Q&A with G. Bernhard Landwehrmeyer

Clinical trials that test new therapies usually get all the attention because they can have a fast payoff if the drug being tested actually works. But an observational study like Enroll-HD, which tracks how people affected by HD change over time, has a potentially transformative impact that goes far beyond one new drug or treatment, argues neurologist G. Bernhard Landwehrmeyer, MD, FRCP, the principal investigator of the study. Enroll-HD will make it easier to understand the biology of HD, more quickly identify physical signs and symptoms that accurately reflect the stage of the disease and, ultimately, enable the trials that will demonstrate effective therapies. It will act like a booster rocket, lifting future clinical HD research into a new realm so that studies are better, faster, and more economical (in terms of burden on participants and research staff alike).

Enroll-HD will create the world’s largest database for clinical research on HD, eventually including information from as many as 20,000 people in around 33 countries. Landwehrmeyer, who is a professor of neurology at the University of Ulm in Germany and chair of the executive committee of the European Huntington’s Disease Network, explains why this type of study is so rare—and why it is so important.

Q: What is Enroll-HD, and why do we need it?

Enroll-HD is a platform that allows health care professionals, scientists, and families affected by HD to work together towards a better understanding of HD and identify effective treatments. Despite the fact we have more than 100 years of clinical observation of HD, our understanding of the biological effects of the mutations and the mutant protein is still far from complete. We’d like to come up with reference values, like physicians do for many other things, such as knowing the number of red blood cells you’d normally have in your blood. In HD, we’d like to un- derstand far better what you’d expect in someone at any given age, gender and CAG-repeat length [the gene mutation that predicts when disease onset is likely to occur].

Since the identification of the HD mutation and gene in 1993, we’ve gained a lot of insights by studying model systems of HD, such as mice with copies of the mutant gene. What we don’t know is whether the mechanisms we’ve identified in model systems are drivers for the real thing in real people. Enroll-HD will help us understand that.

Q: In the past, many studies of HD failed to prove anything one way or the other. Why did that happen, and will Enroll-HD fix that problem?

From the 1950s though the 1980s, most HD studies were performed with less than 100 participants. They were convenience samples. That means that if you, the researcher, had an idea for a study, you might talk to your colleague, who referred the patients he or she happened to have. That results in a cohort of patients that are not systematically collected. So it’s unlikely you’ll end up with a conclusive study. To be conclusive, you have a range of people with different CAG repeats, at different ages and stages of disease. That’s why Enroll-HD needs to be so big, and why it needs to include people in such different circumstances. Enroll-HD helps us to do conclusive studies, ones large enough to provide an answer. We cannot guarantee that the answers will be as we hope they will be. But we can guarantee that the studies will give us answers.

Q: How does Enroll-HD accelerate research into new treatments?

A: We can work together with partners in pharmaceutical companies, for example, to find out whether a planned drug trial is feasible, and can help study sites by flagging participants who might be suitable for a particular trial. Enroll-HD sites see participants on a regular basis, at least once a year, and are more acutely aware of who is interested and who might fit the study requirements. Of course, it’s still the decision of the individuals whether or not they want to participate. But in our experience, having a database with participants who have volunteered for an observational study will tremendously speed up recruitment into clinical trials of potential therapeutics. We were able to recruit 150 participants in four months for the last study we did. That’s pretty good.

“You personally may not benefit… but you’re making a great contribution… you’re doing it to speed up the process”

Also, Enroll-HD provides tools to foster collaboration and stimulate local center-based HD research. All clinical data from all participants at a given study site will be available for HD research at this center in real time, with no strings attached. We’d like to encourage people to do their own research, or team up with like-minded people, so that progress in research is not bottlenecked by a central planning committee. Instead, we’ll have local initiatives that are quick and competent.

Lastly, we would like to make sure that the experience for people who volunteer for HD research is further improved. Nothing is more annoying for patients and families then to have to engage with yet another health care provider every year anew. Enroll-HD should help to build stable HD centers. Also, the burden that comes with additional HD studies should be reduced; you don’t have to go over your medical history and explain your medications yet again, since it will already be available on the Enroll-HD database. That means it’s less time and effort for participants and less burden- some documentation for study sites.

Q: Why does Enroll-HD need to be global?

One main reason is that we need both genetic and environmental diversity. For example, in the New World you have people who are genetically very close to people in the Old World, but they live in quite different environments. We are doing extensive genetic studies. If we also do a good job capturing environmental differences, we can contribute to understanding how the environment modifies disease progression.

Also, from the patient perspective, it makes sense. Otherwise, just because you were French, let’s say, you might be denied the opportunity to contribute to clinical trials. Where’s the justice in that? That’s not fair.

Q: There’s no immediate benefit for people who join the study. Why should they do it?

You personally may not benefit—you may even have to accept some risk—but you’re making a great contribution that changes the landscape for you and your own kids. You’re doing it to speed up the process of getting to solid results, as part of a larger community that is striving toward the same aim. Progress depends on the coming together of science, industry, clinicians and people affected by HD.

Because Enroll-HD is a long-term, open-ended study, there’s the potential for HD centers to have long-term stability. That perspective is good for everyone. It’s also important that young physicians and scientists see that HD research is an exciting field where things are really moving, where cutting edge therapies are being developed. The smart young people will get drawn to it—it’s working, it’s collaborative. That’s how you’ll get the best people.

Enroll-HD is also designed to improve clinical care, which will improve in part because people will talk to each other about intelligent approaches to problems. Also, we’ll have records of the therapies people are receiving, and we can identify centers that have particularly beneficial outcomes, and ask: Why is that? This will help all the centers start to do it better. Through Enroll-HD we want to foster a culture of exchange between health care professionals and families, so that we can talk about a standard of care that truly deserves that name.

This story was originally published in the February 2013 issue of Enroll!