Running Up That Hill: An Interview with Carole Ho, Denali Therapeutics

Carole Ho, MD, is the chief medical officer and head of development at Denali Therapeutics in South San Francisco. A neuroscientist and clinical neurologist by training, she originally planned to be a surgeon because, as she says, she likes to “see impact right away.” But after her first neurology rotation, she was hooked, seeing the unmet need and the lack of scientific understanding of disease, so she opted to become a neurologist. She did a residency at Mass General Hospital and a postdoc in basic research with Marc Tessier-Lavigne, PhD, to learn more about neuroscientific disorders amenable to novel therapies.

After six years as an academic and an attending neurologist at Stanford, Ho moved to industry, where she has spent almost two decades. At Genentech, she headed the early clinical development group, including neuroscience and a pair of late-stage immunology programs. Eager to return to her roots in neurology, she joined Denali Therapeutics more than nine years ago.

On a recent visit to Washington DC, Ho sat down with GEN editorial director Kevin Davies, PhD, to discuss Denali’s progress and plans as it approaches its tenth anniversary. (This interview is lightly edited for length and clarity.)

GEN: Carole, how did Denali get off the ground and what were the company’s objectives?

Carole Ho: When Denali was founded about nine years ago, I joined early before we had a clinical pipeline. We created a strategy to develop both our transport vehicle platform for large molecules as well as advance a number of promising small-molecule programs into the clinic. I’m thrilled to say it’s been very productive. We’ve moved 11 programs into the clinic, and we have several programs in the clinic using our transport vehicle technology, which enables large-molecule protein therapeutics and anti-sense oligonucleotides (ASOs) to get across the blood-brain barrier without requiring intrathecal delivery.

The company’s co-founders were [former Stanford University president] Marc Tessier-Lavigne, PhD, [CEO] Ryan Watts, PhD, and Alex Schuth [chief operating and financial officer]. We worked together closely at Genentech in different capacities—me on the clinical side, Ryan on the research side, Alex on business development. The timing of the launch of the company reflected the fact that the understanding of genetic risk in neuroscience had advanced to a level where multiple new targets were identified that could be relevant in addressing disease biology. The feeling was that this was the right time to create a neuroscience-focused company and leverage the technology that we planned to develop—the large molecule transport vehicle. We now have clinical validation of the large molecule transport vehicle and the ability to get therapeutics across the [blood brain barrier] BBB using this technology.

Over the past 10–20 years, the neuroscience arena has been a hill that many big pharma companies have died on. What gave Denali the confidence that maybe you had an approach or a technology that others didn’t?

We had confidence in building a neuroscience company in part because genetics was identifying many new opportunities. And we were confident in our ability to generate intellectual property around a large molecule transport platform that would get therapeutics across the BBB. One of the founding scientists and drug developers, Ryan Watts, pioneered BBB delivery work at Genentech. There was a realization that there were certain potential liabilities in the published work that could be improved upon. Denali was built on the promise that we could develop a better platform. That’s exactly what we did.

Where did the company’s name come from?

The name reflects the immense challenge of addressing neurologic disease. You referred to neuroscience as a hill that some have died on! Well, this is a mountain that we are climbing—Denali is the highest peak in North America. It reflects our values and our mission—this is hard work and we have to be committed.

To be successful, we had to focus. At Genentech, neuroscience was only one of the things in a large portfolio that I managed, which included everything outside of oncology. In disease areas like asthma and rheumatology, where successful trials and endpoints have been used over and over, the risk is much lower. In a large company, neuro often gets deprioritized, because in terms of cost to next milestone and likelihood of success, the risk is much higher than in other disease areas. Our hypothesis [at Denali] was that if we can build a company focused on neurologic diseases, we could be successful and not be distracted by other areas.

What can large molecules do in the brain that small molecules can’t?

When we started the company, the principles of getting small molecules across the blood-brain barrier, for example, the Lipinski Rule-of-Five, were well known. Denali successfully generated promising small molecule therapeutics and advanced these to the clinic and late-stage development, including an LRRK2 inhibitor for Parkinson’s disease. We also advanced a centrally active RIPK inhibitor into studies in multiple sclerosis and amyotrophic lateral sclerosis (ALS), which unfortunately have failed. We also advanced a small-molecule EIF2B activator for ALS that’s currently in Phase II.

Small molecule therapeutics can cross the blood brain barrier, but they may lack precision in targeting and may have greater off-target effects. And there are certain targets, for example, brain accumulation of tau or amyloid, that are not amenable to a small-molecule approach. We wanted to go after neurodegenerative disease with the ability to be flexible in terms of the therapeutic modality used. As of last year, because of the validation of our large molecule transport vehicle platform, we have now focused our efforts in development for transport vehicle-enabled programs. We spun out our preclinical small-molecule portfolio earlier this year.

We’re still moving our clinical-stage small-molecule programs forward, but our primary focus has shifted to expanding our transport vehicle, large-molecule portfolio, where we hold a distinct competitive advantage.

Are you drawing any guard rails around technologies like gene therapy or gene editing?

Not at all. Right now, this has not been a dedicated focus at Denali largely because there is still technology that needs to be evolved to get, for example, gene editing machinery across the blood-brain barrier. But that’s something we’re certainly interested in for the future.

I’m obviously very interested in gene editing and gene therapy, sitting on the board of a base editing company [Beam Therapeutics]. But particularly in neurologic disease, there are additional challenges compared to other disease areas with respect to delivery to the brain. While gene therapy is exciting and a few therapeutics in neuroscience indications are in the clinic, durability of response is still an issue and tolerability is still an issue. At Denali, we have developed technology to enable large molecule therapeutics, such as enzymes, antibodies and oligonucleotides, to cross the BBB. In the near term, this is going to be very important technology to address diseases of the brain, until we have the gene therapies that have the safety, tolerability, and durability for long-term benefit.

What are these large molecules and their targets where you’re seeing success?

The transport vehicle platform modifies the Fc portion of an antibody and engineers a binding site that binds to a normal transporter mechanism in the brain that gets iron across the brain. The brain needs iron, and we have essentially utilized that transport mechanism to hitchhike our therapeutic cargo. There are a number of flavors, so to speak, where we can take that Fc portion of an antibody and conjugate it to an enzyme, for example. These enzyme programs are the lead clinical programs where we’ve validated this technology. Antisense oligonucleotides, antibodies and proteins are the other versions of the platform that enable delivery of these therapeutic modalities across the blood-brain barrier.

Initially, Denali was very focused on adult neurodegenerative disease. Through understanding disease genetics in Parkinson’s disease, we became very interested in the importance of the lysosome, a cellular organelle, in the pathology of the disease. We learned a lot about lysosomal biology in our work on Parkinson’s disease, and as we were developing Denali’s transport vehicle technology, we recognized that enzyme replacement for lysosomal storage diseases could be an approach to validate this technology in a monogenic disease and therefore get proof-of-concept with this platform technology. So we entered the rare disease lysosomal storage disease field.

We’ve been focused on genetic targets because of the increased probability of success. In lysosomal storage diseases, patients are missing or have a defective enzyme that breaks down a glycosaminoglycan. When that substrate accumulates, neuronal glial dysfunction follows, which causes a pediatric Alzheimer’s-like disease in the brain. The field of rare disease has been very successful in generating enzyme replacement therapies, but those therapies don’t cross the BBB. These children are living longer, but for those lysosomal storage diseases that have brain manifestations, the unmet medical need and the morbidity and even significant contribution to the mortality is now the CNS disease.

We decided to use our transport vehicle technology to achieve proof-of-concept first in these diseases. The two diseases that we’re studying in the clinic are MPS (mucopolysaccharidosis) disorders—a family of disorders that are missing one of the enzymes that breaks down glycosaminoglycans. The first program we advanced into the clinic was for our Hunter disease (MPS II). In the first four weeks after dosing, we measured cerebrospinal fluid (CSF) levels of this accumulated substrate, which is very high in these patients and contributes to brain disease. We measured it at five weeks, after dosing for four weeks, and we normalized these levels in 80% of patients. We realized that not only could we get this molecule across the blood-brain barrier but also it was having a magnitude of effect that was really very different than anything that we had seen on the competitive landscape.

MPS II is a rare X-linked disease, so it primarily affects boys. These children have a devastating clinical course—they develop normally until the age of about two, they start to walk, talk, sing, and then they start to lose these developmental milestones. They generally present to medical attention because of the peripheral accumulation of the toxic substrates. Some present with organomegaly, frequent ear infections or respiratory infections, and then subsequently present with brain disease.

We have an ongoing open-label phase I/II study that the FDA has agreed can be filed to support accelerated approval. We plan to file [in 2025] for accelerated approval. In addition, we have a pivotal phase II/III randomized study comparing our treatment to standard of care that is nearly fully enrolled and would support conversion to full approval. This progress in the clinic is not only a validation of the platform but also enables us to file this data package for regulatory approval, ultimately driving meaningful impact for patients.

What other programs in the pipeline are you particularly excited about?

We also have an MPS IIIA program with our second enzyme therapy conjugated to the Transport Vehicle for Sanfilippo syndrome, following about 18–24 months behind our MPS II program, using the same technology and same biomarkers, with our MPS II program paving the way for this program’s success. We are going to continue to build on our rare disease portfolio, but with this proof-of-concept, we want to address the Denali Mountain— the high unmet medical need in larger adult neurodegenerative indications. We have a number of programs that are moving towards IND filing that utilize the transport vehicle (TV) approach.

We have an amyloid antibody transport vehicle program (ATV) and we’re also using antisense oligonucleotides with the oligonucleotide transport vehicle (OTV) to address tau, both of those programs addressing Alzheimer’s disease. We’re also looking at other genetic diseases that have potential impact in larger indication diseases. For example, for GBA, one of the most common genetic risk factors in Parkinson’s disease, we’re developing a therapeutic that will restore G-case, the enzyme deficient in Parkinson’s disease and a storage disease called Gaucher’s disease.

The Alzheimer’s disease field has very much evolved over the past decade. It has been exciting to see the (non-brain-penetrant) anti-amyloid therapies currently being developed and now are approved. Lecanemab (Eisai/Biogen) is approved and donanemab (Eli Lilly) is approved. These programs have achieved proof-of-concept that lowering amyloid is associated with statistically significant clinical benefit. Prior to these successes, there were questions asked: “Is the amyloid hypothesis amyloid hypothesis dead?” because there had been so many failures. Incremental progress is critical for a foundation on which to build and improve. There is an association now between amyloid reduction and clinical benefit, but there is still room for improvement. The clinical benefit is modest—I compare it to cholinesterase inhibitors, which have about a 2–3 point change on a scale looking at cognition. We see a similar level of change with these recently approved therapeutics, but because these disease modifying therapeutics address the underlying pathology of the disease, we expect over time there would be a greater clinical benefit. It’s not a symptomatic therapy, but it’s still a modest benefit and so there’s a lot of room to improve.

Enabling an anti-amyloid therapy to cross the BBB could potentially have more rapid kinetics of reduction of amyloid and also improve the tolerability profile with respect to vasogenic edema or amyloid-related imaging abnormalities. It can be challenging in practice to monitor some of the safety-related liabilities of these programs. Our anti-amyloid transport vehicle platform is designed to improve upon the safety profile in addition to efficacy.

We believe that combination therapy is likely going to be necessary in the future to enable a clinically differentiated impact. We’re very much thinking about developing a portfolio of Alzheimer’s disease therapeutics that would then be amenable to combinations.

Are you working with any big pharma partners?

Our success has been very much enabled by partnering with large pharma so that we have the capital and resources to grow the company as we have over nine years. Our LRRK2 Parkinson’s disease program is partnered with Biogen. Our RIPK inhibitor was partnered with Sanofi. We have had early partnerships with Takeda with our transport vehicle platform for a TREM2 therapeutic and also a transport-vehicle enabled progranulin replacement program which replaces a defective protein called progranulin that is a genetic risk in frontal temporal lobe dementia. That program is currently in phase I/II.

To what extent is Denali looking at AI as a way to transform its drug discovery initiatives?

There are many ways that AI is going to be applied to the whole drug development spectrum from discovery all the way to how we get molecules approved. We’re still exploring that, but we absolutely feel it’s necessary to embrace [AI] to be successful in the future. On the drug discovery side, we’re looking at using AI to identify more precise and more rapid ways to identify potential therapeutic targets and to reduce the time to screen for potential therapeutics. On the development side, we’re thinking about how to use AI to pull together the vast amounts of information that are required to summarize in documents for filing. We’re exploring many areas, but it’s probably too early for me to give you specifics on what we’re going to do.

What are some specific milestones that you and the Denali executive team has its eyes on in 2025?

One of the biggest milestones in 2025 will be filing for approval for our first program that uses this transport vehicle technology in MPS II. An approval will very much validate the technology and highlight that there are differences in this technology versus other transport vehicle technologies that are being developed. For the program that’s following our MPSII program in the related disease MPS IIIA, we have achieved clinical proof-of-concept and look forward to generating additional clinical data in 2025 to support accelerated approval for that program.

Finally, we look forward to progress on our “Peak 2” programs in 2025, still not in the clinic yet, to leverage this technology for broader indications like Alzheimer’s disease, Parkinson’s disease, and other rare diseases.