Daniel Barvin, M.B.A. on ALS, FTD, and Genetics

Author(s): Scott Douglas Jacobsen

Publication (Outlet/Website): The Good Men Project

Publication Date (yyyy/mm/dd): 2024/09/04

Daniel Barvin joined Coya in 2021. Prior to joining Coya, Daniel spent his time as an advocate fighting for awareness and the rights of Presymptomatic Familial ALS patients. He started the first ever Familial ALS focused team through his work at I AM ALS. During this time, Daniel interacted with presymptomatic patients, researchers, pharma executives, and advocacy organizations. In addition, Daniel has held operations and design positions at Morgan Stanley, Dril-Quip and GE.  Daniel received his B.S. in Mechanical Engineering from Case Western and his M.B.A from Rice University. 

Scott Douglas Jacobsen: Today, we are here with Daniel Barvin. You were found to carry the genetic variant associated with amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). For everyone listening, could you give us a refresher on what ALS is? And can you discuss what it means that you are a carrier of this specific gene??

Daniel Barvin: I am a carrier of, C9ORF72, a genetic variant that could one day cause ALS and or frontotemporal dementia (FTD), and I have lost a significant portion of my family to those diseases. I have experienced the loss and tragedy these diseases bring, which not only shortens one’s life but also strips away the dignity and ability to be a productive member of society. While I’ve seen what my future might hold, I’m fortunate that at 36, I am still healthy and fully engaged in life.

Jacobsen: Regarding this type of diagnosis, the first critical question for me is how previous generations did not know the genetic aspects of these diseases. Now, with advancements in screening technology, at what point did it become possible to take advantage of such screenings? At what point was it possible for people to get tested if they had a risk factor? 

Barvin: My life was profoundly impacted by the ability to undergo genetic testing. I’ve built my advocacy around discovering these risks and taking action. The first time anyone could identify a genetic risk in the ALS space was when the SOD1 gene mutation was discovered in 1993. This discovery marked the first time it became possible to understand a genetic risk for ALS in a family. The genetic variant I carry, C9orf72 (Chromosome 9 Open Reading Frame 72 expansion), was discovered in 2011. Unfortunately, we lost my aunt in 2012, and no one understood that she carried the C9orf72 variant at the time. Although it was discovered, it took time for this information to reach mainstream medical awareness and for frontline neurologists to diagnose the disease and understand the importance of genetic testing. This knowledge is crucial for informing immediate family members about their risks, as these diseases are hereditary. Genetic testing requires multiple steps to take effect and be truly effective.

My journey of discovery began in 2017 after losing my grandfather in 2000, my uncle in 2002, my aunt in 2012, and my father in 2016. I discovered that these losses were hereditary due to the C9orf72 variant in 2017, and I learned that I carried the variant in 2018. While the knowledge of these genetic variants existed, the resources for navigating genetic testing through counselors or receiving care were almost nonexistent. This experience of feeling alone inspired me to ensure that the rest of this community, now known to include about 500,000 people in the U.S. and  millions globally, don’t go down the same blind path that I did.

That’s when I began working with other patients and co-founded a nonprofit called “End the Legacy” to raise awareness, advocate for change, and improve clinical care guidelines for the presymptomatic community. 

Jacobsen: For many families affected by these diseases, it’s a brutal challenge to face. When these genetic markers run in the family, how many family members statistically would be expected to be affected? 

Barvin: This is what is known as “penetrance.”

Jacobsen: What is the penetrance of this genetic variant?

Barvin: In early studies, when I first learned about my genetic status, researchers found the penetrance to be about 50% by the age of 58 and fully penetrant by the age of 80 , so it was quite high. In my father’s generation, 3 out of 4 siblings carried the genetic variant, and 3 out of 4 siblings developed ALS and/or FTD in their mid-forties. 

My father passed away at 60 but had dementia for 15 years. So, anecdotally, the penetrance seems to be  be very high. End the Legacy called for a renewed study, as earlier research was looking at a different subset of data and who developed ALS in this genetic case. We had them redo the study, and now they believe the penetrance is between 25% and 30%, which is still quite high. We can go in many different directions with this. Still, I truly believe that the future of healthcare and humanity lies in understanding our genetic predisposition for diseases.

Whatever the penetrance is for a genetic variant that activates a disease, we will strive through current medicine, longevity doctors, diet, exercise, and other means to tilt the scales in our favor. If there’s a 50% chance of the genetic variant leading to disease, how do I ensure I’m in the 50% that doesn’t develop it? This ties directly into the work at Coya Therapeutics, the company Dr. Howard Berman founded in 2020 and I joined shortly after. Our work is based on the idea that inflammatory pathways drive neurodegenerative diseases.

For someone like me, who has a predisposition to this disease, what am I trying to avoid? High inflammatory loads, head trauma, car accidents, massive gastrointestinal issues—anything that could trigger the disease. I was just at the dentist today, and while discussing my work, she mentioned that in school, they learned that 80% of patients with severe gum disease also have dementia. It’s possible to conclude that severe gum disease creates a massive inflammatory load in the body, which can eventually tip the scales and trigger one of these neurodegenerative diseases.

So, I’m trying to avoid all these precursor events in the hope that I won’t develop the disease. And if I do, hopefully, by then, Coya will have figured out how to alleviate symptoms and turn a fatal disease into something chronic and manageable—like what’s been done for HIV and AIDS. 

Jacobsen: How do you systematically develop a program to reduce inflammatory loads?

Barvin: Our company is based on the scientific discoveries of Dr. Stanley Appel of Houston Methodist, often called the “father of ALS.” He has chaired that department for 50 years and is likely one of the smartest people I’ve ever met, even at 91 or 92. Dr. Appel has been working on solving ALS for decades and discovered that not only ALS but all neurodegenerative diseases trigger an inflammatory response. If regulatory T cells, which are the control system of the inflammatory system, are functional, they can manage the inflammatory load, bring it back down, and stop disease progression. He found a direct correlation between ALS progression, survivability, and regulatory T cell function.

Today, four years later, we have taken a new direction in administering therapeutics for ALS, FTD, Alzheimer’s, and other neurodegenerative diseases. We are using a combination of biologics that, on the one hand, increases the efficacy and number of regulatory T cells and, on the other hand, reduces pro-inflammatory cytokines, macrophages, and myeloid cells that create oxidative stress in the body. In a proof-of-concept study in March 2023, we demonstrated that we could stop the progression of ALS over 48 weeks, showing a decline of only 1.5 points on the ALS Functional Rating Scale (ALSFRS), which measures ALS progression. To put that into context, there are currently only two drugs approved for ALS.

I don’t have the exact numbers for what the currently approved drugs achieved, but the efficacy was minimal. Typically, controls degrade at about one point per month on the ALS Functional Rating Scale (ALSFRS) or about 12 points yearly. Coya hopes to achieve something far more monumental. The treatment involves a subcutaneous injection. We plan to advance into clinical trials for ALS, with a large Phase 2 study..

Jacobsen: Where is the subcutaneous injection administered?

Barvin: Similar to how a person with diabetes injects insulin, it’s administered just under the skin—not intramuscularly. The beauty of this method is that, unlike some other ALS drugs that are administered intrathecally (via spinal tap), which requires inpatient care and weekly hospital visits for infusions, this treatment can be done at home. Spinal taps are painful—I’ve had seven myself in the pursuit of research. The advantage here is that patients or their caretakers could potentially arrest the progression of their disease in the comfort of their own homes.

Jacobsen: When we consider the extension of health span and lifespan with this kind of subcutaneous injection, what practical outcomes can we expect shortly?

Barvin: I can only speak to proof-of-concept data we’ve shown in ALS over 48 weeks. It slowed progression to just a 1.5-point decline on the ALSFRS. We have yet to conduct studies beyond that time, but this result far exceeds what anyone thought possible. I can only imagine the alleviation of symptoms this could offer.

ALS is a complex disease often diagnosed by exclusion, meaning the diagnostic process typically takes about a year. Someone might go to their primary care doctor saying, “I’m falling, I’m tripping.” After 6 to 8 months, they finally see a neurologist who diagnoses ALS. By then, ALS has progressed significantly, and since the disease typically allows for only 2 to 3 years of survival, a year’s delay is substantial.

But imagine if this drug were approved and could be administered early in the disease’s progression. If someone noticed their hand was a little weak, and we could stop the disease right there—if ALS became just “my hand’s a little weak” and nothing more—that would be revolutionary.

Of course, this requires many things:

• Early diagnosis.
• Coya’s success in clinical trials and the regulatory pathway.
• Creating a therapy that is FDA-approved and effective.

But that is very much the dream.

Jacobsen: How long will further research, financing, and deep studies take to achieve your aim of developing these methodologies?

Barvin: We have already completed four rounds of financing. We’re a public company listed on Nasdaq under the ticker COYA, and we went public in January 2023. We also engaged in a licensing deal for our COYA 302 ALS therapy with a large generic drug manufacturer, Dr. Reddy’s Laboratories. Additionally, we conducted a follow-on PIPE (Private Investment in Public Equity) financing. So, our cash runway for pursuing these clinical trials is secured.

We also recently received feedback from the FDA regarding our Investigational New Drug (IND) application for this trial. They requested more data on the preclinical side, and within a few months, we can provide that data and then move forward with the trial.

The trial will have a 6-month enrollment period. So, there will be some time for enrollment, followed by 6 months of administering the drug versus a placebo. After that, there will be about 3-to-4 months of data analysis to crunch the numbers.l. One of our hopes at Coya is to ask the FDA for approval after Phase 2. Drug companies typically must go through all three phases to get FDA approval.

However, there has been a precedent in ALS where, due to the high unmet need and the powerful voice of patient advocates, the FDA has approved drugs at Phase 2 for ALS. So, we believe that if we can demonstrate similar efficacy and safety as we did in our proof-of-concept study, we have a shot at not needing to go through a Phase 3 trial.

Jacobsen: When considering the pretrial work in identifying those with these genetic variants coding for risk or penetrance of ALS or FTD, how many people carry these variants but haven’t been screened?

Barvin: You’re asking how many people out there might carry these variants but have yet to be screened? We know that about 500,000 people in the U.S. are either carrying or at risk of these genetic variants. When you look at the ALS population in the U.S., which is about 30,000 people, and then consider those who carry a genetic risk but don’t even know it, the number is about 10 times larger. It’s a significant figure.

In 2018, which wasn’t that long ago, when I found out that I carried this genetic mutation, no one was talking about the 500,000 people at genetic risk of ALS or FTD. No one. I started telling my story at a local high school because at the ReelAbilities Houston Film Festival.

It was about 3 weeks after I found out that I had carried the genetic mutation. I realized that I had always been the child, grandchild, and nephew of this disease, but for the first time, I was now the patient. I wanted to tell that story, and the gut feeling of being in that room with those kids who genuinely cared was profound. They had watched a movie about a man dying of ALS, and then they talked to me, someone seemingly young and healthy, and it clicked for them.

From that point on, I realized how big this issue was. I knew it wasn’t just me but that this story had to be told. Initially, I planned to travel around the country, raising money for existing ALS organizations with this story. However, the genetic ALS story had never been told. Suppose one case of ALS was terrible enough to inspire the ice bucket challenge. How could an entire generation being wiped out and another generation at risk not generate the same response? But in 2018, ALS nonprofits were not ready to tell the genetic ALS and FTD story.

They weren’t receptive to this new narrative coming onto the scene. Perhaps it was because they prioritized those who were already dying over those who were at risk of dying in the future. It seemed they couldn’t focus on both. Those rejections may have driven me even further to say this is necessary. I began collaborating with patients like myself who carry SOD1 or C9orf72 and have lost similar numbers of family members to ALS.

Now, 4 or 5 years later, we are the leading and the only nonprofit focused on genetic ALS and FTD. We’ve achieved monumental change for patients like myself when it comes to issues like genetic discrimination and clinical care. Before, I couldn’t walk into a doctor’s office and say, “I’m at risk for ALS, treat me.” They could do nothing—no clinical guidelines, and it wasn’t even in their insurance billing codes.

However, people at risk for heart disease receive preventive drugs and regular checkups from their doctors. Women who carry the BRCA mutation go in for preventive screenings regularly. We’ve made strides, but much work remains to be done.

There should be some clinical care for people like myself. We are patients with a medical diagnosis, yet there isn’t any care available. End the Legacy is actually in the process of creating those guidelines right now. We’re also opening one of Philadelphia’s first clinical care practices to care for presymptomatic genetic carriers.

We’re working on a litany of other initiatives and we’re truly revolutionizing what it means to be a genetic carrier. Six years ago, there was absolutely nothing for people like us.

Jacobsen: I’ve heard a lot from people in the futurist community, some of whom I’ve interviewed, talk about individual medicine—”personalized medicine,” as they call it. As new scientific discoveries open new moral vistas, we must become more attuned to new moral problems that arise with this knowledge. But that knowledge was always there; we didn’t know it. Do you think we’re entering an era where, with more genomic data and analysis, people will start considering their genetic risk factors and adopt specific life practices regarding diet and self-care?

Barvin: Absolutely. We’re already at the stage of personalized medicine. With companies like 23andMe, people are already starting to understand their genetic risks. This comes to a head with longevity doctors—those working on the outer bounds of practiced medicine, focusing on treating and preventing disease. While I don’t see one, my brother does, and since we both carry the C9orf72 variant, I get the same insights from him.

This idea that one should understand their risks and then get their biomarkers checked—whether that’s oxidative stress or any other indicator that might one day be linked to the development of a disease—is gaining traction. The goal is to track these markers, implement supplements or lifestyle changes, and continue iterating to lower those risks to normal levels. This approach is happening now.

There’s a recent example involving Chris Hemsworth, the actor. He found out that he carries the APOE4 variant, which significantly increases the risk of Alzheimer’s. He did a whole documentary on it on Disney+. Peter Attia, who is gaining traction  in this space, talks about longevity in his recent book and discusses how everyone has a risk factor for dementia. It’s all about understanding and taking proactive steps to mitigate those risks.

Some people have higher risk factors, and some have lower. At what point do you start making decisions about your future? Years ago, everyone said, “Don’t smoke.” It’s not that different from what we’re doing now, but there’s a direct need to take action for people like me and others in my situation. That’s why we’re creating the resources we need to get there. If anything, people who find themselves at genetic risk for a disease and realize there are no existing resources for their community can look at what I’ve done as a model for how to upend the system and create resources for themselves.

This is a “never again” situation. We talked about the past generation and how these diseases blindsided them. Now, we can do genetic testing. I didn’t mention my children earlier, but now you can do family planning to avoid passing down these genetic variants. Both of my children were conceived via IVF and preimplantation genetic testing (PGT), and they don’t carry the genetic variant that has decimated generations of my family. I will be the last one affected by it, which is unbelievable, but it goes beyond that. There are so many things you can do to save your own life.

Jacobsen: Are there any particular areas you want to cover that we haven’t touched on? 

Barvin: We also have data on Alzheimer’s. We conducted a smaller, 30-person study on Alzheimer’s with one of our drugs, COYA 301. I’ll back up a bit—Coya has developed a combination biologic, COYA 302, that is working to alleviate symptoms of ALS, Alzheimer’s, Parkinson’s, and FTD. It’s a platform drug that can be used for all these diseases. We used COYA 301 in two proof-of-concept studies in Alzheimer’s and showed similar efficacy and safety.

The Gates Foundation sponsored a larger proof-of-concept study through Houston Methodist, and we’re looking forward to that data being released in October. We hope it will be both productive and impactful. Combining abatacept and IL-2 in COYA 302 versus just low-dose IL-2 will be even more effective in Alzheimer’s. We hope the COYA 301 data will provide enough insight, motivation, and need to move forward into a larger trial in Alzheimer’s. That’s another one of our goals.

Jacobsen: What would be, in theory, the next generation of proof-of-concept trials? What’s the next step in dealing with inflammatory and neurodegenerative diseases, particularly those grounded in genetic risk?

Barvin: It’s very challenging to conduct drug trials in healthy individuals who are at risk of disease. I wouldn’t want to sign up for a clinical trial where it’s unknown if the treatment will be effective, especially when I’m perfectly healthy at the moment.

If you’re dying of ALS, you’ll try anything. I’m not dying of ALS, but I do think we need to learn how to prevent these diseases. Drug companies are trying to do that, but none have succeeded. There is a drug that’s been approved for SOD1 carriers where they track you pre symptomatically, and when symptoms develop, they give you the drug immediately. It’s called tofersen, and it’s proven to be effective. C9orf72 is a more complex genetic variant. They’re looking at antisense oligonucleotides (ASOs) and other approaches, but no one has figured it out yet. That’s the golden ticket.

There is a lot of work being done in this space, and a lot more that needs to be done. Thank you for giving me the opportunity to tell my story and talk about the work that Coya is doing.

Jacobsen: Thank you so much, Daniel. I appreciate it.

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