Okay, we're gonna go ahead and get started. Thanks again to everybody for joining us at the Citizens Life Sciences Conference. Happy to be joined next by Minerva Neurosciences, joined by Rémy Luthringer, the CEO, Geoff Race, President. Minerva's developing a novel medicine for schizophrenia and specifically patients with predominant negative symptoms, roluperidone. Been a really interesting year with a lot of clarity from FDA, a phase III trial getting up and running now. A lot to talk about, but maybe just, Rémy, I'll turn it over to you to give a quick intro on.
Sure.
... on the company.
Sure, yeah. First of all, thank you, Jason, for the invite, yes. It's always a pleasure and we went into detail with a lot of good debates and good questions, so I'm sure that we will have good questions. I see that I'm the only one with a tie, yes. Find the error here. I'm coming from Europe, yes. Yeah, now what we have tried since the IPO in 2014 is to come up with treatments addressing unmet medical needs in psychiatry, yes. As you know, there are a lot of unmet needs still to cover. Coming to roluperidone, definitely, this is addressing completely unmet medical needs. There is no approved treatment in the United States for negative symptoms.
People have tried since we have antipsychotics available to treat positive symptoms, but they were not successful. It's not because they have not tried. I think it is really probably the most difficult part to treat in patients suffering with schizophrenia. There is maybe a slide just to explain a little bit.
Sure.
I don't know how to advance it.
Oh. Here.
People understand, yes. This is giving you the time course of the disease and the three types of symptoms. As you can see, what we're treating today is the green curve, yes, which are the positive symptoms. As you know, positive symptoms might have some acute phases, and here definitely when you treat them with an antipsychotic, so it's the drugs available currently, you bring down the patient, and he is no longer agitated, he's no longer hearing maybe voices, and this is definitely what the antipsychotics are doing. What is really the real problem with schizophrenia are negative symptoms.
You see that this is a brown curve, and you see that negative symptoms occur before you have the first event of positive symptoms, before you're doing the diagnostic of schizophrenia. You know, negative symptoms is about evolution. It is about anhedonia. These people had, when they were kids, as they were interested in a lot of things, they were good at school and suddenly they're losing the drive, they're losing the pleasure to do what they were good at before they started to get negative symptoms. You see that these negative symptoms are building up over time, and they are constantly present here. If you go back a little bit to history before we called this disease schizophrenia, it was called dementia praecox. Why?
Because if you're not treating the negative symptoms, these patients are presented like early demented patients. Does not mean that they're cognitively impaired. It just means that they have no longer the drive to do you know a simple classical cognitive task. These are negative symptoms, and this is what we are trying to address. The last point to keep in mind is that you know since 70 years, we have antipsychotics. 70 years ago, 5%-10% of these patients with schizophrenia had a small job. Today it is still the same. What I'm trying to say here is that if you want to give a chance to have a decent life to these patients, you need really to improve negative symptoms.
It is well described that negative symptoms is what is driving the functional impairment. This is the challenge we are trying to-
Just before we jump into the drug itself, roluperidone, can you just talk about the impact of negative symptoms? I think it's very clear how what the burden of positive symptoms is and what the consequences of positive symptoms are to a patient's you know daily function. How does negative symptoms impact? Can you maybe compare what the burden is versus positive symptoms?
Again, as I explained, positive symptoms are really how to say coming going and you have acute phases. It's true that when I mean a patient has an acute phase of positive symptoms or psychosis, yes, because we are mixing always positive symptoms and psychosis, the patient is obviously impaired. He has difficulties to do anything which is meaningful. As soon as a patient is down from his positive episode of acute psychosis, he has a lot of insight. He's able to understand what is going on with his disease. If he has negative symptoms on top of it, here he cannot function. Here, this is exactly the type of patients you know you see in clinical practice coming to see you. He's treated with an antipsychotic.
Just keep also in mind that antipsychotics are treating positive symptoms, but they're impairing negative symptoms. In other words, on top of the negative symptoms related to the disease, what we call primary negative symptoms, you have what we call secondary negative symptoms, which are drug-induced. Speaking about the patient when he comes to see you, he is obviously coming with his family or with his caregiver, and and you ask the patient, "how are you doing?" The patient, "I'm well, yes," but he's not really responding very fast because he has also this problems of giving you just a complete sentence. I mean, you have the caregivers, the parents who say, "You know, he's not standing up, he's not taking a shower, he's staring at the TV the complete day.
He's doing nothing. "So doctor, you have to do something." These are really negative symptoms. This is what is keeping this patient out of any decent life. Really this is what negative symptoms are doing.
Thank you, Rémy. Let's talk about the drug roluperidone. Can you just walk us through the mechanism?
Sure.
There are some similarities to other atypical antipsychotics, but it also has a very differentiated mechanism of action at the same time.
Yeah.
Just walk us through that piece.
Coming back to the antipsychotics. Yes, I mean, as you know, since one year or so, we have a new mechanism of action with KarXT. But all the other antipsychotics are blocking a pathway in the brain which is dopamine. Yes. Blocking the postsynaptic D2, which is a subtype of dopaminergic receptors. This has this effect on calming down the patients, let me put it like this, because these drugs were called major tranquilizers before they were called antipsychotics. The problem is that when you're blocking dopamine in the brain, you're blocking a lot of important things. You're blocking, for example, the prefrontal cortex. The prefrontal cortex is very important in executive functions.
You're blocking the dopamine in the limbic structures, and limbic structures are extremely important in negative symptoms. Clearly, I mean, again, antipsychotics are useful to treat acute episodes of positive symptoms, but they're worsening negative symptoms. What we've tried to achieve with our drug is to, first of all, get rid of the dopamine blocking effect. Yeah. In order to avoid this unwanted side effects of the other antipsychotics. What is important is that you need to keep these patients stable nevertheless, in terms of positive symptoms. There is one pharmacological activity of our drug which is a 5-HT2A antagonist, which is a subtype of serotonergic receptors.
It is very well described in the literature that having a blockade of the 5-HT2A receptors is really having a maintenance or stabilization effect on positive symptoms. What is also interesting, and people are also often forgetting it, is that you are also normalizing with the 5-HT2A antagonist, you're normalizing the ultradian and circadian rhythms.
Mm-hmm.
This is something which is really completely distorted in patients with schizophrenia. Last but not least, you're also improving or increasing deep sleep. Deep sleep is heavily related to memory consolidation, is heavily related to keep this patient stable over time. This is a first activity which was important in order to be able to give our drug not on top of antipsychotics, but in monotherapy. The second activity of the drug, which I think is really key and which is making really this drug probably the only drug really improving primary disease related negative symptoms is what is called the sigma activity. The sigma activity is another pathway which is less known than the serotonergic pathway.
Clearly, when you're doing something on the sigma pathway, I have seen that you have some companies presenting on some sigma molecules. Yes. Developing the drugs for Alzheimer's or for aging. What is very clear is that when you have an effect on the sigma pathway, you're probably improving negative symptoms. First of all, because you're modulating the dopaminergic tone, you're modulating also glutamatergic tone. You know why I got excited about this pathway is a clinical observation. Yes. It's not sophisticated pharmacology. In my past life, I was running a research institute, and I was testing long time ago a sigma ligand. I gave this molecule to patients with negative symptoms and schizophrenia.
You know, after a few days, you could see that these patients started to, what people would say, wake up because they are starting to get interested in what is going on around them. I have had one patient who was opening a newspaper, did not do this for 10 years. This was an improvement of negative symptoms. I had always had this dream, which became true, yes, about not blocking dopamine, keeping the patient stable in terms of positive symptoms and allowing them to improve negative symptoms. This is a drug. Yes. Last but not least, afterwards I stop with the pharmacology. We have also demonstrated that the drug has a huge effect on nerve growth factors, BDNF, GDNF.
Keep in mind that schizophrenia, there is a genetic load, but it is a neurodevelopmental disease. Something is going wrong in the brain when the brain is maturing. Yes. When you have a drug doing something on BDNF, GDNF, you might restore somehow neuroplasticity. Yes. Which I think is also important to improve patients for negative symptoms.
You've generated a lot of data so far for roluperidone in this patient population. You also, I think, hinted at it before. This is an area where you and others have tried to get new medicines to the market, and it's not been easy. Maybe let's just start off with the data that you've generated to date and why it gives you confidence in you know running this new phase III trial.
Sure. Let's go to the data. Yeah. This was the first study we run. Yes. I mean, first of all, we have to keep in mind that here, this study has not been generated to put the drug on top of antipsychotics. This is data where you're looking at the stability of the patients over the last six months before you propose a study to the patients. They have to be stable in terms of positive symptoms. This does not mean that they don't have positive symptoms. They just need to show stability, and they have negative symptoms which are impairing. Yes. There is a level of negative symptoms you need to have in order to be eligible for the study.
When you're doing this, so you take them off their antipsychotic, and you randomize them to placebo, which is a blue curve, and the two doses of roluperidone. Green, you have 32 mg, and in red, you have 64 mg. You see that as soon as two weeks after initiating the treatment, you start to discriminate roluperidone from placebo, and the things are building up over time, and at the primary endpoint, which was week 12 in this study, you see that you have a nice p- value and very decent effect sizes. So this, I think, was the first time ever, you know, you could show in monotherapy such a clear differentiation between roluperidone and placebo in terms of negative symptoms.
Now, what is important is that, it's obviously beautiful that you're improving negative symptoms, but it needs to translate into a functional improvement. To the best of my knowledge, I think we are the only one who have shown a functional improvement, yes. This is the result in functioning. This is a scale which is called PSP, yes, which is looking really to daily living activities. Is the patient taking a shower? Is the patient able to understand what you're asking him to do? Is the patient you know just functioning better than before? Yes. What you can see very well here as well is that the highest dose 64 mgs is really improving functioning. Yes.
Here, obviously, when you're increasing this is an improvement. Yes. You see again, we had a very clear improvement in terms of functioning. Yes. It's always nice to give some examples. I have an example of a patient who was hospitalized for 20 years, and his family was changing the country. Yes. He was in this hospital. Yes. After 20 years, he improved. He found the phone number of his family, and he called his family. Yes. The family of 20 years, they forgot the patient, and he called the family saying, "Okay, I'm here, I'm back. I would like to discuss with you." Yes.
Just to show that, I mean, it's meaningful on a daily rate. It's not just a scale. It is really meaningful what we see here. Yes. This is what we have here as results. Afterwards, we did a second study, and here I'm only showing you the results on 64 mg because this is a dose we are seeking approval. What you can see, what is very important when you're looking to the red line, the improvement we see is exactly the same as the improvement we had in the first study, so around 4 points improvement.
Mm-hmm.
What is obviously different here is that the blue line has picked up and placebo. This is something which is extremely known in psychiatry. What we call placebo effect is extremely well described. What you can see nevertheless, we have a p- value. We have a discrimination between 64 mg and placebo. The problem was and is that we are addressing here a very large patient population. Keep in mind that the incidence of schizophrenia is 1%. If you're in a room of 100 patients, the likelihood that someone is suffering from schizophrenia is there.
Here, you know, when we started to have this exchange, when we shared this data with the FDA, and I have to say it was a long process, but a very constructive process and a needed process in order to come to an agreement. I think we have now really a good agreement, which allows us to run the next study. They said, "Look, you have a very clear positive study. The second one is not so clear. Nevertheless, you have a p-value for the highest dose, but we would like to have a confirmatory study." Yes. The question was afterwards, which kind of study you have to run?
I said, "No, we have complete clarity." Just to show you that functioning is still there. Yes. I mean, again, in this study, the patients are improving their functioning. There is no doubt about it. We have a drug here. Now it's about executing this confirmatory study.
You touched on the FDA piece. Let's talk about that a little bit more. You drove a lot of education with FDA. Walk us through the outcomes, right? How do you think FDA now views this patient population, and what gives you confidence that they're in a place now that they are, you know, if the confirmatory study is positive, they agree that this is a meaningful.
Yeah.
Outcome?
Yeah. So this is before answering your question. This is just to show that, you know, this bar you have here. This is the 12 weeks, and afterwards you're looking to the results on the top left. You have negative symptoms, and you see that they continue to improve over one year. You see functioning on the right. You see improvement and so on. Yes. You see stability of positive symptoms on the bottom left. Yes. Clearly, I mean, this was also an important piece to show that, I mean, it's not just an acute effect. It is really a long-term effect. So what we achieved with the FDA is a lot. Yes.
You know, without going into the details of the minutes, of the official minutes from the FDA, but they are speaking like we are speaking about a paradigm shift.
Mm-hmm.
To come to the paradigm shift, we had to clarify a lot of things. First of all, as you said, is this patient population real? Yes. I mean, does this patient population exist? Is this population a population who does not need continuous treatment with an antipsychotic? I think here we have full agreement. Why? Because as you can see on this slide, they agreed that we have the first 12 weeks exactly done in the same way as the two previous studies. Basically, stability of these patients over the last six months, we stopped the previous treatment, and we randomized them to either roluperidone or placebo. In monotherapy. They agree that there is a population out there who can benefit from roluperidone in monotherapy. No need of antipsychotics.
This is very clear. The other aspect, and I think this is very important, what the FDA asked us to do here, is that, you know, think one second of today, the recommendation from American Psychiatric Association is try to keep patients as long as possible treated with an antipsychotic. The only reason why this is that you have a little bit less relapses of positive symptoms, and you have less hospitalization.
Mm-hmm.
This is a reason why, I mean, what the FDA asked us to do, as you can see in what is called here Part B, is not only to use an open-label extension as we have used in the previous studies, where everybody was switched to roluperidone. What you're doing in this part, we are keeping obviously some patients on roluperidone for one year, and we are switching some patients to antipsychotics. Just to demonstrate on a descriptive level, there is no statistics needed here. On a descriptive level to show that if the patient population we're targeting is treated with an antipsychotic or roluperidone, the risk of relapse is the same, yeah.
Mm-hmm.
By the way, we have already quite a lot of data-
Right.
...about this. I think this part is really helpful because it will help, I think, the FDA to write the clinical section of when we have positive data at week 12.
As you mentioned, a really key part of this is that a lot of this trial design is, as it's intended to be confirmatory of the first two studies that you ran. Are there any major differences apart from the, you know, you talked about Part B there. Not so much in just trial design, but also trial execution, and how are you thinking about no placebo this time?
Yeah. Yeah. It's a great question. Again, I think keeping in mind that, you know, we have the same drug effect in two studies, keeping in mind that we had a very low relapse rate, keeping in mind all the data we just discussed. You know, it's purely on execution. Yes, I mean, you need, we need to execute this study as well as good as possible. This is well described, and this is not specific to Minerva, yes? If you keep the number of clinical sites under control, yes, and the number of patients in your trial under control, you know the probability of success is increasing dramatically.
Mm-hmm.
Keep in mind that in the second trial, we were recruiting 540 patients. Here, we are going with 380 patients. We are running the study with 40 sites and not 50+ sites. This is already something very, very important. We have worked over the last, I think, a year to identify the clinical sites who really show high quality in terms of doing these kind of studies. They have not a lot of experience in studies for negative symptoms. They have mostly experience in schizophrenia for positive symptoms. Nevertheless, you can come up with sites who are really of high quality.
What we have also done here is that in order to really reduce the variability between sites, between raters, you know, we are doing an extensive training of the raters. We are doing an overview of the raters, completely blinded during the study. We are really checking each rater at each, you know, visit. Is he performing in the norms of the overall group, or is he deviating? As soon as we can pick up a deviation, he gets retrained. This is very important. We did this in the previous study. When the study becomes too large, at a certain time point, you're losing a little bit control of what is going on.
Something we also added here, and this is also in complete agreement with the clinical sites, is that before the patient is included, and it is obviously the decision of the PI, there is a small committee who is discussing each patient with a PI.
Yeah.
It is not to decide for him. It is not to say, "No, this patient is not eligible." It is just to discuss the quality of the patient, the quality of the scoring of the different scales in order to really reduce the variability-
Mm-hmm.
...of the data because noise in, noise out here.
Yeah.
We reduce this aspect. The other aspect, which is very important, which gives me extremely confident that, I mean, the study will show what we want to show is that, here we are testing one dose, 64 mg, which was statistically significant in the two previous studies versus placebo. We have no longer two doses. It is very clear that if the expectation to get active drug is higher.
Yeah.
Placebo is picking up. In this case, the expectation to get active drug is reduced compared to the two previous studies. This is something which is also extremely important. Yes, and last but not least, I do not go through all the details here, but I think it's interesting to read all this. In the previous study, because we had two doses, you have to take care of the Type I errors.
Yep.
We used the Hochberg correction, and we could not claim that the first, the previous study was a complete success because when you apply Hochberg, the two doses need to show a p- value. In this case, you don't need to show this. If 64 mg is showing a p- value compared to placebo at week 12, you have a positive study.
Great. Last few seconds here. I just wanted to ask, you had a very successful financing at the end of last year. Just talk us through, you know, how well-funded are you to execute now on this new trial, and can you give us any insights into the timelines for this study?
Maybe Geoff.
Yeah, we did have a very successful funding back in October last year. Details of that financing are available on our website. It was really a culmination of a lot of work with FDA getting clarity on what the next study would look like and looking back at the phase II-B and the phase III data, which I think convinced a group of very high quality investors to put $200 million into the company. That $200 million is split $80 million upfront, $120 million in warrants. The $80 million takes us all the way through the phase A part of the study, which gets us the top line results.
Assuming they're positive, we then pull down the second Q1 20, and that takes us all the way through to resubmission and initiating the launch in the U.S. for roluperidone.
Great. Really appreciate you both being here. Rémy, Geoff-
Thank you.
Thanks for being with us this morning.
No, thank you.
Thank you.