RARE Daily

A Nasal Spray to Curb Excessive Eating in Prader-Willi

May 11, 2023

Parder-Willi syndrome is a rare, genetic disease that is characterized, in part, by hyperphagia—an intense and insatiable hunger. People with the condition are driven to constantly eat and seek out food. The syndrome is associated with severe obesity and obesity-related mortality. Tonix Pharmaceuticals is developing an experimental oxytocin nasal spray to treat hyperphagia in people with Prader-Willi syndrome. The approach, to date, has shown promise in animal models. We spoke to Seth Lederman, CEO of Tonix, about Prader-Willi syndrome, the unmet need for treatments, and why he believes an oxytocin nasal spray has potential to treat the condition.



Daniel Levine: Seth, thanks for joining us.

Seth Lederman: Thank you for having me on.

Daniel Levine: We’re going to talk about Prader-Willi syndrome, Tonix, and its experimental therapy to treat the rare disorder. For listeners not familiar with Prader-Willi, what is it?

Seth Lederman: Well, it’s a genetic disease and it is characterized early on by failure to thrive and later on it’s characterized by obesity and overeating. The medical term for overeating is hyperphagia, but it’s the most common syndromal cause of obesity and there’s no cure and there’s no treatment for the hyperphagia syndrome.

Daniel Levine: I know many people think of the condition in terms of the hyperphagia, but it’s a far more complex condition than that. How does it manifest itself and progress?

Seth Lederman: Well, there are several phases. From the nutritional point of view, people usually refer to four phases where zero is low birth weight. Phase one, which is infancy, is failure to thrive, difficulties in feeding and suck sucking and low tone. There is decreased growth. And then phase two starts, which is from about two to four and a half years old where weight begins to increase without the characteristic appetite increase. And then if the child is allowed to eat what they want, obesity occurs. And in phase three there is the hallmark hyperphagia, which I said is this overeating and life-threatening obesity. And phase four is adulthood, which is usually marked by a return to normal appetite.

Daniel Levine: What are the long-term health effects of the condition?

Seth Lederman: Well, early mortality is common. The average death rate is just under 30 years, so it’s not a benign condition.

Daniel Levine: Are there other issues that people with the condition face beyond early mortality?

Seth Lederman: Yeah, as I said, but I think obesity is one of the biggest problems.

Daniel Levine: And in terms of treatment options, you say there’s none available today?

Seth Lederman: Correct. Growth hormone is approved for treating Prader-Willi because as I mentioned, one of the aspects of it is decreased growth, but that does not address the hyperphagia issue.

Daniel Levine: And what are people with the condition told in terms of how to treat it at this point?

Seth Lederman: Well, there are really great advocacy organizations that have sprung up and there’s a lot of information online. Parents are usually very involved. Interestingly, most of the cases, more than half, like 65 percent are due to new genetic changes. It’s more commonly a new mutation and not something that these families are used to dealing with. So, for two thirds of people, this just comes out of the blue.

Daniel Levine: This is a condition that can affect quality life in a significant way. What do you hear from patients and their families about the impact it has on their daily lives and the need for treatments?

Seth Lederman: Well, this affects all aspects of the life of the affected people and also requires a huge amount of involvement from the parents. I have to say that in my interactions with parents and the advocacy groups, I am always speaking to parents who are extremely involved. So, I imagine that that’s not always the case, but in the cases of people who are involved in advocacy in these groups, the parents are really heroic and involved in every aspect of the kids’ lives and young adults.

Daniel Levine: Well, I’m wondering if you can expand on that. People often just think this condition is these children are overweight, but it strikes me that there’s a lot these families deal with all through the day as a result.

Seth Lederman: Yes. I mean, for the unchecked overeating, it’s a situation, among other things, where restricting food is extremely difficult because of the incredible drive that the affected individuals have in seeking food—so, literally locking the refrigerator and to some extent, standoffs about eating.

Daniel Levine: This is a genetic condition, as you mentioned. How well understood is the underlying biology?

Seth Lederman: That’s an excellent point. A lot is known about the deletion on chromosome 15, and there are some complexities of it, but I think the genetics are extremely well known. But there’s some things that are not well known. For example, the treatment that we’re developing is an intranasal form. Intranasal means administered into the nose, sprayed into the nose, an intranasal form of oxytocin. And it is not really understood why oxytocin is so effective. And when I say effective, it’s effective in animal models where people have made mice with a similar genetic problem to humans. And in those cases when oxytocin can be administered systemically early on, oxytocin almost normalizes the mice. So, it really has a profound effect in mice with this genetic mutation. In humans that has been less well studied, but treating infants is a good idea but it takes a long time to study this. There are groups in Europe who have studied it, but what we’re doing is we’re focusing on adolescents and young adults and using intranasal oxytocin, while testing intranasal oxytocin to see whether it can control hyperphagia.

Daniel Levine: I suspect if listeners have heard of oxytocin, it’s in the context of childbirth. What role does oxytocin have in our daily biology, if any?

Seth Lederman: Yeah, thank you for asking about that. So synthetic oxytocin has been used to induce labor for over 65 years, and the trade name, I think well known to mothers, is Pitocin. And as I understand it, something like 70 percent of births in the United States these days involve Pitocin. And the reason it’s so high is that many women now choose to, or under consultation with their doctors for one reason or another, choose to be induced sometimes because they want to plan their pregnancy or other times, because, I suppose, labor doesn’t progress. But anyway, it’s commonly used in labor. It is less commonly used for other indications, but we believe, and there’s some preliminary data to indicate that intranasal oxytocin could be effective in this way. But let me back up and say there had been an intranasal oxytocin product available in the United States called syntocinon and it was a Novartis product and had the indication for stimulating breast milk in breastfeeding mothers, nursing mothers. So, that was on the market for a number of years. It was withdrawn by Novartis in the United States because they declined to update the regulatory filings, but it is still available with that indication in Europe and many other parts of the world. So, there has been an oxytocin used in the United States for a different indication, and what we’ve done is made a new formulation of that, but we’ve also added magnesium that we believe potentiates the activity of oxytocin. That’s why we think that ours would be superior, even if intranasal oxytocin was available in the United States, which it’s not. We think our potentiated oxytocin has advantages.

Daniel Levine: What was the case for using oxytocin? How did that connection get made to Prader-Willi?

Seth Lederman: I think it was the work of European scientists. Francoise Muscatelli is someone who we collaborate with and from whom we’ve licensed a patent to use oxytocin to treat Prader-Willi. And she works in Marseilles, France, and she’s collaborated with a pediatrician and with a network of people in France. She’s a PhD scientist, and she’s the one who’s done this seminal work on treating the knockout mice that are so-called Prader-Willi mice. She’s collaborated with a noted pediatrician and with a group to show that treatment of infants with intranasal oxytocin has benefits. Now that is a different indication than we are currently seeking. We are seeking the indication to treat adolescents and young adults to address the hyperphagia problem.

Daniel Levine: And what’s the case for using intranasal delivery? This is a substance that could be delivered in many different ways, I imagine.

Seth Lederman: Yes, I’m the CEO of a company called Tonix, and we bought this technology from a professor at Stanford University who had spun out a company and was working on intranasal oxytocin for the treatment of headache and cranial facial pain. So we do have a program in headache. We planned to have a program in cranial facial pain, but it was really because we were working on oxytocin with this professor, after buying the technology, that we learned about the research done by Professor Muscatelli and others about intranasal oxytocin. So, the nose is very close to the brain, obviously, and particularly if you deliver a drug intranasally and it goes to the back of the nose, it’s very close to the brain. But in migraine, a lot of headache pathology is centered around what are called the trigeminal ganglia. And the trigeminal ganglia are outside of the central nervous system but they are also very close to the nose. They’re basically behind the cheek bones. And what Professor Yeomans realized was that using this drug, intranasally delivered oxytocin to the trigeminal ganglia, is what’s believed to have the important effects in migraine headache. So, Prader-Willi is a little bit different where we believe that in order to be effective, it has to get into the brain, but oxytocin is a relatively small peptide and there are certain peptides that are able to get from the nose to the brain.

Daniel Levine: Is there any additional benefit in not having to have give someone with Hyperphasia something oral?

Seth Lederman: That’s an excellent point, but oxytocin orally isn’t really one of the options. The options would really be intravenous, which is how it’s used to induce labor, or potentially intramuscular or intranasal. But since oxytocin is a peptide, it’s not likely to survive being swallowed. So, if it could be delivered by being swallowed it’s potentially an interesting way. But I think that what we’re doing, one of the challenges of developing any drug is to get the drug to the place where it’s supposed to work. And giving it intravenously is kind of brute force. I mean, that’s going all over the body, but we believe that since the Prader-Willi eating problem is a problem in the brain, that delivering it in the nose and to the extent it gets taken up into the brain because the nose is so close to the brain, we think is a better approach.

Daniel Levine: And what’s known about the experimental therapy from studies you’ve done so far?

Seth Lederman: We have not done studies in humans so far. We are preparing our regulatory filings and we expect to begin a study when the regulatory filings are accepted. The work on oxytocin without our magnesium potentiation has been published, but that’s really on infants. So, we’re really basing our work on the animal studies, and on the analogy that oxytocin has such a profound effect on infants. Now it’s a little bit complex because in infants, the eating problem is often in the other direction in that they have problems sucking and don’t eat enough. But we believe, from the knockout mouse and what else is known about the biology or the pathology of Prader-Willi, we think that oxytocin will correct Prader-Willi, whether it’s early on and the symptom is not eating enough or late on when the symptom is overeating.

Daniel Levine: The company announced a pipeline reprioritization in April. Does this have any impact on the Prader-Willi program?

Seth Lederman: No, thank you for noticing that. The Prader-Willi program is still one of our high priority programs, and the reprioritization mostly had to do with Covid programs, particularly Covid antibody treatments. They are very important still for immunocompromised patients, but unfortunately we just didn’t find interest from investors or from the government in terms of funding the development of those programs. But I think it would be the opposite. That prioritization announcement emphasized that we are going to concentrate resources on our high priority programs like Prader-Willi.

Daniel Levine: And what’s the development path forward from here?

Seth Lederman: We haven’t disclosed much in the way of timelines, but we’re actively working on seeking approval to study the drug in humans from the U.S. FDA.

Daniel Levine: Any guess whether you’ll be in the clinic this year or will it be next year?

Seth Lederman: We don’t guide to that and a public company guidance is carefully monitored. So, I guess I don’t want to comment about projecting those events.

Daniel Levine: Seth Lederman, co-founder, chairman, and CEO of Tonix Pharmaceuticals. Seth, thanks so much for your time today.

Seth Lederman: Thank you. This is a very interesting interview and I appreciate the preparation and the excellent questions you asked.

This transcript has been edited for clarity and readability.

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