Are Biomarkers the Key to Accelerated Approvals for Rare Diseases?

#DIA2023 is well underway. One of the more interesting and timely sessions was surrounding accelerated approval in rare disease, highlighting the role of novel biomarkers, surrogate endpoints, and other innovative approaches in expediting development. The panel was composed of two FDA representatives, several biopharma companies, and a patient advocacy organization.

The discussion centered around the current status of the accelerated pathway program, the challenges preventing advancement in rare diseases, and the importance of balancing unmet need with the required thresholds for endpoint biomarkers. 

Current Status of Accelerated Approvals

The panel discussed the recent momentum towards accelerated approval of rare diseases. Having previously been focused mostly on oncology and infectious diseases, the Accelerated Approval Program is now reviewing rare diseases — and addressing the nuances that come along with working with smaller patient populations and high unmet need.

In October 2022, the FDA announced the establishment of a Rare Disease Endpoint Advancement (RDEA) Pilot Program to support novel endpoint efficacy development for drugs that treat rare diseases. 

In April 2023, Center for Biologics Evaluation and Research (CBER) announced plans to launch Operation Warp Speed for Rare Diseases by year end. Lessons learned from accelerating the development of COVID-19 vaccines during the pandemic are being applied to ensure cell & gene therapies for rare diseases enter the market as quickly as possible, without compromising their safety and effectiveness. 

With both of these programs in progress, researchers are looking at the use of intermediate endpoints and/or biomarkers that are well characterized in order to predict a clinical outcome in a disease with a high unmet need. 

Advancing Rare Disease Treatments

During the panel discussion, Dr. Peter Marks, the Director of the CBER at the FDA, addressed the use of novel biomarkers and the necessary clinical evidence for accelerated approval. He highlighted that biomarkers should indicate a deficiency or an elevation of something specific. Additionally, when measuring a biomarker, it is important to do so consistently and reliably, and there should be a clear link between the biomarker and the level of function it represents.

Dr. Marks emphasized that if the scientific research is well-executed and properly planned, there are ways to achieve the desired outcomes. When questioned about the specific level of clinical data required, Dr. Marks clarified that it varies: Better biomarkers require less clinical data. Decisions surrounding the level of data are individualized based on the endpoints under consideration. 

A New Regulatory Precedent - Accelerated Approval of the First Gene Therapy for Duchenne Muscular Dystrophy (DMD)

One hot topic of discussion was the recent approval of the first gene therapy for treatment of certain Duchenne Muscular Dystrophy (DMD) patients through the accelerated approval pathway. 

According to the news release, the FDA concluded that the data submitted by Sarepta Therapeutics demonstrated that an increase in dystrophin (surrogate endpoint) was likely to predict clinical benefit in boys 4–5 years of age. It is important to note that this approval depends on the likelihood of clinical benefit based on biomarker data, and as a condition of approval, the FDA requires a study to confirm the clinical benefit. 

This approval sets a new regulatory precedent, paving the way for further accelerated approvals in the rare disease space, and for the rapidly growing class of gene therapy. 

Rising Importance of Biomarkers

Are biomarkers becoming the key to accelerated approvals for rare diseases? In the case of DMD, the biomarkers are based on levels of dystrophin in the muscle, which can only be done by performing a muscle biopsy. Those samples become incredibly important, especially in the case of rare diseases. Visibility into the end-to-end sample journey — from collection at the site to the lab — is vital to patient outcomes. As an industry, we must look to the future and do whatever is possible to protect sample integrity.

A New Hope for Patients 

The news of the first gene therapy for DMD was especially exciting due to our conversations earlier this year with Terri Ellsworth and her son Billy Ellsworth. It is amazing to see how far research has come since the first U.S. exon skipping clinical trial for DMD. While the gene therapy has yet to prove clinical benefit, it is a necessary step forward to providing treatments for DMD patients. Plus, as previously mentioned, it opens the door for more movement in the rare disease and cell & gene space.