A recent commentary published in the journal Haemophilia, posits that while clinical trials for hemophilia gene therapy approach conclusion, there remain significant unanswered questions and lingering concerns that can only be addressed through rigorous scientific investigation and greater transparency. It was authored by six individuals with severe hemophilia, all of whom are dedicated to working towards better health outcomes for patients with bleeding disorders through various means, including international patient advocacy, NGO leadership, and scientific research.
“With gene therapy, a change from severe to mild or normal phenotypes is a major accomplishment but a discriminating review of the data is unsettling. A framework of known unknown questions has been developed, which remain largely unanswered despite the fact that large-scale clinical trials are moving towards completion.”
Several of the safety concerns raised by the authors focus on the target organ of gene therapies that are delivered via adeno-associated virus vectors (AAVs). Livers that receive AAVs sometimes exhibit mildly elevated liver enzymes known as transaminases, an occurrence that warrants greater investigation for what it might reveal about the long-term effects of the therapy on this vital organ. “Regarding safety, mildly elevated transaminases have been largely dismissed because the increases are mostly transient, explain the authors. “This ignores the cause and whether there is ongoing low-level liver damage, analogous to what our community has seen with hepatitis C. Are we taking AAV-induced liver inflammation as seriously as a ‘one-and-done therapy that cannot be withdrawn’ should dictate?”
The paper references two deaths in AAV-based trials earlier this year to reemphasize the importance of similar safety considerations. These deaths followed liver complications, which occurred in clinical trial participants with a rare muscle disorder known as X-Linked Myotubular Myopathy. Read NHF’s June 29th reporting to learn more.
Additional concerns centered on the sheer volume of vector genome typically dosed in a one-time infusion to a patient, subsequent inefficiencies of AVV liver integration, and the unintended consequences that could result, including unwanted immune responses.
The authors also put forward questions fundamental to the ultimate therapeutic purpose of gene therapy, including long term sustainability of factor levels, and the yet-to-be-answered questions of variability among trial participant responses to the treatment. “We ask, do we have a safe, reliable product to give us the sustained cure we are awaiting? Perhaps, not quite. Our expectations are mismatched to the reality of the available data.”
They urge greater transparency from all those facilitating clinical trials and “meaningful research” to answer key questions going forward. “Only in this environment, we can have confidence in this technology, conclude the authors. “A global registry is a vital and necessary foundation for tracking safety and efficacy, but observational studies alone do not substitute for scientific investigations to further our biologic knowledge of this new and promising therapeutic modality.”
The commentary, “Gene Therapy to Cure Haemophilia: Is Robust Scientific Inquiry: The Missing Factor?” was published September 10, 2020 in Hameophilia.
 A third death in this trial was subsequently reported after this commentary was accepted for publication.