Designing Clinical Trials for Parkinson Disease Gene Therapy Presents Substantial Challenges

Deborah Phippard, PhD

Carefully designing clinical trials for gene therapy programs in Parkinson disease (PD) is incredibly important to effectively evaluating these investigational treatments. Because of the complexity of PD, however, the task is not exactly straightforward.

CGTLive® recently spoke with Deborah Phippard, PhD, the chief scientific officer of Precision for Medicine, to learn more about this topic. She emphasized that challenges like choosing the ideal patient subpopulations and end points for studies do not have immediately clear solutions, and that the scientific community will need to find a way to overcome these questions in order to meaningfully test novel gene therapies in PD.

CGTLive: Can you discuss the potential of gene therapy to address unmet needs in PD?

Deborah Phippard, PhD: It's a really interesting question how we might use gene therapy to address PD. Something that I certainly think about a lot with gene therapy as we move away from less rare diseases is that I think something like 1% of the population may well have PD—what makes that really interesting to me is it's probably not 1 disease, there's probably a lot of different underlying mechanisms. As such, maybe we should think about it as a rare disease in terms of targets. So there is a lot of opportunity to think about how we might want to address PD. I think one of the biggest ones when I think about with gene therapy is actual delivery of the therapy into the central nervous system (CNS). If you look at the companies that are currently working on gene therapy modalities for PD—there's a number of them—Capsida Biotherapeutics, Voyager Therapeutics, Prevail Therapeutics, AskBio—obviously, this is a rich area where research is certainly working. But I think they're all taking different approaches to how to target the CNS—whether you would take the gene therapy and surgically insert it into the CNS or if you're taking an approach where you're designing a capsid to really get that into the CNS.

It's exciting that there's many different approaches, more than one might work, but I'm sure they're all going to have different pros and cons. I think where you use a gene therapy, rather than using a drug, you can avoid those peaks and troughs. Thinking about some of the questions around whether PD therapy has been efficacious—do you keep the dose at the level you want in the area that you need it? When I think about it, I think gene therapy has a lot to offer from getting the therapy to the target and getting sustained expression of whatever it is you're choosing to introduce.

And that's a whole other question, because there's many different targets. There's probably 2 that are currently being explored the most now. But yeah, there's certainly a lot of ways we can think about gene therapy for PD.

Are there any challenges to bringing this modality to PD that you can discuss?

Like pretty much everything in the gene therapy space, I'm like "how long do we have for this interview to talk about the challenges?". Lots of bright people are working on this. What is the target that you're going to go after? Certainly those that are going after mutations in GBA1, that's a subset of something like 10% of PD patients that have that genetic component or driver of their disease. But again, that's only 10% of patients. Great proof of concept, but what about the other 90%?

There's been many different alleles that have been suggested so I think we've got a lot of work to do phenotyping the different types of PD and thinking about getting the right patients into the right trial for a particular therapeutic modality.

Then I think the other big challenge is the stage of the disease at which you recruit these patients into a study. By the time you're showing clinical symptoms, you've probably had PD for upwards of 10, probably 20, years. There's a lot of talk in the literature about whether you can really do much when the disease is at that stage. I hope we can, but certainly in terms of therapy, that's not the easiest way to treat.

If you're talking about recruiting patients into a study before they've got any clinical symptoms, which is probably where you have your best chance of having an effect, you've got to persuade people to go into what is maybe a high risk [trial]—so persuading patients to enter that study, I think is challenging. But also what are you measuring? How are you finding the patients? I assume you'd have to use biomarkers or something like that, but they don't have clinical symptoms. So what are you looking at as a marker of disease modification? If you're looking at time to symptoms, that can make your clinical trial very long duration, which of course is difficult and expensive and patients tend to drop out of long studies. So you open a whole can of worms with just how difficult it is to do this type of gene therapy in PD. I've only touched the surface of considerations here. It’s challenging.

When it comes to clinical trial design specifically, are there any important considerations/challenges that will need to be taken into account when evaluating gene therapy candidates for PD?

It's a multifactorial disease and we probably want to treat patients ahead of clinical symptoms. I think just designing a study is very difficult. When I look at the companies that are working in the gene therapy space, the fact that they are going after patients with mutations in the GBA allele makes great sense to me. Although patients with these mutations don't all go on to develop PD and certainly, when you look at the biomarkers, that doesn't mean you're going to get full blown PD, but I think using that subset population as the first round of patients makes a lot of sense to me... We know these are not completely risk-free therapies and I think using a therapy that you don't have to have direct injection of into the CNS is a lot less scary for patients to think about. As a scientist, I don't know, personally I'd rather have localized application of a gene therapy than take it systemically. But I think if you talk to patients in general, the idea of having an MRI-directed therapy into your brain—I don't know, I think that's quite a heavy lift for people to be able to get past.

Transcript edited for clarity.