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Medicine That Matters: An Interview with Jonas Hannestad

Medicine That Matters: An Interview with Jonas Hannestad, MD, PhD – Chief Medical Officer

We live in a world inundated by metrics and governed by KPIs. Even medicine, with its patient-centricity, is often clouded by the need to achieve. 

The race toward being the first to discover the cure for X disease has overshadowed much of the original purpose of modern medicine: to actually make a difference. Accolades and awards are nice, but what really matters is how the patients receiving these treatments respond to them. What are their experiences? How does drug discovery and innovation benefit their daily lives on a real and practical basis? Not every avenue of medicine cares about that but Jonas Hannestad, Gain’s new Chief Medical Officer, does. 

It’s clear from the moment you meet Dr. Hannestad that empathy is his MO. His warm and inviting smile is unexpected but welcome, especially in the fight for the future of neurodegenerative disease drug discovery. One might expect Hannestad to be all business, and while he’s certainly focused on getting results, his approach sees a bigger picture.

Hannestad cares. His smile shows experience and understanding. Hannestad comes from a blended background of academia and biotech, the combination of which has been instrumental in his ability to translate theoretical concepts into practical applications. Many researchers in biopharma are solely focused on treating the targeted symptoms that define certain neurodegenerative diseases. For example, memory loss with Alzheimer’s disease. And while that is a critical component of developing impactful drugs, there’s another aspect that often gets left by the wayside: quality of life.

How people live with these diseases matters just as much, and Hannestad understands that. Receiving FDA clearance and approval will always be paramount, but how you receive approval  can’t be at the expense of the patient experience. As we sat down to discuss his new role as Chief Medical Officer of Gain, Hannestad explained how he arrived in this position. Passionate, eloquent, and driven to make a difference, he is dedicated to not just hitting numbers but really enacting meaningful change for the patients living with neurodegenerative diseases like Alzheimer’s, Parkinson’s, and ALS.


You’ve had a multitude of experiences throughout your career. Not only have you worked across multiple areas of disease, but you’ve also held different roles in various biotech and Pharma (SVP of Clinical Development at Alkahest, Medical Director at Denali Therapeutics, and Director of Neuroscience Discovery Medicine at UCB Pharma). 

How have your past experiences helped you develop your current perspective on drug development?

Wellworking across several therapeutic areas, not just within neurology and neurodegeneration but also outside of CNS, has helped me understand the foundation of drug development and the commonalities that exist regardless of the specific area of drug development. I find that very helpful because you learn from each experience you have, and over time these diverse experiences coalesce into something larger, and you can apply that learning moving forward.

For instance, say I learn something from an ophthalmology program. I may be able to apply some of that to a Parkinson’s program at a later time. I would say the same is true, but in a different way, for my academic work, which largely focused on basic physiological mechanisms that are common to multiple diseases. Drawing such parallels across diseases and contexts has been very helpful for the roles I’ve held in biotech and pharma. I’ve always been in that early clinical development/ translational space where you have to understand how the mechanism and the target pathways fit with your disease of interest and how you can demonstrate that in a clinical trial. 

Translational medicine was a primary focus of your time in academia. What have been some major influences from your time in the corporate world thus far?

I built my foundation of translational medicine in my academic work, both in basic cell and molecular biology research and then in clinical research. I was then able to take that knowledge base (CNS pathophysiology) and put it to work in the corporate world where the focus is more narrow. Rather than trying to understand the biology underlying a disease process, in biotech you’re evaluating whether a molecule and a mechanism could one day become a new medicine for a certain group of patients. It’s much more focused than academic research, and I fell in love with that as soon as I had my first drug development experience.  

Would you say one has been more rewarding than another?

I would, yes. If I had to pick one, I would say that the biotech drug development aspect is more rewarding to me than academic work because it’s more tangible. You can actually see how this could lead to something that could help somebody. Although there are a lot of failures, obviously, there is a chance that the drug you’re working on could lead to a new treatment one day, whereas the academic work is often very removed, very basic, very theoretical. It’s very interesting intellectually, but it’s not as tangible.

Do you think you would be able to appreciate the value of your work in biotech quite as much without the foundational background of academia?

I probably would be able to appreciate it, but I don’t think I would be as good at it. If I’d gone directly from my clinical training into industry, I may not have been able to contribute as much.

Here’s how I see it: I think that if you “grow up” in the pharma industry by going directly into the workforce right after your studies, you learn a very specific, a very practical way of thinking and working.Whereas if you have prior academic experience, I think it broadens your view and your thinking so you can apply it in a different way.

That’s incredibly valuable, that broader perspective. You’ve certainly had the opportunity to broaden your scope, having worked across a number of neurodegenerative diseases, namely, Parkinson’s, Alzheimer’s and ALS. Can you speak to how you’ve seen the field change? Are there any similarities, any areas of overlap, and any stark differences in the treatment methods for these diseases?

One of the biggest changes that has occurred in the last 10 to 20 years across all 3 of those neurodegenerative diseases is our knowledge of the genetics and the mutations that cause or contribute to diseases. It’s not just the mutations that directly cause the familial forms of these diseases, but also the genetic variants that increase your risk of developing one of these diseases. These are very important, because those mutations in Alzheimer’s, Parkinson’s, and ALS have increased our understanding of the pathophysiology by pointing to specific pathways that are contributing to the onset and progression of these diseases

So many of these mutations are not necessarily a starting place for a treatment. They could be targeted directly in some cases, but not always. Still, they point you to certain mechanisms that may be relevant and that can be targeted in other ways. 

And the interesting thing is that there are a lot of commonalities across those 3 diseases, which 30 years ago, people wouldn’t have thought because they present so differently. They affect different areas of your brain and the symptoms that accompany these diseases are very different, so the symptomatic treatments are very different. Symptomatic treatments for Parkinson’s have nothing to do with the symptomatic treatment for Alzheimer’s, for example. But if you look closely at the underlying molecular biology, which I think has been informed by those genetic discoveries, you realize that there’s a lot in common in terms of mechanisms such as protein synthesis and quality control, mitochondrial function, lysosomal function, autophagy, and inflammation.

Would you say there are similarities in the approach to drug discovery for these diseases? 

Yes, that, too. In my experience, drug discovery efforts for these diseases were based on animal models with face validity (phenotypically similar to the human disease), but this approach didn’t work well. But now animal models are largely used to mimic the molecular biology events that we know occur in the human disease process, more than the phenotype. I think this approach will prove more successful.

So that’s one thing. Then the other is in the early clinical development space, where the focus has shifted from the clinical or approvable endpoints to the biomarkers that measure effects of the investigational drug on the targets and mechanisms. The focus is to basically show that your molecule does what it was designed to do in humans. 

Our goal is to show that the biology fits and the that the drug actually works in the same way in humans as it does in mice and rats.

This leads well into the discussion of the rapidly changing field of drug discovery. How do you stay up-to-date with the latest developments? How do you decipher between what’s just “buzz-worthy” and what will actually make a difference?

That’s very challenging, especially in early research. When somebody identifies a new potential target or mechanism in one of these diseases, it’s hard to predict whether that will eventually have an impact on a patient with that disease. You have to just follow the field and understand what the people who have been working on the disease for a long time think.  

The most relevant thing for me is making sure that we’re developing drugs not just to gain FDA approval but to also treat aspects of the disease that are important to patients. Because those two don’t always match. A lot of the clinical endpoints that have been developed in these diseases have been developed primarily by clinicians who treat the patients. And yes, those clinicians know a lot about the disease, but it’s from the clinician’s perspective. They have not usually lived the experience. Sometimes what a clinician focuses on are the certain aspects of the disease that are easier to observe or measure in the doctor’s office, but those may not be the most important aspects to the patients themselves. There’s been a lot of work on this over at least the last decade. When you ask patients what’s most important to them, it sometimes surprises you as a clinician. 

Do you have any specific examples? 

Yes. Sticking with Parkinson’s, for example. Parkinson’s is primarily known as a disease characterized by certain motor components; tremors, bradykinesia (slowness of movement), muscle stiffness, and impaired gait and balance.Those are the 4 key components that were originally described by Parkinson and are still used to diagnose the disease today.

But there are a lot of other symptoms that go along with Parkinson’s, like depression and anxiety, cognitive dysfunction, constipation, problems with blood pressure regulation, urinary function, erectile function, etc. that were not part of that initial description, and they’re not typically used for diagnosis, but they’re obviously very important to patients. So the symptomatic treatments for Parkinson’s, the dopaminergic treatments, while they treat the motor symptoms fairly well, they often do not improve those other symptoms that are not part of the core syndrome.

So if somebody has mild depression that goes along with Parkinson’s, they may be less likely to exercise, which is something that’s been shown to be very beneficial in Parkinson’s. Or they may be less likely to stick to taking their medications on a certain schedule. It all comes together. So it’s really important to not just address the symptoms that are direct indicators of the disease but also the accompanying symptoms that may seem to be indirectly related, but are just as important for patients. 

Now with all of this a solid groundwork, we pivot to your introduction as Gain’s Chief Medical Officer. What are you most excited about in terms of joining Gain Therapeutics?

I think I’m most excited about the fact that Gain is on the verge of going into patient studies. Taking a new compound from preclinical testing into healthy volunteers is a very important step in drug development, but what makes me most excited is addressing the question: Does this drug have the potential to help people with a certain condition or disease? 

That’s the stage where Gain is; we’re about to go into patient studies, and that’s very exciting. 

In addition, I’m very confident in this mechanism, the development of the drugs that target the molecular pathways affected by GBA mutations. These mutations are associated with an increased risk of Parkinson’s, and the underlying molecular mechanisms make a lot of sense. It has a lot of support. To your earlier question regarding how you know if something’s going to be relevant for patients or not; you don’t really know, nobody really knows, but you can have more or less confidence, I suppose, and for me, having GBA as a target is something in which I have more confidence than some of the other targets. After all, it’s hard to work on something that you don’t really believe in, right? 

In your opinion, what sets Gain apart from other drug discovery companies?

I think many biotech companies and pharmaceutical companies have a lot in common just by the nature of the industry. The way drugs are developed confines you, and things have to be done in a certain way; some of those things simply can’t change and they’re going to be the same across the board. That’s a good thing, having commonalities because they’re foundational to how we determine whether drugs are safe and effective.  

But I think what makes Gain different from some of the other companies that are currently working on Parkinson’s is that it’s not just the target, the GBA mutation target. There are a few other companies working on that, but it’s the specific way in which this molecule was designed by Gain that works in a slightly different way than the compounds from some of the other companies in this space. Other companies that develop drugs for this target are developing molecules that activate the enzyme, whereas the Gain molecule helps the enzyme move along inside the cell in a way that sort of prevents the sort of clogging up of cellular systems that happens in people with this mutation.

So what you’re saying is, Gain isn’t just building a better mousetrap, so to speak; there are actual functional differentiators with the Gain molecule.

Yes; the data that we have in both cell systems and in mouse/rat studies indicates that this molecule works in a different way than other molecules that are purportedly for the same mutation.

What do you anticipate for the future of drug discovery, either within Gain or within the industry as a whole, for the next 5 to 10 years?

The thing that I’m most excited about is that the field has made a lot of progress in understanding the basic physiology of these diseases. But we’re still pretty far from having it figured out. Specifically, we’re pretty far from where other disease areas are. So I’m hoping that the field will continue to progress so we can understand it to such an extent that we can be more confident in developing new drugs.

Trying to come up with a treatment for a disease that you don’t really understand is like a bit of a shot in the dark, and unfortunately that’s kind of what we’ve been doing for the past 40 or so years. That’s why there have been so many failures. So I’m hoping that will start to shift and that the increased understanding will lead us to more confident targets. Right now we’re at a point where we can often only say that there’s statistically about a 10% chance that something will work. I want to get to a point where it’s a 40 – 50% chance because once we do, we’ll develop many, many more new treatments for these diseases. So that’s something I’m very hopeful for in the next 5 to 10 years.

You mentioned a desire to see treatments for these neurodegenerative diseases get to a point where they’re as advanced as some of the others. Which others are you referring to?

In terms of treatments, some areas in which we more or less understand how they work are cardiovascular disease, oncology, metabolic disease, autoimmunity – those are probably the main ones.

So you’re saying the neurodegenerative space is looking to hit the benchmarks those fields hit. How do you feel about the current pace of progression? Do you think things are going at a quicker pace than they used to?

It’s hard to say if it’s going at a quicker pace, but it’s definitely going forward. It’s kind of like 2 steps forward and 1 step back. For example, there was recently an ALS drug in phase 3 that didn’t work. They had gotten accelerated approval based on promising phase 2 data, but then they did phase 3 and it didn’t work out. They had to pull it off the market, which was a good decision, because you don’t want a drug out there that doesn’t work and gives patients false hope. But it’s the same for the anti-amyloid therapies for Alzheimer’s. These treatments probably have some effect, but it’s a very small effect and it’s not to the degree that we’re looking for. So it’s a little bit of progress, but not as much as we want.

Would you say that the progress that it offers is more impactful or more insightful than it has been in the past?

Yes, I think so. In the past, in Alzheimer’s specifically, there were only symptomatic treatments that didn’t have any effect on disease progression. These amyloid treatments, you know Eisai’s drug, and probably Lilly’s drug [donanemab], if it gets approved, they do appear to slow progression. It’s not just symptomatic treatment. Now while that effect on slowing disease progression is very small, if it’s real it means we’ve made progress. We know that we’re on the right path. Or one right path. 

Yes. Even if you’re not all the way there, you’re inching toward something that could really make a huge difference. And essentially, that’s what you’re looking to do.

There’s something happening here. The progress may be slow, relatively speaking, but every step is forward-moving and that’s what matters.


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