2023 World Sickle Cell Day: The Home Stretch for Gene Therapy in SCD?


More work remains to be done to improve accessibility to populations and countries that have the highest unmet need with SCD treatment.

On this year’s World Sickle Cell Day, gene and cell therapies for treating sickle cell disease (SCD) are closer to the market than ever. CGTLive is taking a look at the novel therapies closest to market for the disease and their progress and challenges, with insights from companies developing these therapies and clinicians.

While disease-modifying therapies are available to patients with SCD, these represent a lifelong cost and treatment burden of standard of care (SOC) therapies, which includes supportive care, hydroxyurea, and blood transfusions in some patients. Gene and cell therapies represent a 1-time, potentially curative mode of treatment for these patients.

The closest gene therapy to market for treating SCD is Vertex Pharmaceuticals’ exagamglogene autotemcel (exa-cel), the biologics license applications (BLA) for which the FDA recently accepted for the indications of SCD and transfusion-dependent β-thalassemia (TDT). For SCD, FDA granted Priority Review with a Prescription Drug User Fee Act (PDUFA) target action date of December 8, 2023.1 “SCD is a serious and lifelong inherited blood disease, characterized by unpredictable, and debilitating pain crises called VOCs, which can result in organ damage. People with SCD have a higher mortality rate than the general population and, despite improvements in the standard of care, that has not changed over time,” a spokesperson from Vertex told CGTLive.“ There is a significant unmet need for new transformative therapies in SCD that adequately address the challenges of living with this disease.

The FDA accepted the BLA based on supporting data from the phase 3 CLIMB-121 (NCT03745287) trial and the long-term follow-up study CLIMB-131 (NCT04208529) that also includes patients with TDT. The most recent data on exa-cel, presented at the European Hematology Association (EHA) 2023 Congress, showed that out of 17 patients evaluable patients, 16 (94.1%) achieved the primary endpoint of freedom from vaso-occlusive crises (VOCs) for at least 12 consecutive months (95% CI [71.3-99.9]; P = .0001).2 Patients had a mean duration of 18.7 months VOC-free, ranging up to36.5 months. All patients achieved the key secondary endpoint of being free from hospitalizations related to VOCs for at least 12 consecutive months (95% CI: 80.5%, 100.0%; P <.0001). Fetal hemoglobin of around 30-40% was maintained throughout the study and patients also had clinically significant improvements in patient-reported outcomes. Exa-cel is a CRISPR-edited gene therapy and could be the first of its kind to be FDA-approved.

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“We deliberately chose CRISPR/Cas9 gene editing as our approach specifically because of its ability to deliver precise, permanent edits at a single desired location, without evidence of off-target effects. And we are very pleased with the strength of our data for exa-cel – efficacy, safety and durability of response – and we believe the data presented at EHA established a differentiated profile in SCD,” Vertex said.

Right behind exa-cel is bluebird bio’s lovotibeglogene autotemcel (lovo-cel), the BLA for which was submitted in April 2023.3 The BLA submission and request for priority review is based on data from 36 patientsin the ongoing phase 1/2 HGB-206 clinical trial (NCT02140554), the most recent data from which showed that 96% of patients treated in Group C experienced complete resolution of severe VOcs through 24 months of follow-up. Serious AEs related to lovo-cel included a case of grade 2 febrile neutropenia and 2 cases of development of persistent, non-transfusion-dependent anemia in pediatric patients; the latter AE prompted a clinical hold by the FDA in late 2021. Other deaths previously occurred that were not related to the gene therapy but possibly related to myeloablative conditioning.4

“It is indeed a very exciting time for the field of sickle cell disease. We are looking forward to not just 1 but 2 potential gene therapy approvals this year. These autologous therapies are surely going to remove a lot of barriers and allow many more patients to pursue them,” Akshay Sharma, MBBS, assistant member, bone marrow transplant department, St. Jude Children’s Research Hospital, told CGTLive.

Last month, an Institute for Clinical and Economic Review draft report on the 2 therapies reported that they were cost-effective up to $1.93 million when compared to SOC therapies.5 ICER took into account complications from SCD, effects on income and life expectancy, caregiver costs, and other factors over a lifetime. Looking solely at benefits within the healthcare system, ICER determined gene therapy to be cost-effective between $1.58 million to $1.72 million, with the range increasing to $1.79 million to $1.93 million when considering broader benefits to society.

After reviewing the data available from the pivotal studies, ICER rated lovo-cel with a B+, stating that it provides at least an incremental net benefit compared with SOC and may provide a substantial net health benefit. ICER rated exa-cel with a C++, lower than lovo-cel given the smaller sample size and uncertainty with the newer CRISPR editing technique compared to lentiviral gene therapy, stating that compared with SOC, treatment with exa-cel may be comparable, result in incremental net benefit, or result in substantial net benefit. ICER also noted that there is insufficient evidence to compare the 2 gene therapies to each other.

While the field is closer than ever to an approval, much more work needs to be done to reduce cost and improve accessibility, especially considering that countries with the highest rates of SCD are in Africa.

"The elephant in the room – the cost barrier – needs to be addressed first. These therapies, costing millions of dollars, are going to be out of the reach of most Americans, let alone people in Africa, India and South America who need these treatments the most. We must advocate for equitable access to these novel therapies if we truly want to address sickle cell disease,” Sharma said.

1. FDA accepts Biologics License Applications for exagamglogeneautotemcel (exa-cel) for severe sickle cell disease and transfusion-dependent Beta thalassemia. News release. Vertex Pharmaceuticals. June 8, 2023. Accessed June 19, 2023.https://investors.vrtx.com/news-releases/news-release-details/fda-accepts-biologics-license-applications-exagamglogene
2. Positive Results From Pivotal Trials of exa-cel for Transfusion-Dependent Beta Thalassemia and Severe Sickle Cell Disease Presented at the 2023 Annual European Hematology Association (EHA) Congress. News release. Vertex Pharmaceuticals. June 9, 2023. Accessed June 19, 2023. https://investors.vrtx.com/news-releases/news-release-details/positive-results-pivotal-trials-exa-cel-transfusion-dependent
3. bluebird bio Submits Biologics License Application (BLA) to FDA for lovotibeglogeneautotemcel (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 June 19, 2023. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-submits-biologics-license-application-bla-fda-0
4. Walters MC, Thompson AA, Kwiatkowski JL, et al. Lovo-cel (bb1111) Gene Therapy for Sickle Cell Disease: Updated Clinical Results and Investigations into Two Cases of Anemia from Group C of the Phase 1/2 HGB-206 Study. Presented at: ASH 2022 Annual Meeting. December 10-12, 2022; New Orleans, LA. Abstract 11.
5. Gene therapies for sickle cell disease. Draft Evidence Report. ICER. April 12, 2023. Accessed June 19, 2023. https://icer.org/wp-content/uploads/2023/04/SCD_FOR-PUBLICATION.pdf
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Caspian Oliai, MD, MS, the medical director of the UCLA Bone Marrow Transplantation Stem Cell Processing Center
Genovefa (Zenia) Papanicolaou, MD, an infectious diseases specialist at Memorial Sloan Kettering Cancer Center
Akshay Sharma, MBBS, a bone marrow transplant physician at St. Jude Children’s Research Hospital
John DiPersio, MD, PhD, the director of the Center for Gene and Cellular Immunotherapy at Washington University School of Medicine
Aude Chapuis, MD, an associate professor in the Translational Science and Therapeutics Division at Fred Hutch Cancer Center
Amar Kelkar, MD, a stem cell transplantation physician at the Dana-Farber Cancer Institute
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