Jonathan D. Grinstein, PhD, the North American Editor of Inside Precision Medicine, hosts a new series called Behind the Breakthroughs that features the people shaping the future of medicine. With each episode, Jonathan gives listeners access to their motivational tales and visions for this emerging, game-changing field.
My family and friends often ask me, “Are we close to curing diseases like ALS and Alzheimer’s?” For most of my career, I have given them a blanket “no.” But in recent years, several academic and industry endeavors have given reason to be hopeful.
Toby Ferguson, MD, PhD, is the chief medical officer at Voyager Therapeutics, developing genetic medicines and delivery tools to get across the blood-brain barrier (BBB). In this episode, Ferguson explains the current state of therapeutics for neurological and neurodegenerative diseases, challenges in delivering genetic medicines and other therapeutics to the nervous system, and Voyager’s approach to getting through the BBB.
This interview has been edited for length and clarity.
IPM: What is the state of drug development for neurological and neurodegenerative diseases?
Ferguson: Nervous system disease has seen the fruits of an explosion in genetic understanding. So, we start to have a series of high-quality, genetically defined targets that we think could treat many of these populations of amyotrophic lateral sclerosis (ALS), Parkinson’s, and Alzheimer’s. These techniques could include gene therapy, antisense oligonucleotides (ASOs), and small interfering RNAs (siRNAs). All of these technologies get to this genetic core of the diseases.
One of the continued struggles is getting things into the nervous system in a straightforward and reasonable way for patients. The ASOs are, in general, administered with a lumbar puncture; that can work, and if your disease is severe enough, like ALS, [a lumbar puncture] can make sense, but it can be burdensome to the patients, their families, and the healthcare system. Many neurology clinics aren’t set up to give lots of lumbar punctures.
One key lesson over my time at Biogen was the fundamental issue of getting things to the right place, to the right cells in the nervous system, and across the blood-brain barrier (BBB)—it is critical to success. You can’t access the potential of precision medicine without getting things to the right place. The BBB has evolved explicitly to not let things in—that’s its job. So, you’re working against what nature has evolved.
[Voyager is] starting to identify receptors that either a viral particle or other therapies can bind to and get into the central nervous system: the spinal cord, cortex, and substantia nigra, which is essential for Parkinson’s. You’re starting to understand how to deliver things precisely. The concept of precision medicine has to conceive not only the precision of the treatments but also the precision of the delivery, and that’s what’s exciting about Voyager. We’re trying to combine the genetics with the delivery.
IPM: How does Voyager Therapeutics’ delivery approach differ from existing methods, both technically and in terms of applicability?
Ferguson: A lumbar puncture is a straightforward office procedure, but it’s time-consuming. It requires a nurse and local anesthesia, and you need an hour or so to walk to the patient after the injection. That’s not set up that well yet in all clinics. You can do it, but it’s clunky.
For an intravenous injection, the health system already has infusion centers. There should be simplicity in terms of comfort for the patient, straightforwardness for the physician, and infrastructure. The hope here is that simplicity will ease and allow more frequent access and overcome the logistical hurdles of getting medicines to people.
IPM: What does the clinical pipeline look like at Voyager Therapeutics?
Ferguson: Voyager has done an excellent job of assembling a set of preclinical data in mice from various primates, as well as identifying receptors expressed in mice, primates, and humans. They’ve assembled a very large preclinical data package that suggests this approach should work. We need to do the trials and get the data, but the question we need to answer is, “Does the gene therapy capsid get things into the nervous system in people precisely?”
I’ll highlight two programs. We have an ALS SOD1 gene therapy program, and we have an Alzheimer’s program, which is a tau knockdown program, also using one of our capsids. Both those targets, SOD1 and tau, have been targeted in human beings in other forms, in this case, ASOs. Tofersen is an ASO, and based on the Tofersen program, when you knock down SOD1, which is the goal of the ASO or gene therapy when you knock it down, we know that you can measure the SOD1 protein in cerebrospinal fluid (CSF) and show a reduction of about 30–40%. That reduction in the Tofersen program led to a reduction of neurofilament of about 60%. You had a potential emergent clinical benefit at longer timeframes than six months to a year, 18 months. Based on biomarkers, we know precisely how much reduction of a measurement of SOD1 protein in CSF and a measurement of another protein, neurofilament (NfL), in the blood makes it effective there. In tau, there’s been a similar experience. Reductions of tau can be shown in humans, and there’s earlier data, but there’s also a potential benefit.
We’re putting together well-validated targets with novel delivery capsids and then measuring in human biofluids to say, “Have we got our goal? Have the capsids gotten across the BBB? Are they doing what they’re supposed to be doing?” What’s exciting about that is that at these early stages and with smaller trial populations, the biomarkers offer you a way to get a more precise answer quickly and clearly with fewer people. Our next step is to use these known biomarkers that others and I have worked on to define success or get a read on the nervous system in the way you can in other tissues and for other diseases.
This idea that you can start to measure things in the blood that tell you about things in the nervous system is critical. It’s one of the key changes I’ve seen over the last eight or nine years. We’re starting to get a few very good tools. NfL is a structural protein found in most neurons, and when neurons die or are injured, NfL gets shed into the CSF and the blood. In ALS, it’s particularly useful because what we know about it in ALS is that the higher the levels of NfL, the quicker your disease is going to be—the more quickly you lose function and die. Based on the Tofersen experience, if you knocked it down by a percent, you’re likely to have a positive clinical effect. And so it’s an example of a tool that changes how you think about your programs. Over time, we’ll get these same tools for Alzheimer’s and Parkinson’s, though that seems a bit away. But I’m starting to be optimistic that biomarkers will be a part of that story going forward.
IPM: What are your predictions for the future of genetic medications’ potential to “cure” nervous system disorders?
Ferguson: For neurodegenerative diseases, I’ve got a lot of optimism. I don’t think it will be easy, but we will be in a space where we start thinking about disease much earlier in this course. We start to understand how we can treat people earlier to prevent their disease from emerging. We’ll understand that we’ll start to have several different therapies, say beta-amyloid therapies, on top of tau therapies for Alzheimer’s. We’ll layer these together and understand who will and won’t respond. We’ll probably have other interesting Alzheimer’s targets. You’re going to start to have an armamentarium for patients that really will be able to treat their disease significantly; I feel very confident of that in ALS, Alzheimer’s, and Parkinson’s.
We’re going to have failures. But we’re also going to have some success, like the beta-amyloid therapies for Alzheimer’s, and unlock a set of tools and a bit more understanding of the disease, making it easier to innovate. What I’m optimistic about is not that everything we do will work, but we’ll get more efficient. We have better tools now, and we will encourage investment because there’s some success, and then we’ll keep doing that using better tools. Five to 10 years from now, we’re going to have half a dozen meaningful therapies for Alzheimer’s. Things will come together as we start to have iterative success.
