Expert Clinical Network Insights: April 2024

Sickle Cell Disease

MEDICATION INSIGHTS:

Exagamglogene autotemcel (Casgevy ™)
Lovotibeglogene autotemcel (Lyfgenia™)

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The U.S. Food and Drug Administration (FDA) approved exagamglogene autotemcel (Casgevy™) and lovotibeglogene autotemcel (Lyfgenia™) in December 2023 for the treatment of sickle cell disease (SCD) in patients 12 years and older. Exagamglogene autotemcel is the first FDA-approved treatment for SCD to use CRISPR/Cas9 genome editing technology.1 Lovotibeglogene autotemcel is a cell-based gene therapy that uses a lentiviral vector to genetically modify a patient’s blood stem cells to produce HbAT87Q, a type of hemoglobin (Hb) that functions similarly to HbA.1 Both treatments are administered through hematopoietic stem cell transplant as a one-time, single-dose infusion. Prime Therapeutics and Magellan Rx Management (Prime and Magellan Rx) sought insights from key opinion leader(s) (KOL) within our Expert Clinical Network (ECN) who specialize in the treatment of SCD. This month’s newsletter summarizes KOL feedback on these two new gene therapies for SCD.

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Efficacy and safety

The efficacy of exagamglogene autotemcel and lovotibeglogene autotemcel appears to be similar. Both products require the introduction of a gene product into hematopoietic stem cells in the laboratory, and subacute side effects that occur within weeks of administration are similar as well. Fourteen experts on the Institute for Clinical and Economic Review (ICER) committee agreed that there was no efficacy or safety basis to prefer one treatment over the other at this time.2 In terms of long-term clinical benefits, these gene therapies may result in less overall pain and pain treatment, improved survival, and fewer ongoing medical interventions for SCD patients.

In comparing the two products, exagamglogene autotemcel may have a safety advantage since it has not been associated with secondary leukemia, unlike lovotibeglogene autotemcel. Lovotibeglogene autotemcel is packaged in a lentivirus that invades these cells. This approach is associated with rare cases of a delayed onset of leukemia and related conditions. Exagamglogene autotemcel gains access to these cells with electroporation and has not been associated with leukemia to date. Additional information on long-term adverse events, especially related to the lentiviral-related side effects from lovotibeglogene autotemcel, are needed to elucidate the long-term safety profile of each gene therapy.

Patient access and cost

At this time, each treatment is available primarily at centers that are currently participating in or previously participated in clinical trials. The vast majority of gene therapy programs likely are a component of a health system’s larger cellular therapy program bone marrow/stem cell therapies. These programs may participate in the National Marrow Donor Program and may be accredited by the Foundation for the Accreditation of Cellular Therapy (FACT).

In terms of cost-effectiveness in SCD, ICER rated lovotibeglogene autotemcel as incremental or better than the standard of care (SOC), and exagamglogene autotemcel as comparable to or better than the SOC.2 The basis for ICER’s higher rating for lovotibeglogene autotemcel (B+) versus exagamglogene autotemcel (C++) in SCD appears to be based off a slightly greater experience in clinical trials overall, rather than observed outcomes. Exagamglogene autotemcel presents with additional unknown uncertainties, given a more novel mechanism of action and a relatively low number of patients treated to date. Despite these differences, ICER concluded that existing data was insufficient to compare the two. Efficacy and toxicity outcomes for both treatments in SCD to date are relatively similar.