A clinical development plan for FD

One of the challenges in rare diseases is creating a path for new therapies to be tested in the clinic. Learn how our collaborative effort is forging a path forward for familial dysautonomia.

Kids born with familial dysautonomia (FD) have symptoms from birth. Their sensory neurons fail to develop due to a lack of a protein called ELP1 (or IKAP). By the time they leave the nursery, it’s usually apparent that they have swallowing problems and then lung issues. By the time most of the children reach their teens, the neurodegenerative aspects of the disease strike and they struggle with walking and seeing. It’s a hard disease to treat, as there is no cure, but that doesn’t stop us from trying, explained Dr. Horacio Kaufmann – Director of the Dysautonomia Center at NYU Medical Center, who cares for the largest number of FD patients worldwide.

In a neighboring state, Harvard geneticist and endowed professor Dr. Susan Slaugenhaupt, leads a team of scientists in her lab where they have been studying the genetic underpinnings of FD for over 2 decades. Dr. Slaugenhaupt’s early work showed that although the ELP-1/IKAP gene was mutated, patients were still capable of producing some normal (wild type) protein. In other words, the gene was misread, but not completely defective, opening the possibility of being able to fix the message and restore the protein.

cells stained for ELP-1/IKAP
Cells stained for IKAP/ELP1 (https://www.proteinatlas.org/ENSG00000070061-ELP1)

In many ways FD became the poster child for developing new therapies in a rare disease. It was picked up by NIH’s Blueprint Neurotherapuetics Network, a program designed to help scientists shepherd compounds through the “valley of death”, so they leave with a molecule that can be tested in the clinic.  Fast forwards today, and we have great candidate molecules that cause a potent increase in ELP-1/IKAP levels.  What we need now is to do our due diligence to check these are safe for humans and then effective for FD.

Community organization

For new drugs to be tested in humans, they require the oversight of the U.S. Food and Drug Administration (FDA) and there are several ways to do this. But before embarking on any one strategy we first need the FDA to understand what is FD and what are our unmet needs, explained Dr. Lucy Norcliffe-Kaufmann. Basically, we need the families to convince the FDA why we must think outside the box when it comes to clinical trials in FD; we have small numbers, not every patient is the same, some of the things we are hoping to improve aren’t easily captured in a clinic visit or questionnaire, and patients certainly don’t want to be taking a placebo for extended periods.

The Familial Dysautonomia Foundation is taking on this challenge, by hosting a Patient Focused Drug Development Meeting for the FDA officials (to be held in Washington D.C. on October 19th, 2020).

The voice of the patients can be very impactful. But when it comes to rare diseases like FD, the FDA needs to understand how the disease looks, how it expresses itself differently among patients, and how patients are still suffering. The afternoon for the FDA officials will be a real opportunity for the FD community to speak up. We have kids that can still walk and see, but one day they might not, explained Dr. Kaufmann, we are in a rush. If we choose a genetic therapy based on the best available science that passes the first hurdle of safety checks, the goal would be to get it to as many patients as possible to test if it is effective. Kaufmann was adamant, we are in it to help all patients, not just those that we can most easily measure an endpoint in when they come to the office. Every person with FD deserves a chance to see if these therapies work for them.

Rick Guidotti for Positive Exposure
Dr Horacio Kaufmann and Dr Lucy Norcliffe-Kaufmann have been tasked with creating a clinical development plan for familial dysautonomia (FD). This includes a Patient Focused Drug Development meeting, where families have an audience with FDA Officers. (Photo: Rick Guidotti for Positive Exposure)


With FD being a rare disease, there are only 700 cases known worldwide. But that doesn’t stop us from being well organized, explained Dr. Lucy Norcliffe-Kaufmann. We have a natural history study with 2 additional sites in Israel so that we can follow patients with FD and learn what we can improve. It’s always been a strength to our program.

When it comes to testing whether a drug is effective, we need good endpoints, which are features of the disease that matter to patients and worsen predictably overtime. When you give a new potential disease-modifying therapy, the hope is that you stop or at least halt the progression. For FD patients, the endpoints that show the most promise are scans of the retina and rating scales on walking.

From collecting natural history data, the team have been able to put together a clinical development plan that tells us how many patients we need to enroll to show a measurable difference. Of course, it all depends on how effective a treatment is, explained Dr. Alberto Palma, drugs that are more effective require fewer people to show they make a difference. Now the Center has a sufficient amount of data to make power calculations.  The largest population of FD patients outside of the U.S. is in Israel. The clinical development plan will need both countries, which means more patients will have the opportunity to try potential treatments.

The good thing about our clinical development plan is that it isn’t unique to one drug, explained Dr. Kaufmann. It can be adapted to almost any strategy that we want to test in patients with FD that is aimed at saving the neurons from dying.

All hands-on deck

Working closely with the Familial Dysautonomia Foundation’s scientific advisory board is key to the strategy. Recently, the Foundation reshuffled the members bringing in top FD basic-scientist Dr. Frances Lefcort and drug development expert Dr. Adrian Gilbert as co-chairs. Both have a personal connection to FD and understand the urgency to find new therapies.

 October 19th, 2020 is an important date for our FD community. We have an audience with the FDA to tell them what we need and why there isn’t time to wait when it comes to testing new therapies we think are safe and rational.

What the clinical development plan needs most, right now, explained Dr. Lucy Norcliffe-Kaufmann is for all the families to get behind the motion so we keep the momentum. We need people to enroll in the natural history, donate samples, but right now, we are also asking them to join us at the FDA – in whatever way they can. FD may be small in terms of numbers, but it’s team of dedicated doctors, scientists, families, and advocates are ready to speak up about the unmet needs. Mark your calendars for October 19th, 2020 when we will have an audience with the FDA. News will come soon with further details.

Learn more:

About the natural history study

The natural history dataset