A new frontier: FDA approvals for gene therapy in sickle cell disease

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On December 8, 2023, the US Food and Drug Administration (FDA) approved two autologous gene therapy products, Lyfgenia (lovotibeglogene autotemcel by bluebird bio) and Casgevy (exagamglogene autotemcel by Vertex Pharmaceuticals), for the treatment of individuals with sickle cell disease (SCD) ages 12 years and older with recurrent vaso-occlusive events (VOEs).¹ Lyfgenia utilizes a lentiviral vector (LVV)-based strategy to transduce autologous hematopoietic stem cells (HSCs) with a LVV encoding β^A-T87Q, an anti-sickling globin. Casgevy, the first ever FDA-approved clustered regularly interspaced short palindromic repeats (CRISPR)-based gene therapy product, utilizes CRISPR-Cas9 editing at the erythroid-specific enhancer of the BCL11A gene to enhance fetal hemoglobin (HbF) production. These approvals are the culmination of decades of basic science research, 5–10 years of clinical trial experience, and the brave, altruistic decision by over 50 individuals with SCD to advance science for the 100,000 Americans living with SCD and the millions more worldwide.

As the first discovered monogenic disease to be characterized at the molecular level, genetic correction of SCD has been pursued for decades.² Early work focused on viral based β-globin (or β-like) gene addition strategies, which became feasible with viral vectors based upon HIV1³ and became the first gene therapy product investigated in individuals with SCD (ClinicalTrials.gov: NCT02140554). The approval of Lyfgenia is the result of a US study that evolved over 3 cohorts resulting, ultimately, in sufficiently high gene expression for disease symptom amelioration. The changes implemented throughout this study were shared widely and advanced scientific understanding of protocol-specific requirements for gene therapy applications in SCD. These included the need for a pre-mobilization transfusion regimen, targeted ablative busulfan dosing, improved drug product target yield through the use of plerixafor-mobilized HSCs, and improved drug product processing and manufacturing through the use of transduction enhancers and optimal HSC culture.^4,5 When two individuals from the initial cohort developed acute myeloid leukemia several years after ineffective gene therapy, the field paused to investigate insertional oncogenesis, though this was later ruled out in both cases, and to better understand the unique features of SCD that may have contributed.^6,7 The FDA label for Lyfgenia therefore includes a warning label for the risk of hematologic malignancy, though this risk is not isolated to Lyfgenia, as it is a known risk of autologous transplantation in general and can occur after allogeneic transplantation in SCD. Current data suggest that pre-existing pre-malignant clones expand during the stress of switching from homeostatic to regenerative hematopoiesis after failed allogeneic transplantation or suboptimal gene therapy.⁸ These two individuals gave their lives for a clinical trial that could not guarantee their own benefit, and they leave behind a legacy that is sure to benefit countless lives of people with SCD. Pre-existing clonal hematopoiesis in individuals with SCD is now a major focus of sickle cell investigators,⁹ full myeloid chimerism is now the goal after allogeneic HSC transplant,¹⁰ and inadequate disease correction is not acceptable after gene therapy.⁸

The discovery of CRISPR-Cas9 technology revolutionized what is possible for genetic therapy and initially focused on maximizing the protective effects of HbF in individuals with hemoglobin disorders.¹¹ Whereas the risk of insertional oncogenesis is eliminated using CRISPR editing, the safety of CRISPR technology is not guaranteed. Indeed, the electroporation process used in CRISPR-mediated editing has toxicity to the cellular product that will take many years to assess. Furthermore, off-target effects must be considered, some of which can be predicted by common genetic variants. However, experts and the FDA conveyed agreement with the Vertex investigation of specific off-target risks associated with Casgevy¹² and have made recommendations to monitor for off-target effects during long-term follow-up much as has been done for integrating vectors through insertion site analysis. Overall, the Casgevy guide RNA has high fidelity for its target site, though off-target editing in CD34⁺ cells due to uncommon genetic variants cannot be ruled out and is therefore listed on the FDA label under warnings and precautions.¹³

The FDA labels for both Casgevy and Lyfgenia are similarly broad; treatment is intended for individuals with SCD 12 years and older with recurrent vaso-occlusive crises (Casgevy) or VOEs (Lyfgenia).^14,15 There are no contraindications for either product despite knowing that two individuals with two alpha-globin gene deletions after Lyfgenia experienced erythroid dysplasia that may result from globin chain imbalance and that both trials had clear, specific, and narrow inclusionary and exclusionary criteria. Both trials included individuals who met a pre-specified definition of recurrent VOE in the 2 years preceding enrollment and excluded individuals, for example, with a matched sibling donor, history of stroke, history of abnormal TCD, untreated Moyamoya disease, advanced liver disease, and chronic rather than acute pain. Primary endpoints for both were reduction in VOEs, an easily measurable endpoint that could demonstrate efficacy to the FDA. Both Lyfgenia and Casgevy reported that 94% of participants had complete resolution of VOE as defined by each protocol during their assessment period. Table 1 lists Lyfgenia and Casgevy patient characteristics, drug product information, and reported outcomes.

Table 1.

Patient characteristics, drug product information, and reported outcomes after Lyfgenia and Casgevy

	Lyfgenia	Casgevy
Patient characteristics
Patients treated, n (%)	36 (100)	44 (100)
Patients evaluable for efficacy outcomes, n (%)	32 (89)	31 (70)
β-Globin genotype, n (%)
βSβS	36 (100)	40 (91)
βSβ0	0 (0)	3 (7)
βSβ+	0 (0)	1 (2)
2 α-globin gene deletion, n (%)	2 (6)	2 (5)
Age in years, median (min, max)	24 (12, 38)	20 (12, 34)
Age ≥12 years and ≤17 years, n (%)	8 (22)	12 (27)
History of stroke,a n (%)	5 (14%)	NR
No. of mobilization cycles, n (min, max)	2 (1,4)	2 (1,6)
Time to neutrophil engraftment,b median days (min, max)	20 (12, 35)	27 (15, 40)
Time to platelet engraftment,c median days (min, max)	35 (19, 136)	35 (23, 126)
Drug product characteristics
VCN, copies/diploid genome, median (min, max)	4.0 (2.3, 6.6)	N/A
Percentage of allelic editing in bone marrow, mean (SD)	N/A	88.5 (4.6)d
Outcomes
Severe VOE complete resolution, n/N (%) [CI]	30/32 (94%) [79, 99]e	29/31 (94%) [78,100]f
Globin response,g n/N (%)	31/36 (86)	NR
Proportion of total hemoglobin comprised by HbF (%), median (min, max)	N/A	42.2 (33.3, 49.1)h
Total hemoglobin gm/dL, median (min, max)	11.8 (8.4–15.0)	13.0 (10.5, 17.3)i
Duration of follow-up in months, median (min, max)	38 (12, 61)	19 (0.8, 48)
Notes
Lyfgenia	4/32 patients who achieved VOE-CRe experienced VOEs after primary efficacy endpoint; 17/35 (49%) were prescribed opiates for sickle-related and non-sickle-related pain up to 24 months post-infusion; all 5 individuals with prior stroke remain transfusion independent without recurrent stroke at 44–60 months
Casgevy	6 (10%) patients were unable to receive Casgevy therapy due to not achieving the minimum dose after mobilization; one VF12f responder, after initially achieving a VF12 response, experienced an acute pain episode meeting the definition of a severe VOC at month 22.8 requiring a 5 day hospitalization; this patient was reported to have a parvovirus B19 infection at the time

CI, confidence interval; CR, complete response; HbF, fetal hemoglobin; VCN, vector copy number; VF, vaso-occlusive free; VOC, vaso-occlusive crisis; VOE, vaso-occlusive event; NR, not reported.

^aPatients with a history of stroke were included in early inclusion criteria.

^bDefined as the first day of 3 consecutive measurement of absolute neutrophil count ≥500 cells/μL on 3 different days.

^cDefined as the first day of 3 consecutive measurement of unsupported (no platelet transfusion in last 7 days) platelet count ≥50,000/μL on 3 different days.

^dn = 16 at month 24.

^eDefined as elimination of severe VOE requiring hospital admission or multiple visits to an emergency department and receiving intravenous medications or priapism requiring any level of medical attention between 6 and 18 months post-infusion with Lyfgenia.

^fDefined as no protocol-defined severe VOCs for at least 12 months within the first 24 months after Casgevy infusion.

^gDefined as meeting the following criteria for a continuous period of ≥6 months: weighted average HbA^T87Q ≥30% non-transfused total Hb and weighted average increase in non-transfused total Hb of ≥3 g/dL vs. baseline total Hb or weighted average non-transfused total Hb of ≥10 g/dL.

^hProportion of total Hb comprised by HbF (%) at month 24, n = 17.

ⁱn = 17 at month 24.

In the setting of a broad FDA label indication, the sickle cell community needs the development of well-defined guidance from experts to appropriately use these products in clinical practice. Questions remain about what is required to be a SCD center of excellence in gene therapy. The definition of a VOE is not specified in either label; therefore, patients who may have been ineligible for the trials now potentially have access to this therapy, yet there are no data to support its use in these circumstances. Many patient-specific, disease-specific, and access-specific questions are left unanswered despite FDA approval (Table 2). The majority of SCD comprehensive care centers have not participated in gene therapy clinical trials, which are complex, heavily regulated, and uniform. Consensus recommendations based on SCD expert opinion are therefore also needed to create a uniform care model that can be utilized across gene therapy centers. The FDA requirement of 15 years of follow-up after treatment mandates an accessible registry of outcome data that is essential to understand the long-term effects of these therapies. Until there is long-term, organ-specific follow-up, gene therapy should be considered transformative, not curative. Patients should continue to receive high-quality comprehensive care and maximize the use of disease-modifying therapies to improve health outcomes, quality of life, and survival.

Table 2.

Unanswered questions despite FDA approval of Lygenia and Casgevy

Patient characteristics

•Do results apply to individuals with HbSC disease? •What are the outcomes for individuals age >38 years? •Is Casgevy equally effective in individuals with baseline HbF >15%? •What is the appropriateness of therapy for individuals with a remote history of VOE that are currently doing well on disease-modifying therapy? •Should bone marrow evaluations or peripheral blood next-generation sequencing be performed on every patient before gene therapy to investigate pre-existing myeloid malignancy features? If so, what threshold would exclude a participant from therapy? •Does Casgevy pose any risks to patients with 2 or more α-globin gene deletions? •Should patients with a matched sibling donor be offered gene therapy?

Disease pathology

•What level of HbF and/or HbAT87Q is protective for primary and secondary stroke prevention? •What are the long-term organ specific effects (i.e., brain, lungs, heart, kidney, bone health) after gene therapy? •What happens to pain after gene therapy? Are patients able to wean pharmacologic therapies used for pain management, and if so, what is the expected time course? •What changes, if any, are there to the underlying thrombotic risk posed by SCD?

Access and logistics

•Will patients be able to afford the cost for drug product and the associated care? •How much will insurance cover? •Will patients have access to a qualified treatment center in their state? •Will patients be able to cross state lines to access a qualified treatment center and have it covered by insurance? •The majority of SCD centers did not participate in a clinical trial for gene therapy. How will these centers acquire the skills and resources necessary to provide these therapies? •Will patients have access to fertility preservation and cryopreservation? •Will patients have access and/or financial support to undergo fertility care in the future? •Will patients have access to the mental health resources needed before and after gene therapy? •How will patients continue to receive optimal care if they move states or out of the county in the 15 year follow-up period?

HbF, fetal hemoglobin; SCD, sickle cell disease; VOE, vaso-occlusive event.

Despite therapeutic success, the necessary infrastructure, resources, and cost may continue to render gene therapy approaches largely inaccessible. Only a fraction of patients will benefit and only in high-income countries that carry a minority of the world’s SCD burden. Both Vertex and bluebird bio project 40–50 authorized treatment centers in the US to treat thousands of patients. Even in a high-resource country such as the US, large resource gaps exist among national sickle cell centers.¹⁶ It is unlikely that thousands of patients could be safely treated with these products within the foreseeable future; therefore, efforts to close these gaps are required. SCD comprehensive care centers should be able to offer all FDA-approved therapies, which necessitates having the resources required for a patient to safely undergo gene therapy. In doing so, all patients with SCD will benefit, not merely the few at a given SCD center who undergo gene therapy. Cost, too, will be an issue for successfully deploying these therapies (currently priced at $3.1 and $2.2 million US dollars for Lyfgenia and Casgevy, respectively, not inclusive of the supportive care costs). SCD experts, advocacy groups, hospitals, and payers will need to navigate the financial terrain while simultaneously evaluating alternative approaches to developing and deploying genetic therapies that can reach more patients.¹⁷ One-time high-cost therapies can be cost effective over the lifetime of an individual with a chronic disease such as SCD. The adolescent results, in particular, confirm what is known in allogeneic transplant: that younger patients do better than adults; therefore, we now have the chance to truly change the lives of many young individuals with SCD given the proper resources and cost model.

Over 50 individuals with SCD risked their lives, health, fertility, and time to join two pivotal clinical trials that have now led to the first FDA-approved gene therapies for SCD. The results from their participation have set a high bar for therapeutic efficacy after gene therapy in this disease. The FDA approval, however, is merely a milestone in the advancement of gene therapy for SCD. The work to improve access, decrease adverse events, and reach more lives continues through research of alternative strategies, improved mobilization, elimination of myeloablative conditioning, and, ultimately, in vivo delivery. Scientific advances carried out by brave patients have brought a new frontier of hope for patients and families. Their sacrifices and scientific contributions are indisputable and pave the way for continued, groundbreaking advancements for the treatment of SCD.