Dr Cutler –

Importance to Science: 10
Importance to the Molecule: 10
Importance to the Medication Class: 10

This one is easy and pretty obvious. This is the first new mechanism of action (MOA) for a drug approved to treat schizophrenia in literally over 70 years. All others are D2 antagonists (even D2 partial agonists, which function as antagonists with a little bit of intrinsic agonism). Also, the M1 agonism predicts efficacy for cognitive impairment and possibly for negative symptoms, both of which are the holy grails of schizophrenia treatment, because they are much more related to functional impairment than are positive symptoms, and D2 antagonists/partial agonists are much better at treating positive symptoms then cognitive impairment or negative symptoms. Also, the efficacy demonstrated in 3 out of 3 clinical trials was very robust, with some of the highest effect sizes ever seen for an antipsychotic. A post-hoc analysis of patients with at least 1 standard deviation below normal in cognition showed clear efficacy for cognition. A pooled post-hoc analysis of the 3 studies suggested efficacy for negative symptoms.

As for tolerability, the addition of trospium to mitigate the peripheral muscarinic cholinergic side effects was inspired and actually does significantly improve tolerability, although there can be some initial gastrointestinal issues, but I believe they can be further mitigated by careful dosing. As for safety, there is simply nothing else like it. It has no signal for the safety issues associated with other antipsychotics, including weight gain, metabolic dysregulation, prolactin elevation, or drug-induced movement disorders (eg, extrapyramidal symptoms, akathisia, tardive dyskinesia), and there are no warnings about any of these in the label. By the way, the word “antipsychotic” does not appear anywhere in the label. While it clearly has efficacy to treat psychosis, it is not considered in the same class as the other so-called “antipsychotics” and therefore did not inherit all of the class warnings and precautions, including no bolded boxed warning. This is whatever cliché or platitude you want to use: “Game changing,” “a paradigm shift,” “a new generation,” etc.

For the molecule specifically, getting US Food and Drug Administration (FDA) approval is the whole ballgame. Nothing is more important than getting an initial approval or an approval for a new indication. This medication validates the MOA and the class, and it will spur much more research, development, and investment. This is absolutely groundbreaking and game-changing for the therapeutic area. The studies leading to its approval were some of the best-designed and executed studies I have seen in over 30 years as an investigator conducting clinical trials. I hope others will learn from these and follow this model. I am also impressed that a study of Cobenfy as an adjunct to other antipsychotics for partial response is being conducted (full disclosure: I consulted on the design of this ARISE trial).

While some clinicians might be reluctant to use a medicine with a new, unfamiliar, and to them unproven MOA, I believe that once they try it in some patients, they will see the robust efficacy across a range of symptoms, as well as the very favorable and unique long-term safety profile. I think clinicians will use it in many situations and in various combinations with other medicines, and they will figure it out. I think eventually this will be a blockbuster drug with a very significant impact on the market as the first of a whole new class of psychiatric medications. This moment is analogous to when Prozac or Risperdal were approved.

Dr Correll – 

Importance to Science: 10
Importance to the Molecule: 10
Importance to the Medication Class: 10

This is the first non-D2 receptor antagonist approved and available for the treatment of schizophrenia. The approval gives this a 10, but the molecule itself has issues (rating = 7) due to twice-daily (BID) dosing. Patients need to take the medication without food, and there is the presence of pro- and anticholinergic side effects.

This medication is an innovative, paradigm shift from non-selective, postsynaptic D2 blockade to selective presynaptic D2 release control. This is the beginning of a series of muscarinic modulators for the treatment of psychosis and other disorders or conditions where too much D2 release is part of the pathophysiology. Modulation of M1 and M4 agonism and PAM approaches, targeting both M1 and M4 or one in isolation, will tell us a lot about targeted pharmacotherapy for psychosis, partial non-responders, cognition, and beyond.

This is an innovative disruption in the market, with availability of a truly different MOA, potential for rational polypharmacy, and hopefully benefits for patients currently not served well by currently available D2 antagonists. There is possibly an ability for the treatment of cognition and, possibly, even treatment-resistant patients.

Dr Kunovac –

Importance to Science: 8
Importance to the Molecule: 9
Importance to the Medication Class: 9
 
This update had a major impact on the therapeutic area that has always used dopaminergic/serotoninergic antagonists for the treatment of schizophrenia and many psychiatric disorders. It remains to be shown whether this class will be effective in disorders other than schizophrenia. 

This update will significantly impact the way we think about this molecule, as it will start a new era of therapeutics in schizophrenia. It is the first different class of medication since the late ‘80s. Schizophrenia is a heterogeneous illness, and there is a potential for the effectiveness of different classes of medication. Despite numerous failures of different classes in the treatment of schizophrenia, the field should continue to think out of the box.

Dr Mattingly – 

Importance to Science: 9
Importance to the Molecule: 10
Importance to the Medication Class: 10

September 26, 2024, marked a historic date for the neuroscience field with the FDA approval of the first muscarinic agent for the treatment of schizophrenia.
As an M1/M4 muscarinic modulator of presynaptic dopamine release, this represents a novel approach to schizophrenia treatment and overall management. Important notable findings are that the FDA did not use the term “antipsychotic” and attached no boxed warnings to the label. In addition, the weight, metabolic, and movement disorder findings were very favorable for the molecule.

Limitations include the need for BID dosing without food and the gastrointestinal side effect profile. There are no contraindications for the concomitant use of Cobenfy with standard dopamine receptor modulating antipsychotics, but one would anticipate the need to use it with increased caution with a medication that has significant anticholinergic properties. All in all, this marks a major milestone for patients with schizophrenia, for the class of muscarinic agents, and for the field.