Skip to main content

Biomarkers - What are they and why do we need them?

February 25, 2020

As more and more therapeutic development programs advance from basic scientific research into clinical trials in humans, our conversations with therapeutic development partners have also advanced. Once a company decides there is sufficient scientific evidence to assess efficacy in humans, the focus immediately shifts toward defining the key elements necessary for a successful clinical trial – a trial design that will support FDA approval.

The first challenge is to select the clinical endpoint. As defined by FDA, a clinical endpoint is “a characteristic or variable that reflects how a patient feels, functions or survives. Clinical endpoints are distinct measurements or analyses of disease characteristics observed in a study or clinical trial that reflect the effect of therapeutic intervention”. Basically, how will you assess if the treatment works?

Because no therapeutic has yet been approved by FDA to specifically treat Rett Syndrome, there is no precedent or roadmap to follow that will guarantee success. Each company must individually negotiate with FDA for each therapeutic development program, without complete assurance that the clinical trial results will ultimately satisfy FDA standards for approval. At present all companies developing novel therapeutics for Rett Syndrome are pioneering a new path to FDA approval. To reduce this risk, RSRT is actively collaborating with physicians, scientists and companies to develop and refine clinical endpoints that will be acceptable to FDA. The key next step is to confirm that these clinical endpoints are sufficiently sensitive to detect meaningful improvements.

Another strategy for reducing this clinical development risk is to identify biomarkers that either predict which individuals will respond to the therapeutic, or guide dosing to achieve optimal efficacy. For example, if a therapeutic was available that could completely restore normal brain function, the individual with Rett Syndrome would likely, at best, add skills and abilities at a normal rate. It could take months, or even years, for individuals to add the levels of new skills needed to clearly demonstrate improvements to FDA standards. A biomarker that measured the improvement in brain function could be used to adjust the dose of medication to optimize therapeutic efficacy in each individual and therefore maximize the acquisition of new skills.

Since therapeutics for Rett Syndrome may take a considerable amount of time to show clinical improvement, it is highly desirable to find ways to not only guide dosing but also to predict the ultimate clinical improvement. For these reasons, discussions with therapeutic development partners have rapidly advanced to include potential biomarkers. In anticipation of this need, RSRT launched our Outcome Measures and Biomarker Initiative in 2016.


When used in therapeutic development, the term biomarker has many potential meanings. In fact, FDA defines seven categories of biomarkers: susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamics/response, and safety.

For Rett Syndrome, the most useful types of biomarkers for clinical trials would include predictive and pharmacodynamics/response biomarkers.

Predictive biomarkers identify individuals that are more likely to respond to a therapeutic. For example, in breast cancer, genetic analyses can identify individuals more likely to respond to specific treatment regimens. A predictive biomarker could be used to select individuals for a clinical trial, reducing the number of participants required to demonstrate efficacy, thereby reducing costs to industry and burden on our Rett community. In addition, this type of biomarker could also prevent enrollment of individuals unlikely to respond to a specific treatment and/or those more likely to have negative side effects.

Pharmacodynamics/response biomarkers are used to show that the therapeutic produced the expected biologic response. Measuring blood pressure to guide drug and dose selection when treating hypertension is an example of this type of biomarker. The benefit of reducing blood pressure into the normal range is not immediately obvious, but long-term control of blood pressure effectively reduces the risk of stroke and heart attacks. Similarly, this type of biomarker could guide dosing to optimize efficacy in each individual so that long-term treatment can maximally improve brain function.

Successful development of robust biomarkers has potential to assist in monitoring drug activity, predicting therapeutic response, and guiding the development of safer and targeted therapies for individuals with Rett Syndrome. If validated to FDA standards, biomarkers can provide valuable information to improve efficiency and reduce uncertainty in drug development.

Our science team at RSRT is deeply committed to advancing the research to dramatically change the lives of your children. We couldn’t do this work without all the families that fundraise for us and our generous donors. Thank you for your trust, confidence, and support.


Take Action

It’s not a question of “if” we’ll find cures, but “when”. You’re one click away from bringing that day closer.