Bumps in the Road for Commercial Gene Therapy for Rare Diseases
Authors: Seppo Ylä-Herttuala
Journal: Molecular Therapy (2017)

Despite excellent scientific progress in gene therapy for rare diseases, commercial development of these new treatments faces significant challenges. GlaxoSmithKline (GSK) announced in August that they are “considering options for future ownership” of Strimvelis, an ex-vivo stem cell gene therapy that was recently approved by the European Medicines Agency (EMA) for treatment of adenosine deaminase severe combined immunodeficiency (ADA-SCID), a rare immune system disorder. After much publicity and excellent scientific results, only two patients have so far been treated with Strimvelis, with an additional two to follow. The cost of the therapy is estimated to be $665,000, and GSK is investigating whether other companies or institutions might be better placed to ensure availability for the very limited number of patients. A mere 20–30 children are born each year with ADA-SCID in the European Union (EU) and US. This news from GSK closely follows UniQure’s announcement that they will stop selling Glybera in the EU upon expiry of its marketing authorization in October 2017. Glybera—with an approximate $1 million price tag—has only been used commercially for one patient since its approval in 2012. Glybera is an adeno-associated virus serotype 1 (AAV1) viral vector delivering the human lipoprotein lipase gene to muscle cells. Last year, UniQure dropped plans to seek approval of Glybera in the US. The news clearly indicates that commercial exploitation of gene therapies for rare diseases is just as challenging as their clinical development. Despite these problems, GSK and UniQure will continue to develop gene therapies in other more common areas, such as oncology and the hemophilias. Some other large companies, such as Sanofi and Shire, have also entered the field, targeting both rare and more common disease indications. On the bright side, last year, the US Food and Drug Administration (FDA) approved Spinraza, developed by Biogen for spinal muscular atrophy. The drug is an anti-sense oligonucleotide (ASO) targeting the SMN1 gene. It is currently in clinical use and providing real income to Biogen despite the high cost of approximately $750,000 for only the first year of treatment and fears that repeated intrathecal delivery of ASOs would prove very demanding for both the young patients and clinicians. Some other virus-based gene therapy products are also under development for the same indication. An EMA application for Spinraza is currently under evaluation. Another positive development is the approval of a genetically engineered oncolytic herpes virus called Imlygic by both the EMA and FDA in 2015 for the treatment of advanced melanoma. Even though the indication is limited to more advanced cases, the potential market size is much greater than that of either Glybera or Strimvelis. While Glybera and Strimvelis have turned into money losers for their companies, they nevertheless represent significant scientific achievements. In hindsight, this type of problem might have been expected based simply on the vast resources required for marketing, manufacturing, and fulfilling all regulatory requirements. With new products under development and nearing approval, it is expected that the situation will change with products aimed for the treatment of hematological malignancies, hemophilias and some other rare diseases, such as Leber congenital amaurosis and inherited central nervous system disorders. While more common indications will probably become profitable targets for companies, it is likely that general discussion and joint activities of third parties, such as charities, foundations, non-profit organizations, and research institutions, will be needed to support treatment of ultra orphan diseases that are unlikely to ever be commercially viable. Scientific organizations and infrastructure programs worldwide may also become important players in securing new treatment options for rare diseases that cannot find a home in the commercial world. This should also be reflected in the regulatory demands placed on this type of non-commercial clinical exploitation of new gene and cell therapies because, while not compromising safety and efficacy, barriers to clinical implementation of the new therapies in specific dedicated centers should be adjusted to a reasonable level in trying to secure the best, and often the only, treatment for patients with ultra orphan diseases. This would also help to maintain continuous top-level research and clinical development of gene and cell therapy.