When I became involved in hemophilia in the early nineties, I was asked why I chose a career in this field. At this point, there was a sufficient amount of clotting factors available in many developed countries and it seemed that it was only a matter of a few years before gene therapy would become a reality. In recent years, this breakthrough appears to be within reach.
In November 2014, a very important milestone regarding gene therapy and clinical trials for people with hemophilia B occurred when the New England Journal of Medicine (NEJM) published a paper entitled “Long-term safety and efficacy of factor IX gene therapy in hemophilia B” written by Amit Nathwani Ph.D. et al.
Significant work and interest in gene therapy started with the cloning of the factor genes in the early 1980s. Hemophilia was a very interesting model for gene therapy as only a small increase of factor level can dramatically decrease the number of bleedings and prevent athropathy. Through this type of treatment, patients with severe hemophilia could attain moderate hemophilia clotting levels, thus leading to an increased reduction in bleeding. The clinical principle of changing severe hemophilia into moderate hemophilia is also the basis for the use of prophylaxis on patients with severe hemophilia. However, high treatment costs and lifelong injections would limit access to prophylaxis for many patients, making gene therapy likely a preferred option.
Why did it take so long for gene therapy to become available? The reality was that it took many years until it was possible to produce safe recombinant adeno-associated virus (AAV) vectors that would also reduce the risk of inducing cancer through the infusion of viral vectors. A dramatic event happened in the 1990s when leukemia occurred after gene therapy was given to a child with primary immune deficiency. This event caused regulatory authorities to develop guidelines for the production of safe recombinant AAV vectors and all clinical trials for gene therapy were stopped at that time.
The process to develop safer and more reliable vectors took many years and also the concern that gene therapy could induce immunogenicity hampered much of the initial enthusiasm. The perception that gene therapy has many unpredictable risks is still on the minds of many patients and physicians today.
It is therefore promising that an article on the long-term safety results was published in the NEJM, showing the results of 10 patients with severe hemophilia B who received gene therapy.
The first six patients were enrolled between 2010 and 2011 and they received a low dose of vector. After the low dose was well tolerated, another four patients were enrolled in 2012 with a higher dose in order to increase the overall effect on the factor IX level. In all, 10 patients experienced the effect of the vector infusion which was regular when measured with the analysis of their factor IX level. Also, anti-bodies against factor IX and liver function tests were regularly tested. Since this was the first trial of gene therapy in patients with hemophilia, safety was of utmost concern. All enrolled patients were HIV negative, but 7 out of 10 patients tested positive for hepatitis C virus. The infusion of the vectors was well tolerated with no signs of fever, symptoms, or other general complaints. After a median follow up period of more than three years, the factor IX activity measured in the patients was related to the amount of vector that was initially infused. Patients that received a higher dose have had a higher stable factor IX level than the patients that received the lower dose.
In four out of seven patients, prophylaxis could be stopped and these patients did not report spontaneous bleedings. A large decrease of additional factor IX infusion was observed for all patients and their annual consumption in IU/kg dropped from a median dose of 2613 IU to 206 IU/kg per year after gene therapy was started. This meant an overall reduction of factor level consumption by 90 per cent.
The most reported adverse event was an increase in liver enzymes (ALT levels), this occurred 7 to 10 weeks after the infusion with high dose vector. This adverse event was treated with steroids and during the increase of the ALT levels also a decrease of factor IX activity was found. With steroids the increased levels of the liver enzymes normalized after five days. No factor IX neutralizing antibodies were demonstrated; however a general increase in antibodies against the AAV vector were detectable.
Currently there are several trials ongoing of patients with hemophilia B. However, there is a slow recruitment of patients into these trials, which is caused by both the limited number of patients with no antibodies against AAV vectors and also concern that there is a limited number of of patients willing to participate in these trials.
We have come a long way and success in this area of research is evident, as highlighted in the NEJM paper. We continue to look towards the day that all people with bleeding disorders can benefit from the availability of this life-changing treatment.