2026.09.24 | GP | Pharma | JNJ & RAPP Bipolar Mania

Data, Remaining Unmet Need, and the Bar for RAP-219, Cobenfy, and the Muscarinic Class

Primary:

RAPP

JNJ

Associated:

BMY

MPLT

NBIX

Viewpoint:

Academic KOL - Physician

Moderator: Adam Sandler (AS)

| Sep 23, 2026 | 22 Min Read

Michael Mccarthy (MM), Staff Psychiatrist - VA San Diego Healthcare System

SU MMARY

Overview:

The discussion focused on current and emerging treatments for bipolar mania, particularly highlighting the recent Phase III data for CAPLYTA, the potential of RAP-219, and the role of muscarinic agonists like COBENFY. The conversation provided insights into the unmet needs in bipolar mania treatment, the efficacy and tolerability of new medications, and the competitive landscape of psychiatric drugs.

Key Insights:

The expert expressed moderate satisfaction with current treatments for acute mania, citing efficacy and side effects as areas needing improvement. CAPLYTA's recent trial results were deemed clinically meaningful, with its early onset of action and favorable side effect profile potentially distinguishing it from existing therapies. The expert showed interest in RAP-219 due to its novel mechanism, suggesting it could offer a new approach to treatment, especially if it demonstrates good tolerability. The potential of muscarinic agonists like COBENFY was discussed, with the expert optimistic about their efficacy in mania based on their performance in schizophrenia.

Competitive Landscape:

Company/Product

Positive Aspects

Negative Aspects

Market Position

CAPLYTA

Early onset, benign side effects

Not unique in early onset

Could be top-tier if approved for mania

RAP-219

COBENFY

Quantitative Insights:

Novel mechanism, potential for good tolerability

Uncertain efficacy, early stage

Could offer new treatment pathway

Potential efficacy in mania, bypasses some side effects

Known for cholinergic side effects

Adjunctive use may limit standalone appeal

Metric

CAPLYTA

RAP-219

COBENFY

YMRS Change

-4.8 points

Responder Rate

1. 8% (drug) vs 20.9% (placebo)

Safety

Dry mouth, nausea at 7.9%

TBD

TBD

TBD

TBD

TBD

TBD

The expert predicted a less than 50% chance of success for RAP-219 in its Phase II trial but was more optimistic about COBENFY's Phase III trial as an adjunctive therapy, estimating a 60% likelihood of positive results. The crowded market for bipolar mania treatments suggests that new branded drugs might capture only a small share, around 10-20%.

AS: Ok. Good afternoon, everyone, and thanks for joining us on September 23, '26. And today, we're going to be talking about [INAUDIBLE 0:33] after CAPLYTA's Phase III data, the unmet need, RAP-219 and the muscarinic. So we're going to talk today, we're discussing essentially four quick topics: the remaining unmet need in bipolar mania, the CAPLYTA data, Rapport's RAP-219 read-outs — reading out [INAUDIBLE 0:52] and COBENFY and the muscarinic class, and we have a great KOL to help us with the discussion today.

Joining us is Dr. Michael McCarthy who is professor in residence of psychiatry at UC San Diego. Dr. McCarthy treats patients with bipolar disorder at the VA San Diego. He leads funded research on bipolar disorder, including work on lithium response on the metabolic effects of antipsychotics. Dr. McCarthy, thank you so much for joining us today.

MM: Hi. It's really my pleasure to be here. Thank you so much.

AS: Let's talk a little bit about acute mania. And one of the questions I'd like to ask is on a scale of 1 to 10, 1 being you're completely dissatisfied, 10 being you're completely satisfied, where would you rate your current level of satisfaction with the medications at your disposable for this disorder?

MM: Well, you know, acute mania is a psychiatric emergency, and we take it very seriously when we treat it. Fortunately, we have a lot of good options for acute mania. So my level of satisfaction is higher for mania than it is for a lot of other things in psychiatry. So I'm going to give it a 7 or — yes, we'll say a 7.

AS: Ok. And of the reason it's not a 10 is primarily due to what, efficacy, side effects, speed of onset? Where do you see the biggest unmet need in the space?

MM: Well, it's really all of the above in terms of the things you just mentioned. So let's start just with efficacy. So in terms of monotherapy, the response rates are typically around 50% at the end of a two- or three-week clinical trial. And so that's not bad. And the natural course of mania is to spontaneously resolve at some point anyway. So most of these patients eventually get better, but the efficacy leaves something to be desired. There's still about, you know, roughly 40% or 50% of patients who don't respond well to first-line antipsychotic or mood stabilizer treatments.

And then you mentioned tolerability. A lot of the medications that we currently use have really significant side effects that really across the spectrum of different kinds of things. So a lot of them are sedating and so patients can't really tolerate them for very long, especially when their mania starts to subside. They just become so tired or so sluggish that they can't really function on the medications.

Some of them cause neurological side effects like tremors or muscle rigidity or what we call extrapyramidal side

effects. And then others might be tolerable over the short term. But as patients transition out from mania and into maintenance, they develop long-term metabolic side effects like weight gain or glucose insensitivity that can put the patients at risk for things like diabetes or hypertension.

AS: Ok. So can you just walk us through briefly what your current treatment protocol is for these patients?

MM: Certainly. Well, as I mentioned before, we do regard mania as a psychiatric emergency. These patients often come in with severe psychosis. They may be agitated. They may be at risk for suicidal or violent behavior. They may be doing things that are very disruptive to their lives like spending tremendous amounts of money or ruining relationships or making big mistakes at work that are very detrimental. And so we're pretty aggressive with in terms of pharmacological maintenance. My personal practice is to usually go right to polypharmacy.

So there's clinical trial data that says that going with a second medication such as a mood stabilizer in addition to antipsychotics, so that could be antipsychotic plus lithium or antipsychotic plus DEPAKOTE gives you about a 20% higher likelihood of a response to treatment. So I would often go with an antipsychotic and then depending on the patient profile, either lithium or valproic acid.

And then perhaps even a third medication used on an as-needed basis, often a benzodiazepine to help with sleep or anxiety or agitation in addition to those first two medications. And so these patients often come in very agitated and very energized, and they're able to tolerate a lot of medication. And sometimes it requires two or even three medications to get adequate handle on the patient early on.

AS: Ok. So you provided a nice overview here of the unmet need. Let's talk about now the CAPLYTA data that just came out. So on September 21, just to repeat for our audience, J&J reported that the CAPLYTA 42 milligrams met its primary endpoint in Study number 451. This is the first of two Phase III trials in bipolar mania with or without mixed features.

The second trial, Study 452 is complete, but has not been reported. So the results, and we'll go point by point here, YMRS change at week three was a minus 4.8 of effect size, minus 0.69 with a very strong p-value of 0.0001 and the onset was separation from day three. Is this 4.8 point YMRS separation, a, clinically meaningful; and b, differentiated from what currently exists in the market?

MM: It's certainly clinically meaningful. It's — that reflects a true improvement over placebo and the effect size and the p-value substantiates that. This is a real effect and it's clinically meaningful. It's on the level of what we see with other antipsychotics that have been FDA approved for acute mania. So it's not strikingly different than others, but it's certainly in the same ballpark as what we see with a lot of other effective medications.

AS: Ok. And how significant or how meaningful is separation from day three forward in terms of onset of action?

MM: Yes. So that's another important point. Separating at day three is a nice finding for this drug. It certainly speaks to early onset of action and something that could potentially reduce the length of a hospitalization and potentially shorten the duration of treatment, which could have all kinds of positive benefits. It's not unique. Some of the other medications like olanzapine and risperidone also show day three separation. And so it's certainly a positive for lumateperone or CAPLYTA, but it's not unique.

AS: Ok. Two more data points to get your take on. The CGI-S score at week three was a minus 0.5, also very strong p- value — sorry, 0.0001. And then the responder rate, which they included responder as greater than or equal to a 50% YMRS reduction, 45.8% on drug versus 20.9% on placebo, your take on those two data points.

MM: Yes. So again, I would say that, that's squarely in kind of where we see other FDA-approved antipsychotic drugs

for acute mania. We typically see a pretty significant CGI response. This is the physician-rated improvement in mania or overall mental health. So that's not surprising to see that going down. And I'm sorry, what was the second part of that question?

AS: CGI-S score of negative 0.5 and a responder rate of 45.8% versus 20.9%.

MM: The responder rate. The responder rate is also sort of in that range where we typically see FDA-approved drugs for acute mania.

AS: Ok. And then in terms of what they've released in terms of safety and adverse events, dry mouth, 7.9%, nausea,

1. 9%, that's all we got. What do you make of those? What—

MM: I think that's where the trial really shines. I think CAPLYTA does stand out in that regard in terms of a benign side effect profile. So many of the other drugs that we see have very high rates of things like sedation that might be 20%, 25% or akathisia, which is like one of the movement disorders we talked about, which can also be 20%, 25%.

And so these are often disqualifying for patients over long periods of time. And so the absence of those kinds of more disqualifying or more uncomfortable kind of side effects from CAPLYTA really does have it stand apart from maybe some of the other drugs like olanzapine or risperidone that we are currently using commonly in the inpatient units.

AS: Ok. So that's sort of — you led to my next question. Obviously, we're waiting for the results of Study 452, but you know, how big a deal is this data in terms of, you know, if they get mania label on CAPLYTA, how would this change your — affect your usage of CAPLYTA?

MM: It would certainly improve my CAPLYTA standing on my algorithm. I think it would put it kind of squarely in the top in terms of onset of action. So it would be up there with risperidone and olanzapine in terms of rapidity of response at day three, and it would really help it kind of stand apart from some of the others in terms of tolerability. So it really is the best of both worlds type of situation.

I think the number one thing that would limit my use of it would still just be the widespread availability of generic drugs in this market. I think there are something like 15 other drugs that are all FDA approved for acute mania and the majority of them are generic. And so sometimes getting even if the drug is better, you know, getting the additional cost approved by a pharmacy or by a payor or an insurance program can sometimes be a challenge.

AS: Right. And I imagine a lot of these patients, correct me if I'm wrong, are in an inpatient or psychiatric setting or — is that correct?

MM: Yes, that's typically the case. Acute mania is often handled on an inpatient basis. It's not always the case, but these patients are often brought in by the police or brought in by a concerned family member because they're just not manageable at home. And so it quite often coincides with a hospitalization.

AS: Ok. So you mentioned that about 50% of patients don't respond adequately to existing therapy. So where would CAPLYTA fit? I mean you sort of alluded to it that there's still a lot of generics that it sounds like you use in front of this. But would this be your third-line agent, second-line agent? Where do you think you would use this? Would this drug get that entire 50% of patients who don't respond? Help us kind of understand, you know, where you think this drug would fit.

MM: Well, I think this drug would fit for me very well on a patient — for a patient who has a history of depressive relapses. And so because CAPLYTA is also FDA approved for bipolar depression, it's a little bit distinct from some of the other drugs that we use for acute mania. So let's use risperidone, for example, which is another antipsychotic drug. It does really well at day three in terms of acute mania. It has a response rate that's very similar to CAPLYTA, but

then it doesn't really do anything for bipolar depression.

So after the patient is done with their manic phase and you're ready to start thinking about a maintenance treatment or often the person converts into a depressive episode, you might have to then think about switching risperidone to a different medication that's going to cover depression more adequately.

Because CAPLYTA is well tolerated and also covers depression, you could conceivably start that medication for somebody during a period of acute mania and transition them through the manic phase into maintenance phase and then hopefully have depressive prophylaxis that's going to be well tolerated and something that the patient can continue on for long periods of time. So I think that, that combination of high tolerability with coverage for depression is actually a really important feature that distinguishes CAPLYTA from a lot of the other medications.

AS: Ok. Let's move on to some of the other drugs in development for mania and the next molecule is RAP-219. So RAP-219 is from Rapport Therapeutics is an AMPA receptor modulator selected for TARP-gamma8. This would be a non-dopaminergic approach to mania.

And what's interesting about this drug is already in Phase III for focal onset seizures, the mania trial, which is Phase II, which is a proof-of-concept, randomized, double-blind, placebo-controlled three-week inpatient study. So I guess the first question is here, you know, what do you want to see? This is obviously a proof-of-concept study, but did CAPLYTA just set the bar here for this drug?

MM: Well, so CAPLYTA certainly is going to set a high bar for other drugs to meet. But I wouldn't necessarily say that RAP-219 has to do as well as CAPLYTA in order to be a useful medication. And so I think this is a first-in-class novel mechanism trial, and I'm actually really excited to see how it reads out. I think if this does work, it really gives us a nice — another new path where we can approach acute mania from a completely different angle. And as I mentioned before, we're commonly using polypharmacy to approach acute mania.

We already use two drugs quite frequently. So we're using things like antipsychotic plus lithium or antipsychotic plus DEPAKOTE. And if this anti-glutamatergic pathway turns out to be fruitful, even if it's not quite as good as CAPLYTA or some of the other previously approved medications, the fact that it has a completely different mechanism may be great for tolerability. So there may be patients who are able to tolerate a glutamatergic drug that can't tolerate a dopamine receptor antagonist.

So for example, somebody with Parkinson's disease who's very sensitive to the neurological effect of dopamine blockade might be better able to tolerate a drug that works on the glutamate pathway. Or if there's a patient who's showing some partial response to an antipsychotic medication but needs a second medication or potentially even a third medication, having another mechanism available that you can target pharmacologically gives the physician a lot of flexibility in terms of alternate approaches to a nonresponder.

AS: Ok. So the endpoints here, primary endpoint is change in the YMRS scale from baseline to week three secondary endpoints is CGI-BP mania severity at week three. Safety is being followed out for eight weeks after the last dose. It's a pretty big trial, 253 patients, 56 sites. I think you just mentioned, I think I want to sort of drill down on this point here.

So it sounds like you're saying tolerability here because it's a novel mechanism could really differentiate this. So in other words, help us understand what you want — like would a 3-point separation from placebo be sufficient with better tolerability? Like how should we think about what a "win here" for this trial would look like in your eyes?

MM: Yes. I think a 3-point separation from placebo would be considered a win if the tolerability profile was good, was favorable. I know that's a little bit vague, but there's going to be some trade-off there. So the higher the tolerability,

the smaller the YMRS margin, I would be willing to tolerate and vice versa. So a medication that was showing a lot of tolerability issues and only wins by 3 points versus placebo might not necessarily be as big a win for — but as it would be if there was a better tolerability ratio there.

AS: Ok. And I think you sort of alluded to this before, but do you view — if this drug is supposedly non-sedating supposedly, do you think that could be an advantage or disadvantage in treating mania from your perspective?

MM: Well, it really depends on the patient. There are certainly medications like quetiapine or olanzapine that are highly sedating that are sometimes used specifically for the reason that the patient says that they can't sleep, and we're trying to induce sleep in a patient.

But more often than not, the patient at some point is going to have to leave the hospital and return to their normal life and be able to continue on the medication for some period of maintenance after the time the hospitalization is done. And so as a general rule, sedation is not necessarily always something that we want. So a non-sedating medication would be a really nice option to have in the treatment algorithm.

AS: Ok. And again, you alluded to this point earlier, but I mean, this would be obviously non-dopaminergic. Do you think providers like yourself would be comfortable using this drug as a monotherapy in acute mania without that dopaminergic component? Or do you think this would be used I mean it's being trialed as a monotherapy. And I guess we have to wait and see the data, but do you think this could be a monotherapy? Or do you think the role for this would probably be as an additional therapy as an add-on?

MM: No, I think there's certainly a reason to think that it could be an effective monotherapy as well, too. There's nothing in particular about the mechanism of action that would be disqualifying for me. Like there's nothing about dopamine that makes me think that I need to use a dopaminergic drug in particular, especially if the data look good.

AS: Ok. All right. Let's go on. There's another trial going on in mania. There's a lot, obviously, in mania. So Bristol Myers Squibb is testing COBENFY in mania, but here as an add-on to mood stabilizers, not as a monotherapy. Again, the main precedent is schizophrenia in the ARISE trial, adjunctive COBENFY showed a 2.0 point PANSS reduction versus placebo. It did not reach statistical significance.

But there is apparently good scientific rationale for muscarinic agonists and cholinergic agents, including some older studies in physostigmine and xanomeline for manic symptoms. Neurocrine is also — is an M4 selective agonist is in a Phase II mania trial at US sites, and they're expecting topline data from schizophrenia in Phase III and their mania in

The question for this section is whether muscarinic agonism, which has been, I think, proven in schizophrenia translates to mania. And what do you think the adjunctive design here on the part of COBENFY sort of suggests about expected efficacy? So I guess question first here, you know, what's your expectations here for — well, let's start here. Do you have any experience with COBENFY in schizophrenia?

MM: Let's start there. My experience with COBENFY in schizophrenia is relatively limited. I've been following it quite carefully, but I don't have a lot of firsthand experience using it.

AS: Ok. So again, just to go over the design here. So it's hospitalized patients with a manic episode with or without mixed features already on a therapeutic dose of lithium, valproate or lamotrigine, 424 patients, dosing is flexible. It's dosed twice daily up to 125 mg per 30 mg per kg. Primary is change in the YMR scale at week five, secondary CGI-BP at week five. How should we think about the results in schizophrenia relevant to mania? Does the data translate?

MM: Yes. Well, I think there's reason to be hopeful here and optimistic here. So neurobiologically, cholinergic

signaling typically inhibits dopamine signaling in the parts of the brain that we're most interested in for mania, like the ventral striatum. And so that kind of hyperdopaminergic activity is also what's driving psychosis in schizophrenia. And so there's good reason to think that there's overlap there between the biological systems underlying schizophrenia and the biological systems underlying mania.

So I think from a first principles approach, it certainly seems rational and the neuroscience and the neurobiology would support that approach is a good approach. We know just from experience that a lot of things that work in schizophrenia, other antipsychotic drugs also work in acute mania, almost all of them. So I think that there's good thinking here in terms of if COBENFY works in schizophrenia, it's quite likely that it would work in acute mania as well, too. So I think there's good rationale for doing the study.

In terms of the adjunctive approach, I think it's an interesting approach. I'm not entirely sure what the designers of the study were thinking there, but you could argue that it's a more conservative approach and that they're trying to show that there's some benefit here and some signal here in patients that have already responded to some extent to another mood stabilizer and that COBENFY would be able to get them over the line in terms of a final response. But it's probably a lower bar to cross than maybe a monotherapy where you're really relying on just one drug to make all the difference.

AS: Ok. We talked about now, you know, well, there's — we talked about CAPLYTA now, the RAP drug. We have COBENFY and the Neurocrine drug, which the Neurocrine drug is M4 selective agonist. If you could sort of, you know, we don't have the data for a lot of these, but sort of rank order what you're most interested in and how you see these drugs potentially playing out?

Because there's obviously — I mean, you said you had a 7 out of 10 satisfaction in the current treatment landscape. If you were to sort of rank order your excitement of these molecules, where do you put them?

MM: Well, let's — before I zoom in on the specifics, like the cholinergic approach is a really interesting approach because it bypasses a lot of the tolerability issues that traditional antipsychotics have with neurological side effects and metabolic weight gain. So it doesn't seem to have any of those side effects. Weight gain is a nonfactor and there aren't really any neurological side effects to talk about. So there's potential there for this cholinergic mechanism to bypass a lot of the side effects that we commonly face.

On the other hand, COBENFY has already kind of become known for some of its other side effects. So the cholinergic side effects, things cause things like nausea and digestive problems and can sometimes be upsetting to patients, and there's a certain number of patients that just can't tolerate them because of the acute nausea effects.

These effects tend to wear off over time as the — is the sort of the lore on the street about these drugs. So there is — if the patient — is patient with them and able to sort of titrate up the dose slowly, there's some potential for those drugs to be used in the longer term. But that actually makes me a little bit more excited about Neurocrine's approach, which is the M4 selective.

By involving fewer receptor systems, there's some possibility that maybe we could be more selective in terms of the muscarinic receptors that we're actually stimulating. And that could translate into fewer off-target effects and a more precise CNS effect that wouldn't involve the peripheral nervous system quite as much.

AS: Ok. This is the hardest round but — round that our — a lot of our listeners really want to know, and I know it's very difficult for you. But if you can make a prediction on a scale of 1 to 10 on these readouts, let's start with the RAP readout, the RAP-219. You said you sort of want to see about a 3-point separation from placebo with good tolerability. What's your likelihood on a scale of 1 to 10 that is — that works. I mean it's a Phase II trial — it's proof of concept.

Obviously, it's hard, but what's your gut telling you on that trial?

MM: It's hard to predict. I suppose you — you never lose money by being pessimistic, right? So I'm going to say less than 50-50, let's say, 40% chance. I'm going to say that a lot of things don't pan out that we hope for. But I think it's a realistic chance that it could work.

AS: Ok. And then what — the same thing, how would you sort of handicap the COBENFY Phase III as an adjunctive in mania? Do you think that — what's your likelihood that, that will be a positive trial on a scale of 1 to 10?

MM: I think that one is probably a better bet. I think that one is probably closer to 60%, something like that. I think that the efficacy that we see in schizophrenia is a pretty strong finding. I think that generally — or crosses over as a class. Those drugs that would do well in schizophrenia tend to do well in mania as well, too. So I'm a little bit more bullish on that one.

AS: Ok. And then I guess final question is how — obviously, you mentioned this in the beginning that there's a lot of generics in this space. What do you think the peak share that branded drugs could take, let's say, assuming these are all available on the market, and let's look at branded as a whole, you know, given the unmet need here, how big do you think branded could be in terms of percent penetration in the mania population?

MM: Yes. Well, it's a very crowded market. I believe the number of FDA-approved drugs stands at around 15 right now. And so if one or two of these become FDA approved as well, too, and that number goes up to 16 or 17, it's hard for me to imagine any one of these drugs capturing more than 10% or 20% of the market. I think it's going to remain a very crowded space.

AS: Dr. Michael McCarthy, I think we hit every single topic on this. Thank you for being available on short notice, and thank you so much for your time and expertise this afternoon. Afternoon for us. Obviously, morning for you. Really appreciate your time, sir. Thank you so much.

MM: I really appreciate it. Thanks so much.

AS: Take care, everyone. Bye.

MM: Bye-bye.

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