All eyes are on exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel, which have become the first disease-modifying therapies for sickle cell disease (SCD) and beta-thalassemia, a significant achievement for a patient population with debilitating, life-altering diseases that have limited symptomatic and curative treatments currently available. The excitement around exagamglogene autotemcel also stems from the landmark first approval of a CRISPR/Cas9 gene-edited therapy globally, and the approval sets the stage for upcoming approvals in other regions.
Inherited blood disorders, SCD and beta-thalassemia cause severe pain, organ damage and shortened life span. With only a one-time administration, these therapies aim to treat the underlying cause of SDC and transfusion-dependent beta-thalassemia and result in patients being transfusion-independent or vaso-occlusive crises (VOC)-free, with significant improvement in quality of life and physical performance. The enthusiasm for gene therapies in this space is based not only on the potential curative effect but also concerns about the effectiveness of other current treatments, their accessibility and their side effects. In its recent evaluation of SCD treatments, the Institute for Clinical and Economic Review (ICER) considered both treatments to potentially provide a substantial net health benefit compared with standard of care, given the severity of disease and the rate of treatment success and despite uncertainties around durability and harms.
Approval of lovotibeglogene autotemcel results from more than a decade of work in gene therapy by bluebird bio and represents the company’s third ex vivo gene therapy approved by the FDA for a rare genetic disease and second FDA approval for an inherited hemoglobin disorder. Lovotibeglogene autotemcel is considered the most deeply studied gene therapy in development for these diseases, and ICER rated lovotibeglogene autotemcel, compared with standard of care, as “Incremental or Better.”
Regulatory approvals and submissions were based on data from the pivotal phase 1/2 HGB-206, which showed the following:
In addition, the following phase 3 trial is ongoing:
Participants in the HGB-205, 206 and 210 trials have also been asked to continue in LTF-307, a long-term follow-up trial of up to 13 years for continued safety and efficacy evaluations.
For patients with SCD
For patients with SCD
For patients ≥12 years old with SCD with recurrent VOCs
Actual and expected launch:
For patients with SCD or transfusion-dependent beta-thalassemia
How will lovotibeglogene autotemcel impact the market for SCD and beta-thalassemia?
Challenging conditions to treat, SCD and beta-thalassemia have had few new treatments become available, with the approval of ENDARI ® (Emmaus Medical Inc) in 2017 representing the first in 20 years.
What gaps in treatment does lovotibeglogene autotemcel fill?
Although some medications are available to help manage symptoms, many patients with SCD and transfusion-dependent beta-thalassemia require lifelong monthly blood transfusions, and therefore frequent hospital visits, to prevent extreme pain crises, minimize organ damage, improve quality of life and provide the ability to complete daily tasks. However, regular transfusions require long-term chelation therapy to avoid serious health complications such as heart and liver disease that result from iron overload. Few other treatment options except analgesia have been available. Although HSCT is a potentially curative treatment for SCD, many people do not have a compatible sibling-matched donor, graft-versus-host disease (GVHD) is a serious risk and the risks of HSCT increase with age. Therefore, a significant unmet need for disease-modifying drugs and curative therapies still exists.
What hurdles might it need to overcome to reach blockbuster status?
For SCD and transfusion-dependent beta-thalassemia, multidisciplinary care is required, but this is often hampered by inadequate physician education as well as poor care coordination. ICER reported that additional factors that could represent barriers to access include systemic racism, poverty and insurance systems that have not been designed to coordinate coverage for patients with chronic conditions affecting multiple systems. Furthermore, generalizability of the reported efficacy and safety results outside of the clinical trial setting remains unknown.
Exagamglogene autotemcel will likely be restricted to patients with severe disease initially, the infrastructure for stem cell transplantation (i.e., authorized treatment centers [ATCs]) might not be broadly available at first and the therapy might be cost-prohibitive for many who are eligible. Another concern is the loss of fertility because this therapy will require pre-treatment ablative therapy, and coverage of oocyte/sperm cryopreservation is often limited, which could also limit uptake.
Lovotibeglogene autotemcel uptake could be hampered by the black box label for hematologic malignancy, which requires lifelong monitoring, as well as the high cost, which has been estimated to be higher at launch than that of exagamglogene autotemcel. Treatment access is also limited to Qualified Treatment Centers (QTCs), which receive specialized training to administer complex gene therapies.