New FDA approved drug for schizophrenia: xanomeline and trospium chloride = Cobenfy (formely KarXT).

[shoomer]

What does everyone think about this new medication? Interesting mechanism of action, with xanomeline being an M1/M4 central muscarinic agonist and trospium being the peripheral anticholinergic.

U.S. Food and Drug Administration Approves Bristol Myers Squibb’s COBENFY™ (xanomeline and trospium chloride), a First-In-Class Muscarinic Agonist for the Treatment of Schizophrenia in Adults

COBENFY represents the first new pharmacological approach to treat schizophrenia in decades, with a mechanism of action distinct from current therapies Approval is supported by data from the EMERGENT clinical program demonstrating statistically significant reductions of schizophrenia symptoms...

news.bms.com

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[Cath Up]

5 weeks seems like a pretty short trial period to approve a drug like this on. It’s cool it is effective with a new mechanism though. I look forward to prescribing it in 5-10 years.

 

[psych_0]

Effect size of 0.61 with less side effect burden that traditional antipsychotics? Can't imagine this isn't at least worth a try in patients you are confident will take oral meds.

 

[shoomer]

Effect size of 0.61 with less side effect burden that traditional antipsychotics? Can't imagine this isn't at least worth a try in patients you are confident will take oral meds.

Cost will be prohibitive for many patients unfortunately.

 

[Celexa]

I'm glad have more options and also the "this is revolutionary" rhetoric makes me roll my eyes and is deeply overblown. Particularly articles that say all current antipsychotics work through dopamine blockade, a patently untrue statement.

We'll see what the real world data ends up showing. It doesn't need to be revolutionary to be a much needed new addition to treatment options, if it actually works.

 

[tr]

I'm glad have more options and also the "this is revolutionary" rhetoric makes me roll my eyes and is deeply overblown. Particularly articles that say all current antipsychotics work through dopamine blockade, a patently untrue statement.

Don't they though, more or less (including partial agonism)?
Sure there are pleiotropic effects at other receptors that help with mood stabilization, etc, but the antipsychotic efficacy is usually still via reduction in dopaminergic activity.

This new drug also appears ultimately to work via reducing dopaminergic activity. It's just that the acetylcholine is upstream of the dopamine neuron.

Psychiatry Online

PsychiatryOnline.org is the platform for all American Psychiatric Association Publishing journals, DSM, and bestselling textbooks, as well as APA Practice Guidelines, and continuing medical education.

psychiatryonline.org

 

[Celexa]

Don't they though, more or less (including partial agonism)?
Sure there are pleiotropic effects at other receptors that help with mood stabilization, etc, but the antipsychotic efficacy is usually still via reduction in dopaminergic activity.

This new drug also appears ultimately to work via reducing dopaminergic activity. It's just that the acetylcholine is upstream of the dopamine neuron.

Psychiatry Online

PsychiatryOnline.org is the platform for all American Psychiatric Association Publishing journals, DSM, and bestselling textbooks, as well as APA Practice Guidelines, and continuing medical education.

psychiatryonline.org

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On a strictly technical level, pimavanserin is an antipsychotic with no dopamine receptor activity. And while it does have action at dopamine receptors, clearly it's dopaminerigc properties are not what makes clozapine work so often when other antipsychotics fail because if that was behind the efficacy it wouldnt so obviously separate itself specifically as an antipsychotic from all the others. So I view the 'OMG CAN YOU BELIEVE WE HAVE SOMETHING NEW' as nothing more than marketing hype. Which, to be clear, does not mean I think this drug won't be useful.

 

[Candidate2017]

Effect size of 0.61 with less side effect burden that traditional antipsychotics? Can't imagine this isn't at least worth a try in patients you are confident will take oral meds.

The only patients whom I'm confident are taking their oral meds, are stable. That's the problem. I (and my region's Cobenfy pharma rep) would not be opposed to increasing my clinical knowledge by prescribing Cobenfy to every psychotic patient I encounter over the next 3 months, but insurance and formularies will not approve. That's the other problem.

So, yes, I will look forward to Rx'ing this med in 5-10 years.

 

[Celexa]

The only patients whom I'm confident are taking their oral meds, are stable. That's the problem. I (and my region's Cobenfy pharma rep) would not be opposed to increasing my clinical knowledge by prescribing Cobenfy to every psychotic patient I encounter over the next 3 months, but insurance and formularies will not approve. That's the other problem.

So, yes, I will look forward to Rx'ing this med in 5-10 years.

There's stable and there's well, though. If this can be prescribed in combination with other antipsychotics, the patient population to start trying it with are patients who are stable but whose symptoms are not at goal--without taking them off their current antipsychotic. If everyone you have who is stable is truly at goal in terms of symptom resolution I salute you but I'm skeptical. Unless you're referring out everyone with true treatment resistance to the local academic center or whatever.

 

[Stagg737]

On a strictly technical level, pimavanserin is an antipsychotic with no dopamine receptor activity. And while it does have action at dopamine receptors, clearly it's dopaminerigc properties are not what makes clozapine work so often when other antipsychotics fail because if that was behind the efficacy it wouldnt so obviously separate itself specifically as an antipsychotic from all the others. So I view the 'OMG CAN YOU BELIEVE WE HAVE SOMETHING NEW' as nothing more than marketing hype. Which, to be clear, does not mean I think this drug won't be useful.

Is that true though? I posted the thread a while ago about the study that came out in Nature Neuroscience last year suggesting antipsychotic efficacy is more about balance between D1 and D2 receptor activity and clozapine does appear to have greater D1 receptor agonist activity than other antipsychotics.

That said, Cobenfy doesn't seem to have any dopaminergic activity that I could find with a quick google making me wonder if further studies for using it as an adjunctive treatment for other medications will also be done. Seems like a good path for BMS to study and expand their indications...

 

[TexasPhysician]

The studies make it look promising. We will see how it plays out in the real world.

 

[hamstergang]

Does anyone else hate the name? Just doesn't sound nice to my ears.

 

[Celexa]

Is that true though? I posted the thread a while ago about the study that came out in Nature Neuroscience last year suggesting antipsychotic efficacy is more about balance between D1 and D2 receptor activity and clozapine does appear to have greater D1 receptor agonist activity than other antipsychotics.

That said, Cobenfy doesn't seem to have any dopaminergic activity that I could find with a quick google making me wonder if further studies for using it as an adjunctive treatment for other medications will also be done. Seems like a good path for BMS to study and expand their indications...

I should have been more specific and said d2 antagonism. Most of the lay media articles are saying that this is the 'first antipsychotic that doesn't work through dopamine antagonism' or whatnot in part of their buying into it being revolutionary, and I find it irksome lol.

 

[ObsequiousAplomb]

I should have been more specific and said d2 antagonism. Most of the lay media articles are saying that this is the 'first antipsychotic that doesn't work through dopamine antagonism' or whatnot in part of their buying into it being revolutionary, and I find it irksome lol.

I've also seen a lot of "first new medication for schizophrenia in 30 years" which is just patently untrue.

 

[Stagg737]

I should have been more specific and said d2 antagonism. Most of the lay media articles are saying that this is the 'first antipsychotic that doesn't work through dopamine antagonism' or whatnot in part of their buying into it being revolutionary, and I find it irksome lol.

I've also seen a lot of "first new medication for schizophrenia in 30 years" which is just patently untrue.

True. Honestly, I'm more excited about TAAR-1 agonists as I feel like that is actually a more novel therapeutic approach. Either way, it's good to see more non-dopaminergic or at least Non-D2 antagonist options coming out. I feel like even the potential for an effective treatment that doesn't has all the EPS risk would be a huge step.

 

[Merovinge]

True. Honestly, I'm more excited about TAAR-1 agonists as I feel like that is actually a more novel therapeutic approach. Either way, it's good to see more non-dopaminergic or at least Non-D2 antagonist options coming out. I feel like even the potential for an effective treatment that doesn't has all the EPS risk would be a huge step.

Absolutely. Drug companies can suck and do shady things, but also bring about wonderful things that help a lot of people. Patients' with psychiatric disorders often get overlooked, and there are so many difficulties in the drug development process, that I am always grateful when we see "new" things.

 

[Mad Jack]

The only patients whom I'm confident are taking their oral meds, are stable. That's the problem. I (and my region's Cobenfy pharma rep) would not be opposed to increasing my clinical knowledge by prescribing Cobenfy to every psychotic patient I encounter over the next 3 months, but insurance and formularies will not approve. That's the other problem.

So, yes, I will look forward to Rx'ing this med in 5-10 years.

I've got so many treatment-resistant patients that come through my doors that I might be able to get it approved in some of the ones that fail clozapine for whatever reason. I'll report back

 

[Cath Up]

That brings up a good point. Would anyone approve this before a Clozaril trial? That actually presents a really interesting conundrum in my eyes. Could this lead to less Clozaril usage (which is often well tolerated despite its side effect profile) and ultimately result in fewer people getting to a med they would respond better to? We know shorter time to Clozaril is associated with more favorable response. Or will this med only be approved by insurance after Clozaril, and have too much gate-keeping to be widely useful?

I highly doubt we will have a reliable way of determining best response for Cobenfy vs Clozaril. I'm curious where it will fit into a general paradigm/algorithm. Maybe SGA->M1/4 agonist->Clozaril? Perhaps it will be a good option for patients who cannot tolerate the unnecessary Clozaril REMS lab draws/visits, though I think REMS might change in the not so distant future.

 

[MedMan80]

Should've kept it KarXT

 

[ObsequiousAplomb]

That brings up a good point. Would anyone approve this before a Clozaril trial? That actually presents a really interesting conundrum in my eyes. Could this lead to less Clozaril usage (which is often well tolerated despite its side effect profile) and ultimately result in fewer people getting to a med they would respond better to? We know shorter time to Clozaril is associated with more favorable response. Or will this med only be approved by insurance after Clozaril, and have too much gate-keeping to be widely useful?

I highly doubt we will have a reliable way of determining best response for Cobenfy vs Clozaril. I'm curious where it will fit into a general paradigm/algorithm. Maybe SGA->M1/4 agonist->Clozaril? Perhaps it will be a good option for patients who cannot tolerate the unnecessary Clozaril REMS lab draws/visits, though I think REMS might change in the not so distant future.

I wonder that with every antipsychotic that comes out. Are they all just options that prevent clozapine?
Why would insurance approve it for after clozapine? Is there evidence that it is effective in the post-clozapine population?

I imagine it would be approved after trying 6/6 atypical antipsychotics from a list, and clozapine would not be one of the ones on the list. Risperdal, Seroquel, Abilify, Geodon, Zyprexa, Latuda, and at least one from a list of typical antipsychotics.

 

[Merovinge]

I wonder that with every antipsychotic that comes out. Are they all just options that prevent clozapine?
Why would insurance approve it for after clozapine? Is there evidence that it is effective in the post-clozapine population?

I imagine it would be approved after trying 6/6 atypical antipsychotics from a list, and clozapine would not be one of the ones on the list. Risperdal, Seroquel, Abilify, Geodon, Zyprexa, Latuda, and at least one from a list of typical antipsychotics.

Ergh, are we really doing both Geodon and Latuda? Maybe in bipolar depression there is an appreciable difference with Latuda being superior, but has anyone seen a difference in primary psychosis?

 

[ObsequiousAplomb]

Ergh, are we really doing both Geodon and Latuda? Maybe in bipolar depression there is an appreciable difference with Latuda being superior, but has anyone seen a difference in primary psychosis?

Latuda at 120-160 mg has been helpful for many of my state hospital patients I treated in residency. I've seen plenty of patients do better with Latuda than they did with Zyprexa or Invega.

I was making up a hypothetical ****ty formulary requirement, I wasn't saying what I would do clinically.

 

[aim-agm]

I was making up a hypothetical ****ty formulary requirement, I wasn't saying what I would do clinically.

Well, now you are going to have to do that clinically. Insurance companies have never seen a ****ty formulary requirement they didn't like.

 

[sighchiatry]

Marketing is effective.
I now have patients specifically requesting this medication by name.
I can't even find it (or the generic) in my prescribing software.

 

[FatherPsychiatry]

Lets see what happens but I'm not expecting much given psychiatry's track record with groundbreaking pharmaceuticals. Everything has been marketing hype so far, for pretty much all psych meds. No antipsychotic really superior to Haldol / Clozaril, antidepressant better than Prozac or even an MAOI, or 'mood stabilizer' better than lithium. People have their own idiosyncratic experiences with something being better than something else or somesuch while waving their hands around about this or that receptor. Every now and then a "study" pops up showing something is better, and it turns out to be un-impressive in the end.

Lets get some REXULTI up in here!!

 

[Merovinge]

Lets see what happens but I'm not expecting much given psychiatry's track record with groundbreaking pharmaceuticals. Everything has been marketing hype so far, for pretty much all psych meds. No antipsychotic really superior to Haldol / Clozaril, antidepressant better than Prozac or even an MAOI, or 'mood stabilizer' better than lithium. People have their own idiosyncratic experiences with something being better than something else or somesuch while waving their hands around about this or that receptor. Every now and then a "study" pops up showing something is better, and it turns out to be un-impressive in the end.

Lets get some REXULTI up in here!!

That's true for the core pathology the medications were meant to treat but glossing over some huge points.

MAIOs are dramatically more of a pain to take than SSRIs and way less well tolerated/adhered to. They are also much scarier in OD.

Haldol and Clozaril are both much less well tolerated than newer atypicals and many antipsychotics have amazing efficacy in bipolar disorder which is certainly not the case for Haldol. There is also a lot to be said about Abilify/risperidone for ASD/mod to severe ID aggression compared to those medications.

Lithium is clearly still the gold standard as a mood stabilizer, but again the atypicals have absolutely changed the life experience for patient's with bipolar disorder.

Even small changes like getting XR versions of guanfacine and clonidine have made a huge difference in child psychiatry (particularly being generic). There really have been lots of small wins over the years for psychopharmacology and I do expect that to continue. Of course, everything is overhyped and needs a discerning eye so I do absolutely agree with the overall premise. You don't get your private jet bonus as the pharma ceo unless you can tell a wicked narrative.

 

[ObsequiousAplomb]

I wonder that with every antipsychotic that comes out. Are they all just options that prevent clozapine?
Why would insurance approve it for after clozapine? Is there evidence that it is effective in the post-clozapine population?

I imagine it would be approved after trying 6/6 atypical antipsychotics from a list, and clozapine would not be one of the ones on the list. Risperdal, Seroquel, Abilify, Geodon, Zyprexa, Latuda, and at least one from a list of typical antipsychotics.

I got it covered for someone today. The form only asked for 3 medications tried already.

 

[Cath Up]

I got it covered for someone today. The form only asked for 3 medications tried already.

Omg. Nice. Might have to look for candidates.

 

[Stagg737]

Anyone else had someone on this for more than a couple of weeks? I haven't gotten to try it yet and probably won't for a while d/t my position, but would love to hear how patients are doing with this.

 

[ObsequiousAplomb]

Anyone else had someone on this for more than a couple of weeks? I haven't gotten to try it yet and probably won't for a while d/t my position, but would love to hear how patients are doing with this.

I haven't had my followup yet, but I'll be sure to report anything. He sent an EHR message saying by day 6 he hadn't noticed any side effects at all yet, so there's that.

This was my first time writing an oral medication within the month it was first marketed. I was early to the game for Uzedy, but the pharmacist did the PA work for me at that gig.

I was surprised to get a call just now from a drug representative for BMS who got my number off Google. Apparently he and his boss had been trying to figure out who I was because I "wasn't on their radar" but they learned I had written a prescription. They asked me how I had gotten it approved.

A little unsettling to remember that reps know every doctor who writes a prescription for their drugs / knows it was written.

 

[ObsequiousAplomb]

I haven't had my followup yet, but I'll be sure to report anything. He sent an EHR message saying by day 6 he hadn't noticed any side effects at all yet, so there's that.

This was my first time writing an oral medication within the month it was first marketed. I was early to the game for Uzedy, but the pharmacist did the PA work for me at that gig.

I was surprised to get a call just now from a drug representative for BMS who got my number off Google. Apparently he and his boss had been trying to figure out who I was because I "wasn't on their radar" but they learned I had written a prescription. They asked me how I had gotten it approved.

A little unsettling to remember that reps know every doctor who writes a prescription for their drugs / knows it was written.

It didn't help. We're going to clozapine 6 weeks later than we were planning before this came out.

 

[Cath Up]

It didn't help. We're going to clozapine 6 weeks later than we were planning before this came out.

Did you go up to 125/30 BID?

 

[ObsequiousAplomb]

Did you go up to 125/30 BID?

No. I suppose I could go higher. Still haven't met with him, I've just had a frantic call from his therapist.

Have you gone up to that dose yet?

 

[Cath Up]

No. I suppose I could go higher. Still haven't met with him, I've just had a frantic call from his therapist.

Have you gone up to that dose yet?

Not yet. Medicare leaves a pretty hefty bill for it so we are doing it pretty slow for my patient, still at 50/20 and around $100/month for that, more for 100/30.