The Arrival of Gene Therapy for Patients with Hemophilia A

Abstract

Historically, the standard of care for hemophilia A has been intravenous administration of exogenous factor VIII (FVIII), either as prophylaxis or episodically. The development of emicizumab, a humanized bispecific monoclonal antibody mimicking activated FVIII, was a subsequent advance in treatment. However, both exogenous FVIII and emicizumab require repeated and lifelong administration, negatively impacting patient quality of life. A recent breakthrough has been the development of gene therapy. This allows a single intravenous treatment that could result in long-term expression of FVIII, maintenance of steady-state plasma concentrations, and minimization (or possibly elimination) of bleeding episodes for the recipient’s lifetime. Several gene therapies have been assessed in clinical trials, with positive outcomes. Valoctocogene roxaparvovec (an adeno-associated viral 5-based therapy encoding human B domain-deleted FVIII) is expected to be the first approved gene therapy in European countries, including Italy, in 2022. Some novel challenges exist including refining patient selection criteria, managing patient expectations, further elucidation of the durability and variability of transgene expression and long-term safety, and the development of standardized ‘hub and spoke’ centers to optimize and monitor this innovative treatment. Gene therapy represents a paradigm shift, and may become a new reference standard for treating patients with hemophilia A.

Hepatitis after gene therapy, what are the possible causes?

“…16 Most ALT elevations seen in gene therapy trials are Grade 1 to 2 in severity. 17 In the aforementioned trial for haemophilia A, 86% of 115 participants who received gene therapy had AEs in the form of ALT elevations. 9 Only 8.2% of them were deemed to have Grade 3 transaminitis based on the CTCAE but, critically, none of them met Hy's Law for drug-induced liver injury.…”

“…It is important to note that some individuals develop hepatitis without loss of transgene expression and vice versa. 17 There is also a gradual decline of factor expression over time that seems to be more pronounced in patients with haemophilia A. The mechanism for liver injury is incompletely understood and precludes a more evidence based approach to therapy but there are currently a number of possible causes.…”

CORR Insights®: What is the Effect of Bevacizumab on Cartilage and Synovium in a Rabbit Model of Hemophilic Arthropathy?

“…Nonetheless, it is a good approach, and an important area of future effort should focus on expanding its availability worldwide. In order to overcome the inconveniences of injections, transdermal administration of clotting factors is also an area of inquiry, as is gene therapy, with the hope of achieving clinically important and durable increases in the plasma levels of deficient clotting factors [1]. One way or the other, timely treatment before irreversible cartilage changes occur must be our priority.…”

“…Semih Aydogdu MD 1 Where Are We Now? H emophilia, the most common bleeding disorder, affects approximately half a million people globally, though only about half of those have a severe form of the disease (defined as less than 1% of clotting factor activity in their blood).…”

Bispecific Antibody Format and the Organization of Immunological Synapses in T Cell-Redirecting Strategies for Cancer Immunotherapy

“…Bispecific antibodies (bsAbs) are molecules with binding sites for two different antigens or two different epitopes on the same antigen [ 1 ]. They represent valuable immunotherapy tools and can be designed to redirect T cells to cancer cells, although some of them have been also used to treat other diseases, such as hemophilia A [ 2 ] or Alzheimer’s disease [ 3 ]. The first application of bsAbs in cancer immunotherapy was for redirecting T cells toward tumor cells.…”