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A one-time gene therapy for sickle cell disease (SCD) completely resolved severe vaso-occlusive events (VOEs), according to results from a phase I/II study.

LentiGlobin (bb1111; lovotibeglogene autotemcel) led to complete resolution of these pain crises -- the study's primary endpoint -- in 25 evaluable patients beyond 6 months of follow-up, reported John Tisdale, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, at the American Society of Hematology (ASH) annual meeting and in the .

"And that compares with the 3.5 annualized rate in the 24 months before informed consent," Tisdale noted.

In addition, median total hemoglobin level increased from 8.5 g/dL at baseline to ≥11 g/dL from 6 months through 36 months after infusion, with HbA^T87Q contributing at least 40% of total hemoglobin distributed across approximately 85% of red cells.

Hemolysis markers were also reduced from 6 months through the last follow-up.

"Overall, these are excellent results," Rabi Hanna, MD, of the Cleveland Clinic, told 名媛直播. "To be able to have these patients not have any pain crises -- which was the main endpoint -- after engraftment really demonstrates [the therapy's] efficacy. What always remains a concern is ... secondary malignancies."

Earlier this year, a patient in one of the trial's cohorts was diagnosed with acute myeloid leukemia (AML) 5.5 years after LentiGlobin infusion, as detailed in the . Investigators determined that this patient's AML was unlikely to be related to gene vector insertion.

Hanna, who has also initiated a gene therapy trial in SCD at his institution, pointed out that chemotherapy is used in patients as a conditioning regimen in preparation for the infusion of modified stem cells. "The concern was the AML was related to the gene vector versus being related to the chemotherapy," he observed. "Based on my reading, I agree that it is mostly related to the chemotherapy. And I think that is where the field of gene therapy and gene editing has to focus. Can we develop a regimen that is non-chemotherapy-based that could prevent the development of secondary cancers in these patients?"

In this ongoing study, patients are being followed for 24 months, after which they will enter a 13-year follow-up. Eligible patients (ages 12 to 50) had a history of severe VOEs and a failure with or intolerance to hydroxyurea.

This multi-stage study initially involved nine patients in groups A and B. Group C was established for the pivotal evaluation of LentiGlobin for SCD, with a more stringent inclusion criterion requiring a minimum of four severe VOEs in the 24 months before enrollment.

The primary endpoint of complete resolution of severe VOEs was measured 6 to 18 months after the LentiGlobin infusion.

A severe VOE was defined as one that resulted in a visit to a hospital or emergency department exceeding 24 hours, at least two visits to a day unit or emergency department during a 72-hour period (with both visits requiring intravenous treatment), or a priapism episode lasting more than 2 hours and leading to a medical facility visit.

This interim analysis included 35 patients in group C who had received a LentiGlobin infusion and who were followed for a median of 17.3 months; 25 met the minimum 6-month follow-up required for assessment of VOEs.

Secondary endpoints included change in hemoglobin level from baseline, the absolute total hemoglobin level, and change in hemolysis markers.

In a companion study also presented at the ASH annual meeting, Mark Walters, MD, of the University of California San Francisco Benioff Children's Hospital in Oakland, reported that patients receiving LentiGlobin with baseline quality-of-life scores that were "worse" than the general population had meaningful improvements in quality-of-life and pain-intensity scores.

Pain, fatigue, and physical function domains demonstrated the greatest improvements for patients overall, Walters said. "These findings complement our clinical results of complete resolution of severe vaso-occlusive episodes up to beyond 24 months, and these improvements have not yet been observed in other sickle cell disease modalities," he noted.