NOVEMBER 2023LIFE SCIENCES REVIEW8IN MY OPINIONBy Dr. Linda Randall, AVP, Biologics Development, Manufacturing & Control, Pharmaron [SHE: 300759]THE TIPPING POINT FOR SCALABLE MANUFACTURING PROCESSES TO PIVOT GENE THERAPIESdvanced Therapies, including cell therapies, gene therapies and gene editing products, are one of the leading current developments in the biopharmaceutical world. Buoyed and driven by the promise of creating a life changing treatment for rare diseases and in some cases, offering the hope of a potential cure for patients, this field is revolutionising the way we approach everything from clinical trial design, to regulatory expectations and re-imbursement policies.Yet gene therapies themselves are not new. The first gene therapy human dose administration was just over thirty years ago (1990), however, gene therapy faced several setbacks and challenges, but continued investment in technology and regulatory science in this field has supported the advancement. Recent data shows that the number of clinical trials underway in the US with gene therapies rose during the period 2020 to 2021 from 410 to 522 trials, with approaching 7 percent of those trials in Phase 3 and pre-registration stages. In the same report, data showed that 89 percent of gene therapies utilise viral vectors for delivery, with Adeno-Associated Virus (AAV) being the most prevalent gene delivery vehicle.Two recent approvals of AAV gene therapy drugs are major contributors to the resurgence in investment in gene therapies as medical treatments and potential cures: (1) approval of Luxturna in 2017 by FDA and 2018 by EMA, which is a single injection in each eye of an AAV carrying a functional copy of the RPE65 gene into the retinal cells for the treatment of an inherited form of vision loss and (2) approval of Zolgensma in 2019 by FDA and 2020 by EMA for a one-time intravenous injection of AAV9 which carries a functional copy of SMN1for treatment of spinal muscular atrophy.Having originally focused on rare diseases with small patient populations, such as retinal dystrophy (anticipated 1000-2000 patients in US3) and spinal muscular atrophy (10,000 to 25,000 patients in US), drug developers are now turning their attention to treating prevalent diseases.The Alliance for Regenerative Medicine (ARM) presented data that shows that almost 60 percent of the 2,400 Regenerative Medicine clinical trials at the end of 2021 targeted prevalent diseases, such as diabetes and Parkinson's5.With rare diseases and the very small number of patients, many of the indications require relatively low doses, for example Luxturna (1.5 x 1011 vector genomes in 0.3ml). This translates into a low drug substance and drug product demand and therefore drug substance manufacturing batch size. In early clinical trials there are tens of patients, and the stability demand can outweigh the demand of drug product for the patients in the trial. As Dr. Linda RandallA
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