Rare Disease Report

FDA Releases Guidance to Advance Development of Gene Therapies

JULY 12, 2018
Krista Rossi
The advent of gene therapy represents a shift in medicine as a whole; the thought of modifying an individual’s DNA in order to prevent or treat rare, life-threatening diseases is as profound as it is risky. Currently, this technique is being tested only for diseases that currently have no other options. As such, many rare diseases fall into this category. Often faced with no other alternative, patients are willing to take a leap of faith into the unknown in hopes of obtaining a cure for their ailments.

Although the technique remains risky, many notable advances have been made in the fight against hard-to-treat diseases thanks to its use; this is underscored by the fact that the first such treatments came to market just last year after having received approval from the US Food and Drug Administration (FDA).

And, according to FDA Commissioner, Scott Gottlieb, MD, more research is to be expected in advancing the development of these therapies.

In an official statement, Dr Gottlieb announced that the FDA is working to provide a comprehensive framework for the development process through the addition of 6 scientific guidances which will help advance the field and ensure that all new products are safe and effective.

“In the future, we expect this field to continue to expand, with the potential approval of new treatments for many debilitating diseases,” Dr Gottlieb said. “These therapies hold great promise. Our new steps are aimed at fostering developments in this innovative field. Gene therapies are being studied in many areas…we look forward to working with the academic and research communities to make safe and effective products a reality for more patients.”

He admitted that more knowledge and insight into the mechanics and functioning of gene therapies are needed, as well as their long-term performance outcomes, such as possible adverse side effects.  

Unlike the traditional drug review process, challenging questions pertaining to durability of response, and product manufacturing and quality may remain unanswered at time of approval. As such, tools for reliable post-market follow up—such as required post-market clinical trials—are imperative. In order to facilitate timely access to potential effective therapies, many of these uncertainties are accepted with the idea that the payoff may outweigh the risk. However, with these policies, the FDA is working to creating more of a regulatory path to maintain the “gold standard” pertaining to safety and effectiveness of these therapies.

“These policies are part of our efforts to communicate the steps we’re taking to provide clear recommendations to sponsors and researchers, so that we can better support innovation,” Dr Gottlieb explained. “The documents are being issued in draft form so that we can solicit public input on these new policies. As with all draft guidances, all of the comments we receive will be carefully considered prior to finalizing these documents. We’re committed to working with stakeholders to bring novel treatments to the market while ensuring the safety of patients.”  

To do this, the FDA will also be issuing 3 new draft guidances pertaining to human gene therapy in the following: hemophilia, retinal disorders, and rare diseases as a whole. These guidelines will offer preclinical, manufacturing, and clinical trial design recommendations for all phases of the clinical development program for these variants of gene therapies. They will also aim to assist sponsors in the clinical development of programs in which limited study population sizes, potential feasibility and safety issues, and questions pertaining to the interpretation of effectiveness are present.

In addition, the FDA has provided new and comprehensive updates to 3 existing guidances dating back to 2008 and 2006, which focused on the chemistry, manufacturing, and control for human gene therapy investigation new drug applications, testing of retroviral vector-based gene therapy products for replication competent retrovirus during product manufacture and patient follow-up, and long term follow-up administration of gene therapy products.

As Dr Gottlieb mentioned, gene therapies have been making waves in the rare disease community for some time now, but especially recently. One such therapy, the AAVrh74.MHCK7.micro-Dystrophin vector, displayed outstanding preliminary results in its phase 1/2a trial in Duchenne muscular dystrophy (DMD) patients.

Advances were made in the battle against hemophilia as well, with several recent gene therapies, such as SPK-9001 in its phase 1/2 trial, valoctocogene roxaparvovec in its phase 1/2 study, and AMT-061 in its phase 1/2 clinical trial, showing promising potential.

A recent phase 1/2 clinical trial looking at the gene therapy FCX-007 in patients with recessive dystrophic epidermolysis bullosa (RDEB) was found to be well-tolerated and safe, with no serious adverse events reported. EB-101was recently evaluated in a phase 1/2 trial for the treatment of EB and was granted a regenerative medicine advanced therapy designation, and the first patient has been dosed with the gene therapy KB103 in a recent phase 1/2 clinical trial for the treatment of DEB.  

Another gene therapy, Lenti-D, was assessed in a recent phase 2/3 study for the treatment of patients with cerebral adrenoleukodystrophy (CALD) and hit its primary efficacy endpoint; as such, it was granted a breakthrough therapy designation by the FDA. Furthermore, ABO-102, an adeno-associated viral-based (AAV) gene therapy, was found to be effective for the treatment of Sanfilippo syndrome type A (MPS III A) in a recent phase 1/2 trial; AAV gene therapy MYO-101 was recently granted a rare pediatric disease designation for the treatment of limb girdle muscular dystrophy (LGMD); and the FDA accepted an investigational new drug application for the gene therapy, BIVV003, for the treatment of sickle cell disease.

As the previously listed gene therapy candidates are just a selection of the many in development, the FDA’s additional guidance will help break through the many unknowns associated with the rare disease and the gene therapies available to treat them.

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