In Conversation: Dr. Shane Hegarty from Axonis Therapeutics

AXONIS Therapeutics is a Boston-based biotech dedicated to advancing breakthrough therapies in the field of neurotherapeutics. Backed by a team of accomplished scientists, researchers, and industry experts, Axonis is developing novel treatments that target the underlying mechanisms of neurological diseases.

I sat down with Axonis' Co-Founder and Chief Scientific Officer, Dr. Shane Hegarty to capture a behind-the-scenes perspective on the inner workings of an emerging biotech company. We discussed the economic climate and its influence on drug development strategy, partnerships with service providers, artificial intelligence, and... sending neurons to space. 

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What made you want to start Axonis?

My burning desire was to test whether the exciting preclinical breakthrough discoveries we made at Boston Children’s Hospital and Harvard Medical School could truly help patients. A biotech company seemed to be the most efficient and robust way to translate these technologies into medicines so that we could test their potential health benefits in patients, and we were in a unique position to be able to leverage the thriving biotech ecosystem in Boston.

I was lucky to have a partner in our CEO, President, and Co-Founder Dr. Joanna Stanicka who has been instrumental in spearheading the efforts to build Axonis in order to translate the science we did when we co-led research projects under the guidance of Professor Zhigang He in his lab. Axonis is also blessed with an incredible board and investors, especially Co-Founder and Executive Chairman Corey Goodman who has guided Axonis' successes to date. While Corey has been a world-leading drug developer, company founder, executive, and VC in more recent years, he is also one of the greatest neuroscientists of our time along with Zhigang.


What unmet needs are you hoping to address for patients?

Axonis aims to develop first and best-in-class medications for patients living with neurological disorders, with a focus on epilepsies, chronic pain, and neurotraumas.


What were some of the obstacles faced early on? Anything unexpected?

The biggest obstacle at the beginning was identifying investors. The strategy to overcome that was to participate in many accelerator & innovator programs locally in Boston, as well as virtual ones. We also applied for golden tickets and were very proactive in unearthing grant opportunities, mainly NIH SBIR grants, as well as support from patient foundations.

Securing non-diluted funding helped validate our science for others, which in turn attracted more VC-backed funding. The neuroscience space is perceived as being more risky in general, so we felt extra pressure and motivation to prove that our approaches are truly better than other therapeutics that have been tested in the past.


What makes Axonis different?

At the beginning, it was our ambitious, unbiased, and large-scale in vivo phenotypic screens that identified novel therapeutic targets, which were substantially more potent than other targets that had been identified in the past. Doing large-scale tests of thousands of genes one by one, using AAV-CRISPR and over a dozen small molecules, led us to find the most effective therapeutic targets in CNS animal models when compared to the current standards.

In vivo phenotypic screening is quite labor-intensive which is why it isn't commonly done to identify new therapies, but we think the data collected is of much higher quality and translatability than most in vitro screening systems. At this scale and standard, we demonstrated that our therapeutic targets were superior in these neurological disorder models, and in the last couple of years, we've focused on the huge therapeutic potential of KCC2. Over this period, Axonis has brought together and become world leaders in KCC2 biology, which has further separated us from our competition. We have built a unique KCC2 drug discovery engine and testing capability that is not easy to recapitulate, and expect to have the first- and best-in-class oral KCC2 therapeutic in the clinic.


What impact does a market correction/looming recession have on funding?

In 2019-2021 when the market was more open and risk-tolerant, investors were looking for multiple things in the pipeline and wanted to see diverse and early assets in the pipeline. We had our in vivo screening platform and validated multiple therapeutic targets, some in stealth mode, with our lead program being on KCC2.

In response to the more recent market correction, we focused on our promising asset. Luckily we can show that we are world leaders in KCC2 drug development for neurological disorders. With KCC2, we really feel like we’ll be able to introduce meaningful change to patients' lives, rather than a marginal improvement on the current standard of care. More specifically, we feel that our drug for a novel target will have a unique impact on patients refractory to existing therapies.

Thankfully we’re in a position where we have great relationships with our existing investors who really believe in what we’re doing. As we continue to hit key milestones, the support from those who have already invested in our success grows, and we can attract new high-quality investors and partners.

It’s a fortunate position to be in during this market and economic climate, not having to continually seek funding from external groups. That being said we’re still being prudent and capital-efficient in our overall approach to ensure that we deliver on the objective of having a first-in-class oral KCC2 potentiator drug in the clinic in 2024.


To what extent has the prospect of a looming recession influenced your research & development strategy?

It’s not an ideal situation, you always want to be developing all your programs as efficiently and as quickly as possible, especially when you believe in their huge therapeutic potential as we do. In this climate you have to evaluate which assets have the maturity to reach FDA approval as quickly as possible, then we redirect most of our capital towards that effort.

We continue to work on the other projects and assets with non-capital intensive research while seeking out non-dilutive grant funding to continue to de-risk them. Then once our lead assets reach the clinic, hopefully, it becomes more logical to fundraise to accelerate research on the earlier programs that were had to deprioritize.


Leveraging Artificial Intelligence in Drug Development

At this stage, I believe AI is only as useful as the data it’s being fed, but we all need to consider employing it as a computational tool. We didn't employ AI in our target discovery workflow but we have generated quality proprietary data, primarily from screening thousands of genes 1 by 1 in vivo for their effects on neuron survival and regeneration. Because of the dramatic neuroprotective effects we discovered, it was very obvious which hits were the most potent in these screens. It could be interesting to have an AI/machine learning algorithm to analyze the entire data set, but we haven’t dug too deep in terms of how we can implement such technology into our programs to date.

That being said, we believe that it’s an important new avenue for the life sciences space and would surely be excited about combining AI with our rich datasets.


What’s the outlook on your two assets in discovery?

Because of the strong therapeutic potential demonstrated with KCC2 therapies by our company and dozens of leading academic labs, we are laser-focused on the development of a portfolio of KCC2 potentiator therapies, matching the modality to the patient's needs. That being said, our other earlier programs also hold a lot of promise.

Despite placing the majority of our efforts and capital into our lead program, we’re continuing to work on our earlier programs using non-dilutive funding. We’re hoping, with the help of Series A fundraising, to generate an additional budget to ramp those stealth program R&D activities back up.


Last time we spoke, you were on your way to drop off some cargo that was being shipped to the ISSNL with NASA. Can you tell us about how that project came to fruition?

That grant proposal went better than anyone could have expected. It went from being a crazy idea and risky side project to everyone saying “Wow, I can’t believe that worked so well”.

Before Axonis was operational we had enrolled in MassChallenge in Boston, which involved a competition to apply for a grant with an award of over half a million dollars, so it was too good to turn down. It was a “Technology in Space” grant put together by the ISSNL, NASA, and Boeing.

So we sat down as a group to come up with an idea to test a proprietary gene therapy that we were developing at the time. The experiment we came up with was to use human iPSC-derived neurons and glia to assemble them into a 3D model and use that model to test an AAV therapeutic that would selectively target the neurons. Luckily we were selected and so we spent the last few years developing and refining a protocol for the experiment, taking into consideration what was logistically possible for the astronauts in orbit. The experiment ended up being a success, and we just received the experimental cargo back from the most recent SpaceX expedition so we’ll be running more follow-up tests. We believe this is the first time that mature iPSC-derived neurons and glia have been rapidly self-assembled into a 3D model of the human brain, and I am excited about the potential of this disease model platform for precision CNS therapeutic discovery and testing.

You can read more about the experiment in the Wall Street Journal.


Have you formed any partnerships with service providers? What criteria do you take into account when evaluating these types of relationships?

Well, above all, the first thing you want is quality. We rely on the contractor's track records and shared data, in addition to the opinions of some of our advisors and their respective knowledge of the service providers we’re evaluating.

Next of course is cost and timeline. Are they affordable and do they have the bandwidth to execute the project within our desired timeframe, or will we be put at the back end of a long queue? It’s a critical part of the business because while we do have a certain amount of work done in-house, a lot of it is being outsourced. We have consultants that help manage and plan these projects, and they span from academic partners to CROs and CDMOs, to ensure that we can get everything done efficiently and cost-effectively to the highest standards, without having to build out our own capabilities in each part of a drug development program.


At what point in Axonis’ lifecycle did you start to entertain partnerships with service providers?

Even if you have a stealth program, you need to work in collaboration with the best partners and service providers for it to move forward at the right pace. Partners are brought on far before any information about patents or the program as a whole are made public. Then of course you run the risk of some information getting out there before you’d like it to, so despite confidentiality agreements there needs to be an element of trust and reliability between you and the service provider so that you can maintain your competitive advantage for as long as possible.

To answer your question, even for our most important or sensitive intellectual property, we’ve needed to bring on the right partners to help with the assays and progression of the program.


Have you had any meaningful interactions with service providers at conferences? What separates them from the rest?

In life sciences there are endless possible ways to try and solve a given problem, and more likely than not you haven’t thought of all the options. So it’s always interesting to meet someone who

introduces you to something completely new, like an assay or technology that wasn’t even on your radar, which then opens new doors for you to explore.

If I decide to meet with someone, it’s extremely helpful when they come prepared and are aware of what we are doing in our drug development journey. Having that base understanding enables them to point out what help they could potentially give, rather than going through all of their capabilities and asking me to determine what might be useful to Axonis at that particular time.




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