Gene therapy

Moving gene therapy out of the lab and into the clinic requires support from Big Pharma. No one else has the massive resources and expertise needed to develop, manufacture, market and gain regulatory approval of new conventional drugs, let alone an entirely new drug category, José-Alain Sahel MD told the Ophthalmology Futures European Forum 2016. Interestingly start-up companies have led the path and provided the most relevant proof-of-concept studies. After years on the sidelines, major players are now stepping up, said Dr Sahel, who is Director of The Vision Institute, Paris, France, Professor at Pierre and Marie Curie Faculty of Medicine in Paris, Professor and Chairman of the Department of Ophthalmology at the University of Pittsburgh School 
of Medicine, USA, and a founder of GenSight Biologics. However, significant technical and economic challenges remain that will take time to overcome, several presenters said. These include the rarity of many genetic diseases, difficulties developing safe viral delivery vectors and precisely delivering them, and scaling up production to commercial levels. The good news is ocular applications are particularly attractive in part because they require only minute doses, said Vivian Choi PhD, Head of Gene Therapy Research, US, Shire Pharmaceuticals, Lexington, Massachusetts, USA. The action of ocular therapies also can be readily observed in a segregated, relatively immune privileged, anatomical space. RARE DISEASES Diseases treatable with gene therapy tend to be rare genetic disorders, such as Leber’s congenital amaurosis and choroideraemia, which attack the retina, Dr Choi said. Low volume of ultra-orphan indications limits both availability of research candidates and potential market size, posing challenges to the financing of the high development and testing costs. For ethical reasons, human tests are usually initiated in patients with advanced disease, presenting another challenge, said Simon Chandler PhD, Head of Clinical Research and Regulatory Operations at Ora Inc, London, UK. “Most of the cells we need to treat aren’t there anymore,” he said, which may make it impossible to restore vision to levels detectable with traditional acuity or visual field tests. Therefore, surrogate endpoints must be developed, Dr Chandler said. These include biochemical and anatomical markers, as well as newly developed vision function tests, such as one developed by Spark Therapeutics, Philadelphia, USA. The test measures patients’ mobility improvements due to the restoration of enough vision to detect light sources and orient themselves in space. Changes in how clinical trials are designed, allowing patients involved in early safety and efficacy trials to roll seamlessly into later dose-finding and pivotal clinical trials, will also help by reducing the total number of patients required for discrete phase 1, 2 and 3 trials, Dr Chandler said. In recent years, the US FDA has been increasingly supportive of such adaptive trial designs. This includes the enrolment of earlier stage patients, who have no other treatment options, into safety trials, he noted. VECTORS AND DELIVERY Replacement genes are delivered by modified viruses, and these must be carefully developed for each therapy to ensure they both work and do not provoke immune reactions or other severe side effects, Dr Chandler said. The technology to measure the quality of these vectors also has to be invented from scratch, customised for each therapeutic vector. The requirements can be punitive – for example in one Ora trial, a vector required the development of 24 quality control assays. Gene therapy must also be delivered precisely to be effective. For example, a choroideraemia treatment developed by Robert MacLaren FRCOphth at Oxford University, UK, must be injected into the 
subretinal space. “Very skilled surgeons such as Dr MacLaren can get back to the same hole and put it in the same space, but for the typical surgeon that is much more difficult,” said Marc de Smet MD, PhD, co-founder and Chief Medical Officer of Preceyes BV, Eindhoven, The Netherlands. Disseminating the procedure requires development of instruments that make it easier, such as robotic injectors or specially designed needles. Industrial organisations that had experience in developing traditional biologics can leverage their knowledge to tackle the challenge of producing gene therapies which meet industry standards for consistency and volume, Dr Choi said. “Manufacturing for gene therapy has been a continuous challenge in the field, but much progress has been made to develop manufacturing technologies and to build capacities to support clinical testing and commercial supplies,” she said José-Alain Sahel: j.sahel@gmail.com Vivian Choi: vivian.choi@shire.com Marc de Smet: mddesmet1@mac.com Simon Chandler: schandler@oraclinical.com