SAN DIEGO – The number of painful vaso-occlusive events (VOEs) a patient with sickle cell disease has experienced before receiving Bluebird Bio's Lyfgenia (lovotibeglogene autotemcel) is associated with the likelihood that the gene therapy will rid them completely of VOEs, researchers reported this weekend.
Researchers presented their findings on early predictors of long-term clinical response to Lyfgenia during a presentation of updated data from the Phase I/II HGB-206 trial, the Phase III HGB-210 trial, and a long-term extension study of the gene therapy at the American Society of Hematology's annual meeting. The analysis focused on patients who received Lyfgenia within clinical trials, in which the gene therapy was produced using the process for stem cell manufacturing that Bluebird currently uses.
VOEs per year at baseline are a known marker of disease severity, Stacey Rifkin-Zenenberg, a pediatric hematologist/oncologist at Hackensack University Medical Center in New Jersey, said during a session on gene therapies for hemoglobinopathies on Sunday. But while patients with fewer VOEs before treatment tended to fare better after receiving the gene therapy, "regardless of baseline VOEs, all patients had clinical benefit," she added.
The US Food and Drug Administration approved Lyfgenia as a treatment for sickle cell patients with a history of VOEs in late 2023. Lyfgenia and its primary competitor Casgevy (exagamglogene autotemcel), developed by Vertex Pharmaceuticals and CRISPR Therapeutics, were simultaneously approved and became the first sickle cell gene therapies to reach the US market.
Lyfgenia, which aims to reduce or even eliminate VOEs for sickle cell patients, is a one-time infusion created from patients' own hematopoietic stem and progenitor cells. These cells are extracted and genetically modified ex vivo, using lentiviral vectors to deliver a functional copy of a modified beta-globin gene designed to produce a type of anti-sickling hemoglobin, HbAT87Q. Bluebird has said HbAT87Q functions similarly to normal adult hemoglobin, which is the protein that's abnormal in sickle cell disease, a rare and inherited blood disorder.
Thirty-three of 38 patients in the clinical trials, or 86.8 percent, were free of VOEs between six and 18 months post-treatment, and 36 patients, or 94.7 percent, were free of severe VOEs during the same period. The majority of these patients remained free of VOEs through their last follow-up, at a median of 47.7 months, or nearly four years.
Whether a patient had a complete resolution of VOEs was associated with the baseline number of annualized VOEs they experienced before treatment, the researchers found. In eight patients who had more than 10 VOEs per year before treatment with Lyfgenia, only half achieved complete resolution of VOEs after gene therapy, compared to 29 of 30 patients who had experienced fewer than 10 VOEs at baseline.
Even among patients for whom the gene therapy did not eliminate VOEs, it did lead to a stark reduction in their number, Rifkin-Zenenberg said. In 11 patients who had VOEs after six months of treatment, all patients experienced, on average, an 84 percent reduction in annualized VOEs, with seven participants having more than a 90 percent reduction.
"Even though they had defined VOEs post-infusion, they still had a significant reduction in annualized VOEs, showing a transformative benefit for even these patients," she said. There may be confounding clinical factors that impact the occurrence of VOEs after treatment, such as baseline disease severity, researchers noted.
In a post hoc, exploratory analysis, researchers tested whether measurements of various pharmacodynamic factors could predict whether patients would experience a complete resolution of VOEs. They found that patients with at least 30 percent of peripheral blood globins that were HbAT87Q by six months post-treatment were more likely to achieve that outcome.
Meanwhile, they also found that assays that detect the percent of lentiviral vector (LVV) transduced cells in the gene therapy product could predict HbAT87Q expression, suggesting such testing could indicate the likelihood of patients experiencing durable clinical benefits.
"Of note, [measuring the percent of LVV transduced cells] is even more predictive than the in vitro anti-sickling assay that is the functional potency assay required by the FDA," Rifkin-Zenenberg said.
The median percent of LVV transduced cells in the gene therapy product was 83 percent for patients in the clinical trials but ranged from 63 percent to 93 percent. This corresponded to a median 48 percent peripheral blood globins that were HbAT87Q.
As a commercial product, Lyfgenia must meet a minimum threshold of 60 percent LVV transduced cells.
"We can predict the benefit [of the gene therapy] by looking at HbAT87Q levels at six months, and we've shown you a model that drug product characteristics can predict those HbAT87Q levels," Rifkin-Zenenberg said. "Hopefully, we've been able to show you from these post hoc analyses that when you pick up the commercial product, you can see the percent LVV on the spec sheet and be confident on what the HbAT87Q value will be."