How a Drug Setback Became a Patient Community’s Gain

In December 2020, Ovid Therapeutics’ experimental therapy OV101 for the rare, neurodevelopmental condition Angelman Syndrome failed to meet its primary endpoint in a phase 3 clinical trial and the company chose to discontinue development. But rather than let the data from the study languish on the shelf, Ovid made the decision to contribute it to the Angelman Syndrome Foundation’s LADDER database. We spoke to Ovid CEO Jeremy Levin and Angelman Syndrome Foundation CEO Amanda Moore, about the LADDER database, Ovid’s decision to contribute its data to it, and why the two believe other drug developers should take similar steps to share their data with patients and researchers to advance the understanding of rare diseases.

Daniel Levine: Amanda, Jeremy, thanks for joining us.

Amanda Moore: We’re so happy to be here. Thank you so much for having us.

Jeremy Levin: It’s a great pleasure, Danny. Thanks for having us on.

Daniel Levine: We’re going to talk about Angelman syndrome data and Ovid’s recent decision to provide data from its clinical study on Angelman syndrome to the Angelman Syndrome Foundation. Let’s start with Angelman syndrome itself, though. Amanda, for listeners not familiar with the condition, what is it?

Amanda Moore: Angelman syndrome is a rare neurological disease that can happen and manifest in several different ways with the genotype, but typically, something has happened to the 15th chromosome, whether it’s a mutation, a deletion, a dup, anything that could cause something to happen to that 15th chromosome then ends up displaying as Angelman syndrome.

Daniel Levine: How does Angelman syndrome manifest itself and progress?

Amanda Moore: So, this is interesting because it’s very diverse, depending on who and what parent you’ve talked to. In most cases this is not something that’s discovered at birth. Typically, there’s normal births, nothing really displays at the beginning. Sometimes there is an issue with maybe swallowing, eating, some GERD, but for most families that can be something that’s typical for any neurotypical child. So, it’s hard to know, and Angelman syndrome isn’t quite diagnosed right from the beginning. But it manifests around three or four months. You start seeing that they’re not progressing or developing like other children around them. You might start seeing, like I said, some issues with feeding, some issues with low muscle tone. You’ll see some issues with possible seizure activity. And typically, what happens is families start seeing this and they start asking questions and they go to every doctor known to man, neurologist, pediatrician, whoever it may be, to try to get an answer to find out what is actually going on. And the only way to really determine that it’s Angelman syndrome is through genetic testing. And typically, genetic testing in the past was not the first go-to. They would do plenty of tests, EEGs, MRIs, EKGs, you know, it could be years. We weren’t diagnosed until Jackson was two and a half years old because he had his first seizure and they finally did genetic testing. So, it manifests in many different ways, but typically it starts off with those developmental delays.

Daniel Levine: What treatments are available today and what’s the prognosis for someone with the condition?

Amanda Moore: So, the prognosis is typically a long life, but right now there is no therapeutic treatment or curative treatment. But there are symptomatic treatments. A lot of our individuals with Angelman syndrome are on seizure medication. They could be on some sort of gastro medicine, whether it’s MiraLAX, something for GERD. They could be on sleeping medication, anxiety medication. So, right now we treat it very symptomatically. But currently there are three different clinical trials in process right now, which is really exciting for the community of trying to activate that paternal gene because that maternal gene is either deleted, mutated, or something’s going on with it that’s not activating that paternal gene to create that UBE3A that’s actually missing. The great thing is that these trials are really working hard to activate it. So, there are three clinical trials happening currently, but right now as we speak, there’s no therapeutic or curative treatment.

Daniel Levine: Jeremy, Ovid was one of the first drug developers to work in Angelman. What are the challenges of pursuing a condition like this?

Jeremy Levin: Well, I think first of all, you need to look at this not just about Angelman, but about CNS generally, the brain. And the reason why is that each disorder of the brain teaches you about other disorders in the brain. Now, I think one of the great problems with discovering medicines for any disorder of the brain is that over the years we’ve had to tackle enormously problematic issues. We’ve seen only incremental progress, but the real problems were longer costly trials; challenges and specifically, it’s very important, determining what is the trial endpoint that you are going to see. How will you demonstrate that you have a clinically meaningful effect of your medicine? Essentially what you’re looking for is if you have broken your arm, you know when your arm’s healed because you can use that arm again normally—that’s an objective endpoint. So, for the brain, it’s very difficult to do that. For many disorders, regulators and physicians want a hard endpoint—tough to do. And of course, in cancer [it’s] the same kind of thing—cancer hard endpoint: can you make people live longer? Very easy. The second, that’s another aspect which is really important for the brain, is that there is an enormously high placebo effect. And that means when you give a drug to people, you expect to see a change. But sometimes when you give a drug to a patient who’s got a disorder, such as depression, schizophrenia, and many other disorders with the brain, the very act of taking something into their mouth, be it a drug or a sugar pill, changes them. So the risk of a late stage trail trial failure in placebos is enormously higher. Sometimes we also have biomarkers, which are common. For example, if you take a blood test for a cancer, you can see if the cancer’s there or not. Prostate cancer, this is good. You don’t have similar biomarkers in the brain. And it’s only been over the last few years that we’ve started to be able to use EEG and a number of others, but it’s really been tough. And then the last two elements that one should consider here, and then we’ll dive into Angelman, is that it’s really difficult, more difficult than any other organ in the body, to be able to understand how to target the very specific cells in the brain that are causing the problem. Very difficult. The brain is an enormous organ, very difficult, locked up in a skull surrounded itself by very impermeable membrane—the blood brain barrier, and very tough to get to. And as a consequence, a lot of people have just abandoned the area. And unlike cancer and other research areas, until recently it hasn’t seen an enormous resurgence. Now it is, and that’s because we’re learning how to deal with all of these. Now with regard to Angelman, it was particularly challenging because we were the first ever company to tackle it. And we worked with the community. We didn’t have any other clinical trials to follow. And people like you, Amanda, we worked with you to essentially create a completely new way of measuring how the medicine might work. That’s called the clinical Global Impression Improvement Scale and making it specific for Angelman syndrome. Unfortunately, that itself is a very difficult thing to measure because you have to have physicians measure it, otherwise it is very subjective. Much of what was even unknown about this was simple facts. We didn’t know how the disorder progressed from childhood into adulthood. And of course, those with Angelman can live well into their seventies. So, there was a real progression from childhood to adolescence to adulthood that you had to deal with. And it wasn’t like a disorder like cancer, where you know that if you don’t treat the patient, the patient will die. This is not the case. This is an evolution. So what’s really interesting is that cancer has taught us a lot over the last 10 years. Much of the problems that we’ve faced in the past with all these difficult disorders related to CNS—that’s going away. It took 15 years of development in immuno-oncology to teach us in other areas how we can break it open. Now how do we break it open? Those things that are being broken open is we’re becoming really [able] to understand what’s causing the disease, what genes, what proteins are really important. We’re being able to diagnose people much easier with MRI. Indeed, with MRI, we can even begin to understand how particular molecules bind in particular places of the brain. And then understanding how we get drugs to penetrate the blood brain barrier has advanced enormously because of the work that was done previously in cancer. We’ve understood how to manipulate molecules much better. And finally, now we can begin to understand how to map different parts of the brain. There’s a huge initiative in mapping different parts of the brain. So, all this to my mind is very good news for the Angelman community. And from my perspective, although we were the first, we weren’t the last. And there are now –when we showed people that you could do it, then all sorts of other companies came in. And I don’t know the exact number Danny, but it’s probably close to between 15 and 20. And I’m very sure that promise something will come.

Daniel Levine: Given that you have such a rich pipeline and no shortage of opportunities to pursue. What compelled you to make Angelman syndrome your lead program?

Jeremy Levin: Oh, that goes to the heart of why one’s in the world of biotech and why one’s in medicine. You do things that are important to patients and families. And what you need to do is identify, for me, I have a covenant with patients. I believe strongly that you need to find the best possible medicine. And if there’s nobody who has a medicine, then you go exactly where nobody else is if you believe you could make a difference. So, I co-founded Ovid because I wanted to serve patients and families who didn’t have any therapeutic options. And I did a full review of Angelman, and I did that knowing that having come from large companies, that inside these companies, there were many programs that had been developed—stealth programs, you might say, by really well-meaning scientists who wanted to convince their bosses that they had something wonderful, but in fact, never saw the light of day. They were there; we knew it. And what I wanted to do was to see if we couldn’t match one of these programs to the needs of a rare disorder area, and I’d studied Angelman, and of course, as you know, Angelman is not that rare, it’s one in 15,000 live births. They’re about 4,000 individuals in the United States with Angelman. And they range in age from birth all the way to about 70 years old. And when I knew that nobody had truly dug into how you would change this, we did. And we looked at the genetics, we looked at the way people were working on it, and we decided we could make a difference. And bottom line is we really believe that by doing this we would pave the way, not just for ourselves, but for others, and we have paved that way. And furthermore, we now still have in our pipeline a really important potential medicine OVI882, which is what’s called a short hairpin RNA (shRNA). It’s one which we will now build on the back of having watched others who followed us try and have learned more about Angelman and hopefully we’ll have a very important medicine there.

Daniel Levine: In December 2020, your experimental therapy for Angelman failed to meet its primary endpoint and the company chose to discontinue development. As you mentioned, you’ve got another earlier stage therapy in development for the condition, but Ovid made the decision to contribute data from the study to the Angelman Syndrome Foundation. Why did Ovid decide to do this?

Jeremy Levin: Well, yes, very important. Right now, although we’re focused on rare and we do have the Angelman program in our pipeline, we learned a lot in our process with Angelman. We chose to share the baseline data from our phase 3 Neptune trial with LADDER, and basically LADDER—it’s L A D D E R—stands for linking Angelman and Dup15q data for expanded research. It’s a great name actually. That is really an excellent database and it review this as something which is designed to help the scientific and medical research community create a much more complete picture of the condition and actually potentially draw insights. So, our view was: given the enormous collaboration that we’d had with the community and that we had likely the largest compilation of baseline data in Angelman syndrome, probably it’s well over a hundred patients, we felt it was our responsibility, donating was our responsibility. This is one way, when you’re not successful in a clinical trial, that you can then move straightforward, take the learnings you have from their clinical trial, which although the molecule may not have been successful, the trial itself harvested an enormous amount of information that could potentially help break open the disorder. So, what we hoped, by donating this data, is that the scientists will use it to begin to paint a much more sophisticated picture of the condition and its progression. And that’s what our intent was. Our intent is let’s together tackle this disorder.

Daniel Levine: We know that failure is far more common than success in drug development. There’s a lot of data held captive within biopharmaceutical companies from failed studies. Why don’t pharmaceutical companies generally share this data?

Jeremy Levin: Boy, what a great question. We always hear that it takes one drug out of 10 to make a successful one and that’s why it costs so much money. Well, the real point here is that those other nine have informed you of all sorts of things. And why don’t we see that data? Well, I think companies tell themselves that they can’t share this data for many reasons. I am not convinced by them. Let me walk you through some of the reasons that we hear about it. Some are legitimate, some aren’t. Concerns about data privacy are important but can be solved. These data privacy and rights, for example in Europe, are very important such as the GDPR in Europe, very important. But you can deal with it. The second is that by not ad hoc assuming that you may not be successful, we don’t seek informed consent from patients in sites to share. We should do. There’s no reason why you can’t. It’s difficult, but you can. Now the other thing about this is that some companies and investors are concerned about is they may have a secondary program and what they don’t want to do is to advantage their competitors who might be there. We choose a different reason. We think that if you’ve got a great medicine and even if it’s a follow up to one that hasn’t been successful, you can learn a lot and you improve the patient understanding, the family, understanding, the community, the physician understanding so that your drug can enter into the marketplace as soon as possible. And here’s perhaps the one that is least acceptable. People feel embarrassed over setbacks. My view is very simple. We should feel super sad. We should weep. And I did when our trial was not successful, but we should never feel embarrassed about it. We invested millions of dollars, we did it the right way. The only way that embarrassment is really real is when in fact you know you’ve done something wrong and we never did. We did everything right. So, in the condition like Angelman, I think that it’s important for all involved to understand that there is a range of data and that data that comes from the clinical trials is very important. For LADDER, what we did is we provide what’s called baseline data. This is essentially the data that is inherent in the individuals that have gone through the trial, but before they’ve ever had a drug. So in fact, we’re just simply looking at them and studying them. This is very important because this data helps the community paint a much richer and much more complete picture of people living with the condition. So, something that had never been done before, but we are able to provide this and it means you have a standardized way of looking with it. That’s the most important thing about this. You can look at it as the disorder changes and affects individuals over age. After all, we looked at babies, we looked at adolescents, and we looked at adults. And that’s so important because this is what’s called a neurodevelopmental disorder. It affects the development of the individual and therefore the progress through different stages of life. So my view is very straightforward. By collecting and mining the data researchers in the community may be able to make connections and see insights that we could not previously see.

Daniel Levine: The data Ovid is providing will be housed on the LADDER database. Amanda, what is the latter database and how is it used?

Amanda Moore: So, as Jeremy was just talking about the LADDER learning database and LADDER means linking Angelman syndrome and Dup15q data to accelerate research. It was created first and foremost to collect clinical data. We have close to 23 clinics in the United States that are seen individuals with either Angelman syndrome or Dup15q syndrome. And we thought to ourselves, this is excellent data that hasn’t been collected for years. So, LADDER was actually created to be the place where we could collect clinical data to help accelerate treatments, to help accelerate standards of care in both disease areas. But what it’s turned out to be is really the brain of data for the Angelman syndrome community because what we found was we had so many data sources that were siloed and not being used. When it comes to data, especially maybe in the industry field with clinicians, researchers, they tend to keep that data close, right? And so, what we did as a foundation was say we need to create something that is a place where people can add their data, that we can link it to other data sources and then we can expedite getting this data out to industry, to researchers, to clinicians to really expedite this idea of getting us to the finish line of a therapeutic treatment. So, that’s kind of what LADDER has become. LADDER now holds all of the natural history study data that has been done by Dr. Wynn Hinton at Boston’s Children. It now holds all the clinical data that’s happening in the clinics. It holds the registries of both Angelman Syndrome Foundation and Dup 15q Alliance. It holds some research data that’s been done for years. And now, luckily enough, we we’re here to talk about getting really important data that we’ve gotten from Ovid.

Daniel Levine: Why is the Ovid data of interest? In what way might it improve the understanding of Angelman syndrome or help advance the development of therapies to treat it?

Amanda Moore: Well, in my opinion, data, no matter what data it is, is important when you’re in the kind of landscape that we’re in with Angelman syndrome. We have so many different pharmaceutical companies in this space. And a lot of what they need is to understand the natural history of the natural progression of this disease in order to be able to find endpoints and biomarkers and be able to truly run a clinical study with the hope that the ending result will be getting these medications, these treatments to market. So, the more data that we can have, the better. And the great thing about the Ovid data, Ovid was one of the first clinical trials that was out there and they collected such a robust data set and the fact that they are willing to now give that data set to LADDER, which essentially you’re giving it back to the community that you’re serving, we’re able to use that data to help other researchers, help other industry understand some of the progressions here, but also understand the importance of when we move into these invasive trials, it’s going to be important that we’re going to have a placebo arm. And so, a lot of what happened with the Ovid trial is huge around this idea of the placebo control. So, being able to use that data and see that data is going to be really important to help us sidestep some of that stuff in the future. And I think the one thing that’s really important to mention here is that the community, the families, are really the ones when it comes to these trials that are putting themselves out there. They’re traveling, they’re entering their individual with Angelman syndrome into a trial. So, they’re taking that risk, they’re taking time away from their family, from work. So, what we try to tell industry, one beautiful gift you can give back to all those families is the data you collected in that trial. And the LADDER is a great place that people can put that because there’s a data access committee that oversees that. We clean it up and we get it. We make sure that it’s getting used and getting to the right people.

Daniel Levine: Jeremy, Ovid is developing OVI882. As you mentioned earlier, this is an RNA therapy for Angelman syndrome rather than targeting a neurotransmitter as OVI101 did. This is designed to target the underlying genetic cause of the condition. Where you in development and what’s the path forward?

Jeremy Levin: Boy, it’s such a fun program. I really admire this. First of all, while we weren’t successful in our first molecule in the molecule itself, we were successful in getting a very deep understanding of the disorder. And so we committed ourselves to the Angelman community and we are very committed and what we want to do is to see effective therapies for these families. Now for those of you who are listeners who are not familiar, and I suspect you maybe, but just let me just touch on this for a second, the most common cause of Angelman syndrome is related to a defect of the maternal UB3A gene of the mother. Essentially it’s a loss of a functional UB3A protein. And this UB3A protein does many things. And we targeted one of those things in our first trial. In contradistinction, our OVI882 program is designed to go right to the heart of the genetic cause of Angelman syndrome. The whole concept behind this is to deliver an optimal dosing that will for longer treat and will allow for longer treatment durations—perhaps once a year, perhaps even once every two years—than many of the other medicines that we’re seeing in the developmental pipeline. Now, the reasons that we believe that is the current medicines that are targeting the genetics are what are called ASOs and have to be given every three months. Our view is that OVI882 is a what’s called a short hairpin noncoding RNA vector. What it does is it tackles the UB3A antisense molecule, and we want to reduce that so we can restore the UB3A expression in the paternal gene in the father’s genetic copy. So, this is something that others haven’t done. It’s something that we know we’ve been able to do and that we know that as we study the thesis behind this, we believe that administering a medicine once every three months is going to be tough for many people, particularly as they have to go to a hospital and you have to have this put into your spinal cord. This is something which is called intrathecally for the children. That’s a lot to endure. So what we want to do is something that can avert frequent administration and where we’ve been working intimately with the University of Connecticut and although it’s early preclinical stages, we’re optimistic that it will actually be very successful over time.

Daniel Levine: Jeremy, do you think Ovid’s decision to share its data might help encourage other drug developers to take similar steps and share their data from failed studies?

Jeremy Levin: Boy, I hope so. I think it’s a very serious matter not sharing your data. I think that by sharing your data, you advance the field. If you don’t advance the field, true cures can’t ultimately be achieved. Let me give you an example of this. Why is it important? It’s important to know what the baseline of these individuals are. In other words, remember what I said to you about what a placebo effect is? A placebo effect is one where you don’t know what the drug is actually doing. Now I know when I take an individual with Angelman out of their home, take them to a clinical trial site, their behavior changes. And if you are looking at an endpoint like the CGII, unless you know what the simple moving of the individual to that site does, how are you going to then measure what the drug is doing? So, the only way you can do this is by having a fundamental understanding of what the baseline is. What happens to these children when they go through a clinical trial without ever giving them a drug. That’s what’s important. And then, the old only alternative to this is running what’s called a placebo control trial where individuals enter a trial, some are given the drug, some are not given the drug. And that’s very difficult when you’re giving intrathecal injections because you now have to give an intrathecal injection that doesn’t have the drug with one that does have the drug. Others have done this. There are such trials that many of the families don’t want to go through. The knowledge of the child is simply getting an injection without a drug. So sharing the data is critical for people to understand what the placebo effects are. And for my mind, it was that kind of mentality that brought us into the Angelman syndrome development area. And from my way of thinking, that’s why it’s so responsible to share data.

Daniel Levine: In closing, I’d just like to ask each of you, what’s the case you would make to other drug developers for them to share data? Jeremy?

Jeremy Levin: Yeah, and I’m sure that Amanda’s got a perspective on this and Amanda, I’m really looking forward to listening to what you have to say here. But look, it’s really simple. This is the future. There are responsible and transparent ways to share data that can have a very important and significant scientific and public health benefit. And when we look at communities such as the Angelman community, this is what we should be doing. For example, you look today at the COVID 19 pandemic, which demonstrated categorically how important it was to share data. It advanced therapeutics remarkably rapidly. Now we can do the same with Angelman if we chose to do so. So to my mind, data sharing can lead to greater collaboration and increased confidence in findings and sharing insights across communities.

Daniel Levine: Amanda?

Amanda Moore: Well, I think this is a beautiful example of how industry and patient advocacy organizations can and should work together. I get the idea of this data and how much money industry puts in to getting this data. But, to set the tone for the Angelman community that Ovid is set to say, “we invested a lot into this program and we really care about the Angelman community and we care so much that we are going to give this data back so you can use it to continue the hard work and the fight that you’re doing to find treatments for your individuals with Angelman syndrome.” So my hope is that all of the other industry that are in the space, maybe are listening right now, and they can see the importance that this has on our community and the beautiful gift they have the power to give back to the community in order for us to get to that finish line.

Daniel Levine: Amanda Moore, CEO of the Angelman Syndrome Foundation and Jeremy Levin, chairman and CEO of Ovid Therapeutics. Amanda, Jeremy, thanks so much for your time today.

Amanda Moore: Thank you so much for having us on this very important topic.

Jeremy Levin: Thank you Dan, much appreciated.

This transcript has been edited for clarity and readability.