Genetic Epilepsy Team Australia’s 2024 Genetic Epilepsy Conference

Thank you, good afternoon. I’m Sal Rico, Chief Medical Officer of Encoded Therapeutics, and I really want to thank Kris, David, and Professor Scheffer for the invitation to be here before you today. I am tremendously energized and I think that call for action and a message of hope that I heard earlier today is really going to change how we treat genetic epilepsies in the coming years.

So I’m going to tell you a little bit more about how we can change the lives of kids like Malcolm. Malcolm is a kid. He’s slightly over three years of age, and he lives with Dravet syndrome. Incidentally his father is from Australia. They live in the U. S., and that picture was taken a couple of years ago in what was the last trip that they could take as a family together, because he has extreme photosensitivity, so he seizes when exposed to the sun.

In spite of multiple anti seizure medications that he takes, he’s not seizure free. And those anti-seizure medications that he’s taking are not doing anything for the developmental stagnation that he’s experiencing. So what I’m going to tell you over the next few minutes is how companies like Encoded are developing gene therapies for genetic epilepsies such as Dravet syndrome. So that we can offer kids like Malcolm a brighter future. And if there’s one message that I would like you to take away after this 20 minute talk is that the treatment of genetic epilepsies will improve. And that there will be better solutions for these patients in the coming years. And it’ll be thanks to all of you being here and all of your combined efforts because together I think that we will be changing the face of epilepsy treatment for these kids.

First a little bit about my company, Encoded is a gene therapy company based in San Francisco. We use and harness the power of non coding elements of our DNA to generate precision medicines for neurological disorders, mainly pediatric, and our lead indication is Dravet Syndrome.

Dravet Syndrome needs no introduction in this audience. You all know that it’s a severe treatment refractory epilepsy that carries an up to 20 percent mortality risk before adulthood. Very high risk of refractory epilepsy and an unacceptably high risk of developmental stagnation. So how do we go about developing a gene therapy for a rare disease such as Dravet syndrome?

Well, admittedly, the process is complex and it requires a lot of interdependent elements. First we must have the exquisite understanding of the pathophysiology of the disease because with that, we will be able to test potential drug candidates in predictive animal models and create a comprehensive preclinical package that will allow us to then test them in the clinic.

Besides that, we need to have a very robust understanding of the natural history of the disease so that we can really understand what happens in these patients over time and put some context into the potential benefits that we may see in the interventional trials that we’re going to be running.

And we need to use all of those learnings to design clinical trials that are tailored to the diseases that we’re trying to address as well as to the drugs that we’re trying to develop. And these programs will receive input from the patient community, the clinician expert community, as well as from regulators. Last but not least, one of the important things that we need to tackle is the development of new paradigms, new commercial paradigms that allow all patients and families who can benefit from these therapies to get access, timely access to these therapies.

And clinical development for gene therapies doesn’t really follow the traditional paradigm that you may be familiar with of small molecules and other biological products, where after preclinical testing, you go into healthy volunteers in a phase one study, a small phase two study that is dose ranging, and a couple of phase three studies that allow for therapies to be approved for commercial access.

What we have is something slightly different because of some of the unique aspects of gene therapy products, such as the fact that in the case of AAV based gene therapy products, you can only administer them once. You cannot take them away. As well as the potential transformative effects that have been witnessed with many of these therapies in order disorders.

So besides a robust preclinical package, we also need to have that very good understanding of the natural history of the disease. That is quintessential. And then, we are not going to be testing the gene therapies in healthy volunteers. We need to test these gene therapies directly in the patient populations who we are trying to help.

So then that forces us to combine a Phase 1 and 2 study in a Phase 1 2 study that will hopefully allow us to understand the safety and preliminary efficacy of those drug candidates to then hopefully seamlessly transition into a Phase 3 study or a confirmatory study that will lead to the eventual commercialization of a product.

Importantly, because durability is one of the key aspects that we need to continue monitoring, we will be expected and we’re expected by regulators to run very long studies up to 15 years in duration to really monitor whether the effect that we’re finding is durable over time. That doesn’t mean that we’re gonna open the box in 15 years, that means that there’s an ongoing analysis of data, but that it’s important for us to understand whether indeed these gene therapies are as transformative as we think they are.

Over the next few minutes, I’m going to use our ETX101 example for Dravet syndrome, it’s our candidate therapy for this disease, to tell you how we’ve tackled this, and how we’ve tried to use a holistic approach to understand the patient journey. To generate a preclinical data package that is robust to allow us to go into the clinic, how we have obtained feedback from the community and from expert clinicians to then design what we call now POLARIS, our overarching clinical development plan for the development of ETX101 for Dravet syndrome. So first, how do we design a gene therapy for Dravet syndrome? As I said, it’s very important to understand the pathophysiology of the disease. So here, countless investigators did a lot of work to really understand the pathophysiology that Ingrid just covered very elegantly. That is, in the majority of these patients living with Dravet syndrome, there’s a variant of the SCN1A gene. We know that the SCN1A gene codes for the alpha subunit of the NAV1.1 channel that modulates GABA release. And that this is a disease of haploinsufficiency. So there’s one allele that is mutated and one that is working. So there’s insufficient density of nav 1.1 channels, mainly in the GA inhibitory inter neurons of the brains of patients living with Dravet syndrome. And there’s insufficient inhibition, runaway excitation that leads to the phenotype of the disease. To use an analogy that will help explain the mechanism of action of our drug. I’m going to ask you to think about the two alleles of the SCN1A gene as two assembly lines in a factory. These two assembly lines are in charge of manufacturing NAV1.1 channels, and one of them is broken, so there’s only one assembly line manufacturing those NAV1.1 channels. We need a gene and cell specific approach to try to address that problem. And that’s precisely what our non clinical team did at Encoded. We developed a potential one time gene therapy or gene regulation therapy for SCN1A positive Dravet syndrome that works, if we think about our assembly line example, as a boosting element that will force the working assembly line to produce more of those channels and in so doing compensate for the loss of the mutated allele. That’s how we are leveraging the disease pathophysiology to try to address the clinical problem.

Now, we have a candidate. What happens next? We need predictive and validated animal models that help us understand whether these candidates are safe and whether they are potentially efficacious. And some models in some diseases occur naturally, and in some other cases we have to genetically engineer them. And we are assessing many different aspects in those animal models, but among the primary ones that we need to assess for the development of a one time AAV based gene therapy are how well this is distributed and where in the bodies of those animals. Whether the different doses that we’re testing are safe and well tolerated in those animal models, and whether they’re efficacious and whether there’s a dose response.

That information is incredibly important for us to design the clinical trials later because that will help us determine what is going to be the starting dose in our clinical trial. One important thing that we need to do for a first time human clinical trial of any kind is to determine that starting dose.

But in chronically administered drugs, You have the benefit of starting with a dose that is not going to be efficacious. You’re just testing safety. But it would be criminal for us to test these therapies at a suboptimal dose because there’s not a chance to re dose for the time being. One day we’ll resolve that issue, but for the time being, we need to get it right from the beginning.

The starting dose is very critical, and that is why we do a lot of work in different animal models, to try to triangulate data and understand what is that starting dose that we’re going to be using. We need to determine the dose range that we’re going to be testing in the clinical trials. And we need to understand when we are going to be expecting the onset of action and the durability of the effect of those drug candidates. And last but not least, and in fact front and center for our first time in human clinical trial, the side effects that we may need to be ready for and to monitor for in the clinical trials that we’re going to be running.

In the case of Dravet Syndrome, what we did is we took advantage of two of the mouse models that already existed in the literature and tested the safety and efficacy of ETX101 in these two mouse models. After a single administration directly into one of the lateral ventricles of mice, we were able to witness how we could extend survival of these mice for up to 470 days. And this is the longest study of its kind that has been conducted. We just stopped the study right there, and we saw that there was a durable effect all the way to up to 470 days. We also noticed how the drug, in a dose dependent way, reduced the number of seizures, or the frequency of seizures, and reduced the sensitivity to heat induced seizures in hyperthermia induced seizure assay. We have also extensively tested ETX101 in non human primates, because they represent the closest animal model where we can test the safety of this product before going into a clinical trial. And we have shown that the administration directly into the ventricle of a non human primate is well tolerated, and that the drug goes to all the areas of the brain where we need an effect. Then, I told you that we also need to have an exquisite understanding. of the trajectory of the disease. The first thing that we need to do is go to source. The source is all of you. Back in 2020, we initiated our project called Dravet Engage that consisted in discussion groups, one on one interviews and surveys with multiple caregivers from many places of the world to really understand the patient perspectives, the needs, the wants, the desires from the patient community as it relates to the treatment of Dravet syndrome in general, and the hopes they had from a one time AAV gene therapy program such as ETX101.

And we learned that the number one thing that most parents want is obviously addressing the unrelenting seizure burden in these patients. But second to that is really aspects of neural development, specifically communication that needs to be addressed in these kids. I think that the quote on the right on the bottom right, is quite telling of that. One of the mothers said, It would be amazing to hear my daughter’s voice express preference, needs, wants. It would remove frustration barriers and learning barriers, and help her live an independent life. Besides that, we also noted that there was a dearth of data on natural history, especially in the very young patients. Those patients under two. So that’s where natural history studies come in, at least in our case. In natural history studies, we typically try to collect health information to understand how the disease evolves over time. What are the domains that are affected? Is there, are there oscillations? Are there common trends? Is any of these affected by the variant that these patients have? And we also try to identify different tools, neurodevelopmental assessments or tests that we will then use in clinical trials. So it allows us to learn what to use in later phases of development. So we conducted ENVISION. ENVISION was a multi centered, prospective, observational study that we conducted at 16 international sites. I’m going to start with a little bit of background on Australia, because Australia rocks us, UK, Spain, and Australia. And because Australia rocks, Professor Scheffer was one of the top enrollers of the world in a minimum amount of time. So I was quite impressed and thankful with experience, because the other thing that I would add is this happened in the middle of the worst pandemic that this generation has seen. So I was just humbled by the experience and the commitment of the clinicians and the families to really make this happen.

And this is something that we’re putting to good work as we have discussions with regulators because this is the foundation of our clinical development program. So in this study, we had 58 participants, half of whom were under two years of age, who were followed up every three months for up to two years. And what we tried to do is to assess the developmental progression of these kids from a cognition, communication, motor function, quality of life, As well as the seizure burden over time in the context of the currently approved antiseizure medications. There’s a lot of data published elsewhere, but Stiripentol hadn’t been approved, Cannabidiol was not available, Femfluramine wasn’t available. So we needed contemporary data to really guide our decisions on the design of our trials. As I told you, we also needed to test the different tools that we were considering for the interventional trials. We met with many different neuropsychologists, physical therapists, epileptologists, immunologists, etc. to try to come up with a plethora of tools that we were going to pilot in that natural history study that would assess aspects of seizures, neurodevelopment, functional ability, motor function, social, behavioral, and language aspects, quality of life sleep, safety, etc. And some of the learnings that we got I think that we’re just reiterating or confirming what expert clinicians had already been telling us, but now we have actual evidence over time in a very important sample size. One of them is that the seizure burden increases over time. And the seizure burden, although quite variable, in 20 percent of these patients can be quite high. And about 20 percent of the patients experience more than 14 seizures a month or required more than four times rescue medications per month. And in some of those cases, some of those participants experience hundreds to thousands of seizures per month. Something that really impressed us is how a patient can live with 3, 000 seizures a month as we had one little kid. In Texas in the study. And this is in spite of using one to six anti seizure medications. The best medications that are out there in the market now for Dravet. The median was three anti seizure medications per patient. And the most frequently used anti seizure medication regimen included clobazam, Valproic acid, and Stiripentol. From a development perspective, one of the key things that we understood, and this was an important learning, is that we could reliably measure aspects of development as early as the first year of life. And that unlike neurotypical kids who acquire foundational skills from a motor function, cognitive, and communication perspective over time, kids living with Dravet Syndrome don’t, and by the time they are seven, the vast majority of them are performing at a two to three year old level. Now, how do we develop or design a clinical development plan once we have all of that information? We use all of that information to come up with a robust phase one, two program that will allow us to understand whether the different doses that we’re considering for the clinic are appropriate are safe, and whether the potential benefit justifies the potential risk associated with administration of this therapy, and whether there’s going to be enough information that will allow us to progress into later phases of development. And later phases of development can be a seamless transition of the same trial into a phase three trial or a separate phase three trial.

We’re going to answer whether there’s confirmation that the possible benefit is outweighing the possible risk associated with administration of the therapy, and if this potential therapy is better than the current existing alternatives to treat the disease. Now one of the most important questions that we have to answer as we design these clinical trials is, who do we dose first? We cannot dose everyone at the same time. That wouldn’t be safe. We need to stagger dosing and assess safety and efficacy over time. So there’s evidence that indicates that earlier can be better to try and maximize the potential scientific validity of the study and to really also understand and maximize the risk benefit for patients because some of the younger patients may actually see the greatest benefit in the shortest time frame so that we have a good foundation and foundational understanding of how good the drug is and that we can then progress into a phased expansion into older patients and more lax inclusion exclusion criteria.

So if the data is really transformative in those patients where we expect to see the most rapid effect or the one with the largest magnitude, then it will allow us to progress more rapidly into other patient subpopulations. So we’ve taken all of those learnings and all of that knowledge and designed our Polaris program. Polaris, because that’s our North Star, and this is the name of the overarching clinical development program for ETX101 for Dravet Syndrome, and it comprises three studies: WAYFINDER ENDEAVOR, in the US, and then EXPEDITION in the UK. We’re gonna be testing, initiating these trials that were just approved by the three different regulators TGA, FDA, and MHRA.

In three small open label studies where we will be assessing different dose rate, dose levels of ETX101, all of which are expected to be efficacious based on the animal data that we have generated to date. And we will be staggering dosing of patients in the different studies and assessing all of that information to eventually select a single dose level that we can then progress to test in a potential confirmatory study that is ENDEAVOUR Part 2.

And therefore, part two for the time being is only approved in the U. S., but we intend for that study to become a global study. That study will have all the rigor that Professor Scheffer covered as the gold standard. Double blind, sham, delayed treatment control. But it’s also something that is very important in the context of developing gene therapies that all participants who sign up with clinical trials, such as this one, get their investigation therapy in a timely fashion. So they can really get the potential benefit from this investigation of therapy. So patients randomized to sham would eventually get access to the investigational therapy. So all patients would be getting it. Now, I truly hope from the bottom of my heart that ETX 101 is all that we want it to be. And that eventually, a few years from today, we get a marketing authorization in Australia and many other places. very much. But the work does not end there. We then, in the context of gene therapy studies, as I mentioned, need to conduct longer studies to really understand the real world evidence and to generate evidence of durability of the effect of this type of drug. And these studies will be fundamental to speak to the value of these therapies because then we’ll have conversations with payers, health technology assessment organizations, where they will say, yes, your drug was safe, your drug was efficacious, but are they as valuable as you think they are? And that conversation on value needs to be contextualized yet again with natural history. So we will be seeing all the data in the clinical trials, multiple years of data, and those patients who participated in the clinical trials, and compare them back to the natural history of the disease that we have generated, and that we’ll continue to generate because I completely agree with Ingrid, two years is just the beginning, we need more. We really need a longitudinal trajectory of these patients over many years.

In summary I hope that I made it clear that understanding the disease pathophysiology is fundamentally important for us to design drug gene therapy candidates that then we can test in different animal models that are predictive and validated. That we can generate generate a preclinical package that will support the transition into clinical trials. And that this needs to be combined with a solid understanding of the natural history of the disease. That those initial phase one clinical trials need to be very carefully designed That the selection of the patient population we start is intentional to try to maximize the benefit in the shortest time frame that we’re looking at, and that the commercialization of these therapies will require evidence of value. As you may imagine, it really takes a village, and I think that the participants are the center of it all, but obviously their families and caregivers as well. We need to liaise and partner with expert clinicians who see these patients every day. We need input from regulatory agencies such as TGA, health technology assessment organizations, etc. And we also need companies that are committed to really develop these therapies because it’s a multi year exercise. I really want to thank all the children and the families, and especially the Australian ones who participated in ENVISION. It’s really only thanks to their efforts that we are here today and that we’ll hopefully be successful. I want to thank the entire patient community for the continued support and collaboration.

Our principal investigators, especially Professor Scheffer and Dr. Howell, our advisors, and my entire team at Encoded, because I think that together we will be able to bring about a better future for families living with Dravet syndrome, but also for other genetic epilepsies. Thank you.