FDA Experts Weigh In on Exa-cel and Lovo-cel Approvals for Sickle Cell and Corresponding Black Box Safety Warnings


The FDA’s Nicole Verdun, MD; and Peter Marks, MD, PhD, offered insight on the recent approvals of exa-cel and lovo-cel, answering questions about the safety of the gene therapies and the continued collection of data on their use.

Nicole Verdun, MD, the director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research

Nicole Verdun, MD

Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research

Peter Marks, MD, PhD

On Friday, December 8, 2023, the FDA made a landmark decision to approve a pair of gene therapies for the treatment of sickle cell disease (SCD)—bluebird bio’s lovotibeglogene autotemcel (lovo-cel), marketed as Lyfgenia; and Vertex and CRISPR Therapeutics’ exagamglogene autotemcel (exa-cel), which is to be marketed under the name Casgevy.1,2

Bluebird’s biologics license application for lovo-cel was supported by efficacy data from 36 patients from the ongoing phase 1/2 HGB-206 clinical trial (NCT02140554) and 2 patients in the phase 3 HGB-210 clinical trial (NCT04293185). Its efficacy was assessed based on the complete resolution of vaso-occlusive events between 6 and 18 months after infusion, at which time 88% (n = 28) of the 32 included patients achieved this milestone.3 Of note, hematologic malignancy has occurred in patients treated with lovo-cel, and as such, a black box warning was included in the label with information regarding this risk.

Likewise, the application for Vertex and CRISPR’s product was based on results from the phase 1/2/3 CLIMB-121 clinical trial (NCT03745287), which was conducted exclusively in patients with SCD, and the phase 3 long-term follow-up study CLIMB-131 (NCT04208529), which includes both patients with SCD and patients with transfusion-dependent β-thalassemia. Among 31 evaluable patients with SCD treated in CLIMB-121 and CLIMB-131, 29 patients (93.5%) achieved the primary end point of freedom from vaso-occlusive crises for at least 12 consecutive months during a 24-month follow-up period.4

Shortly after the announcement of the approvals, the agency held a call with the media, which included Nicole Verdun, MD, the director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research; and Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. The pair answered questions from several media outlets, such as NBC News, the Pink Sheet, Politico, CNN, and Washington Post, offering responses to a collection of reporters, including those on CGTLive's staff, who joined the briefing to provide coverage of Verdun’s and Marks’ comments.

See below for a transcription of the briefing's questions and the answers given by the FDA representatives.2 For more of CGTLive's coverage of the FDA approvals, see the following links:

What data did the FDA look at to support that box warning for bluebird bio’s lovo-cel, and why didn't Vertex/CRISPR’s therapy, exa-cel, get that same warning? Could exa-cel eventually get that same warning?NBC News

Nicole Verdun, MD: The black box warning, and the bluebird bio label, specifically, was for myeloid malignancies—2 cases, in particular, of AML that happened during the clinical trial for Sickle cell disease. Those 2 patients actually ended up having death as a result of their malignancies and so we thought that that rose to the level of a black box warning. Vertex, at this time, has not had malignancies that have occurred and so for that reason, we did not think that it warranted a black box warning at this time.

Peter Marks, MD, PhD: The bottom line, to finish up adding to that, is that obviously, as we have follow-up time that elapses, we'll just have to see what comes up with these therapies. They do have different mechanisms of action, so we'll just have to see what comes up with time.

The advisory committee meeting5 on the Vertex/CRISPR product was focused on the company's analysis of the potential for off-target effects and the theoretical risks related to those effects. How, if at all, did FDA deal with that in the labeling and the patient information?The Pink Sheet

Nicole Verdun, MD: The advisory committee meeting was to look at the potential for these off-target effects. Although, as we noted, we have not seen them to date, and [are determining] what the best way to study those are moving forward. The way we handled it in the label and the prescribing information is to put that potential risk into that label, so that patients are informed. We will, as Dr Marks said, make adjustments as needed in the future, but it is listed as a potential risk.

Can you tell us more about the long-term follow-up that the companies are going to have to conduct for these products? What specifically are you asking them to collect data on and do you have any guidance on when and how FDA would consider either or both of these therapies as actual cures for sickle cell?Politico

Nicole Verdun, MD: In terms of the follow-up we have reached an agreement with both sponsors to conduct long-term, follow-up studies for 15 years but, in addition, have encouraged, with the label, to continue to monitor for malignancy for the rest of a patient’s life after they receive these therapies. So, specifically that involves getting blood counts and also monitoring of the bone marrow and we have some have had significant conversations with the sponsors who have both agreed to that follow-up.

Doctors who treat sickle cell, and also bluebird bio itself, have said that the deaths (at least in its own work) were more related to the chemotherapy conditioning regimen than the gene therapy itself, and since both treatments require that conditioning regimen, could you walk through how you thought about whether lovo-cel–treated patients should be monitored for a lifetime risk of cancer?CNN

Nicole Verdun, MD: In terms of the malignancy risk, in addition to the 2 AML cases there was also a case of [myelodysplastic syndrome], and so to your point, in terms of a causative [relationship], we have to inform the public—we're about transparency and informing the public of the risk—there's not, at this point, definitive evidence to say specifically sort of what you were asking about, that it is just due to the conditioning regimen. There is a risk whenever you're editing genomes, that is a known risk. I think that, again, the point of the black box warning is really to inform the public of this risk, and that is in the setting of the entire regimen.

Peter Marks, MD, PhD: I think I know what you're getting at here. We will continue to look at both of these. I think you could argue that from the fact that the way these therapies work, this is like giving someone a stem cell transplant, so [patients] get busulfan, which is a chemotherapy agent, upfront, and then they get the modified stem cells that have been generated by 1 of 2 means—for one of the products, it is using the CRISPR-Cas9 that is put into the cells using a nonviral means; and then for the other, it's having the corrective gene therapy construct that’s put into the cells using a lentiviral vector—and so it's plausible that they could have the same set of side effects due to the busulfan, or it's plausible that there could be interactions between the busulfan and each of the different products themselves, so they may have different overall safety profiles.

What we can only do at this point is put on the label what we've seen, and I don't think that it would be fair to dismiss that as something due to the conditioning regimen because, ultimately, I think we need to step back and think from a larger standpoint about what these therapies are. They really are potentially transformative, but it's not just about the conditioning regimen, it's about the totality of therapy that's given. And not even just the totality of the cell therapy with chemotherapy that's given to get the cells engrafted—it's also about the total care of the patient that will need to happen. There will be additional care that will be needed to actually transition people—some people, once they have received these therapies, will need additional care to come off of opioids and other medications that they may have been on previously. This is really a total package; we’d like patients to be aware of all the potential side effects that they may encounter that we’re currently aware of.

Nicole Verdun, MD: And in terms of curative intent, with the long-term follow-up studies that we have discussed with the sponsors that are 15 years, in addition, we will be looking at efficacy over time, and I think that will be quite informative. Both therapies that were approved today, through slightly different mechanisms, do decrease the number of vaso-occlusive events and have the potential to take a [patient with sickle cell] who has had several of these events to not have any of these events. So, I think over time, in terms of getting to that place where we’re saying, at what point are we curative, we have to just follow over time [to ensure] that they’re [still] quite encouraging, and the results of both trials were quite encouraging as well.

Is the only eligibility criteria that there are 12 years old with recurrent vaso-occlusive crisis or is there any other upper-age restriction or anything else?Washington Post

Nicole Verdun, MD: There's no upper age restriction, yes that's correct, 12 and older.

Peter Marks, MD, PhD: Let me just clarify that probably, my suspicion is, that most providers will be thinking of this for patients who are in the hospital at least several times a year and not just somebody who has had a painful crisis and been managed as an outpatient. Although it's not labeled exactly that way, I think in terms of a benefit-risk calculation, that's how it will be put forward. I think just to inform you, although the population is 100,000 people with sickle cell disease in the country, the population that really fits this is probably 20% of that, in terms of people who have more frequent crises and who end up in the hospital more frequently, whereas many patients living with sickle cell disease do so with only occasional crisis. This is really for those whose lives have been significantly impacted, who sometimes potentially look like they're going to suffer end-organ damage from their sickle cell disease.

Transcript edited for clarity. To listen to the media briefing, visit the FDA's YouTube channel.

1. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. News release. FDA. December 8, 2023. Accessed December 8, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
2. MEDIA CALL: FDA Approves First Gene Therapies to Treat Sickle Cell Disease. US Food and Drug Administration. YouTube. December 8, 2023. Accessed December 8, 2023. https://www.youtube.com/watch?v=7m6kENCvx3Q
3. bluebird bio Submits Biologics License Application (BLA) to FDA for lovotibeglogene autotemcel (lovo-cel) for Patients with Sickle Cell Disease (SCD) 12 years and Older with a History of Vaso-Occlusive Events. News release. bluebird bio, Inc. April 24, 2023. Accessed December 8, 2023. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-submits-biologics-license-application-bla-fda-0
4. Vertex and CRISPR Therapeutics Complete Submission of Rolling Biologics License Applications (BLAs) to the US FDA for exa-cel for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia. News release. Vertex Pharmaceuticals Inc; CRISPR Therapeutics. April 3, 2023. Accessed December 8, 2023. https://www.businesswire.com/news/home/20230402005036/en/
5. 76th Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting. October 31, 2023. Accessed December 8, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-october-31-2023-meeting-announcement-10312023
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