Gene Therapy Development: The Past and Present
By: Sunish Patel
Tags: Cell And Gene Therapy, Gene Therapies, Drug Development, Biotechnology

The year is coming to an end and the end of the decade is fast approaching; much development has taken place across 2010–2020 in gene therapy.

Two interesting commentaries have been published in Nature recently; the first discusses the progress in gene therapy development in the last decade, and the other discusses the future opportunities from the current challenges in gene therapy.

The first clinical research dose of a gene therapy product was on 14 September 1990, for a child with a genetic defect that results in a severe immune system deficiency (SCID). The first gene therapy medicine, Gendicine, was approved by the Chinese State Food and Drug Administration (CFDA) in 2003 to treat head and neck squamous cell carcinoma. It wasn’t for nearly another 10 years before the EMA approved Glybera in 2012 for lipoprotein lipase deficiency. In 2017; the US FDA approved the first gene therapy in the USA; Kymriah. Since then there has been a steady number of gene approvals per year worldwide; an overview of approved gene therapy products up till 2019 was published recently.

These first approvals instigated an increased level of focus on cell and gene therapeutics (CGT). This pace has picked up in the last few years, with more than 1000 on-going clinical trials in 2019, with more than 50% of these in Phase II. The US FDA Commissioner Scott Gottlieb predicts that the FDA will be approving 10 to 20 CGT products per year by 2025.

The regulatory agencies have also supported this growth across the last decade. Before 2018 CGT clinical research required dual review; by the NIH Recombinant DNA Advisory Committee and the FDA, since 2018, this review is only conducted by the FDA to bring in line with other medicines. And in 2020 the US FDA finalised a series of guidance documents for gene therapy development.

However not everything has been good news, Glybera’s was withdrawn by its developers uniQure in 2017, not due to safety issues but due to commercial challenges. This has brought an increased focus on the challenges and opportunities ahead. CGT presents a novel solution for some conditions that do not have any treatments or those with very complex medical treatments; many of these are children who have a heavy burden of both condition and treatments.

Aside from the commonly discussed challenges such as; patient access and treatment budgets, the authors in the commentaries point out other clinical development and technical development challenges.

Clinical Challenges

CGT creates an opportunity to develop medicines for diseases that do not have any or limited therapies, but this requires additional work in drug development to design and validate novel clinical end-points.

Potential immune responses to the gene delivery vectors and products of foreign transgenes.

CGT are a new first in class for many diseases. In combination with a lack of large animal models that closely model the human disease; developers need to be prepared for clinical results that had not been predicted by the pre-clinical animal models.

Current gene therapies are being developed for smaller populations; this means that the gold standard of a double-blind, randomised trial may not be possible.

The earlier the intervention in genetic disease, the better the outcome and the sooner an improvement in the quality of life; however, children will need to be part of clinical trials.

Technical Challenges

Limited worldwide CGT manducating capacity.

A limited number of individuals with training and experience in CGT drug development

Regulatory authorities need to increase resource to keep with the development and technology advancement pace of CGT.

Limited locations for CGT clinical trials due to the need for specific site requirements such as cryopreservation facilities

Change in operation model of building up of inventory to providing Just in Time (JIT) products; this will challenge the traditional models of pharmaceutical manufacturing processes and established supply chains (e.g. made to order)

US FDA CGTx Guidance finalised in 2020:

Originally published at https://www.pipelinescientist.com on December 5, 2020.