The molecular basis of sickle cell disease (SCD), an inherited blood disorder characterized by red blood cells (RBCs) that carry mostly an abnormal form of hemoglobin that sometimes results in sickle-shaped RBCs, has been well-understood since at least the 1950s.^1,2 Despite this knowledge of its pathophysiology, however, treatment options for SCD were quite limited for many decades afterward. Up until about 10 years ago, the main treatment option for SCD was the small-molecule drug hydroxyurea.

Now, the landscape of care for SCD is rapidly changing. On a single day in 2023—December 8—the field of hematology was shaken by the FDA’s simultaneous approval of 2 gene therapy products for the treatment of SCD: Vertex Pharmaceuticals' and CRISPR Therapeutics’ exagamglogene autotemcel (exa-cel; marketed as Casgevy) and bluebird bio’s lovotibeglogene autotemcel (lovo-cel; marketed as Lyfgenia).³ Both therapies involve genetic modification of patients’ red blood cells outside the body to address the underlying mutation that causes the disease and subsequent infusion back into the patient, but the mechanism by which this is done is quite different in the 2 therapies. Exa-cel utilizes editing of the cells’ genome with CRISPR/Cas9 and lovo-cel involves gene addition, which is accomplished with a lentiviral vector. Both therapies are administered as one-time treatments and are considered to have curative potential.

With the introduction of these and other new, and in some cases curative, treatment options, such as haploidentical bone marrow transplant (haplo), the process of choosing the right treatment option for any individual with SCD is now more complex than ever. The question of how to approach navigating this process from the perspective of doctors, other healthcare professionals, and patients and their families/caregivers, was at the forefront of the minds of many experts who spoke at the 2024 Tandem Meetings |Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held in San Antonio, Texas, February 21-24, 2024.

In honor of World Sickle Cell Day, which is observed annually by the patient and clinician communities on June 19 for the purpose of expanding public understanding of SCD and the challenges it brings to patients, families, and caregivers, CGTLive^® has brought together insights from several of these and other experts focused on the topic of navigating this new—and still changing—landscape.

The FDA's Verdict on Exa-Cel and Lovo-Cel

The FDA’s approval of exa-cel was based on data 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 (TDT).^3,4 In terms of efficacy, the company reported that among 31 evaluable patients with SCD, 29 (93.5%) achieved the primary end point of freedom from vaso-occlusive crises (VOCs) for at least 12 consecutive months in a 24-month follow-up window. Exa-cel's safety profile was deemed consistent with what would be expected in patients receiving myeloablative busulfan conditioning and hemopoietic stem cell transplantation, with the only risk specific to the gene-editing product identified as delayed platelet engraftment.

READ MORE: FDA Approves Exa-cel, Vertex and CRISPR Therapeutics’ Gene Therapy, for Sickle Cell Disease

Meanwhile, the approval of lovo-cel was supported by efficacy data from 36 patients from the then-ongoing phase 1/2 HGB-206 clinical trial (NCT02140554) and 2 patients in the phase 3 HGB-210 clinical trial (NCT04293185), showing 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.^3,5,6 Notably, 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.

READ MORE: FDA Approves bluebird bio's Lovo-Cel Gene Therapy for Sickle Cell Disease

“The black box warning, and the bluebird bio label, specifically, was for myeloid malignancies—2 cases, in particular, of acute myeloid leukemia that happened during the clinical trial for SCD,” Nicole Verdun, MD, the director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research, said in a December 2023 media call hosted by the agency.⁵ “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.”

Weighing Gene Therapy Against Haploidentical Transplant for SCD

Haydar Frangoul, MD, the medical director of pediatric hematology/oncology at Sarah Cannon Research Institute and Pediatric Transplant and Cellular Therapy Program at TriStar Centennial, gave a presentation at Tandem 2024 entitled “Sickle cell disease: haplo versus gene therapy debate”.⁷ In an interview with CGTLive prior to his presentation, Frangoul gave an overview of the clinical trial data regarding the gene therapy products, emphasizing their strong efficacy and safety profiles. He also pointed out drawbacks of both the haplo and gene therapy modalities, noting that haplo carries the risk of graft versus host disease and infections and that the gene therapies have a less extensive history of testing and require a busulfan conditioning regimen that poses a fertility risk. Frangoul also emphasized the importance of continuing long-term follow-up studies for the gene therapy products in order to learn more about their efficacy and safety on an extended timescale.

When Curative Treatment Options Should Be Considered for Sickle Cell Disease

Although potentially curative treatment options like exa-cel, lovo-cel, and haplo have garnered much attention, these are not the only new treatment options for SCD that have been introduced in recent years. New drugs, such as the small molecule voxelotor (marketed as Oxbryta) and the monoclonal antibody crizanlizumab (marketed as Adakveo), have also joined hydroxyurea as noncurative options for management of SCD.^8,9 Indeed, many patients may begin treatment of their disease with measures for symptom management before the curative treatment options—which are substantially more expensive, complicated to administer, and may carry greater safety risks—are considered.

At Tandem 2024, CGTLive also spoke to Shalini Shenoy, MD, MBBS, the director of the Stem Cell Transplant & Cellular Therapy Program at St. Louis Children’s Hospital, who spoke in a session entitled “The evolving paradigm of sickle cell disease management.”¹⁰ Shenoy, who discussed allogeneic hematopoietic stem cell transplant (including haplo) in the session, gave CGTLive her perspective on the emerging new treatment landscape as a whole. She emphasized that when children and adults with SCD are not able to achieve a normal lifestyle on drugs for symptom management, curative treatment options should be considered.

Centering Patient Choice in the Treatment of Sickle Cell Disease

CGTLive also interviewed Vivien Sheehan, MD, PhD, an associate professor of pediatrics at Emory University, at Tandem 2024, who spoke in the same session as Shenoy. Sheehan emphasized that providers are faced with the choice to either take a paternalistic approach in deciding patients’ treatment for them, or to enable patients and their families to choose their own treatment path.

Sheehan argued in favor of the latter option, noting that methods such as matching patients’ symptoms to clinical end points and evaluating patients’ particular pathophysiology may help with the decision-making process. Sheehan also stressed that doctors should not push patients toward exhausting all symptom management drugs before the new gene therapies are considered, as their efficacy cannot equal the curative potential of exa-cel and lovo-cel.

Choosing Between Exa-Cel and Lovo-Cel

After the close of the conference, CGTLive also reached out to Akshay Sharma, MBBS, the attending physician and assistant member of bone marrow transplantation and cellular therapy at St Jude Children’s Research Hospital, another speaker in the same session as Shenoy and Sheehan. Sharma gave his own insight on the evolving range of treatment options for SCD, and zeroed in on the choice between the 2 new gene therapy options as opposed to comparing the gene therapies against other treatment modalities for SCD.

Sharma pointed out the slight, but important, difference in indication between lovo-cel and exa-cel and the different ways these 2 therapies address the root cause of SCD. He also gave his perspective on the black box warning issued by the FDA for lovo-cel and briefly touched on 2 notable investigational gene therapies that are currently still in clinical trials for SCD, but may one day become additional options for patients.

Hemoglobinopathy Gene Therapies From a Pharmacist’s Perspective

In addition to doctors and patients themselves, pharmacists can also play a critical role in the choice of treatment option for SCD. Alexis Kuhn, PharmD, BCOP, a pediatric oncology pharmacist at Mayo Clinic, spoke about exa-cel and lovo-cel in Tandem 2024’s pharmacy track.¹¹ In addition to SCD, her talk included discussion of exa-cel's use in TDT, another hemoglobinopathy for which the gene therapy was approved by the FDA in January 2024.¹²

In an interview with CGTLive at the conference, Kuhn emphasized that because these exa-cel and lovo-cel are given to patients in a multistep process that involves apheresis, preconditioning, and administration of the gene therapy itself, providers need to be mindful of other medications and therapies the patient may be on during each step of the process, determine whether a hold is necessary, and continuously monitor patients closely. Kuhn also encouraged doctors to work with their clinical pharmacy support if they have it and to integrate this support early and often into their treatment plans for patients.

The Big Picture

Ultimately, choosing the right treatment option for SCD is a careful balancing act that involves input from multiple parties in each case. The risks and benefits of each individual treatment, including the short-term effects, known long-term effects, and potentially unknown long-term effects, all need to be considered carefully.

In June 2024, CGTLive reached out to Mark Walters, MD, a professor in residence for pediatrics at the Sickle Cell Center of Excellence at the University of California, San Francisco, to add his perspective to the views expressed on choosing treatment options for SCD. Walters noted that although doctors and comprehensive healthcare teams will play a principal role in treatment selection for patients who are considering the available gene therapy products, mental health professionals may also be able to assist patients with the decision and provide support during treatment, which can be a mentally taxing process to go through. When asked whether he had a take-home message for the community with regard to World Sickle Cell Day 2024, Walters shared a message from a patient with SCD who received exa-cel successfully.

“My message isn't from me," Walters told CGTLive. "It's actually from a Sickle Cell Warrior who I heard talk about his experience of receiving the exa-cel treatment. His experience was such that he predicts that these kinds of therapies will transform the future of SCD. Specifically, he said that with regard to the life that he has lived, living with pain and all the other problems of SCD—in the next generation he predicted that will be a thing of the past. How exciting would it be to really have an impact on this disorder and to improve people's lives? That's the message I would leave people with and it's a message from a Sickle Cell Warrior who's gone through a curative therapy.”

REFERENCES
1. Ingram VM. A specific chemical difference between the globins of normal human and sickle-cell anæmia hæmoglobin. Nature. 1956;178(4537):792-794. doi: https://doi.org/10.1038/178792a0
2. What is Sickle Cell Disease (SCD)?. Sickle Cell Disease Association of America, Inc. Website. Accessed June 19, 2024. https://www.sicklecelldisease.org/sickle-cell-health-and-disease/types/
3. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. News release. FDA. December 7, 2023. Accessed June 19, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
4. 76th Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting. October 31, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-october-31-2023-meeting-announcement-10312023
5. 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
6. 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
7. Frangoul H. Sickle cell disease: haplo versus gene therapy debate. Presented at: 2024 Tandem Meetings, February 21-24, San Antonio, Texas.
8. FDA approves novel treatment to target abnormality in sickle cell disease. News release. FDA. November 25, 2019. Accessed June 19, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-treatment-target-abnormality-sickle-cell-disease
9. FDA approves crizanlizumab-tmca for sickle cell disease. FDA. November 15, 2019. Accessed June 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizanlizumab-tmca-sickle-cell-disease
10. Sharma A, Sheehan V, Shenoy S. Tandem Thursday breakfast symposium: the evolving paradigm of sickle cell disease management. Presented at: 2024 Tandem Meetings, February 21-24, San Antonio, Texas. Session #S-B1.
11. Kuhn A. Geneie in a bottle: Gene therapy for hemoglobinopathies. Presented at: 2024 Tandem Meetings, February 21-24, San Antonio, Texas.
12. Vertex Announces US FDA Approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia. News release. January 16, 2024. Accessed April 19, 2024. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-casgevytm-exagamglogene