Annualized bleed rate and FVIII infusion rates significantly decreased after infusion with the gene therapy.
The adeno-associated virus gene therapy SPK-8011 (Spark Therapeutics) demonstrated durable expression of factor 8 (FVIII) in patients with hemophilia A in participants enrolled in a phase 1/2 trial (NCT03003533).
These data were presented at the 64th American Society of Hematology (ASH) Annual Meeting, held December 10-13, 2022, in New Orleans, Louisiana, by Stacy Croteau, MD, MMS, Medical Director, Boston Hemophilia Center, and Assistant Professor of Pediatrics, Harvard Medical School.
“As we consider the progress in gene therapy as a hemophilia therapeutic, it’s important to keep in mind 4 key pillars: safety, efficacy, predictability, and durability... The goals and design of [SPK-8011] were to target the lowest effective dose to minimize risk of liver toxicity and anti-capsid immune response while achieving durable expression following single vector administration,” Croteau said during her presentation.
Adult male patients with FVIII activity of less than 2% of normal and no history of FVIII inhibitors, hepatitis, or serious liver fibrosis were enrolled in the study (median age, 35.5 years).Participants received 5x1011 (n = 2), 1x1012 (n = 3), 2x1012 (n = 9) or 1.5 x 1012 (n = 12) vg/kg in 4 cohorts.
Safety data were reported from 24 participants that had a median follow-up of 292 weeks (range, 2-285). There were no deaths, thrombotic events, or development of FVIII inhibitors. Adverse events (AEs) related to SPK-8011 included 1 infusion reaction and 11 cases of elevated liver function tests (9 grade 1, 1 grade 2, and 1 grade 3) which were transient, asymptomatic, and resolved. One AE was counted as a serious AE in a participant that elected to go to the hospital for intravenous steroid administration for grade 2 transaminitis. Other AEs, in 8 participants, were related to immunomodulatory agents and included insomnia, fatigue, weight gain, irritability, hypertension, neutropenia, decreased appetite, nausea, headache, stomach pain, hot flushes, acne, generalized edema, hypomagnesemia, and muscle cramping. These AEs all resolved except a few cases of hypertension (n = 1), headache (n = 1), and nausea and stomach pain (n = 1).
Investigators found that alanine aminotransferase elevations were transient and were consistent with the expected window of presumed capsid immune response. SPK-8011 was undetectable by 12 weeks post-treatment.
Most participants with at least 1 year of follow-up maintained FVIII expression within mild hemophilia range.With a median efficacy follow-up of 172.1 weeks (range, 2-285), annualized bleed rate (ABR) decreased significantly after treatment with SPK-8011, with an 82% reduction in participants on prior prophylaxis (95% CI, 55-93) and a 99% reduction for participants with prior on-demand treatment (95% CI, 98-100). Furthermore, 76% of participants had an ABR of less than 1 for treated bleeds and 90% had an ABR of less than 1 for spontaneous bleeds. Annualized FVIII infusion rates decreased from a median of 85.5 (interquartile range [IQR], 49.0-104.0) to 0.3 (IQR, 0.0-1.4) after infusion.
“With up to 5 years of follow-up after a single infusion of spk8011 we see a result of durable FVIII expression with the majority of participants experiencing levels in the mild hemophilia range. Investigations are ongoing to overcome the challenge of managing a presumed capsid immune response to further reduce variability in FVIII expression following AAV-mediated gene transfer for hemophilia A,” Croteau concluded her presentation.