Gene therapy fails to induce sustained factor IX activity for patients with hemophilia B
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The novel gene therapy BAX 335 did not induce sustained factor IX expression among patients with hemophilia B, according to an interim analysis of a phase 1/phase 2 dose-escalation study published in Blood.
“Patients with hemophilia, particularly in the most severe form, suffer from recurrent, sometimes life-threatening bleeding events, long-term disability and reduced life expectancy,” Bruce M. Ewenstein, MD, scientist at Brigham and Women's Hospital and part-time lecturer on medicine at Harvard Medical School, told Healio. “Despite the significant progress in the development of factor VIII and factor IX [FIX] replacement products, as well as nonfactor products that partially overcome the hemostatic defects in hemophilia, there is widespread belief that gene therapy, by enabling persistent endogenous expression of the missing coagulation factors, has the potential to provide long-term benefit after a single administration. Early clinical trials demonstrated the feasibility of gene therapy for hemophilia B but failed to produce sustained therapeutic levels of FIX.”
BAX 335 (Baxalta Inc.; Baxalta Innovations GmbH, Takeda) is an investigational gene therapy compromising an adeno-associated virus serotype 8 (AAV8) vector with the naturally occurring Padua human FIX variant gene.
The open-label, dose-escalation study included eight men with hemophilia B (age range, 20-69 years; 87.5% white; range FIX activity, 0.5%-2%) who received a single infusion of BAX 335 dosed at 2 10¹¹ vector genomes/kg (cohort 1), 1 10¹² vector genomes/kg (cohort 2) or 3 10¹² vector genomes/kg (cohort 3).
Patients could receive standard-of-care treatment for hemophilia B as necessary.
For the 1-year interim analysis, researchers assessed the safety, pharmacokinetic variables, effects on FIX activity and immune responses for each of the three doses.
According to study results, three men (37.5%) experienced four serious adverse events unrelated to BAX 335 gene therapy, including rhabdomyolysis, bacterial infection of the tonsil, tonsillar hemorrhage and squamous cell carcinoma of the tonsil. All serious adverse events, except the tonsillar carcinoma, were resolved at 1-year follow-up.
Researchers observed no serious adverse events leading to death and no clinical thrombosis, inhibitors or other FIX Padua-directed immunity.
Seven patients had measurable FIX expression, with FIX activity that was dose-dependent and observed as early as 1 to 2 weeks following infusion in the higher-dose groups. During the first 6 months after BAX 335 infusion, patients achieved mean peak FIX activity of 2.8% (range, 2.7-2.8) in cohort 1, 12.8% (range, 3-26.2) in cohort 2 and 45.3% (range, 32-58.5) in cohort 3.
One patient experienced sustained therapeutic FIX activity of approximately 20% for 4 years without bleeding events or requiring replacement therapy; however, the other patients did not exhibit FIX activity beyond 5 weeks to 11 weeks, researchers noted.
The researchers noted that long-term follow-up of the participants from this and other gene therapy studies is paramount, including the one patient who retained circulating FIX activity from the FIX Padua transgene.
“Our study provides evidence that innate immune responses, potentially stimulated by clusters of CpG motifs through TLR9 signaling, may contribute significantly to the loss of AAV vector-mediated FIX expression,” Ewenstein said. “Elevations of the proinflammatory cytokine, IL-6, may serve as an indicator of TLR9-dependent activation. Our hypothesis that innate immunity pathways contributed to the loss of FIX activity in the majority of the participants in our study was supported by the finding of potential IL-6 receptor haploinsufficiency in the one participant who exhibited sustained FIX expression.”
The study provides insight into mechanisms that could contribute to the adeno-associated virus immune response, with implications for the future design of adeno-associated virus vectors, according to an editorial accompanying the study by Lindsey A. George, MD, attending physician in the division of hematology at Children’s Hospital of Philadelphia.
“The outlined observations and hypothesis generated by [Ewenstein and colleagues] highlight the importance of thoughtful analysis of clinical trial data, irrespective of clinical success,” George wrote. “There are a remarkable number of hemophilia gene therapy trials underway, including licensing studies. Realizing the potential of gene therapy to alter the paradigm of hemophilia care will undoubtedly be predicated on a commitment to investigate and publish unexpected clinical trial observations.”
References:
George LA. Blood. 2021;doi:10.1182/blood.2020009285.
Konkle BA, et al. Blood. 2021;doi:10.1182/blood.2019004625.
For more information:
Bruce M. Ewenstein, MD, can be reached at bruce.ewenstein@takeda.com.
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