De-Risking the Brain: A Conversation with Dr. Stacie Weninger, President of the F-Prime Biomedical Research Initiative

In the high-stakes, rapidly advancing field of neuroscience, few leaders have been as instrumental in shaping the landscape as Dr. Stacie Weninger. As President of the F-Prime Biomedical Research Initiative (FBRI) and a Venture Partner at F-Prime, she operates at the nexus of foundational science and company creation, identifying transformative research and building world-class teams to translate it into new medicines. With a track record that includes co-founding industry pillars like Denali Therapeutics and Neumora, and recently co-leading a $200 million financing for Tenvie Therapeutics, Dr. Weninger has developed a clear thesis for success: de-risk novel targets, double down on the enduring power of small molecules, and re-focus clinical trials on biomarkers and real-world data. We spoke with Dr. Weninger to understand her strategy for building the next generation of neuroscience companies, and her vision for ushering in a new era of therapies for devastating brain disorders.

Stacie, thank you for speaking with us. We'd like to start with your recent work, beginning with a $200 million round for Tenvie Therapeutics that you co-led. What made that specific opportunity stand out, and what does it say about the key characteristics you look for in neuro-focused companies?

Stacie Weninger: To me, it’s always a combination of science and team. Previously, I co-led the founding of Denali, and part of the excitement there was the broad scope: new technologies were emerging and our understanding of the biology was improving. While Denali decided to double down on its exciting blood-brain barrier platform, it also had a promising program of small molecules. We decided those programs would be better financed privately, so we spun them out with a stellar team to give them the attention they deserved. That created the ideal combination: a phenomenal team and exciting foundational programs.

There's a lot of excitement in neuroscience right now as new modalities emerge. For instance, I was just listening to the latest Huntington's disease data from uniQure, which involves an MRI-guided neurosurgical administration of gene therapy. While that kind of therapy is a heavy lift and challenging to scale, it's an incredible proof of concept showing we can affect these diseases. Ultimately, however, small molecules are going to be among the best drugs. Once we de-risk targets and show that modulating them affects the disease, the ultimate goal will be a pill that can do the same.

You've made a strong case for refocusing on small molecules. At the same time, you mentioned the excitement around new modalities. What other therapeutic approaches for brain aging do you find most promising?

Stacie Weninger: Blood-brain barrier technology is proving to be quite powerful. The original idea was to deliver antibodies that can’t otherwise easily cross into the brain. We've since realized there's so much more we can deliver, such as oligos and enzymes. The data Denali has shown on delivering the missing enzyme to treat Hunter syndrome is very exciting. In addition, the ability to manipulate gene expression through technologies such as RNAi holds great promise. As these technologies achieve further POC with direct CNS administration, it will be exciting if we could further combine technologies to allow peripheral administration.

If we could zoom in on a specific and challenging area like Alzheimer's, what do you see as the most impactful advances over the past decade, and where are the next big opportunities for investment?

Stacie Weninger: First, if we don't have the right targets, we can’t make the right drugs. The advancements in our biological understanding of these complex, multifactorial disorders have been key. I also think examining genes that affect the rate of disease progression will be transformational. To date, most genetic research has focused on what increases disease risk. But the biological pathways and genes that affect rate of progression might be more tractable as therapeutic targets for patients who are already symptomatic. We've barely scratched the surface there.

Biomarkers are also completely changing drug development. I can't stress their importance enough. Trying to measure a drug's efficacy based on a cognitive test in a doctor's office is extremely noisy and difficult. Many factors influence the result, like how well you slept or how stressful traffic was getting there. We need objective, quantitative biomarkers of disease subtypes and disease progression. This is crucial because Alzheimer's isn’t the same across all patients; for example some may have a more immune-mediated disease while others have issues with their endolysosomal system. Using biomarkers to identify the right patients for a trial and measure the therapeutic effect will be truly game-changing.

You've highlighted the power of biomarkers, particularly the move towards multiplexed panels. As we develop these complex diagnostics, what are the key challenges, both in terms of the science and in ensuring they remain affordable for patients?

Stacie Weninger: I think the future is multiplexed panels of biomarkers. It’s not going to be one single marker; you're going to want a blood test that can measure dozens of different markers at once. As co-pathologies are the norm, not the exception, we really need broad neurodegeneration panels that examine key proteins and various biological systems, not just an "Alzheimer's panel" or a "Parkinson's panel".

As for affordability, I’m not worried about that with this technology. I was worried about how to keep things affordable when we were relying on PET scans and MRI scans, which are very expensive. But I have no doubt that we will have affordable blood biomarker panels.

Another hurdle you’ve focused on is the clinical trial itself. How can we redesign neurology trials to better reflect the day-to-day reality of living with a disease?

Stacie Weninger: Infrequent cognitive tests in a doctor's office aren't particularly meaningful. Having cared for both my parents with neurodegenerative diseases, I've seen how massive the daily fluctuations are, not to mention the burden of care appointments. We need to move toward using continuous, real-world data from technologies such as wearables, combined with objective biomarkers, as our endpoints.

Noninvasive wearables that continuously measure activity could be very effective, particularly for diseases like Parkinson’s where you want to monitor motor function. Measuring activity 24 hours a day, on meds, off meds, etc., is much better than a three-minute assessment in a doctor’s office. We really need to embrace these tools.

Shifting to the business side, let’s discuss the strategy behind building these companies. Given the notoriously long and expensive timelines in neuroscience, what financing and partnership models do you see working best?

Stacie Weninger: It's difficult for small biotech companies to take a therapy all the way through a Phase III trial in a neurodegenerative disease, so it requires a combination of models. You need a partnership among everyone, from private investment in early-stage work to public investors and, of course, big pharma. We will always rely on big pharma for large Phase III trials.

Philanthropy also plays a big role in early-stage de-risking. Neuroscience is hard, and it can be a long time before you reach those high-value inflection milestones. Additional financing, whether from family offices or large public charities, helps de-risk projects in the early stages and convinces other investors this is worth investing in. It’s about assembling an A-plus team that can move the needle, and philanthropic funding can encourage these A-plus teams to work on higher-risk targets that could be transformative if they succeed.

Looking at the state of the field, it’s been 25 years since that famous Time Magazine cover on Alzheimer's. When you look back at that time, where do you feel we have fallen short? And when you look forward, what developments in neurodegeneration and psychiatry get you most excited?

Stacie Weninger: When I look forward, I'm excited by our improved biological understanding of targets in neurodegeneration, especially the role of the peripheral immune system in the brain, which has been woefully underappreciated. In psychiatry, I’m excited that we’re moving beyond the "sledgehammer" drugs of the past. We're now understanding the specific receptors that matter, so we can design therapies that maintain efficacy with far fewer side effects.

When I look back, I wish we had been faster. However, we were lacking so many tools that we have now. In some of the early Alzheimer's trials, for example, we couldn't even definitively diagnose someone; some trials enrolled people who didn’t have amyloid in their brains because we didn't have the tools to detect it. PET scans, and now blood tests, have changed that. Using biomarkers to enroll people earlier and run shorter trials to see if a drug is working will accelerate everything.

On a more personal note, you’ve spoken about your family’s experience with these diseases. From that perspective, how should we think about the ultimate goal of our work? Is it about extending lifespan or closing the gap between lifespan and healthspan?

Stacie Weninger: This is very personal to me. I lost my dad in January to Parkinson's Disease Dementia, and I care for my mother, who has Frontotemporal Dementia. People sometimes compare extending life by a few months in dementia to doing so in oncology, and I think there's a huge difference. To your point on healthspan versus lifespan, we want to extend healthy life. When someone is in the late stages of dementia, to me, it is not about extending life.

I want to see us doing more prevention and early-stage slowing. That means we need to be treating people earlier, often before symptoms appear. If we could delay the onset of neurodegenerative disease symptoms by five or ten years, it would significantly change an individual’s healthspan, even if it doesn't dramatically alter their lifespan. To me, giving people more years of being cognitively intact and living independently should be our goal.