CONVERSATIONS IN HEALTHCARE — A novel approach to treating neurodegenerative disease
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Mike: Hello, everyone. I’m Mike Ward, and welcome to Conversations in Healthcare, a series of interviews with industry leaders, brought to you by DRG, part of Clarivate. While many of the conversations that we’ve had in recent times have focused on the impact of COVID-19 and the efforts that the sector has made to find ways to help patients, it is important to remember that we should not ignore other potentially devastating unmet medical challenges, such as the blight of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. So, with this in mind, I’m delighted to be joined by Leen Kawas, who is the founder, President and CEO of Athira Pharma Inc, which is a publicly quoted clinical stage biopharma company. It’s headquartered in Seattle, Washington. And it’s focusing on developing small molecules to restore neuronal health and stop neurodegeneration. The company’s lead candidate, ATH-1017 is a subcutaneous administered BB penetrating small molecule, HGF/MET activator. And it has completed both Phase 1A and Phase 1B clinical trials, in which 88 subjects were recruited. And this included 11 with mild to moderate Alzheimer’s disease. And they were assigned to treatment and control groups for the treatment of Alzheimer’s disease. The company has also been successful this year in raising new money to pursue its ambitions. First, with an $85 million series B round in June, just before floating on NASDAQ in September, when it raised $204 million in an IPO. So, thank you for joining me, Leen.
Leen: Thank you, Mike, for the generous introduction.
Mike: So, yeah, as I said, you’re not taking an easy route by focusing on neurodegenerative diseases such as Alzheimer’s. While it’s clearly a well-established medical need, there has been little success in resolving them. So, it might be helpful if you could first explain what are the key challenges with current AD therapy approaches? And how does the Athira’s approach differ?
Leen: Yeah. Alzheimer’s disease is a complex indication where there’s multiple things that are changing, are impacted. And what the industry have been pursuing in the last 10 to 15 years is a single model type of approach, trying to address an underlying pathology, which we don’t fully understand how these types of pathologies impact the clinical outcome of disease presentation. So, there’s definitely a need for innovation in Alzheimer’s disease, like what we’re doing in Athira, where we’re targeting, as you highlighted, my recovery of network activity, neuronal transmission. And having an approach we are targeting, as highlighted, a single target, but the outcome of activating the HDGF met is multimodal aspect, where you have recovery of synaptic density, which ultimately leads to recovery of signal transduction and network in the brain, enhancing neurotransmission, which enhances information transmission and memory recovery. As well as blocking and inflammation and different aspects that recover degeneration. And I think this is where we need to start targeting is understanding the presentation of the disease where we can be agnostic of the underlying pathology to potentially, not only slowing down the disease, but also improving the disease.
Mike: So, where did the idea to focus on HGF/MET system actually come from? And what evidence have you seen of its role in, for example, maintaining neuronal health and function?
Leen: So, the idea of targeting HGF/MET as a neurotrophic factor or as a critical brain growth factor, or neuronal growth factor has been well studied in the last 15 years. The name is a little bit misleading because ‘hepato-’ comes from the lever. But there has been a lot of work in the last 10 to 15 years around this target and its critical function in normative brain function. And recovery of neuronal health. Now, the idea that we have, the origin of the idea that we have in Athira is from Doctor Joe Harding’s lab at Washington State. But we’ve transformed the technology into a fully owned pipeline by Athira. All of these compounds are novel, new composition of matter that we’ve developed internally in Athira. And some of the evidence that really creates excitement in Athira around the target is the work that has been conducted at the Allen Institute for Brain Sciences here as well in Seattle, where they mapped the human brain and rank ordered 30,000 genes in an effort to identify new targets that might impact the brain health and function. And what was very interesting for us is our target, the MET receptor, was at the top, listed at the top, the number 1 gene out of 30,000 gene in normative or stable expression, and very controlled levels in the cortex, which is an area that we know is involved in Alzheimer’s disease and memory and learning. And when you look at Alzheimer’s patients, what you see is there is a significant reduction in the expression of this target. So, there is also a pathological change in this target. And what we’re trying to do in Athira is rescue this critical brain growth factor and neuronal regenerative pathway.
Mike: Alright, alright. In the clinical trials that I mentioned, the Phase 1 and Phase 1B, you know you showed that multiple dosing of ATH-1017. You described it as significantly improving P300 latency. Now, that is a functional measure that is highly correlated with cognition. However, a connection between these P300 latency results and improved cognition has yet to be established. So, what are you doing to establish that connection?
Leen: Yes. Thank you. So, as you highlighted, the actual correlation between this objective measure of cognitive processing, namely, evoked response potential P300 and general cognitive state, the correlation between these 2 in general has been established. Specifically for 1017, this is what we’re working on right now. We’ve used P300 in an early… in our earlier stage trials to confirm that we are inducing a recovery or a change in brain network activity. Currently, we are running 2 trials, the LIFT-AD, which potentially can be our first pivotal trial, and the ACT-AD, which is a smaller trial that is running in parallel. And both have very similar designs and recruiting the same patient population, mild to moderate population, where we’re going to be studying the overall effects of ATH-1017. We’re looking at cognitive improvement, functional and global improvement as well, behavioral change. And with those 2 studies, we’re going to be able to appreciate the clinical effects of 1017. Now, the smaller study, the ACT-AD, again, has a very similar design component, is what’s really going to help us have an initial look to the overall effects of 1017. And what that means because it’s a smaller study, it will read out earlier, and we’re going to be able to appreciate the effects of 1017 on the disease overall, including P300. It will enable us to confirm our design assumptions in the LIFT-AD, and if needed, make some adjustment or optimization to increase the confidence in the outcome of the LIFT-AD, which is the potentially pivotal trail.
Mike: And sort of the end points that you’re going, I mean, are they the sort of endpoints that the regulators considered to be sort of validated and sort of good evidence that there might be a reason to approve the drug?
Leen: Yeah, great question. Yes and no. So, yes, because we are including the validated endpoint ADAS-Cog, CGIC which is a global end point, ADL which is a functional endpoint. But what we’ve done as part of our innovative clinical design, first of all, because we expect improvement, so the trials will be shorter, it’s not the 2 to 3-year study, it’s 26 week studies because we anticipate improvement, and that gives us the opportunity to have more efficient clinical design. As well as, again, because you expect improvement, or we believe we will have an improvement, we have higher power than the traditional disease modification where they need over 1000 patients per trial. This is a smaller, more realistic size of a trial. But what we’ve used innovatively (which we’ll need a whole new forum for just discussing our primary endpoint) is the global statistical test. And it’s really a mathematical algorithm that we’ve included as our primary endpoint to understand, in an unbiased way, the overall effects of 1017. And that gives us an enhanced sensitivity to our primary endpoint, because it captures the change from the different endpoints that we have in the trial and gives you an appreciation of what the drug is doing on the totality of the disease or the totalities of the symptoms of the disease.
Mike: Right, right. So, I mean, we’re all aware of the devastating impact that the neurodegenerative diseases have, both on patients and those who that are caring for them. To what extent is engagement with patients and patients in groups influencing the development of your approach?
Leen: Well, everything, right? Because everything we’re doing is for the people that are impacted by these neurodegenerative indications. And what we’ve done at a very early stage for Athira, while we were running the Phase 1A and B is we started running studios with patients and caregivers and physicians that are living with the disease, or seeing the disease, or interacting with the disease on a day-to-day basis. And we started asking about the different components in the study, and what’s really important for the patients. Because, ultimately, we want to have a product in the market that helps patients and is easy to use, but that it’s around the product profile that it’s a Sub-Q injectable, or it’s the different components in the clinical design. For me, personally, and the team also shares this, I think, core mission, in addition to developing treatments that are effective, we want to make sure that we’re celebrating the patients and appreciating their participation in our trials and enhancing the user experience in our trials. So, very early on, we’ve asked feedback on the design, “What are the critical important for both the patients and the caregiver?” Because Alzheimer’s is a 2-people disease, not 1. And then continuously, as the trials are being conducted, we are getting feedback from the key stakeholders that are involved in our trials.
Mike: Alright, right. So, could you sort of outline sort of the business model that you’re pursuing? I mean is it, are you looking to become a sort of a fully integrated biopharma company in this space?
Leen: Yeah. I mean, we’re building a pipeline. As you probably know, our lead asset ATH-1017 is starting its pivotal trial, which really positions Athira in a really attractive place. Because this could be a really… one of the big catalysts in biotech if we see the benefits that we expect from 1017. But we also have additional assets. We have compounds that we are developing. We’ve differentiated product profiles, orally available compounds that we anticipate that we’re going to be developing as pills for neuropsychiatric indications, like depression and schizophrenia and anxiety. We’re also interested in indications where there is peripheral damage of the neurons, and because it’s a very common underlying representation of multiple indication diseases, right? They all share the outcome of aging and disease pathologies where you have degeneration. So, we do think recovery of neuronal health can address both the central nervous system and the peripheral nervous system. So, we also have compounds, groups of compounds or families that are being advanced to explore the potential and peripheral neuronal indications. And we’re going to continue with our discovery programs to try and address brain function and brain regeneration. So, the idea, yes, is to build a company with a very strong pipeline to address both central and peripheral neuronal health and neuronal regeneration.
Mike: Yeah. I mean, I was sort of thinking, are you sort of looking out for partners who are going to help you with the sort of the later stages of clinical development and the sort of the regulatory processes, i.e., going all the way to the marketplace, or would you have partners?
Leen: It’s a little bit early to make comments about this point, but we’re going to be opportunistic, keeping in mind that increasing the chances for a successful outcome for the product, our goal is to get assets to patients as soon as possible. And we’re going to have an open mind to engage with conversations that might lead to a faster outcome to drug registration and patients. But right now, we are in the mindset that we’re building Athira, we’re advancing our technologies. And we want to have a company that delivers treatments that can help improve the quality of people’s life. Mike: Nice. So, I’ve been doing sort of asking questions to biotech CEOs for a few decades now. And sort of one of the key questions that always comes to mind is there…? What experience do you actually already have in the company or sort of taking your discoveries from the lab bench and translating them into promising drug candidates, and ultimately medicines that help patients? Do you have the sort of the bandwidth to be able to do that?
Leen: So, we have… at Athira, we have a nice mix between innovation and expertise, specific field expertise. We do have our… within our management team, our Chief Medical Officer, Hans Mobius. You probably know him. He was the Chief Medical Officer that led the team that ultimately led to the approval of Memantine. And we’re actually taking some of the aspects of that strategy for 1017 to potentially accelerate its approval and address the key components for Alzheimer’s disease. But as you see, we’ve also included innovation that… because Alzheimer’s disease, it also needs this fresh look and fresh strategies around how can we use established methods like P300 to accelerate drug development and have increased confidence in drug outcome? So, I think we have this really nice collaboration between innovation and also experience that has the open mind to endorse new ideas and new methodologies in Alzheimer’s drug development. Also, our Chief Operating Officer, Mark Litton, has extensive experience in and different operational aspects of drug development and biotech development. Within our discovery team and clinical team, honestly, we have a fantastic team that is on a mission to change the reality for people impacted by neurodegenerative indicate.
Mike: So, as I mentioned in my intro earlier, in the summer, you raised first 85 million a series being round before taking the company down the IPO route, where you netted approximately… I mean, you raised 204 million, but that sort of nets out to about 186 million. What, however, were the biggest challenges raising money during the pandemic when we had all that social distancing and travel restrictions in place? And what did you do to overcome those challenges?
Leen: Yeah, I think people just needed to adjust to a new transient normal, I would say. So, we were in the midst of raising the crossover or Series B round for Athira when… and we were very close when the pandemic hit. And that created a significant slowdown initially. And but we just needed to appreciate that there’s something that everyone was dealing with, and that we needed to give people time. We needed investors to digest what’s going on. And what was very critical at that point, and obvious, is our investors, they were mission oriented. And, yes, as you highlighted, I think your intro is very important, they appreciate that there is an immediate challenge, which is the pandemic, but the impact of Alzheimer’s and the potential upside for an effective Alzheimer’s drug is not going to go away because of COVID. So, that type of appreciation from the investors keep them engaged and ultimately led to a successful crossover round and IPO. I also have to… Perceptive and Joe Edelman who joined our board, they’ve been extremely supportive during the peak of the nuclear winter, which is March. We were closing around in March-April timeline, which was the peak of the events and uncertainty. But they are partners that they’ve been partners in the way to the point that we’re at right now at Athira.
Mike: So, when you were raising money, what did you tell investors you were going to do with the money that they were going to give you?
Leen: Running the 2 trials that highlighted, Mike. The LIFT-AD is a significant pivotal trial, which could be registrational if positive. The ACT-AD is another trial that is running in parallel. We are also planning a Parkinson’s disease dementia next year. Because mechanistically, the way that the ATH-1017 works, we really anticipated to address the larger dementia definition, including Alzheimer’s disease and Parkinson’s disease dementia. We also want to maximize our pipeline, at least have 1 additional asset in the clinic in the next 12 to 15. And support building the infrastructure for Athira. Also, we are, since it’s a registrational trial… and, actually, that was the main incentive for us is because LIFT-AD can be registrational and it could be pivotal, is we wanted to build or start working on additional aspects that needs to be done in parallel towards and in India, whether it’s manufacturing quality. And it’s etc., which requires the support that we have from our crossover and IPO funds.
Mike: Right. And you mentioned that there were some other areas you’re also looking on. I mean, there, you just sort of you mentioned the fact that you’re planning to start sort of Parkinson’s trial. But depression and some of the other sort of neuropathies that you’re looking at, what’s the sort of the timeline [inaudible]?
Leen: So, that’s we are in the development stage for these assets. So, as highlighted targeting, we’re trying to move as quickly as possible to the clinic. So, hopefully, within 12 months, 12 to 15 months, we’ll have an asset for neuropsychiatric indications in the clinic. We’re going to be using very similar strategies where we want to implement objective measures at earlier stage of clinical development to give us increased confidence in the potential clinical outcome.
Mike: So, how big is the company now in term terms of employees? And do you sort of foresee that growing much larger in the coming 12 months or so?
Leen: Yes. We are adding to our team every week. And we’re hiring, as you would expect, in a very rapid… I don’t know the exact number. It’s between 25 to 30 people, because every week, we’re adding. And I know people are being hired as we speak. So, we we’re growing very rapidly with a focus. I think we’re trying to capture talent that has the same passion and mission that we have at Athira.
Mike: Right, right. I mean, you founded the company in 2011. What…? I’d be interested to understand, what were the hardest challenges you faced at that time? And then knowing what you now know, what would you do differently? And also, what would you do the same?
Leen: Yeah. That’s an interesting question. Needs a lot of reflection, but every period has its own challenges. And I tell my team that challenges are just opportunities that we need to discover. So, I don’t dwell on things that happened. So, I can’t really highlight what are the biggest challenges. I think that being a first-time entrepreneur and going out, I tried to solve for that by creating a team that has a lot of experience but balancing it out with innovation. I think as entrepreneurs, you’re too busy to like to dwell on challenges. Of course, you need to learn from the lessons. If I would I do anything differently? Probably not. Because whether we made decisions that were perfect or not, it’s led us to where we’re at today. And the other thing is we need to make decisions and deal with the outcome. You need to be moving very quickly. And I wish I had a more like deep answer for you, but I mean, we’re at a very exciting time for Athira that it’s hard for me to think about past challenges.
Mike: That’s absolutely fine. So, Leen, look, thanks very much for taking the time to talk to us today. And I’m sure that what you’ve shared is going to be fascinating to a lot of our listeners and also leaders who are in your position. So, if after listening to this broadcast, you’d like to tune in to future conversations in healthcare, follow our LinkedIn page where we’ll be posting alerts to other episode releases. So, in closing, I’d like to thank Leen again for joining us, and also thank all our listeners for tuning in. So, until next time, stay safe and healthy. I’m my Mike Ward, and I’ll see you in the next episode.