The dawn of gene therapy for rare diseases

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Andrew Obenshain, Chief of Wings at biotechnology firm bluebird bio, tells HEQ about the future of gene therapies in the treatment of rare diseases

Up to 30 million EU citizens are affected by a rare disease, many of which are chronic and life-threatening. HEQ spoke with Andrew Obenshain, SVP, Head of Europe at Massachusetts-based biotechnology firm bluebird bio, about the future of gene therapies in the treatment of rare diseases.

The European Union defines a rare disease as one which affects less than five in 10,000 of the general population: how wide-ranging are these diseases in terms of severity and the impact on patients’ quality of life?

There are between 6,000 and 8,000 known rare diseases, and around five new rare diseases are described in medical literature each week. In Europe, a disease or disorder is defined as rare when it affects less than one in 2000 citizens, but all together, rare diseases may affect 30 million European Union citizens. 80% of rare diseases are of genetic origin and are often chronic and life-threatening.

Most rare diseases have no cure, so living with a rare disease requires continuous management of patients. Although each individual disease may itself be scarce, a lot of the challenges facing patients are common to many. In severe cases, rare diseases can be highly disabling, limit life expectancy; and can lead to profound social and economic consequences.

According to the NGO Committee for Rare Diseases Task Force, the combined uncommon, complex and disabling nature of most rare diseases leads to serious unmet health and social needs for people living with these diseases and their families’ wellbeing, autonomy and fundamental human rights.

Take the example of thalassaemia. People with Transfusion Dependent Thalassaemia (TDT), the condition’s most severe form, require lifelong supportive care with regular blood transfusions — typically given every two to five weeks — to treat anaemia. Without regular blood transfusions, people with TDT cannot survive. Despite the availability of supportive care, many people with TDT experience serious complications and organ damage due to iron overload, which is an unavoidable side effect of regular transfusions.

Iron overload, in turn, can cause tissue damage and impaired function of affected organs such as the heart, liver and endocrine glands. Iron-induced cardiomyopathy, a disease of the heart muscle, has been recognised as a leading cause of death in patients with TDT. That’s why blood transfusions require iron chelation therapy and iron monitoring. By eliminating or reducing the need for blood transfusions, the long term complications associated with TDT may be reduced.

Living with thalassaemia can greatly affect an individual’s quality of life. For example, chronic blood transfusion requires missing school or work for one day every three to four weeks. Having a child with thalassaemia can also negatively impact the welfare of the family, limiting family activities and negatively impacting parental time.

How available are gene therapies for patients in Europe and how can this be improved? To what extent is cost a factor?

Since the first gene therapy was approved in Europe in 2012, the pace has picked up; and regulators are creating a specific path for rapid access of those new therapies, providing hope for manufacturers, healthcare professionals, and patients. The US has seen a similar growth and the FDA expects an approval rate of 10 to 20 cell and gene therapies every year by 2025.

Gene therapy is a technology with the potential to herald in a new era of ways to treat genetic diseases, with a potential one-time treatment. However, this dawn of gene therapy also calls for new approaches to the way that treatments are evaluated and reimbursed to ensure that patients get fast access and health care systems remain sustainable. This will be a critical part of getting these new treatments from ‘bench’ to ‘bedside’.

The European Medicines Agency (EMA) has been extremely supportive of the concept of gene therapies and has been open to establishing an early dialogue with companies and introducing its PRIority MEdicines (PRIME) initiative in 2016 with the aim to bring promising medicines meeting regulatory requirements to patients earlier.

PRIME was launched to enhance support for the development of medicines that target an unmet medical need. This voluntary scheme is based on enhanced interaction and early dialogue with developers of promising medicines, to optimise development plans and speed up evaluation so these medicines can reach patients earlier.

But if we are going to get gene therapy to patients, all European health systems need to be ready to work collaboratively with industry to remove possible barriers. All parties involved must be prepared to move away from those traditional approaches that have been adopted for chronic therapies, towards one that reflects the precise nature of advanced medicines. This also requires the industry to be flexible and prepared to share risk when it comes to possible payment models.

An example of this would be the concept of outcome-based commercial agreements that enable commissioners to pay over an extended period, such as a five-year window, tied to specific clinical outcomes. This approach would necessitate that industry underwrites some of the ambiguity that could otherwise be a barrier to achieving reimbursement. This is something that we take very seriously at bluebird bio, and we have publicly stated that we are prepared to put the majority of the price of our therapies at risk, meaning that we will only get paid if our treatments perform over time.

bluebird bio’s first treatment for beta thalassaemia was cleared by EU regulators in June 2019. What was behind the decision to file this with the EU first, rather than the FDA?

We made a conscious decision to launch in Europe first, ahead of the US. Several factors informed this: the higher numbers of beta thalassemia patients in Europe compared to the US, the flexibility of the EMA’s PRIME fast-track process for cutting-edge therapies, and Europe’s single-payer healthcare systems.

We are optimistic that the simplicity of talking to one payer in each country will help to negotiate our novel risk-sharing outcomes-based deal more easily than in the US. We endeavoured to engage in early dialogue with the EMA, including with its scientific advice office, and the review, under the PRIME scheme, took just 150 days. In a recent statement, the EMA regulator referenced a new paper published in the journal Clinical Pharmacology & Therapeutics that describes these exchanges, using our gene therapy as an example case.

Is there any stigma or misinformation surrounding gene therapy and its ethical implications? How can this be addressed?

There is still a limited public understanding and confusion around gene therapy, as well as some concerns, suspicion and misinformation around the topic, which need to be overcome. There is misunderstanding around what gene therapy actually means and what it consists of; and it is sometimes confused with germline genome editing, which has captured consumer media headlines from time to time.

Although gene therapy has the potential to inactivate or ‘silence’ a gene, to interrupt a disease process or introduce a new or modified gene into certain cells to help treat a disease, the changes made to a person’s DNA using gene therapy only affect certain cells in the body; and the changes may be permanent. In either case, the changes will not be passed on to a person’s offspring, since they are not made to the cells that are involved in reproduction.

The key to addressing any misinformation or stigma is open conversation. As advances are made in the field of gene therapy and it becomes a reality for patients, many of the residual concerns should be dispelled as understanding of the field progresses.

Andrew Obenshain
bluebird bio

Please note, this article will appear in issue 12 of Health Europa Quarterly, which will be available to read in February 2020.

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