Turning the Tides on Neurodegeneration the Denali Way, A Conversation with Ryan Watts, CEO.

Innovation That Matters
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While striving towards success in an area of imperative medical need, Denali Therapeutics looks to set a new bar in neurodegenerative clinical research. Established in 2015, Denali has built an impressive product pipeline, with over 30 partnerships, 15 pipeline programs, 5 clinical stage programs and multiple modalities – a notable accomplishment in light of the difficulty associated with neurodegenerative treatments.

The company develops approaches to neurodegeneration using three principles: (1) genetic disease linkage – which highlights the important disease pathways for therapeutic intervention; (2) targeted approach to crossing the blood-brain barrier for optimal brain delivery of small and large molecules, and (3) biomarker-driven clinical trials to enhance the probability for success.

As a company that is dedicated to a single disease area–neurodegeneration in diseases such as Parkinson’s, Alzheimer’s, ALS, and Hunter Syndrome–Denali credits over 30 collaborative partnerships covering industry and academia as a key element to its success.

Rich Soll, Senior Advisor, Strategic Initiatives, and WuXi AppTec’s Content Team had an opportunity to discuss neuroscience, Denali and personal perspectives with Ryan Watts, CEO and co-founder of Denali Therapeutics.

WuXi AppTec: Your thoughts on the “State of Innovation,” where are we?

Ryan Watts: Having founded a company five years ago, and having been in the industry for twenty years, what’s pretty incredible is seeing new technologies enormously accelerate the drug development process. Within five years at Denali, for example, we now have five clinical stage programs. I think what’s happened with the speed of invention is that we can develop clinical candidates much faster and begin clinical trials sooner.

WuXi AppTec: The FDA approves forty to nearly sixty new drugs per year. Do you think over the next ten years we’ll get approval for 100 new drugs? Do you think this is realistic?

Ryan Watts I think the challenge in neurodegeneration is that the time to see a clinical benefit remains long and the costs remain high. Nevertheless, we have a deeper understanding of disease now, and have been developing molecularly targeted medicines in neurodegeneration that have the potential to be transformative. I certainly hope that new approvals will soon include a number of medicines for Alzheimer’s disease, Parkinson’s disease and other neurodegenerative diseases.

WuXi AppTec: Do you see current approaches taken across the industry as incremental or transformative in your view?

Ryan Watts: I think there’s great diversity across the industry, but certain approaches have become transformative. We’ve introduced new modalities to treating disease like antisense oligonucleotides and gene therapy. We have gotten so much better at molecular therapies and biologics and so you’re starting to see better and more transformative medicines. In neurodegenerative diseases, the ability to bring drugs across the BBB in therapeutic concentrations will be transformative.

WuXi AppTec: How does technology shape the future and what kind of technological breakthroughs might be game changing in the next five years for you?

Ryan Watts: I’d like to talk about what happened in the last five years and what’s been game changing, which is the ability to engineer the genome not only for a therapeutic approach, which still is a ways off, but also for research tools that are critical to developing medicines. Being able to generate cell lines or mouse models has been one major advantage; the ability to do high-content imaging and assess thousands of compounds rather than hundreds; and we can generate a variety of cells that are genetically engineered.

In the last five years we’ve been able to do much more than we’ve been able to do in the previous twenty-five years. In the next five years I see these applications becoming translational.

WuXi AppTec: What we see for the drug approvals today is kind of the fruits of what happened ten plus years ago so you can imagine that the work done today will translate into yet more transformative medicines. Thank you for your perspectives.

Let’s discuss Denali itself, a company formed around neurodegeneration in an era where companies were just basically bailing out of the neurosciences.

Ryan Watts: Yes. There are three broad buckets of neuroscience: neuropsychiatry, pain, and neurodegeneration and they’re all distinct in terms of their biology and genetic underpinnings. For us at Denali, we are looking to tackle big problems.

Denali was founded with a singular purpose: defeat degeneration. Marc Tessier-Lavigne, Alex Schuth and myself previously worked together and founded the company in 2015. We have a very clear goal to invent medicines that slow or halt or cure Parkinson’s disease, Alzheimer’s disease, and ALS.

As a smaller company that takes bigger risks while maintaining focus on the underlying mechanisms, we built the company around three principles.

First is genetic pathway potential. So using genetics to define the targets and the pathways we work on, and most of that information is new within the last decade.

The second is engineering brain delivery, or inventing medicines that cross the blood-brain barrier (BBB). Engineering small molecules and large molecules (antibodies and proteins) to cross the BBB is foundational. To do it, we have a biology team that’s focused on the BBB that teams up with the engineering team. Together this group is focused on technologies to help small and large molecules cross the BBB. We think that this is critical and in fact some of the disease areas we work on, like rare neurodegenerative diseases or liposomal storage diseases, have less biology risk. We know that in fact, the enzymes that are deficient in these diseases can be delivered systemically to treat as enzyme replacement therapy, but they don’t get across BBB. We see demonstrating that as one step toward a bigger challenge of solving Parkinson’s and Alzheimer’s.

The third principle that we focus on is biomarker-driven development to show target engagement, pathway engagement, and or patient phenotyping; this is essentially integrated into everything we do. Developing and utilizing biomarkers allows us to de-risk and better predict success for our therapeutic programs.

Now we are at a point where we have five clinical stage programs, four of which are small molecules and one is a biotherapeutic, and we’re expanding our biotherapeutic platform.

WuXi AppTec: Can you elaborate?

Ryan Watts:   LRRK2 is a gene that has been shown to be mutated in a subset of Parkinson’s patients resulting in hyper-activation of the kinase. We’ve developed kinase inhibitors that can cross the BBB that enter the brain, coupled with a biomarker-driven development plan.

We also have RIP kinase inhibitors that are engineered to cross the BBB and are currently testing these in Alzheimer’s disease and ALS, and multiple inflammatory indications that are being developed in partnership with Sanofi.

We have an EIF2B activator program, focused on ALS and maybe a subset of Alzheimer’s and vanishing white matter disease. It’s a modulator of RNA stress granule formation as a result of the integrated stress response. Again, it’s a small molecule engineered to cross the BBB.

Denali has an enzyme containing biologic that we are testing for Hunter’s syndrome, in which about 70% of the patients have neurological disease with an early onset of neurodegeneration. Leveraging our transport vehicle (TV) technology, our investigational biologic has been shown to cross the BBB in animal models.

This year is exciting for us as we have just read out our first Parkinson’s disease study. We plan to have four indications in which our medicines have been in patients. We’re planning on smaller biomarker studies initially, so that we can collect dose-related data to inform larger efficacy studies.

WuXi AppTec: How did those partnerships arise?

Ryan Watts: Partnering has been at the heart of building Denali. We’ve entered into over thirty partnerships. We have a number partnerships where we’ve brought technologies, molecules, or biomarkers into Denali from academic groups and other biotech companies.

We have, for example, a license agreement with Genentech around LRRK2, which enabled us with intellectual property and molecules.

WuXi AppTec:  This is a very significant pipeline. Given that the company came together in 2015, this is a very short time to have such a rich pipeline.

Ryan Watts: We had a solid five-year incubation period. When we thought first about Denali in 2010, we didn’t feel like the time was right, for a number of reasons. The biggest is that we were just at the beginning of this uptick in genomic discovery for neurodegenerative diseases. We were just at the beginning of technologies to help therapeutics cross the BBB, and it was also early days with new CNS biomarkers such as imaging biomarkers in Alzheimer’s disease. That was the state of the field in 2010.

Within five years, we have seen this incredible acceleration of genetic understanding of disease and new technology and that meant it was the right time for Denali.

WuXi AppTec: Denali has a very rich and a very exciting pipeline. I wish you a lot of luck with that.

Ryan Watts:  I think what’s great is even though some big pharma partners or pharma players are exiting neurodegeneration, I don’t think they’re exiting permanently. I think they’re expecting that companies like Denali are going to solve many of the foundational issues and look to future partnerships to be able to commercialize the medicines that we and others invent.

WuXi AppTec: What do you see coming down the future? What’s the next breakthrough?

Ryan Watts: I would foresee a world of more prevention. In Parkinson’s disease, for instance, it’s amazing how effective exercise is in helping slow progression. There will always be a role for medicines in disease management but I would hope that those medicines would be really focused on maintaining health and prevention, and then to the other extreme, to basically correcting disease.

What does that mean for neurodegeneration? Right now the number one risk factor for neurodegeneration is aging. And then, combined with that, are the genetic and environmental factors. We don’t know yet what the environmental factors may be that are a risk for neurodegeneration. What we do know is that there are over fifty genetic associations in Alzheimer’s and fifty to seventy in Parkinson’s and maybe forty or fifty in ALS; genomics allows us to understand the pathways that are dysfunctional.

WuXi AppTec: What do you see are your challenges? Or where do you see Denali five years from now?

Ryan Watts: I would hope five years from now that we’re at the point where we are about to have our first medicine approved. Then we would be able to basically continue to invest in the discovery of these tailored medicines for neurodegeneration using, obviously, the success of those early programs. I also think a goal is to solve the BBB challenge in delivering drugs to the brain. To have technologies and enable medicine to readily cross the brain vasculature to treat neurological diseases including Alzheimer’s disease, Parksinson’s disease and ALS but also other diseases like glioblastomas, cancer metastasis, and neuropsychological diseases.

WuXi AppTec: An exciting story, I must say and a great set of accomplishments.

Ryan Watts: Thank you. We’re just getting started.

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