The approval of HEMGENIX, the first-ever gene therapy for hemophilia B, by the U.S. Food and Drug Administration (FDA) followed by the European Commission, has been momentous in rare disease therapeutic research, paving the way for various gene therapies that are currently being studied. As we observed World Hemophilia Day on April 17, let us take a look at how transformative gene therapy could be for the treatment of hemophilia B.
Hemophilia B, also known as Christmas disease – not related to the holiday but the first person diagnosed with the disorder in 1952, five-year-old Stephen Christmas – is a rare bleeding disorder. Affecting more than 230,000 people worldwide, it is caused by the lack of, or the presence of a defective clotting protein factor IX, due to a spontaneous mutation on the factor IX gene. Classified as a genetic condition because of the gene’s location on the X chromosome – one of the two sex chromosomes involved in sex determination – hemophilia B is an X-linked disorder. Females with one defective X chromosome are carriers of the disease, and their sons have a 50% chance of being a hemophiliac.
The condition is characterized by symptoms such as excessive bleeding and bruising after surgery or injury and even spontaneous bleeding from deep tissues such as joints and muscles. With cases ranging from mild to severe, the typical treatment option for the disease is prophylactic factor IX replacement therapy.
However, as routine prophylactic treatments in order to maintain factor IX levels in the body and prevent prolonged bleeding are considered to significantly impact one’s quality of life, with patients having to inject themselves with the missing factor IX protein on a weekly basis, there is also the burden of treatment that comes with having to do an intravenous injection by yourself. While some people are confident doing so, others find the process tedious. Besides, it is not the most convenient method for children with hemophilia B. Moreover, some people with hemophilia B also develop venous access issues over time, a challenging barrier in long-term prophylactic care.
Owing to how current treatments markedly alter patients’ lives, as well as having a psychosocial impact of worrying about routine injections and having to tailor their treatment regimen frequently, there is a need for less cumbersome therapies to treat the disorder. Gene therapy aims to address these unmet needs.
Potential of ongoing gene therapy studies
According to Jefferson Courtney, the policy and public affairs manager at The Haemophilia Society in the U.K., HEMGENIX could massively reduce the treatment burden and maybe even effectively ease symptoms from severe to mild, which is more manageable.
Developed by Amsterdam-based biotech uniQure in partnership with global biopharma CSL, HEMGENIX is a one-time gene therapy for people with severe and moderately severe hemophilia B. The drug, which is an adeno-associated virus serotype 5 (AAV5) based gene therapy containing the active ingredient etranacogene dezaparvovec, is designed to deliver a copy of a gene that encodes the Padua variant of human coagulation factor IX (hFIX-Padua) via an intravenous infusion. As a result, its mechanism of action is to elevate factor IX levels, which in turn, facilitates the formation of blood clots to restrict bleeding.
Extensively studied in its Hope-B trials which enrolled 54 participants, it was deemed successful after the annualized bleed rate (ABR) – a critical factor in assessing the therapeutic potential for hemophilia – saw a distinct drop in its percentage. In its third phase of clinical research, patients who were undergoing regular prophylactic therapy were under observation for six months, and were then administered the gene therapy. The trials witnessed a durable improvement in mean factor IX levels, with a mean factor IX activity of 36.9%, which led to 64% reduction in ABR. The outcome of the study persuaded 96% of the participants to quit routine prophylaxis, a win for hemophilia research.
Although not as advanced in therapeutic development as Hemgenix, U.K.-based Freeline Therapeutics conducted a phase 1/2 study, which concluded in July 2022, to determine the efficacy of its drug candidate FLT180a. The trial, where all patients had dose-dependent increases in factor IX, observed that 90% of the participants sustained factor IX activity at the follow-up period of more than two years after the dosage.
However, Freeline’s decision to halt its studies, as it was in pursuit of a partner for the development of FLT180a, came after questions about its longevity were raised. As patients saw a dip in factor IX levels, the recurring need for prophylactic therapy is yet to be determined and further research is required to confirm the candidate’s durability.
Another drug candidate is multinational pharmaceutical Pfizer’s collaboration with Swiss biopharma Roche. Fidanacogene elaparvovec, which is an investigational gene therapy with a mechanism similar to that of HEMGENIX, contains a bio-engineered AAV capsid. The therapy aims to produce factor IX, with the hope of maintaining the levels in the body. In December 2022, Pfizer announced positive results from its phase 3 study where 71% reduction in ABR was measured.
Challenges of gene therapy for hemophilia B
While the promise of gene therapy for hemophilia B has been realized, it is not without its challenges.
“I think there are quite a few considerations that people need to to think about when they’re deciding whether gene therapy is right for them… These are viruses that affect the liver in order to put the transgene in. So, that means most people end up with liver issues that need to be treated with steroids,” said Courtney, who expressed that the extended use of steroids can greatly impact people’s lives.
Even though the vector that is inserted is a non-integrating one – where the DNA in the human cell and the genetic material from the vector remain separate – and consequently reduces the risk of integration in the cell, still, the chances of non-integration are not zero.
Courtney also explained that the variability of the results from gene therapy is massive, although it is less so with hemophilia B when compared with hemophilia A – a condition caused by a deficiency of factor VIII protein which is encoded by a different gene than in hemophilia B. Despite retaining 30 to 40% of normal factor IX levels on average with HEMGENIX, which offers patients adequate protection, for some people, the drug has not succeeded in preserving factor IX levels, a drawback that is yet to be further investigated.
Gene therapy is “not a cure” for hemophilia B
Moreover, gene therapy is not a cure for hemophilia B, according to Courtney.
“They’re not cures for hemophilia for two reasons… They’re not, in most cases, taking people into the normal range of clotting, they’re taking people to levels around 30-40%, which is still kind of below normal below average… It’s not that they don’t have mild hemophilia, they still need to manage that. Accordingly, management for that tends to be that if you’ve had major trauma or you’ve had surgery, you might still need to have some factor replacement, or some care in order to ensure that you’ve had appropriate levels of clotting,” he said.
“The other thing is that you still have the hemophilia gene in your DNA,” said Courtney, who added that men who undergo gene therapy could still pass their gene to their daughters who could either be carriers, or would themselves have hemophilia.
Notwithstanding the challenges that need to be addressed, gene therapy has been regarded as a feasible option to treat hemophilia B, and HEMGENIX is proof of that.
Ross Bennett, the ambassador of The Haemophilia Society said: “I manage my hemophilia well but I still feel that there are things I can’t do, and I have to adapt my life around my hemophilia and my treatment. A gene therapy for hemophilia B should be an option for people as it offers the potential to significantly reduce the burden of my treatment and give me more reassurance that I am protected from painful bleeds.”
Having been granted conditional marketing authorisation by the U.K. Medicines and Healthcare products Regulatory Agency (MHRA), the drug will be able to obtain a U.K. license and MHRA license shortly, according to Courtney.
For this to go as planned, the clinical and cost effectiveness of HEMGENIX is under way. However, the drug being priced at $3.5 million in the U.S., makes it the world’s most expensive medicine. This has raised concerns over how accessible it would be for people in low and middle-income countries – which is where the majority of people with hemophilia B live – where they already have limited access to prophylactic care.
As the cost of the therapy looms across the globe, in the U.S., it is still predicted to save around $5 million as it eliminates the necessity for routine factor IX replacement injections.
Scope for hemophilia A research?
The approval of HEMGENIX also widens the scope for gene therapeutic research for hemophilia A. In 2022, the European Commission (EC) granted conditional marketing authorisation for the U.S.-based pharmaceutical BioMarin’s Roctavian (valoctocogene roxaparvovec). The drug has been issued for the treatment of adults with severe hemophilia A who do not have a history of factor VIII inhibitors. The data from the clinical trials demonstrated that transgene-derived factor VIII supplied similar protection to factor VIII that is produced by the body.
“Gene therapy is entering a space that already has good treatment options, some of which have the potential to be a treatment that’s delivered subcutaneously rather than intravenously, and that is often a lot easier for children in particular,” said Courtney.
However, he recognizes that the decision to undergo gene therapy is a challenging one. He explained that because the body produces antibodies against the AAV vector, it is a single dosage therapy. Hence, patients will have to be aware of alternative treatment options as well.
He also believes that people with hemophilia should be able to choose the kind of therapy that they deem fit for their condition and lifestyle.
“People who are athletes, or even just people who regularly take part in sports, may need a very different treatment regime to people who live a more sedentary lifestyle… And so, the important thing is that patients are presented with a range of treatment choices, and are able to pick the one that best suits them and their lifestyle.”
For Luke Pembroke, who has been diagnosed with hemophilia B, the choice he made was to opt for gene therapy. Having received immunosuppression as part of the trial which coincided with the pandemic, he had to shield for nearly a year.
“Gene therapy has without doubt changed my life. I feel free from my condition and I don’t find myself worrying about my hemophilia anywhere near as much as I did before. But it wasn’t a walk in the park to get to where I am now. The demands of the gene therapy trial were high.”
“I spent a lot of time in and out of my treatment center for follow up tests. Three years later, I’m now enjoying the benefits of life, post gene therapy. I’m mindful that I still have mild hemophilia and sadly, I can’t reverse my joint damage from a life lived with severe hemophilia B, but right now, I am focused on all the positives. I feel like I can live life more spontaneously,” said Pembroke.