremely pleased that that was chosen for one of their abstracts.

I was also very excited about some of the new work in some of the up-and-coming gene therapy clinical trials. Looking at the presentation for EDIT-301 and some of the early discussions around the BEAM-101 clinical trials for sickle cell disease—these may be additional approaches for durable long-term control of sickle cell disease. Seeing these other emerging discussions is often something I find pretty exciting about the meeting.

This transcript has been edited for clarity.

REFERENCES
1. FDA approves first cell-based gene therapy to treat adult and pediatric patients with beta-thalassemia who require regular blood transfusions. News release. FDA. August 17, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-treat-adult-and-pediatric-patients-beta-thalassemia-who?utm_medium=email&utm_source=govdelivery
2. Thompson AA, Olson TS, Walters MC, et al. Sustained efficacy, safety, and improved quality of life in adult and pediatric patients with transfusion-dependent β-thalassemia up to 9 years post treatment with betibeglogeneautotemcel (beti-cel). Presented at: ASH 2023 Annual Meeting & Exposition. December 9-12; San Diego, CA. Abstract #1102
3. Kwiatkowski JL, Olson TS, Walters MC, et al. Improvement in iron burden in patients with transfusion-dependent β-thalassemia (TDT) treated with betibeglogeneautotemcel (beti-cel) gene therapy: up to 9 years of follow-up. Presented at: ASH 2023 Annual Meeting & Exposition. December 9-12; San Diego, CA. Abstract #2480