S4, E04: AviadoBio: Bold and Courageous

Lisa Deschamps (00:02):
If we can crack this delivery hurdle that many companies have faced and will continue to face with these unique and bold approaches, again, around enhanced construct, routes of administration, different delivery technologies.

I believe we can really make huge advancements in certainly FTD and ALS, but even more broadly in all neurological conditions.

Gina Mullane (00:36):
Alzheimer's, Parkinson's, ALS, these are some of the most common and most devastating neurodegenerative diseases affecting millions worldwide. Because of their prevalence and the dozens of mutations that exist for each disease, they have been a focus of the pharmaceutical industry for decades. Like other therapeutic areas, researchers face hurdles like a long discovery process, multiple preclinical and clinical studies, and a rigorous regulatory review.

But for drug developers focused on neurodegenerative disease, the challenge really begins with the red tape of the human body, the blood-brain barrier. This complex network of blood vessels and tissues protects the brain from harmful substances, and often blocks neurodegenerative therapies from achieving optimal results. I'm Gina Mullane, and in this episode of Vital Science, we talk with Lisa Deschamps, CEO of AviadoBio, about how her organization is exploring new routes of drug delivery to break through the blood-brain barrier.

We'll discuss the development of their novel gene therapy for frontotemporal dementia, the research that's underway for ALS treatment, and how the organization is giving hope to rare disease families worldwide.

Todd Poley (01:59):
Welcome to Vital Science, Lisa. We are really honored to have you. Would you share a little bit more about yourself and your role?

Lisa Deschamps (02:05):
Thanks, Todd. It's really great to be here. Currently, I am the CEO of AviadoBio, which is a London-based, globally-focused gene therapy company. My background prior to joining AviadoBio was on the big pharma side of the world. I spent over 25 years at Novartis. Started carrying the bag and worked my way up through the different years in various roles. My last few roles at Novartis, which are probably most relevant to my time here at AviadoBio, I was leading our US neuroscience business and our global neuroscience business based in Basel.

My team had done the acquisition of AveXis into Novartis, I had led the integration. Then about a year and a half later, went over to lead the commercialization worldwide of the first asset, which is Zolgensma. It's a gene therapy, an SMA, spinal muscular atrophy for children. By the time I left, we had brought Zolgensma to over 41 markets all around the world, 29 reimbursements. Most importantly, treated a little shy of 2,000 patients at that time. Launching Zolgensma was such a privilege.

Being able to see the impact that it could have on patients and families sitting next to a child, who may not have been there, or let alone was running around playing hide-and-go-seek, still gives me chills every day. It's what brought me here to AviadoBio, and it is the North Star for us as a team to be able to bring transformative gene therapies to people living with neurological conditions.

Todd Poley (03:36):
What an incredible launch to be a part of. It sounds like that experience really propelled you to where you are today with AviadoBio. When you think about your time at AviadoBio, is there a particular accomplishment that you're most proud of?

Lisa Deschamps (03:50):
That's a great question. For me, it's all about the people. It begins and ends with the people, and so from the teams that you build. We have really built an organization, a team of passionate people who work relentlessly each day towards our mission and being able to bring these therapies to patients who need them.

As well as, of course, it ends with the people, being able to have the impact on patients and families as we go forward. For me, what I'm most proud about is the team that we've built to date, and the inspiration behind what started the company. How hard everybody works each and every day to make our mission a reality for patients.

Todd Poley (04:31):
I love that. AviadoBio focuses on developing transformative medicines for patients living with debilitating and life-threatening neurodegenerative disorders. What's driving this important work?

Lisa Deschamps (04:44):
Well, at the most simplistic view of that question, it's the significant unmet need that exists. If you look at neuro CNS disease overall, and particularly neurogeneration, there's still such an unmet need. There's very little transformative therapies. In many of the disease areas, certainly the ones that we're looking at, there's little to no treatments that even exist today. More broadly, as you look at MS and Alzheimer's, of course, there are treatments but they're symptomatic at best, symptomatic relief.

There's been nothing to date in neurodegeneration, that has been able to truly prevent or certainly transform the lives of patients. For us, we see this as a heavy responsibility. We believe that our mission is strong, the need is strong. For us, the hyperfocus is around the delivery and being able to crack the number one key challenge for all companies in this space, to cross the blood-brain barrier. And to be able to find the right balance between delivering a transformative, therapeutic benefit for patients in a way that is safe and tolerable.

Our goal as a team, is to really focus on the delivery, focus in areas of high unmet medical need, and focus and work hard each day to bring these types of transformative treatments to patients.

Gina Mullane (06:11):
The mission of AviadoBio is to develop breakthrough therapies for life-threatening neurodegenerative disorders, among those conditions is frontotemporal dementia or FTD. The organization has developed a program for FTD patients who have a genetic mutation in their GRN gene. This gene is responsible for producing progranulin, which regulates cell growth, survival, repair, and inflammation in the central nervous system and peripheral tissues.

Patients with this form of dementia, produce only about 20% to 30% of the progranulin a healthy individual produces. The resulting symptoms are devastating for patients, as they encompass everything from executive function and language, to personality and behavior. The average survival time from time of diagnosis is just five to seven years. To date, there are no treatment options, including symptomatic therapies, for the 13,000 individuals in the United States and Europe carrying this mutation. Let's hear more from Lisa on what life is like for these patients.

Todd Poley (07:22):
You've mentioned that at AviadoBio, your current research focuses on frontotemporal dementia or FTD, and amyotrophic lateral sclerosis or ALS. Can you tell our listeners a bit more about how these diseases typically present in patients?

Lisa Deschamps (07:38):
Sure. For FTD, we're starting to meet a lot of families and it's a little bit different. But for the most part, for FTD, it does typically present more commonly with behavioral type of symptoms. Things that you might not even expect, where you could have a patient who all of a sudden always drank a glass of wine on the weekend, and all of a sudden started to have symptoms almost to be an alcoholic, right? Or have an addictive type of personality where they never did before.

Or it might have been a very benign, calm, kind personality and they're very rude all of a sudden just out of the blue. FTD typically starts with the behavioral aspect so personality and you wouldn't necessarily think. The feedback from a lot of the families that we've met, is you wouldn't necessarily think this is related to something that's medically going on. At first, it's like, "Oh, are they having a midlife crisis, or is there something stressful, stress related going on in the peripheral of their lifestyle, et cetera?"

It often takes people a good amount of time to actually get to the right doctors. As the disease progresses, then over time the cognitive impacts and impairments come to be. You will then start to see memory loss and other forms of cognitive impairment, which then is followed up usually by mobility and the lack of function, executive function overall. It can stay in that early phase for quite a while, and then rapidly progress to the point where again, it's unrecognizable.

It's really important that we raise awareness certainly for these forms of dementia that are the second. It's second to Alzheimer's, as far as the incidents concerned in patients under the age of 65. FTD is second most common form of dementia to Alzheimer's in patients who are under the age of 65, so relatively young patients. Unless you know there's a known family history, like as just mentioned, these initial symptoms are not necessarily obvious that there's something medically going on. In ALS, it's a bit different.

It is considered, as you rightfully said, motor neuron disease or Lou Gehrig's disease a lot of people know it. It's also a devastating neurodegenerative disease characterized by upper and lower motor neuron impact in the brain and the spinal cord. It leads to progressive paralysis and also death, but it is a bit more physical than behavioral in comparison to FTD. Unfortunately, patients survive only on an average of two to five years as well post their diagnosis.

That can also affect very young individuals, 30, 40-year-olds, and then of course, onward. Both have a familial component. In FTD, you can have anywhere from a quarter to half can be familial, which is good because if you have a known family member through the generations who you've seen, you may recognize the symptoms a bit more upfront. If you don't, it's even harder because there's no general, standard testing. It's not like when you turn 40 or 50 where mammograms or colonoscopies are part of normal medicine.

You don't typically get an MRI or get these cognitive tests, or other forms, genetic testing, et cetera. You really have to look for it and really follow the symptoms if there's not a known family component. In ALS, it's a little bit smaller. Familial ALS accounts for about 5% to 10% of all causes.

Gina Mullane (11:30):
The caregiving burden on families of patients with FTD and ALS is heavy. These diseases can affect a patient's whole being, from the physical to the cognitive, and are often accompanied by comorbidities. For example, up to 50% of patients with ALS, which primarily impacts mobility, are diagnosed with FTD resulting in significant cognitive impairment. FTD patients may also over time have mobility and motor neuron impacts, as seen with ALS.

According to the Partnership to Fight Chronic Disease, for patients living with dementia, 70% of the lifetime cost of care is born by families. The single patient cost for ALS exceeds two million over 10 years. For families who are caregivers for one patient, let alone for those who have carried the load of disease through the generations or the complications of co-occurring conditions, treatment cannot come soon enough.

Let's hear more from Lisa about how gene therapy is opening new doors in the treatment of neurodegenerative disease.

Todd Poley (12:43):
It's clear that it's been a challenge for the pharmaceutical industry to fulfill the therapeutic needs of these patients. What's unique about the gene therapies AviadoBio is developing?

Lisa Deschamps (12:54):
Our mission is to develop and deliver transformative gene therapies to people living with neurological disease. We're doing a bit of what we know and then adding a flare. The what we know piece of it is we're using AAV9, which is obviously a vector that is commonly characterized and available in other approved gene therapies today, as we know. But what the flare is, is the delivery aspect.

As mentioned earlier, we are really hyperfocused on delivery and really overcoming this key challenge in crossing the blood-brain barrier in the disease. It's the only way in the short-term to overcome these challenges and again, be able to provide a maximal, therapeutic benefit for patients in a safe and tolerable way. In our lead program, we are in frontotemporal dementia with mutation in the GRN gene, we are using an AAV9.

We've optimized our construct to enhance, to be neuronal specific and enhance the delivery. We are using a unique route of administration, so we're going into parenchymal, which others are doing, but we are going directly into the thalamus. We believe the thalamus, from what we know about the thalamus, is a central relay hub to the brain. Being able to go in there directly and in a sense, inject the medication there for patients will have a really... What's the right word I'm looking for?

A really significant biodistribution of the therapy for patients. Again, because it's so directly targeted going direct into the brain, you can use very little amounts. Which again, goes back to the maximal therapeutic benefit with the very targeted approach, and in a way that's not toxic, and is safe and tolerable. That's in our first program. In ALS, our programs are still in the discovery phase. There we have a proprietary microRNA platform where we're also looking at a unique delivery approach.

We're looking at a subpial delivery for diseases that have more spinal cord involvement such as ALS. That should also be, again, a very targeted approach, to be able to use very little drug and have the right balance between a maximal therapeutic benefit, and a safe and favorable tolerability profile for the patients. We haven't yet disclosed the targets that we're going after, but obviously in ALS, there are a number of key targets that have tremendous incidents as it relates to disease.

Gina Mullane (15:42):
At the annual meeting of the American Society of Gene & Cell Therapy earlier this year, AviadoBio presented preclinical data on its gene therapy treatment for FTD patients with GRN mutations, an investigational, one-time adeno-associated virus, or AAV called AVB-101.

Because patients with FTD GRN experience profound subcortical and cortical degeneration, the ability to treat these regions is essential to therapeutic success. In preclinical studies, a large animal model underwent intrathalamic delivery of AVB-101, and demonstrated widespread cortical and subcortical distribution of progranulin.

Notably, no progranulin or AVB-101 vector was detected in the serum and liver respectively, which may minimize off-target tissue effects. On the heels of this success, the organization will submit to regulatory bodies in Europe, and subsequently the United States, with a goal of getting to the clinic this year. Let's hear from Lisa about what goes on in this submission process.

Todd Poley (16:58):
In terms of what's next for AVB-101, I know the FDA and European Commission's recently granted you orphan drug designation. Could you explain to our listeners what orphan drug designation is and what it means for AVB-101?

Lisa Deschamps (17:12):
Sure, happy to. Then, yes, as you rightfully mentioned, we did announce that earlier in the new year, that both the FDA and the European Commission has granted us the orphan designation. Orphan destination, as it relates to the FDA, is when you're going after a disease that affects less than it could be 200,000 or less individuals in the United States. Again, this is a little bit different in Europe, because in Europe you have various countries with different population sizes.

In Europe, this is typically five in 10,000 people, so less than five in 10,000 people in each of those respective countries. What basically orphan designation does, is it gives you this opportunity to put in a new drug application granting this orphan designation, reflecting really the significant unmet need that exists in these disease areas. In a sense, it's meant to be an incentive for sponsors to invest in research in areas that are not as common.

Obviously, there's always a significant cost in research and development. For me, the most important thing of it is that it really recognizes the unmet need that exists. It's a validation when you get that, that there are no treatment options today for these patients. There's a lot of support by the regulatory authorities to work with you, to work with the sponsors individually to bring these drugs to the market.

Todd Poley (18:39):
Are you seeing a benefit for patients that are suffering from other diseases like ALS, Huntington's disease that are benefiting from your investigational approach?

Lisa Deschamps (18:49):
Yeah, it's a good question. As mentioned to you, I think we're all trying to solve for the key challenges in treating these rare diseases in CNS today, and everyone's doing it a little bit differently. There are others that are also going direct into the brain. Then there are others that are working on capsids and doing capsid development to really enhance that delivery aspect.

I do think that the more therapies that are focused on the delivery, will give us our best shots on goal to bringing these types of transformative therapies for patients. I do think that any advancement in the field today is a positive. All of us working relentlessly, collectively will really make a difference.

It creates precedent, it creates more understanding by the regulators, the more programs that are focused on solving this challenge. I do think it's a positive.

Todd Poley (19:53):
It is absolutely a positive to have more scientists focused on this area of research. On this podcast, we have the privilege of discussing groundbreaking gene therapies and how they have the potential to transform lives.

But an important part of this conversation is also the hurdles patients face in accessing investigational treatments. In your opinion, Lisa, how can we make these therapies more accessible to the patients who need them?

Lisa Deschamps (20:20):
Yeah. It's a great question and it is one of the number one key objectives you need to keep in mind when you're developing therapies like this. Of course, every step of the development process is critical, from the nonclinicals all the way through to going into human. But you always have to have your eye at the end of the day of, "Can we get them to patients who need them?" Because if not, why are we doing this? There's so many components of it.

You need to work with the community, both the clinicians as well as the advocacy groups, and the caregivers and the patients themselves where it's possible, along the clinical development process. You want to input into your studies endpoints that are meaningful to patients that can truly help them manage and potentially transform the way they can live with the disease. You want to know that upfront.

Then as you continue on, you want to work with the regulators and the reimbursement bodies, and again, the community the whole time. It continues, it's not a one and done, to ensure that you're creating that awareness and that education you're conveying. People understand actually the burden that exists from this disease today, because as it relates to access to patients, it'll always come down to the value proposition that these therapies provide, right?

There's lots of ways you can provide access to patients, as we all know, whether it's through compassionate use. But ultimately, you want to get these products approved by the regulators and approved by the reimbursement bodies, and going through the normal channels we have today in the quickest way possible. I think there's some really good precedent out there in programs from other recently launched gene therapies where access was not the barrier.

I do think it's possible, but it does take a conscious eye on that right from the beginning of the starting of the development programs, all the way through working with the communities, working with the regulators and the reimbursement bodies, to ensure that you always have the right understanding of what value these medicines can bring to patients. It will be our North Star as well because at the end of the day, that's what our mission is all about, is bringing these therapies to patients.

Gina Mullane (22:40):
This end goal of bringing therapies to patients, of course, must be top of mind even as early as the discovery process. Because at the end of the day, researchers must ask themselves, "Does what we're creating in the lab transfer to the clinic?" Particularly in the development of gene therapies, this answer cannot be found in a vacuum. Drugs are brought to market through a continuum that begins with discovery, continues to put clinical and clinical trials, and succeeds in its final step of commercialization.

In each of these steps, drug developers must anticipate what is needed to pass the checkpoint in front of them, from proof of concept to regulatory enabling studies. For AviadoBio in particular, this is meant thinking ahead to the go-to market model and its impact on clinicians, patients, and caregivers. The organization's lead program for FTD has a unique delivery approach, which requires a non-invasive surgical procedure for administration. From the start, their team has had to envision how this therapy will ultimately be put in the hands of patients who need it most.

From the training of neurosurgeons, to enabling patient access worldwide, by working together and learning from the scientific community, AviadoBio has found ways to overcome these challenges, setting a precedent for future drug developers in the process. Let's hear more from Lisa on how AviadoBio's partnership with Charles River helped them in their development journey.

Todd Poley (24:15):
You've talked about the role of collaboration in bringing about scientific breakthroughs. I know your team at AviadoBio partnered with Charles River to ensure the safety and efficacy of AVB-101. What would you say makes a partnership like this successful?

Lisa Deschamps (24:31):
Well, I think as always with all partnerships, it requires a strong group of individuals willing to come and work together. Charles River brings a significant amount of expertise to the table that we very much were appreciative and certainly in need of. It's really been overall, a fruitful partnership to date. They engage with us so closely from the beginning to the end and throughout, of course. One of the aspects that made the difference was the agility and willingness to adapt to our study design and the requirements for really solid output, nonclinical data package.

They've helped us with method development and qualification for some of our protein assays and safety biomarkers. The nonclinical assays were developed in collaboration obviously with Charles River. Provided a real understanding for us on how much of our product can actually reach the brain, back to our core emphasis and areas of focus. Following our intrathalamic delivery in the nonclinical animal models, of course. In addition, we were able to build a very robust package related to our safety profile for our product.

Very much focused on the nonclinical work leading in human studies and being able to really help us bridge from some of these assays into clinical samples and overall support, our regulatory enabling studies to be able to get to the next step in our journeys. It's been a very strong partnership, great expertise by the teams and just really collaborative back to the sentiment of collaboration.

Todd Poley (26:12):
It's so great to hear that we were able to help progress AVB-101 to where it is today. How do you think this work will help pave the way for future innovation in the treatment of neurodegenerative disorders, whether it's at your company or with fellow travelers in the FTD and ALS space?

Lisa Deschamps (26:29):
Yeah. I think from my lens, the answer to this question is really around the emphasis that we're putting on delivery. If we can crack this delivery hurdle that many companies have faced and will continue to face with these unique and bold approaches, again, around enhanced construct, routes of administration, different delivery technologies. I believe we could really make huge advancements in certainly FTD and ALS, but even more broadly in all neurological conditions. It takes some courage.

It's not a common path. We're not popping a pill in the mouth or giving a short IV. It is a much bolder approach, but one that has a lot of good precedent and some really good experience and data in other areas like deep brain stimulation, et cetera. But if we can bring that to some of these disease areas. Again, comes back to providing that therapeutic benefit for patients in a way that's truly meaningful with a very clean safety profile, I think the opportunities are really endless.

I think we can go much more broad in much larger disease areas, and really have a significant impact, of course, on the patients within those diseases, but even on society at large, right? When you think about the impact of neurological conditions to society in very young patient segments and demographics of the economy, it can be quite significant. I think there's so much opportunity. I'm really excited. I think we're off to a good start, and I think we'll be joined by many others around us.

Todd Poley (28:12):
Yeah, I agree. Maybe looking towards AviadoBio and in the year ahead or the long-term future even, what do you really hope AviadoBio's legacy is going to be?

Lisa Deschamps (28:25):
Yeah. For me, I want to be the company that has really cracked this delivery challenge, and has successfully brought transformative gene therapies to the people living with CNS conditions. And whether that means those rare diseases that we're focused on today, or even through collaborations and partnerships, much broader disease areas, that the work that we have done has really benefited so many.

For us, I think that is our legacy. I can tell you, you have a group of extremely passionate, inspired individuals on our team, who we're working relentlessly every day to make that mission a reality for patients. It's not easy, but it's so important.

Todd Poley (29:09):
It's worth it. If you could think about one thing that you could leave with our listeners to share with their close communities to spread awareness, what would you want them to know?

Lisa Deschamps (29:22):
That's a good question, let me think here. What would I want them to know? I would want them to have hope and be bold. We shouldn't be accepting that the best we can do for patients is either nothing at all or just symptomatic relief. We need to believe that we can do better.

That takes a whole group of community, caregivers, patients, different stakeholders like our patient advocacy groups, regulators, clinicians, all coming together to really invest the time and effort.

A lot of these are not chartered territories. We have to be bold and courageous if we truly want to make an impact and transform care for people living with these types of diseases.

Todd Poley (30:13):
Well said. Well, Lisa, thank you so much for joining us on Vital Science. I learned so much and your story is inspirational.

I think it's also informative for so many people that struggle with these different diseases or are connected to them through a family member. So just thank you for sharing your vision for AviadoBio and your insights.

Lisa Deschamps (30:37):
Thank you, Todd. Thank you for your interest in listening.

Gina Mullane (30:41):
Lisa Deschamps is CEO of AviadoBio. Looking ahead to our next episode of Vital Science, in February, we'll talk with Dr. Wise Young of the W.M. Keck Center for Collaborative Neuroscience about his team's work developing novel treatments for individuals living with spinal cord injury. Until then, thanks for listening.