CSO Corner Volume 10: Establishing the Natural History of Kleefstra Syndrome

Hello fellow members of our KS family!

I’d like to reach out today to talk about ways we in the community can work towards understanding the natural history of Kleefstra syndrome (KS). Spoiler alert: at the end I am going to ask you to jump in and help us with this effort! This is one area where community participation is simply essential…

When I talk to drug developers about KS, one of the first questions I inevitably get is something along the lines of: “what is known about the natural history?” The reason they are asking this question is that they are savvy: without a well-established natural history, a future clinical trial becomes very challenging to conduct. And drug developers have to see a path to a future clinical trial before they will commit resources to developing a potential treatment.

It’s worth spending a little time on the term “natural history”: simply put, it means how a disease is expected to progress in the absence of treatment. It’s what you would expect to see if you did nothing (beyond the current standard of care). You might think: we already know a lot about KS, don’t we? And the great news is: we do! KS is a well-studied syndrome and we have a strong understanding, that is constantly improving, about the clinical presentation and what is expected in general.

But truly understanding natural history is about getting very specific: when will certain changes take place, and what will be the magnitude of those changes? If a patient has one complication, what is the probability they will have another related complication? If a patient scores well on one measure, how common is it for their score to worsen, or to improve? It is this level of specificity that is required to design a clinical trial and choose the appropriate tests and measures that will eventually be used to ask the essential question: did the patients improve when treated? 

To build this kind of natural history, we will need data, and lots of it. And collecting that data takes time, so we need to start right now! The great news is that this absolutely a known challenge in the rare disease space, and there a lot of groups and platforms exist to help us establish a natural history. The U.S. Food and Drug Administration (FDA) has even produced draft guidance on best practices for developing natural histories in rare diseases.

There are two primary types of natural history studies: prospective and retrospective. Today, I’m going to focus on retrospective (we’ll return to prospective studies in a future article). The concept of these studies is to gather as much data as possible about patients looking at how they have done up to now, and then chart all of that data to find trends. Done with a large enough group of patients, we can start to build up a pretty detailed profile of what we can expect as far as the progression of KS.

We’ve partnered with two platforms, RARE-X and Citizen Health, to help us gather data that can be used to develop a retrospective natural history for KS. Each takes a different core approach.  RARE-X is based primarily on the gathering of information about patients from surveys filled in by caregivers. Citizen Health, in contrast, pulls in the medical records of patients and then automatically extracts all the relevant information from those records to build a model. Each approach has strengths and weaknesses, but both are powerful, and potentially complementary. The value of this type of data is already being leveraged in scientific publications to better understand other neurodevelopmental disorders.

By collecting this type of data for our community now, we will be in position to generate similar types of natural history results in the future. This is a core part of the work we need to do as a community to ensure we are clinical trial-ready.  So what can you do? Join the effort! If you haven’t joined RARE-X and Citizen Health, now is the time to do so. Here are the links to sign up:

RARE-X (147 KS patients currently enrolled): https://rare-x.org/kleefstra/

Citizen Health (66 KS patients currently enrolled): https://www.citizen.health/partners/kleefstra-syndrome

Just as important: If you have already joined RARE-X, log in and make sure all of your surveys are completed. Also, make sure to fill in surveys as they are released to you. You’ll get an email when a new survey becomes available. Although we have an amazing number of our community signed up for RARE-X, we won’t be able to retrieve quality data from it without everyone completing their surveys. It really matters!

On a personal note: I know surveys can be tiring to fill out. The way I get mine done is to choose one to do per day. For me, this prevents “survey fatigue” and before you know it, they are all done.  Below is just a sampling of some of the data that RARE-X has already shared with us, but this is just the beginning of what will be possible with more complete data. Let’s do this!

Until next time,
Eric Scheeff, PhD
IDefine Chief Scientific Officer