NEW YORK – Bluebird Bio's and Vertex Pharmaceuticals' competing one-time and potentially curative gene therapies for sickle cell disease both sharply decreased painful vaso-occlusive crises (VOCs) in patients, researchers reported Monday at the American Society of Hematology's annual meeting in San Diego.
The data comes on the heels of the US Food and Drug Administration's simultaneous approval last Friday of Bluebird Bio's Lyfgenia (lovotibeglogene autotemcel), a gene therapy that is delivered using lentiviral vectors, and Vertex Pharmaceuticals and CRISPR Therapeutics' Casgevy (exagamglogene autotemcel), the first drug that uses CRISPR gene-editing technology to reach the market.
Now, as the companies set out to differentiate their products, the most immediate distinction is price. Bluebird Bio, which is preparing to launch Lyfgenia in early 2024, has priced the gene therapy at $3.1 million. Vertex, meanwhile, has priced Casgevy at $2.2 million.
In terms of efficacy, data presented at ASH showed that Lyfgenia and Casgevy can significantly reduce VOCs and improve SCD patients' outcomes over more than a year.
Investigators presented long-term efficacy and safety data on 47 SCD patients who suffered from recurrent, severe VOCs or had a history of overt stroke and received Bluebird Bio's Lyfgenia in the Phase I/II HGB-206 trial or Phase III HGB-210 trial. Patients in the analysis were followed for a median of 35.5 months and for as long as 61 months.
Hemoglobin, the protein that carries oxygen, is dysfunctional in patients with SCD. Bluebird Bio's gene therapy involves genetically modifying patients' own hematopoietic stem and progenitor cells (HSPC) ex vivo so that they carry a modified beta-globin gene that produces an anti-sticking, normally functioning hemoglobin called HbAT87Q. These modified cells are then infused back into the patient.
A single infusion of this treatment, investigators at ASH reported, led to significant reductions in VOCs, sustained decreases in pain intensity, and increases in levels of hemoglobin. "We couldn't really ask for too much better from this initial assessment," Julie Kanter, codirector of the Lifespan Comprehensive Sickle Cell Center and a professor in the hematology and oncology division at the University of Alabama at Birmingham, said during a press conference Saturday. "We're really talking about highly durable therapy."
Of 34 patients who had at least four VOCs in the two years prior to the clinical trial, nearly 90 percent reported complete resolution of such events six to 18 months after infusion. Of the few patients who continued to experience VOCs after treatment, all reported a reduction of at least 50 percent compared to baseline. None of the four patients who had a history of overt stroke nor the two patients with a history of silent stroke experienced another stroke after treatment.
Patients' median total hemoglobin levels increased from 8.7 grams per deciliter at baseline to 11.8 grams per deciliter at their last visit. Patients had sustained HbAT87Q production, with all maintaining stable levels from six months to the most recent follow-up visit.
Patients also reported improved health-related quality of life in terms of decreased pain intensity, pain interference, and fatigue for up to 48 months post-infusion, according to an analysis of mean scores of the Patient-Reported Outcomes Measurement Information System-57.
Also at the meeting, researchers presented new data from a Phase III trial of Vertex's gene-editing therapy Casgevy, which, in addition to its US approval, has also received conditional marketing authorization in the UK. Casgevy is designed to increase production of fetal hemoglobin by using CRISPR-Cas9 to modify the BCL11A gene in patients' own CD34-positive HSPCs ex vivo.
The analysis involved 44 SCD patients who had at least two VOCs annually in the two years prior to receiving Casgevy in the ongoing CLIMB SCD-121 study. Of the 30 patients who had at least 16 months of follow-up data, 29 were free of VOCs and all were free of hospitalizations due to VOCs for at least one year post-treatment. Prior to treatment, these patients had an average of 3.9 VOCs per year and 2.7 hospitalizations from severe VOCs per year.
The one patient who was not free of VOCs had complex comorbidities and a history of chronic pain, said Haydar Frangoul, medical director of pediatric hematology/oncology for the Sarah Cannon Pediatric Transplant and Cellular Therapy Program at TriStar Centennial in Tennessee, at the meeting. He noted that the patient hadn't been hospitalized for VOCs as of the last follow-up visit, which was more than two years after treatment.
The average hemoglobin level among Casgevy-treated patients in the trial was 12.1 grams per deciliter at three months post-treatment, which was sustained at 11 grams per deciliter or more from month six onward. The proportion of edited BCL11A genes also remained stable over time in bone marrow and peripheral blood, suggesting that the effects of the gene editing are durable.
"There was rapid, robust, and durable increase in total hemoglobin to normal or near-normal levels," Frangoul said. "Exa-cel has the potential to provide a one-time functional cure to patients with sickle cell disease."
All patients that received Casgevy reported at least one adverse event and around 95 percent had an adverse event of grade 3 or higher. About 45.5 percent of patients reported at least one serious adverse event, though none were deemed related to Casgevy. The most common adverse events were nausea and stomatitis.
There were no malignancies detected in the trial, according to Frangoul. One patient died due to respiratory failure caused by COVID-19, which was not deemed related to Casgevy.
Similarly, in the Lyfgenia trial, all patients also experienced at least one adverse event and about 94 percent had an adverse event of grade 3 or higher after infusion, most commonly stomatitis and thrombocytopenia. Fifty-five percent of patients experienced serious adverse events, mostly chronic pain or acute exacerbation of chronic pain, chronic neuropathic pain, and chronic pain associated with anxiety.
Unlike with Casgevy, however, the FDA added a black box warning to Lyfgenia's label cautioning that patients should be monitored lifelong for hematologic malignancies, which have been observed in some patients on the treatment.
There were no reports of veno-occlusive liver disease, graft failure, replication-competent lentivirus, or vector-mediated insertional oncogenesis with Lyfgenia. One patient with two alpha-globin gene deletions was diagnosed with myelodysplastic syndrome 30 months after the infusion. This patient is currently doing well and has stable hemoglobin, Kanter said. One patient died, but investigators attributed this to the fact that the patient had significant baseline sickle cell-related cardiopulmonary disease and not to Lyfgenia.
"Many of these individuals come into this therapy with significant disease and organ complications," Kanter said. "This will be something we really need to follow long term, to understand how much this therapy can reverse or stabilize these complications."