To be joined by the team from Minerva. Up on stage with me, I've got Rémy Luthringer, the CEO, and we're joined by Jim O'Connor, the Chief Business Officer, in the audience. Thank you both so much for coming. To get us started, could you give us a quick snapshot of Minerva today?
Yeah. First, thank you for the invitation. It's been really nice to be here and to enjoy the conference, which is great. I think in just one minute about history, what we have tried to achieve with Minerva was really to address unmet medical needs in the space of psychiatry, overall neurosciences, but mostly psychiatry. I think we have been quite successful because as you probably have seen, one drug we co-developed with Johnson & Johnson went back to Johnson & Johnson, seltorexant, and I think the drug is doing very well. Our lead molecule, roluperidone, is also addressing a huge unmet medical need, which are negative symptoms in patients who have a diagnostic of schizophrenia.
This is a disease or a type of symptoms from schizophrenia, which people have tried to address since 70 years or so, since we had the first antipsychotic, and nobody was successful. We have really a drug here with a lot of hope for patients.
This is what we are doing at Minerva.
Great. Let's dig into negative symptoms of schizophrenia. Can you tell us more about them and how and when they present over the course of a patient's disease?
Yeah. First of all, I think negative symptoms, people are forgetting it because, since, again, 70 years, we have antipsychotics treating positive symptoms, agitation, hallucination, delusions. We forgot a little bit about what is really the disease. The disease is about three types of symptoms, negative symptoms, positive symptoms, and cognitive impairment. What is very clear is that the first type of symptoms which occur are negative symptoms, and this occurs very early on in the life of these patients, usually when these patients are at around 15, 16 years of age. These are good kids. They're good at school, having friends, interested in whatever music or sport, and slowly but surely, they are losing the drive to do something. This is what we call amotivation or avolition, and this is one of the key driver of negative symptoms.
They're also afterwards losing the pleasure to do something they were liking to do before, which is anhedonia. These are really the two pillars of negative symptoms. The National Institute of Mental Health has called these the five A's, but avolition and anhedonia are really the main symptoms. The diagnostic will not be done there at this age, but the diagnostic will be done when you have a first episode of positive symptoms, whatever, between 18 and 25 years of age. But when you're looking backwards, you see that what is really driving the disease are negative symptoms. This is, by the way, recognized by the FDA, by the regulator, and I think by the scientific community.
The impact on cognitive impairment, do you see correlations between negative symptoms and cognitive impairment? Do negative symptoms lead to cognitive impairment?
It's a great question, and to be completely fair, I think there are currently two schools of thinking. One school is thinking that these patients are cognitively impaired and you have to improve cognition, which is one way to see cognitive impairment in schizophrenia. There is another school, and I'm more in favor of this school, and I will come to our data because our data are more in favor of the second school, which says these patients are not cognitively impaired, they're just not able to execute because they have negative symptoms, and particularly because they have avolition. In my previous life, I was running a research institute. When you are pushing a patient with schizophrenia to do a cognitive task, he's performing quite well. But because he has not as a drive to do it, he has avolition, he has negative symptoms, he's not executing basically.
I personally think that if you improve negative symptoms, you have a chance to improve cognition. I think there is a real link here between the two, and we have published data on two studies where we used cognitive testing and definitely our drug is improving cognition as well.
Yeah.
This might be, by the way, another indication we could follow after we have the drug approved for negative symptoms.
Yeah. Great. We will get to that shortly. To finish up on just some background on negative symptoms, can you talk us through the proportion of patients with schizophrenia that do present with negative symptoms and how they get treated today?
Also big debate. But if you are going according to publications, at minimum, you are coming to the conclusion that 60% of the patients have negative symptoms with diagnostic of schizophrenia. Keep in mind that the incidence is around one person. So we are speaking here about a lot of patients, around 3 million people only in the U.S. But if you are putting the disease in a dynamic way and looking to the course of the disease, I think it is fair to say that 100% of the patients with the right diagnostic, there is also an issue about diagnostic, but this is maybe a discussion we can have another time. But patients who have real schizophrenia during the course of the disease, they might have negative symptoms during their lifespan. So I would say that 100% of the patients are suffering from negative symptoms at a certain time of the disease.
How much stopping antipsychotics could that impact negative symptoms? How many of those patients are having them because of the medications that they are taking?
Let us be clear. When we speak about antipsychotic, we should speak about the dopamine-blocking molecules, which are most of the dopaminergic molecules, part of COBENFY, who has a different mechanism of action.
Yeah.
It's clear when you are blocking dopamine, definitely, you have the limbic structures, you have the prefrontal structures which are impacted by blocking dopamine. So definitely, negative symptoms are, how to say, enhanced. So the primary negative symptoms, disease negative symptoms, are enhanced, and we call this secondary negative symptoms.
Yeah.
When you're stopping antipsychotics, there is an improvement, there is no doubt, because all the, again, the meta-analyses are showing that you have secondary negative symptoms when you're treating someone with an antipsychotic. I think, you see an improvement, but coming one second to our studies, because what we are doing-
Yep
We take patients who are treated, most of them are treated with an antipsychotic. It's obviously not fair or not ethical to take someone off an antipsychotic if the patient is functioning well, yes?
Yep.
We are only taking off antipsychotics patients who show a functional impairment. Everybody knows, there is a consensus, that the impairment, the functional impairment, is related to negative symptoms. You need to have the right study design to come to the right conclusion.
Yeah
What we are doing, we take off the patients from antipsychotics. They are randomized to either our drug in monotherapy or placebo.
Yep.
The treatment duration is long enough, 12 weeks, in order to, when you see a difference at the end of the 12 weeks, because double-blind, placebo-controlled, randomized.
Yep.
You can come to the conclusion that this is related to the drug. But overall, if you take off someone from an antipsychotic, you are improving negative symptoms, but not the primary one, not the disease-related one, but secondary negative symptoms.
Tell us about the process of taking a patient off of an antipsychotic to come onto your study, and then potentially in the future, if roluperidone is approved.
It's not very specific to our studies because when you think about what the patients are wishing to do, there is a study out there which is scientifically very well carried out. When you give the possibility to patients to decide about their treatment, 70%-75% of the patients are willing to stop their antipsychotic treatments after 18 months of treatment. There is definitely a problem with antipsychotics. I'm not saying that antipsychotics are not useful. They're useful to treat an acute episode of psychosis or positive symptoms. If you think one second, the name of these medications were called major tranquilizers when they were developed. We changed the name. We can also debate about this one, but I think these are really major tranquilizers. I think this debate about continuous treatment with an antipsychotic versus intermediate treatment is going on since decades.
I think more and more, the intermediate treatment is becoming more and more liked.
More and more support. There are even big studies going on in the U.K., in the Netherlands, to really confirm that someone can be without an antipsychotic, and I think there is a reality. What we are doing, and this has been discussed with the regulator, we are mimicking what you're doing in clinical practice. Someone is not responding well to a treatment. What you're usually doing, you're not doing five half-life of washout. You're switching from one treatment to the other. This is basically what we are doing. We are nevertheless putting a minimum request of few days of washout before we're randomizing the patients.
Yeah.
There is a theory out there saying that, if you are stopping abruptly an antipsychotic, you might have such kind of boost because when the dopamine receptors are getting washed out, you might have a worsening of symptoms. Again, two schools debating here. In our experience, having done this with around 800 patients, and others have done it, yes.
Lundbeck has done a study very similar to us.
Yep.
You can do this extremely safely. The other aspect which is obviously important is, are you able to pick up patients when they are starting to have a relapse?
Yep.
I think this is also now really evolving a lot. I think most of the clinicians are able to pick it up very easily because it's not coming from one second to the other.
Yeah.
First, the patients are not sleeping well. After, they are getting a little bit agitated. This is a process which is going on over several days. You can really take the decision before something happens, like a relapse of positive symptoms.
Yeah. Let's talk about roluperidone. Very different mechanism of action here. Can you talk us through it and how roluperidone addresses negative symptoms?
Sure. I think roluperidone addresses negative symptoms, and it's probably improving primary negative symptoms. We have a lot of data showing that it is primary. By the way, we are in the process to publish even more data, showing that it is an effect on primary negative symptoms. But I think it is important to mention that roluperidone is a drug which is able to keep someone stable in terms of positive symptoms. This is probably, and I'm always hesitating to take this risk about saying, "Okay, this target is explaining this.
Nevertheless, the 5-HT2A antagonism of the drug is really helping to keep someone stable in terms of positive symptoms. It is doing much more than this. It is also helping in terms of improving sleep, which is part of the symptoms we have in schizophrenia. 50% of the patients have insomnia. It is increasing deep sleep, which is related to memory consolidation, so we can speak about cognition. But I think it's not enough, yes, because a lot of companies have tried. I mention Acadia, for example. I think it's not enough to improve negative symptoms. I think really what is helping roluperidone to improve negative symptoms is the sigma activity of the molecule.
The combination between 5-HT2A keeping the patients quite stable in terms of positive symptoms, improving sleep, deep sleep, cognition, and the sigma activity, this is what is explaining why the drug is improving negative symptoms. It's not really based on a complete, how to say, basic pharmacology.
It is based on an observation I made with a drug in the past.
Yep.
The sigma pathway becomes richer and richer in terms of understanding. It is modulating dopamine, not blocking dopamine. It is modulating glutamate. There is a rationale which is explaining why this approach is improving negative symptoms.
Tell us a bit more about that path, the clinical development path, and those signals that you've seen for roluperidone to date.
We have run for the moment two large studies. One is called phase II-A, but it has been carried out and analyzed like a registrational study. The second study, which is the phase III study. The first study, which was again a monotherapy, so switching from an antipsychotic to our drug or placebo. Two doses were tested, 64 milligram and 32 milligram, 12 weeks primary efficacy endpoint, showed a huge, statistically significant with huge effect sizes for the space. More than 0.5 effect size in psychiatry is quite unheard. The two doses made it very clearly compared to placebo. We also were measuring functioning with a scale called PSP, and again, functioning also improved. We were running a second study, larger study, more patients, more clinical sites, more expectation to see an effect, which is never good.
Also, the probability to get drug, which is higher than getting placebo, and this is really helping, in brackets, placebo to pick up. So what was the outcome of this study was that the highest dose, 64 milligram, was definitely showing a P value compared to placebo. PSP functioning was also highly differentiated between placebo and treatment, but unfortunately, 32 milligram did not reach a P value.
We were so optimistic that we used the Type I error correction, which is called the Hochberg correction. When you are using the Hochberg correction, if one dose is not hitting a P value, you have divide your dose hitting a P value by 2. So our P value was 0.043, it should have been 0.025 to claim that this is a completely positive, successful study.
We went with this package to the FDA because unmet medical need, normally one very positive study and confirmatory evidence is what you need. The feedback was, and I think it is completely fair, is that here we are not dealing with an orphan indication, we are dealing with a large population. It is a paradigm shift, so we would like you to run the study we are currently running. Since this is what we are doing currently, we are running the study with the design we discussed in length and in depth with the FDA.
It seems like there was also one site that had an issue in that phase III, the implausible data. Could you tell us more about that and what you think happened at that site?
Yeah, for sure. First of all, if you're looking to the approvals of drugs, most of the approvals are done on MITT data, not on ITT data. It's not uncommon. Importantly enough, and I will come to the reason why we have proposed to exclude this site from the analysis, we picked up this site before unblinding the data. This is not post hoc analysis, this is definitely a priority. We have put this in our statistical analysis plan, and we shared it with the FDA before unblinding the study, before analyzing the data. But so what you could see at this site is that patients were definitely existing. But what happened is that the patients have not been tested during the first 12 weeks, going to the primary efficacy endpoint because looking to some clinical scales, they did not move by one iota.
Afterwards, when you have some doubts, you're going to look to vital signs, you're going to look to these kind of things. Guess what? The vital signs also did not move. So the plausibility of this data was really doubtful. And so we discussed this in length with the agency and we all came to the conclusion that this data should be excluded from the analysis.
Okay. And you also agreed with the agency to do a confirmatory phase III study, so that's ongoing.
Yeah.
Could you walk us through the design there, and any changes that you've made to the study conduct compared to the previous two?
Yeah. The study is in two parts. The first part is again, with the primary efficacy endpoint at week 12, like in the two previous studies. There is a big difference, is that in this study, we are only testing 64 milligram and not 64 and 32 milligram versus placebo. Remember, the 64 milligram made it in the two previous studies. This is reducing the expectation to get active drug, so should help us to really discriminate between placebo and roluperidone. We have added a few things we did not have in the previous study, so I'll give you an example. When a patient is selected or becomes a candidate for the study, this is a decision of the PI to include the patient or not.
But there is a small committee which is helping the PI to decide, is this really the right patient or not the right patient for the study? So to reduce the variability of the data, so to avoid noise in, noise out. So we are reducing the noise in. Yes. There is another aspect which is important, is that between the first study we run and the second study we run, the agency asked us to have more interaction with the patients. If you think one second about these patients, the more you're stimulating them, the more you see an improvement.
Yeah.
This improvement is obviously not lasting. It is just the time of interaction. This is what I call the nursing effect. We had really a lot of interactions in the second study, and I think this contributed to increase the placebo effect, particularly because our drug, you cannot discriminate our drug based on side effects. Excuse me. In this ongoing study, we are not interacting with the patient between the visits, but with the caregiver.
Yeah.
In order to avoid the nursing effect. There is a second part of the study we call phase III-B, which is a one-year comparison, purely on a descriptive level. No statistics, no inferiority study or whatever. Because, I mean, we have so limited numbers of relapses.
Here we are comparing, excuse me, antipsychotics to roluperidone 64 milligrams, looking mostly particularly to relapses of positive symptoms.
Study design is quite, I think, nice because we are using a double dummy study design. We have over-encapsulated three antipsychotics, so to really minimize guessing activity from the patients and from the PI, and we are comparing this to, excuse me, roluperidone.
What will be a good outcome in that second part of the study?
The outcome is if the relapse rate is comparable between the two conditions. This will give the possibility that the agency can say, "Look taking off someone in this targeted patient population, taking someone off an antipsychotic and moving into roluperidone, there is no risk of increasing the risk of relapse and hospitalization." Because this is the reason why antipsychotics are currently prescribed.
Minimizing the risk of relapses and hospitalization. Sorry, I just drink.
Sure. With the primary endpoint at 12 weeks, when will you be able to resubmit the NDA? Will you need to wait for that 52-week data, or will the FDA allow you to submit earlier?
We are committed to run the complete trial.
Okay.
Because I think the phase III-B is an important part as well, to reassure prescriber, patients, agency, about the fact that the drug is having the same relapse rate, the same low relapse rate as when you treat them with an antipsychotic. This said, the good news is that we have an ongoing continuous dialogue with the FDA. Obviously we will discuss the results of the first 12 weeks with the FDA.
We'll see what happens.
Okay.
I think the good news is that we have a very open discussion with the FDA, which might allow different options, but definitely we are willing to run the complete study.
Talk us through the other things that you agreed with the agency from after the CRL. Are there any other outstanding areas that you need to generate evidence for the resubmission?
When you're receiving a CRL, you get a shopping list. Basically. I think we agreed on a lot of things. First of all, we agreed to run the study.
I think it's not only an agreement between the FDA and us. Remember, the FDA organized a public meeting about how to develop drugs for negative symptoms. I think a lot of clear messages came out from this, which we are applying in this ongoing study. When you're going back to the CRL, for example, the FDA was speaking about the fact that even if the studies are positive, it's not clinically meaningful.
Everybody knows that when you have no previously approved drug, you cannot speak about clinically meaningful, because nobody knows what is clinically meaningful. What you can speak about is number of responders, or you can speak about these kind of criteria. I think we really clarified this with the FDA. We don't need to show clinical meaningfulness because this will happen when the drug is with patients and people are doing continuous research on it. This has been clarified, for example.
Yeah.
There was also an item, you have not enough patients exposed to the drug at one year. Because ICH guidance tells you 100 patients. We were at 90 patients with 64 milligram, this will also be covered with the ongoing study. I think we agreed on most of the items. There are also ongoing CMC work. As you know, the hot topic currently is nitrosamines and all of these kind of things. We are obviously following this extremely carefully, and our data are looking very good, so I have no real concern about all the other aspect, part of the executing well this clinical trial, showing again that we have efficacy. This I think, is the basis of what the FDA would like to see.
Remind us of the timelines here. When will we be seeing-
Timelines, we have started recruitment end of March. As we have disclosed, we will see that the results of the phase III-A, the 12-week efficacy part, during the second half of next year. We are taking a little bit precautions here, just half a year. What I can tell you today, we are executing according to plan.
There is nothing to worry, and I think I can confirm that we are on track for second half of next year.
Okay. The sites that you are going to, could you just talk about the selection of sites and the overlap with the previous two studies that you have run?
Yeah.
Hopefully not the bad one.
The bad one is obviously not part of it.
Okay.
What we have to be cognizant of is that a good site two years ago is maybe not a good site today. We did really deep due diligence. I think we can call it deep due diligence on the sites that we are using in this study. It was based on our previous experience, deep due diligence, plus experience of the CRO we are using, plus experience of a provider who is providing the tablets to carry out the clinical scales. We really collected and compared the data from these three sources to come up with our sites. What I can tell you is that it's only a small percentage of sites who have participated to the previous trial who are part of this trial, just because the PI has left, because, I don't know, the study nurse has left.
Study nurses are very important because they are usually running the study or recruiting the patients. All these kind of criteria, we integrated them in order to come up with over 40 sites.
Before we end, remind us of the IP position of roluperidone. The composition of matter's gone, but how much comfort can investors take in your other patents, the formulation metabolite?
It's a great question, yes. We have seven families of patents. As we speak, we are working on some additional IP, and I'm really confident that we will be able to generate additional IP. But there are some IP of these seven families which are really very strong. To name one, it's called a formulation patent, but it's not really a formulation patent because it needs to show ratios between parent compounds, metabolites. It's a very sophisticated recipe here to crack. As you know, in the past, some of companies financing us was Boehringer Ingelheim, for example. They did a lot of due diligence. We are continuously speaking with pharma companies. They're doing due diligence on IP, and definitely, they come to the conclusions that we have really strong IP protections at minimum until 2038 without extension.
Okay. Remind us of your cash balance and the mechanics of the second PIPE tranche, where that gets to.
The overall raise was $200 million. Again, I think we have to thank all the investors just because it was not an easy decision for them because there was no event. It was really doing a lot of work on our data and coming to the same conclusion as we came to that we have a drug here. The upfront was $80 million. There is a tranche A, which can be exercised today until 10 days after we release the top-line results of the phase III-A.
Wow.
Yeah.
Hopefully we've been hearing you all this time.
Nobody was hearing me? No, no problem. Okay. I will not repeat. [audio distortion]
We have disclosed this in the release that impressed me that, and I think this is really, really, really assuring, showing the ability that a lot of trust.
... Some of the investors have already exercised the tranche A. I think it was around $10 million plus. We already received from the tranche A, which is a good sign that there is trust from our investors.
Great. Well, thank you so much for joining us, Rémy.
Thank you.
Thank you, everyone, for coming.