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The new world of gene therapy: five questions answered


Gene therapies offer the hope of a cure for many devastating diseases, a one-time treatment that modifies a person’s gene to remove the disease completely. For patients suffering from a wide range of diseases, the promise is immense. Sounds good? Of course, as with all science, as with all medicine, the reality is considerably more complicated. At Inizio, we work with patients, healthcare professionals (HCPs) and pharmaceutical industry clients on some of the most exciting developments in healthcare solutions. In this article, our team answers five key questions about the future of gene therapy for rare diseases

By Amanda Henkel, practice area lead, rare diseases; David Gibson, chief global scientific lead; Jo Fearnhead-Wymbs, SVP patient engagement; Alex Morton, SVP patient engagement from MEDiSTRAVA, an Inizio company.

Why is everybody talking about gene therapy?

Gene therapy is one of the fastest growing areas of healthcare. Rather than just treating symptoms, gene therapy has the potential to get right to the core of the disease—modifying a person’s genes to treat a disease. This can be achieved by replacing a disease-causing gene with a healthy copy of the gene or inactivating or removing a disease-causing gene. Hundreds of clinical trials are currently ongoing, with research efforts predominantly focusing on oncology and rare diseases, such as haemophilia, cystic fibrosis and Huntington’s disease (many of which are ideal candidates for gene therapy, as they are caused by mutations in a single gene). However, the broader potential for gene therapy is huge, with pharmaceutical companies investigating its application in a wide range of disorders, including heart disease, diabetes, AIDS and Parkinson’s disease.

Gene therapy research began over 40 years ago and while progress has been slow to reach patients, several products are now authorised for use in a range of conditions (notably spinal muscular atrophy, retinal dystrophy, and more recently haemophilia), with that number expected to increase exponentially over the next few years.

Gene therapy offers tremendous hope, particularly in the rare disease setting where treatments are often unavailable or only provide short-lived quality of life (QoL) benefits because they do not target the actual cause of the disease. With gene therapy, there is potential for cure, or at a minimum, for a restoration of function that can lead to significant improvements in quality of life. Consequently, patient communities are keen to understand what these therapies could mean for people living with these genetic conditions; there is real public appetite for developments in this space. But reality and expectations are not always aligned. Health systems face logistical issues, and must navigate complex social, ethical, health and economic concerns. Gene therapy may not be curative, and it may not be suitable, or indeed available, to everyone. Gene therapies frequently make news headlines because of their extremely high price tag, and even when they are approved by regulatory authorities, unfortunately, there is no guarantee of access for the individuals that most need them. Moreover, understanding of gene therapy can often be limited in patients and caregivers, and the benefits overestimated.

What kind of an impact could gene therapy have on people living with a rare disease?

In many cases, it is hoped that gene therapy will result in a “cure”, abolishing symptoms so that “management” of a condition is no longer required. For some conditions this may be the case, for example with the inherited blood disorder beta-thalassemia, gene therapy can free patients from the burden of regular blood transfusions. However, in other conditions, patients can overestimate the benefits and expect a “cure”, but in reality, their condition is improved but not eliminated. An example of this is seen with gene therapy for haemophilia A and B. Again, the burden of treatment can be significantly reduced, but some individuals may need to receive ongoing infusions of factor replacement; furthermore, joint damage that occurred prior to the gene therapy infusion cannot be reversed. Durability also remains a question, and in some conditions, such as some forms of hereditary blindness, after initial results, the retina may continue to degenerate, with gene therapy offering only a temporary respite.

Managing the divergence between expectations and reality for all stakeholders is essential. All too often gene therapy is described as a “one-and-done” treatment, but for many this is unlikely to be true. As a relatively new innovation, many questions remain outstanding, even amongst therapies that are already approved.

Safety considerations are also of paramount importance and will be a factor for many people. Early research studies with gene therapy triggered leukaemia in some patients—a concern that has since been alleviated with use of newer, safer viral vectors, but are there unforeseen safety considerations we are not yet aware of? Long-term safety data are elusive, and the “unknowns” remain unknown. Patients suffering with a severe life-threatening or life-limiting disease who had little hope of normal life may express minimal concern about safety in the face of a potential cure with a gene therapy. In contrast, younger patients may tend to be more questioning of potential safety issues. Regulatory authorities require long-term follow-up of any individual receiving gene therapy to adequately assess the safety profile, typically for a minimum of five years, but ideally over their lifetime.

Anyone considering gene therapy (or any family members/caregivers considering gene therapy for their child) needs to fully understand all aspects of the treatment, the benefits, risks, and also be willing to make a commitment to long-term follow-up. In the short term, monitoring of their condition may even increase. It is important to also remember that gene therapy only represents a cure for the individual receiving treatment. For families with hereditary conditions this means their condition can still be passed on to their children.

How could gene therapy impact the wider healthcare paradigm?

Gene therapy has the potential to significantly improve the lives of people suffering from a genetic condition; however, the cost of the treatment represents a significant hurdle. For example, a gene therapy for haemophilia recently approved in the US has a price tag of $3.5 million. The pharmaceutical company feels the cost is justified, saving the US healthcare system $5–5.8 million per person treated, but high upfront costs such as these are challenging for many healthcare systems to absorb. Access and reimbursement are obstacles that will take time to remove—payers and insurance companies need to adapt existing frameworks or develop new payment models. For institutions such as the UK’s National Institute for Health and Care Excellence (NICE), funds are limited and so understanding the impact of gene therapy and its cost effectiveness is critical. While gene therapy may be a reality for patients in advanced, industrialized countries, or those with personal wealth and robust insurance coverage, for many others it remains a distant unobtainable prospect.

Gene therapy is typically administered at specialist centres (hubs), with long-term monitoring undertaken at a local (spoke) centre. These requirements mean patients may need to travel significant distances to receive their treatment, and it also necessitates transfer of patient data—which adds another layer of complexity. Funding, resourcing and training will be required. In some cases, patients may even need to travel to another country to receive treatment, adding further complication and cost.

Even in countries that can offer gene therapy, not all individuals will be eligible for treatment—not just within the controlled confines of a clinical trial but also in the real world after approval. For example, age may be a limiting factor, or in the case of gene therapy using viral vectors, previous exposure to the wild-type virus. These restrictions could create a two-tiered system—for those that have had gene therapy versus those that haven’t. Additionally, gene therapy may not work for everyone—what happens then? Can gene therapy be re-administered if you fail to respond the first time? These questions remain unanswered. An additional consideration is that, for many individuals, families and caregivers, integration into the patient community is significant, and their (or their child’s) condition may be tied into their identity—along with their friends and social lives. Concerns over these psychological aspects should not be downplayed.

Despite these challenges, the huge potential for gene therapy remains, with the possibility for some previously undertreated diseases to literally become a thing of the past, with a real reduction in demands on healthcare services for some conditions.

What are the key challenges in making gene therapy a reality?

Gene therapy has come on in leaps and bounds, but challenges remain. The process of developing a gene therapy can be very lengthy and patients and their families sometimes have unrealistic expectations. In particular, scaling up the manufacturing process and delivering the therapy in the real world (not just in the confines of a clinical trial) takes time. The situation can be particularly difficult in rare conditions, where small, disperse patient populations may make it hard to gather sufficient data. The safety of any new therapy is of upmost importance to regulators, and consequently they often require long study lengths in order to feel comfortable—for example BioMarin’s gene therapy for haemophilia A was initially rejected by the United States Food and Drug Administration (FDA), requiring an additional two-year period of follow-up, and disappointing the rare disease community who had anticipated its approval.

Even if approval is granted, reimbursement can be a huge barrier to access. Pharmaceutical companies face challenges from payers and, as in the case of Bluebird Bio in 2021, may feel they have no option but to withdraw from Europe to focus on more profitable markets, such as the US. The significant price tag means gene therapy may only ever be reimbursed in some markets or paid for privately. Health equity is increasingly part of the healthcare debate, and we must ask ourselves—how can a life-changing drug be approved but not made accessible to the people that most need it?

Education is key. This is complex science and can be difficult for patients, HCPs and regulators/funding decision-makers to understand. We need to have meaningful discussions about safety and durability. We need to determine what happens if the treatment fails. What are the ethical considerations and motivation for treatment? Does everybody want to be treated in this way? Where do we draw the line? The diseases that potentially could be treated with gene therapy are typically poorly served by current therapies and the burden of disease suffered by patients and their families is immense. Patient communities must be involved in the decision-making process.

What should we be looking out for in the next five to ten years?

For many of the questions posed, we don’t yet have all the answers. Indeed, gene therapy is still a relatively new field and we’re still learning. Importantly, as more patients are treated, we are constantly gathering important safety information. Approvals are expected to exponentially increase, with more than 30 gene therapy launches anticipated across a range of conditions in the next two years. With this expansion, we will surely resolve some of the current challenges around access and reimbursement. The FDA, EMA (European Medicines Agency) and WHO (World Health Organization) have all provided guidance to support the development of gene therapies—with the aim of improving access to ensure health equity for all.

Open discussions, debate and education about what is considered a complex therapeutic option are needed, and the support of patients and patient advocacy groups can help to drive these discussions forward, championing the cause of those without a voice. The future is incredibly exciting and the potential for gene therapy is huge for patients and caregivers—but to deliver a global solution and true health equity, pharmaceutical companies, payers, policymakers and advocacy groups need to work together.

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