SPK-8011, an investigational adeno-associated virus (AAV)–mediated gene therapy for hemophilia A, provides stable and durable factor VIII expression with no major safety concerns, according to findings at least 2 years after a single treatment in patients from a phase 1/2 trial.
The first 5 of 14 adult men with hemophilia A and who had factor VIII (FVIII) activity of 2% or less before treatment with SPK-8011 (at single doses of either 5 × 1011 or 1 × 1012 vg/kg), showed no development of FVIII inhibitors or evidence of FVIII cellular immune response at 106-142 weeks’ follow-up after vector infusion, according to Lindsey A. George, MD, at the International Society of Thrombosis and Haemostasis 2020 virtual congress.
At follow-up, the two who had received a 5 × 1011 vg/kg dose had FVIII activity of 6.9%-8.4%, and the three in the 1 × 1012 vg/kg cohort had FVIII activity of 5.2%-19.8%, said Dr. George, of the Children’s Hospital of Philadelphia.
Overall, 12 of the 14 patients in the study had sustained FVIII expression, including 7 of 9 who received the highest SPK-8011 dose of 2 × 1012 vg/kg. In the 12 with sustained expression, a “remarkable” 91% reduction in the annualized bleeding rate from the year prior to vs. the year after vector infusion was observed, she said.
“Similarly, looking at number of factor infusions before vector infusion relative to the number of factor infusions after vector infusion ... [there was] evidence of remarkable preliminary efficacy,” she added, noting a 96% reduction in factor consumption.
The findings are of note because, while clinical studies of Spark Therapeutic’s SPK-8011 product in hemophilia B and preclinical models in hemophilia A showed promising reductions in bleeds and stable, durable levels of FVIII expression after therapy, the first successfulof an AAV-mediated gene therapy in hemophilia A – the BioMarin AAV serotype 5 human FVIII-SQ (valoctocogene roxaparvovec) – showed an unexpected decline in FVIII expression at 1, 2, 3, and 4 years.
“This may be particularly relevant in the context of development of multi-serotype AAV neutralizing antibodies (NAb) following AAV vector administration,” Dr. George said, referencing a small study in which she and her colleagues showed long-term persistence of cross-reactive AAV NAb. The findings of that, which is currently in press in Molecular Therapy, “suggest that repeat AAV vector infusion is unlikely to be possible with current methods.”
Initialfrom the SPK-8011 study were presented at the 2018 American Society of Hematology annual meeting. No major safety issues have emerged since those data were presented at ASH; no deaths have occurred, and none of the patients developed FVIII inhibitors.
Treatment-related adverse events were limited to an infusion reaction in one patient, which resolved completely, and liver enzyme elevations in three patients, which also resolved. One serious adverse event – a grade 2 transaminitis that resulted in elective hospitalization for intravenous steroid administration, also resolved.
With respect to vector clearance, there was “no evidence of vector in either saliva, semen, serum, urine, or peripheral blood mononuclear cells by 6 weeks after vector infusion,” Dr. George said.
One-stage assay determination of FVIII activity showed that activity greater than 10% permits an absolute bleeding rate (ABR) of less than 1%, which is consistent with hemophilia natural history studies. Therefore “these data support that FVIII activity that is approximately greater than 10% “may be adequate to either eliminate or achieve an ABR of less than 1,” she said.
“With respect to assay discrepancy, our data at least preliminarily support that the one-stage assay determinant of hepatocyte-derived FVIII correlates with clinical phenotype,” she added.
The findings in the first five patients demonstrate preliminary stability of FVIII expression at follow up between 2 and 3.3 years, she said.
Further, of the nine patients who received the 2 × 1012 vg/kg dose, seven had sustained FVIII expression at about 1.5 years, five of the seven had no bleeds, and two lost FVIII expression and returned to prophylaxis uneventfully, she noted.
“The future directions of this work are ultimately to explore the optimal vector dose and immunosuppression regimens to achieve predictable, safe, efficacious, and durable FVIII expression,” she said.
Asked during a question and answer period about potential reasons for the differences in durability seen with SBK-8011 versus valoctocogene roxaparvovec, Dr. George said they remain unclear but could be related to differences in vector doses and manufacturing platforms.
Emerging data may allow for better comparisons, she added.
Session moderator Sebastien Lacroix-Desmazes, MD, of Centre de Recherche des Cordeliers, Paris, further asked about plans to optimize the immunosuppression regimen.
Plans are indeed in the works to identify the optimal immunosuppression regimen and to optimize immunosuppression in this trial, Dr. George said, noting that Spark Therapeutics “has outlined a plan to further investigate this in phase 1/2 trial before progressing into phase 3 study.”
Spark Therapeutic sponsored the SPK-8011 study. Dr. George disclosed consulting and/or data safety monitoring board activity for Pfizer and AvroBio.
SOURCE: George L et al. 2020 ISTH Congress, .