What About Gene Therapies?

When discussing the potential of precision or personalized medicine, cell therapies are often the first to spring to mind – and such therapies are certainly causing a stir in the industry. But there is also another contender in the precision medicine field that potentially offers significant benefits: gene therapy. Gene therapies work in one of three ways: i) replacing a mutated (improperly functioning) gene that causes disease with a healthy copy of the gene, ii) inactivating a mutated gene, or iii) introducing a new gene to the body to provide a treatment or cure.

The first gene therapy was administered to a human in 1990 but, since then, gene therapies have faced several challenges and setbacks, including unexpected side effects and, in one case, a tragic death. Over the years, knowledge and understanding of the field has increased, along with relevant technologies and regulatory acceptance. From 1990 to 2015, more than 2000 clinical gene therapy trials were approved worldwide. Data from the Gene Therapy Clinical Trials Worldwide database shows that the number of trials has risen steadily from 102 in 2012, to 163 in 2015. And in 2017, a handful of gene therapies are expected to move into the EU and US approval processes.

The increase in gene therapy activity is attributed, in part, to the first EU approval of a gene therapy agent in 2012 – Glybera for the treatment of lipoprotein lipase deficiency, which leads to severe or multiple pancreatitis attacks. Many challenges faced Glybera and uniQure has since decided not to seek market authorization renewal in Europe, but the fact that it was approved signals to researchers, drug makers and investors alike that the regulatory pathway for gene therapy for rare diseases is open.

Gene therapy is most commonly delivered via viral vectors, with recombinant adeno-associated virus (AAV)-based vectors being the most widely used. One significant advantage of AAV vectors is the availability of different recombinant serotypes, which means that therapy can be targeted to specific tissues or organs in the body. For example, the AAV2 serotype is being used in early phase clinical trials to deliver a gene that encodes channelrhodopsin-2 (ChR2) – a light sensing protein – to the eyes of patients suffering from blindness due to retinitis pigmentosa.

Research around gene therapies is now moving at a rapid pace, and scientists have a number of techniques in the toolbox to help identify mutations and create therapies to correct them. But what about manufacturing? It’s still relatively early days for gene therapy commercialization, so it’s fair to say that manufacturing is a big challenge. Current processing methods have been well placed to provide early clinical trial material for proof of concept (typically tens of patients), but these processes are frequently low yielding, laboratory-scale processes that are difficult to scale up. At later stages of development, drug product demand escalates as material is required for analytical method validation and product stability, as well as late-stage clinical studies – and, at this point, the manufacturing challenges become very apparent. As an industry, it is important that we continue to develop scalable, robust process technologies, as well as orthogonal analytical techniques that ensure the right balance of quality, yield and manufacturing costs. At the moment, there is a shortage of GMP manufacturing capacity and routine manufacturing expertise for gene therapies, but more contract manufacturing organizations and companies are now seeing the dawn of a new era of commercialized therapies and subsequent investment in internal capabilities will help to drive the field forward.

As more gene therapies reach the market, manufacturing will become more efficient as companies learn through repetition. So, does that mean we are poised to overcome the major gene therapy hurdles? The elephant in the room is cost – a highly controversial topic that is common to all precision medicines. Many say that the price for a single dose of Glybera ($1 million) is extraordinary, but others believe that a lifechanging therapy – that only requires one dose – is surely worth the cost, particularly given the fact that Glybera treats an inherited, chronically disabling diseases for which there is no other cure. Like Glybera, most gene therapies in development also target rare diseases and conditions of unmet medical need, and R&D investment and the cost challenge associated with small scale production of a single-dose administration for a small patient population will force health economists, drug companies, insurers, and health service providers to re-think their approach. Perhaps in time, these discussions will lead to innovation in healthcare provision.

Nevertheless, I believe that we are on the edge of a major transformation in the biopharmaceutical world. With increased collaboration and investment in developing manufacturing platforms for these therapies, as well as innovation in health economics, I think gene therapy has a real chance to make a difference to medicine.