SAN DIEGO — A newly approved gene therapy product for sickle cell disease, lovotibeglogene autotemcel (lovo-cel, marketed as Lyfgenia), led to durable disease remissions for up to 5 years and almost complete elimination of dangerous and debilitating vaso-occlusive events, according to results of a long-term follow-up study.
More specifically, a single infusion of lovo-cel led to complete resolution of vaso-occlusive events in 88% of patients, with 94% achieving complete resolution of severe events. All 10 adolescents in the study achieved complete resolution of vaso-occlusive events. Most patients remained free of vaso-occlusive events at their last follow-up.
"This is a one-time, truly transformative treatment with lovo-cel," lead author Julie Kanter, MD, director of the adult sickle cell clinic at the University of Alabama in Birmingham, said in a media briefing here at the American Society of Hematology (ASH) 2023 annual meeting. The gene therapy can essentially eliminate vaso-occlusive events in patients with sickle cell disease and lead to normal hemoglobin levels, Kanter added.
For "anybody who has rounded on the inpatient floor and taken care of adolescents admitted with a pain crisis multiple times a year," seeing these results "is so compelling," commented Sarah O'Brien, MD, a pediatric hematologist at Nationwide Children's Hospital in Columbus, Ohio, who moderated the briefing but was not involved in the study.
One and Done
Sickle cell disease, a debilitating and potentially life-threatening blood disorder, affects an estimated 100,000 people in the US.
People with the condition have a mutation in hemoglobin, which causes red blood cells to develop an abnormal sickle shape. These sickled cells block the flow of blood, ultimately depriving tissues of oxygen and leading to organ damage and severe pain, known as vaso-occlusive events.
On December 8, the US Food and Drug Administration (FDA) approved lovo-cel for patients aged 12 years or older with severe sickle cell disease alongside another gene-editing therapy called exagamglogene autotemcel or exa-cel (Casgevy, Vertex Pharmaceuticals and Crispr Therapeutics). The two therapies use different gene-editing approaches — exa-cel is the first to use the gene-editing tool CRISPR while lovo-cel uses a lentiviral vector.
Both are one-time, single-dose cell-based gene therapies.
With lovo-cel, patients first undergo a transfusion regimen and myeloablative conditioning with busulfan to collect cells that can then be genetically modified. A patient's harvested cells are modified with an anti-sickling version of hemoglobin A, HbAT87Q. Patients then receive an infusion of these edited cells and remain in the hospital during engraftment and reconstitution.
Kanter presented long-term follow-up data on 47 patients enrolled in phase 1/2 and phase 3 studies of lovo-cel.
All patients had stable HbAT87Q levels from 6 months to their last follow-up at a median of 35.5 months.
Most patients achieved a durable globin response through their final follow-up visit.
Among the 34 evaluable patients, 88% had complete resolution of vaso-occlusive events 6 to 18 months after their infusion, including all 10 adolescent patients. Almost all patients (94%) achieved complete resolution of serious vaso-occlusive events.
In the few patients who experienced posttreatment vaso-occlusive events, these individuals still achieved major reductions in hospital admissions and hospital days.
Among 20 patients followed for at least 3 years, more than half had clinically meaningful improvements in pain intensity, pain interference, and fatigue.
Most treatment-related adverse events occurred within 1 year of lovo-cel infusions and were primarily related to busulfan conditioning. No cases of veno-occlusive liver disease, graft failure, or graft vs host disease occurred, and patients did not have complications related to the viral vector. No patients who had a history of stroke prior to lovo-cel therapy experienced a post-therapy stroke.
One patient died at baseline from significant cardiopulmonary disease related to sickle cell disease, but the death was considered unrelated to lovo-cel therapy.
To see a one-time treatment that essentially eradicates vaso-occlusive events is "really unparalleled," said Steven Pipe, MD, from the University of Michigan School of Medicine in Ann Arbor, who presented data on a different study at the briefing.
However, Kanter noted, "it's important to highlight that many of these individuals come into this therapy with significant disease and end-organ complications, and this will be something we will really need to follow long-term to understand how much this therapy can stabilize or reverse these complications."
The studies were funded by bluebird bio. Kanter disclosed honoraria from the company and consulting/advising activities and receipt of research funding from multiple other entities. O'Brien disclosed consultancy for AstraZeneca, honoraria from Pharmacosmos, and research funding from Bristol Myers Squibb. Pipe disclosed consulting activities from multiple companies, not including bluebird bio.
Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.
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