Good morning and welcome to Guggenheim's inaugural Healthcare Innovation Conference. I am Debjit, one of the therapeutic analysts out here, and joining me on the stage is Dr. Anish Bhatnagar, CEO of Soleno Therapeutics. Also in the audience is Jim Mackaness, company CFO. Thank you both for being here.
Thanks, Debjit. Thanks for having us.
December 27th, PDUFA. Do you think any interactions with the FDA, any showstoppers as yet?
So yeah, we have an ongoing back and forth and productive, I would say. No reason to believe today that the decision would be delayed, but obviously can't really tell what they're thinking.
Let's talk in terms of the original expectations of having an Adcom and then FDA deciding not to have an Adcom. Just walk us through how, what transpired, what led to that conclusion.
Yeah, so if you remember the verbiage around the original, "We may have an Adcom situation," what they had said was, "At this time, we expect to have an Adcom." And what we realized is that they never actually put a date in the Federal Register. So in the back of our minds, there was always the possibility that there may not be an Adcom, but nevertheless, we were surprised. And the next verbiage, which was, "At this time, we do not plan to have an Adcom," did not come with any explanations either. So not a shock, but a surprise.
Got it. Now, in your recent press release, you still kept the, let's call it the boilerplate language, that FDA can still change their minds. But you also just said very unlikely that PDUFA is getting pushed out into 2025. So does that automatically rule out any PDUFA between now, any adcom between now and December 27th?
I think that's a fair assessment because I think putting together an Adcom is a lot of work, not just for us, but for the agency as well. So I'd be very surprised if there was any way that they could do it between now and the end of the year, and just back to my words around very unlikely that the PDUFA would be pushed out. At this time, we don't have any reason to believe it, but as you know, the FDA has the ability to make the call on whatever can be a major amendment, and they can decide to postpone, so we'll just have to see.
Got it. Now, your interactions with the FDA, do you think that sort of initiated pretty much when you submitted the NDA and not August 27th when the NDA was accepted for review?
Yeah, I think it's fair to say that we've had ongoing back and forth in terms of information requests or IRs since the time we submitted. Obviously, they need time to digest the application. So it's fair to say that there've been a lot more as the review has gone on, but they certainly started soon after the submission.
Got it. So given the back and forth that you've had so far, and there has been at least one prior Adcom with respect to PWS, do you think the agency is completely up to speed with the disease and the unmet clinical need for this disease?
I think they're a lot more up to speed than they were to begin with. There's no doubt in our minds about that, and I think it's a combination of things. It's the fact that pretty much every PWS drug that's being evaluated today has a primary endpoint of hyperphagia and is therefore in the psych division, so they're getting to see a lot of it. I think the Levo submission, the subsequent Adcom has to have been a big education for them, and then, as you may remember, last year in June at the PWSA conference, there was an externally led PFDD meeting, so that was several hours of listening to testimony from physicians, from caregivers, and patients about the disease, and that was introduced by Dr. Patrizia Cavazzoni, which was in itself a big deal, so I think there is visibility at the agency for the disease.
I think there is a significant understanding of the disease, and I will say that the questions that we get reflect that understanding today.
Got it. And diazoxide, which is basically the parent molecule for DCCR, FDA is familiar with that molecule. So overall, do you think they are less concerned about the risk and not actually having a therapy available for hyperphagia? One would hope so.
I think we'll find out if that's the answer. But I think conceptually speaking, that makes sense because diazoxide as a drug has been used starting in infancy and up to adulthood. And there's chronic data available for years of use. And the side effect profile is well understood. And we believe what we have seen in the DCCR program for PWS is a side effect profile that's actually more manageable than what might be seen in the hyperinsulinism setting. So yes, I think the things are in place for them to feel that way. Whether they end up feeling that way or not remains to be seen.
Got it, and just late in the game, I would think the onsite inspections are already behind you right now, third-party inspection for manufacturing.
So, no comments on the review, specifics of the review, or the actual inspection. But what we have said is that if you think of our vendors, these are the two main vendors, drug substance and drug product, are both U.S.-based. They're mainstream. So this is a relatively simple chemical and formulation process. So we are not that concerned. And the sites are also mainstream sites. So we believe that we don't see a high risk in that.
These sites, have they been previously inspected by the FDA and there is no Form 483s or whatever associated with the sites in general?
So we normally, we have a process for evaluation of our sites. So we typically will assess the sites to see if there are any deficiencies in the past, what are the deficiencies, if there are any, are they correctable or not. So all the sites that we use in our program would have gone through that process. So we generally speaking have a high level of confidence that the sites that we use would pass any FDA inspections without major findings. But we'll see.
Got it. So inspections aside, you're about six weeks away from the PDUFA, roughly give or take.
Six weeks, yeah.
Do you think labeling discussions should begin anytime soon?
Generally, labeling discussions are about four weeks before PDUFA. So I expect we'll be seeing them in the near future.
Got it. But you still haven't initiated labeling discussions?
No specific comments, but I think it's fair to say that generally speaking, it's about four weeks before.
Got it, and then on the PDUFA side, what do you think is the biggest risk to the December 27th PDUFA?
So at this time, we don't have reason to believe that there is a delay. But as we understand it, in general, the agency is supposed to do a delay in the PDUFA if any material that has been provided to them has impact on approvability. In reality, they can consider any submission of information to be a major amendment, which would qualify them to delay it. So like I said, at this time, we don't have reason to believe that's the case. But we also know that the agency has many times at the last minute done a delay. So we'll see.
With respect to that major amendment, they haven't really asked for any major new information which would trigger a major amendment.
So the determination of what's a major amendment is a subjective definition. So they are the ones who will define if it's a major amendment or not. So we get a question, we answer the question, whether it's new analysis of the data or providing new data, et cetera. That determination is more from them as to whether it's a major amendment or not.
Got it. One lingering concern that we keep hearing about is the randomized withdrawal study design. Do you think the stats team has long past any issues with that?
I always disagreed with the contention that randomized withdrawal was a problem. I've always believed that it's a robust evidence of efficacy. There is plenty of evidence in the neuropsych space in particular that randomized withdrawal trials can be successfully used. This thesis was that they won't grant you, they will not accept your NDA for review, they won't grant you priority review, they won't give you breakthrough. All of this is, it takes time. I think when you look at the data, when you look at the p-value, it's hard to disagree with the evidence of efficacy. If this was a p-value of 0.045 or something, I'd agree with that thesis a little bit more. This one's hard to agree with.
Is the FDA, in your view, to all the conversations you've had with them, completely understand the challenges COVID posed during the conduct of the original phase III study?
I don't think there's any disagreement that COVID posted challenges. I think the disagreement was more around the impact of those challenges on the trial results, and that's where we have traditionally differed from the agency, where we have believed that there is enough evidence to show that COVID made a difference, and at least in their initial assessment back then when we first presented the data, they believed that it could be an artifact and they couldn't finally give an answer on whether it was impacting the trial or not. Where they stand today is something that we don't know. We'll find out.
Got it. And then August 2nd, I believe the PWS advocacy coalition submitted a petition asking for a priority review. Any other interactions that the advocacy coalition has had with the organization or with the FDA? And are you seeing any impact of that?
We're not aware of any more interactions. I'm not sure that there is more forum for interaction for them. It would have been the advisory committee, which obviously is not happening. They may be doing something on their own. We're just not aware of it.
Got it. Then from a market access perspective, how are the payer discussions going?
Payer discussions are going well. I think it's fair to say that this is not a disease that payers are familiar with to begin with. But at the end of 15-20 minutes of description of the disease and the challenges and the fact that there's no treatments available, I think it's fair to say that pretty much every payer that we talk to sees why they need to cover it. I think the sort of top line is that we're in the business of providing care. And these are patients who have nothing. So yes, we would cover it. The corollary to that is what is the pricing and what is the impact of pricing, et cetera.
I don't think there's any price where someone says, "We are not going to cover it." I think it becomes more a question of what are potential pre-authorization requisites that you might have, et cetera. But in general, I'd say payer discussions have been going well.
From a pricing perspective, we kind of know the range where rare disease medicines are priced at. Where would you think you would like to see DCCR priced at?
Obviously, I can't give you a number, but I think we have to price it in a way that does justice to the effort that's gone into developing the drug, the impact of the drug, and the fact that we have to ensure that there's access for everyone, so we're more focused on the fact that we need to make sure that patients have access to the therapy, and that's what we need to ensure while making sure that we're doing justice to ourselves and the investors.
In terms of a private-public payer mix, is it close to 50/50 or?
So it's about a third, a third, and a third. So commercial, Medicare, Medicaid.
Got it. From a market access perspective, help us understand how, where these patients are concentrated, if they are concentrated, both from an age group, younger patients versus the older patients who probably might be in some sort of a care facility.
Yeah. So when we look at the data, we've tried to cut it in many different ways. But one reasonable way to do this is that who's living at home versus not. Because if you're living at home, you're likely to be with family. And you're more likely to be sort of better cared for in the sense that you're seeing a physician four to six times a year. And we think that cutoff is around 25 years of age. When you're older than that, you have a higher likelihood of living in some kind of care situation. So I would say if you take the 85%-90% of the patients that are above four years of age, there's about half of them who are below 25 and another half that are above 25.
Of the older patients, I'd say about 20% of them, so maybe about 1,000 patients or so, are in formal group home settings.
Do you think the label will capture the entire spectrum of all patients impacted by hyperphagia? Or do you think it's going to be, say, between four or five to, call it, 20, 25?
So our trial population was a minimum of four years of age. And it's rare to have hyperphagia before four. So we expect and we are fully okay with a label that says four years and up. The trial did not have an upper age limit. And the oldest patient treated on the trial was 44 years old. So we are not expecting an upper limit to the age range. So that effectively means that a base case scenario for us is if you're above four years of age and you have hyperphagia, you should be on label.
Got it. And as you move to the older end of that spectrum, what percentage of these patients have type 2 diabetes? And how many of those patients were in the study? How might it impact the label? And what do you do to control type 2 diabetes?
So when we look at the published data, we're seeing about, and these are rough numbers just based on smaller subsets, but we think about 20% of patients with PWS have a lifetime prevalence of diabetes. We think that as you grow older, that number goes up substantially. However, we think that a number of them are controlled diabetics. There is metformin or GLP-1s, et cetera, for blood glucose control. We think that the proportion of uncontrolled diabetics is relatively small, at least in the younger age groups, which are sort of the most likely patients to get the drug early. The numbers are hard to combine, though, because these are not clear data sets. We have treated patients with diabetes in our trials. So we've had patients who are on metformin, on GLP-1s, and other drugs on our trials. And we've treated them successfully. So that's not a contraindication.
We do think that there is a reasonable possibility that there might be an exclusion for uncontrolled diabetics, which we agree with.
Got it. And there are sort of varying estimates of the total prevalence that DCCR could address, 9,000, 12,000. What do you think is the right number as you get ready for the launch?
We are seeing 10,000-ish patients pretty clearly in the claims data. And we think that about 10%-15% of those are probably below four years of age. So on any given day, think of it as 85%-90% of those as being kind of the top line number for a total addressable market. Obviously, patients who are below four are going to age up into that population over time. So that's probably the best prevalence numbers to go from.
Got it. And I believe your company is about 75 FTEs right now.
Approximately, yeah.
You plan to get to about 120 at the time of launch?
Yes.
So how many of these are real boots on the ground, knocking on the doors, et cetera?
So the total commercial footprint is about 60+. About 30-ish are sales. We have already hired sort of the regional sales leadership type of people. We'll probably be bringing on at least some true salespeople before launch. But most of the salespeople will come on around the time of launch. So that 30-ish people, most of them will be around launch.
Is there a geographic concentration where, let's say, Florida or North Carolina has docs with 1,000+ patients?
Yeah. Field force planning is a big thing, apparently, I'm finding out. And it definitely depends on where the patients are. So it's mostly related to population centers. But it's also related, a good example is Florida, where the KOL might live that people want to see. So we see a somewhat disproportionate population in Florida, Atlanta-ish areas. But other than that, it tracks mostly the population centers.
Got it. And in your sort of company-sponsored market research, what do you think the feedback has been for likely adoption of DCCR post-launch?
Hi. I think there's a lot of demand for the drug. And whether it's a, for the most part, it's a pull. I think you see a lot of families who are interested in the drug. You go to these conferences. You have a lot of people coming to us talking about how do we get access, et cetera. So there's no doubt that there's a desire there. For the most part, the work that we have done suggests that physicians are very interested in using the drug.
I think pediatric endocrinologists, in particular, who will be the primary prescribers of the drug, have a high level of comfort with a version of diazoxide as a parent molecule, which is better tolerated, has low peak-to-trough ratios, has a stable intraday level, and therefore has a side effect profile which is likely to be a lot more beneficial in a situation like PWS. So we feel good about the fact that ped endos is our primary prescribers. They seem interested. They feel comfortable with the drug because they've seen sort of much larger doses of it being given in hyperinsulinism or of the parent molecule, at least. So yeah, we generally see a pretty high level of interest from patients and physicians.
Got it. And for your ideal label, do you think it'll just reflect the randomized withdrawal side of the story or the long-term extension data where you keep seeing deepening of response? Because that's what the docs we have talked to point out. Their original assessment was the treatment effect would fade after one year, but this keeps on deepening.
Our ideal label would have that data because we think it's a very important part of it. The randomized withdrawal, and there's interesting ICH guidelines that tell you about what is the duration of efficacy. Is it the duration of the randomized withdrawal? Or is it the duration of treatment prior to randomized withdrawal that talks about duration of effect? It's actually the latter. We think it's really critical to know that long-term data, particularly because it's going to be relevant for people to understand whether or not the drug is working. You don't want someone saying at the end of three or four months, the drug worked or didn't work. You want them to try it out for six to nine to 12 months to see what the drug can actually do.
Got it. And based on the available data, both from the original phase III, the randomized withdrawal study, OLE, what do you think the compliance is going to be? Because obviously, some patients dropped off the initial study.
We think compliance is going to be high because of a couple of reasons. One is these patients are obsessive-compulsive. So they like a routine. And in general, they want to take the drug that they've been taking every day. And it's not just the drug. It's everything. It's going to school at a certain time, eating certain foods, et cetera. So we think there's this interesting inherent compliance ability built into this population. But also, when you think about the dropout rates in the trials, we are seeing a 30-ish% dropout rate over three to four years. So in a population like this, in a situation where these patients have to come into the clinics periodically, which is a huge task for them, it's not a very high number. So we think overall, compliance persistence is going to be fairly high.
Got it. And plans for Europe?
So as we have said, we intend to submit the MAA in the first half of next year. We are continuing to evaluate the market. And we're liking what we see. When you look at the EU4 plus the U.K., we see about the same number of patients as the U.S. So it's a large number of patients. When we look at analogs for rare disease pricing, we like what we see. It's a lot better than some of the other indications. So we are continuing to evaluate it as something that we might want to do. But we are also entertaining outreaches from companies that are interested in partnering. Don't feel like we're in any crisis to make any decisions on that, though.
Got it. I mean, this comes up a lot as given that you're a single-product company, is the goal really to partner the drug and limit, let's say, M&A options? Or try to do it on your own and maybe sell the whole company?
I think the decision to partner or not partner is driven more by what's the best decision for us as a company to make the drug available. It's not driven by ultimate strategic value. That will be what it will be. It's really important to figure out how to make the drug available and do what's the best thing for the company.
Have you had any initial interactions with the CHMP as you get ready for the submissions?
So we have had interactions dating back to 2016, 2017 with the EMA. And as we have said, we did not discuss this randomized withdrawal with them prior to initiating it. But back then, when we submitted our initial thoughts on trial design, we had recommended a six-month study to both the U.S. and Europe. The U.S. wanted a shorter study. Europe wanted a longer study. So we did the shorter study. But the EMA did point out that one of our options for getting long-term control data was going to be a randomized withdrawal. So we find ourselves in a situation where sort of years later, we've done what they were asking for. So we feel that this should be a data set that will work for them.
Awesome. Closing thoughts on the IP and how that might evolve? Because I think pretty much everybody is stuck with this seven-year exclusivity.
Yeah. I mean, yes, there's seven years of exclusivity here, 10 years in Europe. We have a composition of matter, salt polymorph patent that expires with primary expiration end of 2026. If PTA applies, that's another 800 days. If PTE applies to it, that's till 2034. We have method patents with primary expirations in the mid-2030s. If you apply PTE to one of those, that could go to the late 2030s. So I think it's not unfair to use seven years as kind of a base case scenario. But we think there is substantial possibility of having more exclusivity on this drug.
Awesome. Any closing thoughts?
No. Thank you for having us. Great conference.
Appreciate it. Thank you so much and good luck.
Thank you.