The approval of HEMGENIX, the first gene therapy for hemophilia B, by the US Food and Drug Administration (FDA) followed by the European Commission, has been pivotal in rare disease therapy research, paving the way for a variety of gene therapies currently under development. being studied. As we observe World Hemophilia Day on April 17, let’s see how transformative gene therapy can be made for the treatment of hemophilia B.
Hemophilia B, also known as Christmas disease – unrelated 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 a lack of, or presence of a defective clotting protein factor IX, due to a spontaneous mutation in the factor IX gene. Classified as a genetic condition due to the location of the gene on the X chromosome – one of the two sex chromosomes involved in sex determination – hemophilia B is an X-linked disorder. Women with one defective X chromosome are carriers of the disease, and their sons have a 50% chance of being hemophiliac.
This 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 this disease is prophylactic factor IX replacement therapy.
However, because routine prophylactic care to maintain factor IX levels in the body and prevent prolonged bleeding is considered to have a significant impact on a person’s quality of life, with patients having to inject themselves with the missing factor IX protein weekly, there is also a burden of care that comes with having to do the injection. intravenously alone. While some people are confident doing it, others find the process tedious. In addition, it is not the most convenient method for children with hemophilia B. In addition, some people with hemophilia B also experience venous access problems from time to time, a challenging barrier to long-term prophylactic care.
Because of how current treatments markedly change patients’ lives, as well as having the psychosocial impact of worrying about routine injections and having to adjust their medication regimens frequently, there is a need for less complex therapies to treat the disorder. Gene therapy aims to address these unmet needs.
Potential ongoing gene therapy studies
According to Jefferson Courtney, policy and public affairs manager at The Haemophilia Society in the UK, HEMGENIX could massively reduce the burden of treatment and might even effectively move symptoms from severe to mild, which are more manageable.
Developed by Amsterdam-based uniQure biotech in partnership with global CSL biopharma, HEMGENIX is a one-off gene therapy for people with severe and moderate 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 the gene encoding the Padua variant of human coagulation factor IX (hFIX-Padua) via intravenous infusion. Consequently, its mechanism of action is to increase the levels of factor IX, which in turn facilitates the formation of blood clots to limit bleeding.
Extensively studied in the Hope-B trial enrolling 54 participants, it was deemed successful after the annual bleeding rate (ABR) – an important factor in assessing therapeutic potential for hemophilia – saw a distinct percentage reduction. In the third phase of his clinical research, patients who underwent regular prophylactic therapy were under observation for six months, and then given gene therapy. The trials witnessed a lasting increase in average factor IX levels, with an average factor IX activity of 36.9%, leading to a 64% reduction in ABR. The study results convinced 96% of participants to discontinue routine prophylaxis, a win for the hemophilia research.
Although development of the therapy is not as advanced as Hemgenix, UK-based Freeline Therapeutics is conducting a phase 1/2 study, ending in July 2022, to determine the efficacy of its drug candidate FLT180a. The trial, in which all patients experienced dose-dependent increases in factor IX, observed that 90% of participants maintained factor IX activity at follow-up more than two years after the dose.
However, Freeline’s decision to halt its studies, as it was pursuing partners for development of the FLT180a, came after questions were raised about its longevity. Because the patient saw reduced levels of factor IX, the need for repeated prophylactic therapy has not been determined and further studies are needed to confirm the candidate’s durability.
Another drug candidate is multinational pharmaceutical Pfizer’s collaboration with Swiss biopharma Roche. Fidanacogene elaparvovec, which is an investigative gene therapy with a similar mechanism to HEMGENIX, contains a bioengineered AAV capsid. The therapy aims to produce factor IX, with the hope of maintaining its levels in the body. In December 2022, Pfizer announced positive results from a phase 3 study that measured a 71% reduction in ABR.
The challenge of gene therapy for hemophilia B
While the promise of gene therapy for hemophilia B has been realized, it has not been without challenges.
“I think there are several considerations that people need to think about when they are deciding whether gene therapy is right for them… This is a virus that affects the liver to insert a transgene. So, that means most people end up with liver problems that need to be treated with steroids,” said Courtney, who stated that prolonged use of steroids can have a major impact on people’s lives.
Even if the inserted vector is a non-integrating vector – where the DNA in the human cell and the genetic material of the vector remain separate – and consequently reduces the risk of integration within the cell, still, the probability of non-integration is not zero.
Courtney also explained that the variability of outcomes from gene therapy is enormous, although less so with hemophilia B when compared to hemophilia A – a condition caused by a deficiency in the factor VIII protein encoded by a different gene than hemophilia B. Although maintaining 30 to 40% from the average normal factor IX levels with HEMGENIX, which offers adequate protection to patients, for some people, the drug has not been successful in maintaining factor IX levels, a drawback that has not been investigated further.
Gene therapy “is not a cure” for hemophilia B
Also, gene therapy is not a cure for hemophilia B, according to Courtney.
“They’re not a cure for hemophilia for two reasons… They don’t, in most cases, get people into the normal clotting range, they bring people to levels of about 30-40%, which is still somewhat below normal. below average… It’s not that they don’t have mild hemophilia, they still need to work on it. Therefore, the management for it tends to be that if you have had major trauma or had surgery, you may still need some factor replacement, or treatment to ensure that you have an appropriate level of clotting. ” he says.
“The other thing is you still have the hemophilia gene in your DNA,” said Courtney, who added that men on gene therapy can still pass their gene on to their daughters who may be carriers, or they will develop hemophilia themselves.
Despite the challenges that need to be overcome, gene therapy has been deemed a viable option for treating hemophilia B, and HEMGENIX is proof of that.
Ross Bennett, ambassador for The Hemophilia Society said: “I manage my hemophilia well but I still feel like there are things I can’t do, and I have to adapt my life to hemophilia and my medication. Gene therapy for hemophilia B should be an option for people because it offers the potential to significantly reduce my medication burden and give me more reassurance that I am protected from painful bleeding.”
After being granted conditional marketing authorization by the UK Medicines and Healthcare Products Regulatory Agency (MHRA), the drug will soon be able to obtain a UK license and an MHRA license, according to Courtney.
For this to go according to plan, the clinical effectiveness and cost of HEMGENIX are underway. However, the drug is valued at $3.5 million in the US, making it the most expensive drug in the world. This raises concerns about how accessible it is for people in low- and middle-income countries – where the majority of people with hemophilia B live – where they already have limited access to prophylactic care.
As the cost of therapy soars worldwide, in the US, it is estimated that this would still save about $5 million by eliminating the need for routine factor IX replacement injections.
Scope of research on hemophilia A?
HEMGENIX approval also broadens the scope of gene therapy research for hemophilia A. In 2022, the European Commission (EC) granted conditional marketing authorization for US-based BioMarin pharmaceutical 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 inhibition. Data from clinical trials show that factor VIII of transgene origin provides protection similar to factor VIII produced by the body.
“Gene therapy is entering a space that already has good treatment options, some of which have the potential to be treatments that are administered subcutaneously rather than intravenously, and are often much easier for children in particular,” Courtney said.
However, he realized that the decision to go for gene therapy was a challenging one. He explained because the body produces antibodies against the AAV vector, it is a single dose therapy. Therefore, patients should be aware of alternative treatment options as well.
He also believes that people with hemophilia should be able to choose the type of therapy that suits their condition and lifestyle.
“People who are athletes, or even just people who exercise regularly, may need very different treatment regimens than people who lead sedentary lifestyles… So the important thing is that patients are given a variety of options maintenance. , and can choose the one that best suits them and their lifestyle.”
For Luke Pembroke, who had been diagnosed with hemophilia B, the choice he made was gene therapy. After receiving immunosuppression as part of a trial that coincided with the pandemic, he had to protect himself for nearly a year.
“Gene therapy has undoubtedly changed my life. I feel free from my condition and I don’t feel as worried about my hemophilia as before. But it wasn’t a walk in the park to get to where I am now. The demands of gene therapy trials are very high.”
“I spent a lot of time in and out of my treatment center for follow-up tests. Three years later, I am now enjoying the benefits of life, post gene therapy. I am aware that I still have mild hemophilia and unfortunately, I am unable to recover from the damage to my joints from living with severe hemophilia B, but right now, I am focused on all the positives. I feel like I can live life more spontaneously,” says Pembroke.