The future of gene therapies

Making gene therapies economically viable 

 Rare diseases – and even ultra-rare diseases – predominate in the gene therapy world. These treatments are very well suited for monogenic disorders where replacing a single deficient gene can have a dramatic effect on disease progression, or even provide a cure. But the small numbers of patients makes the financial models very challenging, with the costs necessarily based on extremely small batch sizes. As a one-off disease-curing treatment, with all the development and manufacturing costs loaded onto very few doses, the cost-per-dose is always going to be extremely high.  

The economics are very different for more common disorders such as cardiovascular problems, diabetes and the more prevalent cancers. The issue facing gene therapy here – regardless of how effective it is – is that the cost may well be higher than for existing treatments. Improving yields and quality will be crucial to make the economics work for such disorders.  

Spinal muscular atrophy (SMA) has become the poster-child for successful gene therapy, despite the astonishingly high cost of the treatments. It has been hugely helped by very active patient associations who have pushed for reimbursement for these life-changing treatments. But as the field moves into more prevalent disorders, reimbursement will only happen if the prices are more sustainable for the healthcare system. Without significant advances in manufacturing technologies, this is never going to be possible.  

Redefining cell and gene therapy manufacturing 

 Gene therapies need to find the right patient population. Leber congenital amaurosis (LCA) and SMA have been successes because the impact of the therapy is huge compared to the risk, and there were no real alternatives. Other examples such as haemophilia have been more challenging, where it’s not just about the cost but about the existing alternative therapeutic options that already provide substantial benefit. 

An example that falls between the two is the chimeric antigen receptor T-cell (CAR-T) therapies that have been developed for cancers. These involve harvesting cells from patients, using a viral vector (usually a lentivirus) to manipulate the genes, and then returning them to the patients within a few hours. While there have been therapeutic successes, it remains a manufacturing challenge as the treatment center where the cells are genetically modified has to be near to the cancer patients. This has led to a great deal of interest in generating the CAR-T cells in vivo by injecting the vector directly into the patient. This would remove the ex vivo manufacturing challenges, and provide a scalable manufacturing solution.  

And this is where the quality concern comes in. Vectors designed for use directly in patients will always have higher quality requirements than those used ex vivo. While most vectors currently used in vivo are AAVs, lentiviruses are increasingly being used in this way and higher purity will need to be achieved for these, too. QC analysis will obviously also need to be more in-depth.  

Yes, there are significant challenges that need to be overcome. But vector-based therapies have so many potential advantages for patients that if productivity can be improved and manufacturing issues can be overcome, then they may prove life-changing for patients who have few – or no – alternatives.