Immediate Impact

NBI-1117568 is the first and only M4 selective orthosteric agonist in clinical development. There are 5 muscarinic acetylcholine receptors involved in neurotransmission. Muscarinic receptors are central to brain function and validated as drug targets in psychosis and cognitive disorders. As an M4 selective orthosteric agonist, NBI-'568 offers the potential for a novel mechanism with an improved safety profile without the need of combination therapy to minimize off-target pharmacology-related side effects, while also not being dependent on the presence of acetylcholine for efficacy.​

The phase 2, multicenter, randomized, double-blind, placebo-controlled, multi-arm, multi-stage inpatient dose-finding study was designed to assess the efficacy, safety, tolerability, and pharmacokinetics of NBI-'568 compared with placebo in adult subjects with a primary diagnosis of schizophrenia who are experiencing an acute exacerbation or relapse of symptoms. The study enrolled 210 participants.

On August 28, 2024, Neurocrine Biosciences announced that the once-daily 20 mg dose met the primary endpoint, demonstrating a statistically significant 7.5-point improvement (p=0.011, 0.61 effect size) in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo at week 6, with an 18.2-point PANSS total score improvement from baseline. ​

The once-daily 20 mg dose met additional endpoints, demonstrating statistically significant improvements in the Clinical Global Impression (CGI) of Severity Scale and the Marder Factor Score Positive Symptom Change and Negative Symptom Change.​

NBI-'568 was generally safe and well tolerated at all doses studied.​ The once-daily 20 mg dose efficacy, safety, and tolerability phase 2 results support advancement to phase 3 in schizophrenia in early 2025. ​

For more information about this study, visit ClinicalTrials.gov.

Dr Cutler –  

Importance to Science: 8
Importance to the Molecule: 9
Importance to the Medication Class: 9  

Despite the financial community being underwhelmed with these results and Neurocrine’s stock dropping as a result, this is a positive study for the 20 mg dose. The study used a very unusual adaptive design, where additional arms of increasing dose were added to the study once a lower dose demonstrated acceptable safety. I think the signal was lost for the higher doses based on this noisy design, which inflated placebo with each successive arm (dose). It is important because with the failure of AbbVie’s emraclidine phase 2 EMPOWER studies, Neurocrine’s muscarinic M4 agonist could now be second in line after BMS’s Cobenfy. This is very important to science and to the therapeutic class, not only because it further validates the muscarinic agonist mechanism, but it also demonstrates that M4 agonism alone (without M1) could potentially have antipsychotic efficacy. As this drug is described as an M4 agonist, and emraclidine as an M4 positive allosteric modulation (PAM), it also raises the question of whether agonism is more effective than PAM at muscarinic receptors. It is obviously critically important to the molecule, as it supports further development. 

I think the molecule suggests that it can be effective, although we need more studies to see if M4 agonism alone is as effective for all symptoms, including cognition and negative symptoms, as a dual M1/M4 agonist. Again, this is also important because it supports further development. Many studies in psychiatry fail, and this one was positive. This medication further validates muscarinic agonism, but also raises some questions, including the relative efficacy of an M4 vs dual M1/M4 mechanism for all of the symptoms of schizophrenia, and the relative importance of an agonist vs PAM mechanism. It is very exciting to have a new and very effective mechanism of action (MOA) after 70 years of D2 antagonism.  

I think it was a mistake to use this unusual adaptive study design. In phase 2, you want to keep the design very simple with as few arms as possible to maximize the chances of beating placebo, and you don’t want too much noise or too many bells and whistles. While I understand the rationale of not wanting to expose patients to higher doses until they have been established as safe, dose exploration should be done in phase 1 and not in a phase 2 efficacy study like this. I hope this is a cautionary tale of what not to do. 

This medication won’t have a lot of impact on practice or the market yet, other than perhaps to give some clinicians a little more confidence in this MOA, which might lead to more use of Cobenfy, which is the only muscarinic agonist on the market at this time. I think that it might also give investors a little more confidence to invest in companies with muscarinic drugs in development, after the pause that was caused by emraclidine’s failure in phase 2. 

Dr Correll –  

Importance to Science: 8 
Importance to the Molecule: 8 
Importance to the Medication Class: 8 

This is the first M4 agonist with positive phase 2 data vs placebo. The effect size of 0.6 for the 20 mg arm is consistent with Cobenfy. There were few side effects, no anticholinergics needed, no food effect, but 3 other doses were negative. The unclear dose-response relationship increases the risk of a lack of replication in phase 3.

Innovation may continue with different types of and differentiated muscarinic receptor activators having a potential role in the treatment of schizophrenia and beyond. Cobenfy is highly likely 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, with NBI 1117568 likely being the second in class to market should phase 2 results for the 20 mg dose be replicated.

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.

There is careful optimism that a second muscarinic agonist may become available, but potential problems with successful drug development remain. 

Dr Kunovac –  

Importance to Science: 7
Importance to the Molecule: 8 
Importance to the Medication Class: 8

The major knowledge gap regarding these data is the complete lack of evidence of a dose/response. Although the change observed with all doses is numerically superior to placebo, the probability of replication in a larger study remains low. The sponsor will need to 1) be convinced that this is not a "by chance" finding and 2) justify the dose(s) that will be used in the confirmatory study.  

The impact on the class, therapeutic area, and practice is relatively high, as the confidence in this mechanism of action is gaining credibility in the field. The therapeutic area remains quite attractive and is gaining momentum in neuroscience research. Muscarinic agonists are increasingly adopted for the management of schizophrenia. However, the concept of treating schizophrenia with nondopaminergic therapeutics is currently well established. 

Dr Mattingly –  

Importance to Science: 7 
Importance to the Molecule: 8 
Importance to the Medication Class: 8  

This phase 2 study of NBI-568 is a mixed blessing for the M4 class in schizophrenia. The 20 mg dose separated from placebo with an impressive 0.61 effect size. Of concern is that the 3 higher doses (40 mg, 60 mg, and 30 mg twice daily) did not separate from placebo.  

This may represent a true optimal dose effect for this M4 selective orthosteric agonist, but optimal dosing deserves further clarification. Of note, the 20 mg dose had an 18.2-point improvement in the overall PANSS and showed significant improvement in the CGI-Improvement and CGI–Severity scales for both positive and negative symptoms.   

Overall safety and tolerability were reported as favorable, with no new safety signals. Discontinuation rates due to adverse events were similar between NBI-568 and placebo. Adverse events with the highest incidence were somnolence, dizziness, and headache. Gastrointestinal adverse events were low in frequency and similar to placebo. Cardiovascular-related events were also low in frequency and were not deemed to have clinical relevance at any dose tested. NBI-568 was not associated with a greater increase in weight than placebo. Few extrapyramidal symptoms and adverse events were reported. All in all, this is a positive finding for this molecule and for the M4 class of medications.