Giroctocogene Fitelparvovec Well-Tolerated in Hemophilia A Patients

New data from a multi-center study in the United States found that a single infusion of giroctocogene fitelparvovec gene therapy was well tolerated among patients with severe hemophilia A.

The therapy was also associated with increased factor VIII (FVIII) levels in the mild-to-normal range without sustained adverse events ad with minimal bleeding in the highest-dosed cohort.

The study was presented the American Society of Hematology (ASH) Annual Meeting and Exposition.

Investigators led by Andrew D. Leavitt, MD, University of California, noted the rarity of hemophilia A, which is caused by pathogenic events in the F8 gene.

However, adeno-associated virus (AAV)–mediated gene transfer has allowed for the delivery of a modified functional F8 coding sequence to hepatocytes, which subsequently synthesizes FVIII at levels that could potentially prevent bleeding events in the absence of exogenous FVIII.

As such, Leavitt and colleagues presented updates from a near-2-year follow-up of the Alta study, an ongoing gene therapy study in those patient population.

The Methods

A total of 11 patients had participated in the study, which 1 patient excluded after not completing 2 years of follow-up.

Phase 1 and 2 of the Alta study consisted of a dose-ranging study of the recombinant AAV serotype 6 vector giroctogene fitelparvovec, which was previously known as SB-525, which encoded a modified B-domain-deleted F8 coding sequence.

Giroctocogene fitelparvovec was infused into adults aged ≥18 years with severe hemophilia A in 4 cohorts of 2 patients each across 4 ascending doses, which were 9e11, 2e12, 1e13, and 3e13 vg/kg.

The 3e13-vg/kg dose cohort was later expanded with 3 additional patients.

Investigators included safety, circulating FVIII activity, use of FVIII replacement therapy, and frequency of bleeding events for key end points for the study.

The cutoff date for the Alta study was set as May 19, 2021.

The Findings

Leavitt and investigators reported that the most commonly reported treatment-related adverse events (AEs; n/N [%]), included elevated liver enzymes and infusion-related reactions: increased alanine aminotransferase (ALT; 5/11 [45.5%] overall; 3/5 [60.0%] in the 3e13-vg/kg cohort), increased aspartate aminotransferase (AST; 3/11 [27.3%] overall; 2/5 [40.0%] in the 3e13-vg/kg cohort), pyrexia (3/11 [27.3%] overall; 3/5 [60.0%] in the 3e13-vg/kg cohort), and tachycardia (2/11 [18.2%] overall; 2/5 [40.0%] in the 3e13-vg/kg cohort).

Additionally, treatment-related serious adverse events were reported in 1 patients who experienced hypotension and fever with onset ≈6 hours after giroctocogene fitelparvovec infusion. However, the events fully resolved with treatment and did not delay post-infusion discharge the next day.

The team also reported observing ALT elevations requiring >7 days of corticosteroid treatment

In 4 of the 5 patients in the 3e13-vg/kg cohort, which were managed with a tapering course of corticosteroids.

Patients in the 3e13-vg/kg cohort had mean FVIII activity maintained in the mild-to-normal range through week 104 for the 4 patients in this cohort.

In this cohort, the annualized bleeding rate 3 weeks after study drug was 0 for the first year post-infusion and 0.9 throughout the total duration of follow-up.

In addition to the phase 1 and 2 data presented at ASH, Leavitt and colleagues added that “a phase 3 study (NCT04370054) of giroctocogene fitelparvovec in patients with hemophilia A is ongoing."