Immediate Impact

Emraclidine is an investigational medication being developed as a once-daily treatment for schizophrenia and psychosis related to Alzheimer’s disease, with no need for dose titration. It acts as a selective positive allosteric modulator (PAM) of the M4 subtype of muscarinic acetylcholine receptors in the brain. By targeting these M4 receptors, emraclidine could potentially help regulate excessive dopamine activity in the striatum without directly blocking dopamine D2 receptors. This selective mechanism may ease psychotic symptoms while avoiding interactions with dopamine, serotonin, or histamine receptors, which are thought to be responsible for many adverse effects of current antipsychotics.

The EMPOWER clinical program investigated the use of emraclidine in patients with schizophrenia during acute episodes through 2 placebo-controlled phase 2 trials, EMPOWER-1 and EMPOWER-2. These trials tested various dosing options to assess the drug’s therapeutic range. Additionally, a 52-week open-label extension study, EMPOWER-3, is evaluating the long-term use of emraclidine in individuals with schizophrenia whose symptoms are stable and who are not undergoing an acute psychotic episode.

On November 11, 2024, AbbVie announced that its phase 2 EMPOWER trials did not meet their primary endpoint of showing a statistically significant reduction (improvement) in the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo at week 6.​

"While we are disappointed with the results, we are continuing to analyze the data to determine next steps," said Roopal Thakkar, MD, AbbVie's executive vice president, research and development, chief scientific officer. "We would like to extend our gratitude to the study participants and their loved ones as well as to our network of clinical investigative sites for their participation in these trials. We are confident that our innovative pipeline will continue to bring meaningful therapies to patients, and we remain committed to finding better treatments for people living with psychiatric and neurological disorders.”​

Emraclidine was well-tolerated in the EMPOWER trials. Its safety profile was comparable to that observed in the phase 1b trial. The most common adverse events in EMPOWER-1 and EMPOWER-2, respectively, were headache (9.4% and 10.8% in placebo, 14.1% in EMPOWER-1 10 mg, 14.6% in EMPOWER-2 15 mg, and 13.2% and 13.0% in 30 mg), dry mouth (2.3% and 0.8% in placebo, 3.9% in EMPOWER-1 10 mg, 0.8% in EMPOWER-2 15 mg, and 9.3% and 5.3% in 30 mg), and dyspepsia (3.1% and 1.5% in placebo, 3.9% in EMPOWER-1 10 mg, 3.1% in EMPOWER-2 15 mg, and 7.8% and 2.3% in 30 mg).

Dr Cutler –

Importance to Science: 6
Importance to the Molecule: 9
Importance to the Medication class: 8 

I’m a little conflicted here. I think these were failed vs negative studies that are not truly informative about what this medicine can do. There were issues with execution and placebo response, and it is very likely that it was underdosed, as the previous company, Cerevel, did not adequately explore the dose range. This is why I rated it lower for science. It is obviously important for the molecule, as it could halt or even stop development. AbbVie needs to do a very careful post-mortem and hopefully will move ahead with new studies. Failed studies are not unusual in psychiatry, and some estimates are that up to 50% of our studies fail. They don’t usually fail because the drug doesn’t work, however. They usually fail because placebo worked too well, or the wrong dose was used, or because of a failure to select the correct patient population, or because of study execution errors (including too much emphasis on rapid enrollment, using the wrong sites or the wrong countries, having too many arms in the study, which inflates placebo response, etc). Of course, these results do raise 2 very important questions in my mind. First, emraclidine is selective for M4, which in preclinical models looks like an antipsychotic mechanism, but is a dual M1/M4 mechanism better for positive symptoms? I strongly believe that M1 adds significantly to efficacy, not only for positive symptoms, but especially for cognition (the original xanomeline study for cognition in Alzheimer’s Dementia was positive!), and maybe also for negative symptoms. Second, how important is agonism vs PAM? It is possible that agonism for muscarinic receptors is better, but we are also learning that binding to and activating muscarinic receptors is very complicated.   

As noted above, I have seen some companies stop development of a drug based on negative phase 2 studies like this, but I think there are lots of reasons to believe this mechanism and this drug should work, so I strongly believe they should do a careful post-mortem of these studies to learn as much as they can and move forward with new studies. I would also very much like to see higher doses studied, as this drug has been so well-tolerated and safe at the doses studied so far. 

This is very disappointing for the class of muscarinic agonists/PAMs, as it looked like emraclidine would be the second one to market after Cobenfy. With this failure, it is possible that Neurocrine’s drug will leapfrog this one. I think this throws a bit of damp water on the excitement and enthusiasm we all had for the muscarinic agents, but my hope is that this is only a speed bump and not a roadblock for the development of more muscarinic agents. From what I know so far (and I consult with AbbVie and have access to confidential information, which I will not disclose), there were issues with these studies that could have confounded the results. This includes issues of both design and execution, as well as the very real possibility that the drug was underdosed. This gives me some hope that AbbVie will make adjustments and move forward with new studies to further investigate emraclidine. 

I see very little impact on clinical practice or the market unless these failed studies give clinicians pause about the muscarinic mechanism of action or if investors get spooked. 

Dr Correll – 

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

It’s a huge upset that the phase 1B study results that were very positive and consistent with effect sizes for Cobenfy were not at all replicated, with a big placebo response and even some loss of change from baseline with emraclidine. But it was very safe, with no relevant adverse effects. 

Not all muscarinic modulators are created equal. Questions are raised whether M1 and M4 stimulation is superior to stimulation of only one of the muscarinic receptors, whether agonism is more powerful than a PAM mechanism, whether expectation bias worked against showing efficacy vs placebo with emraclidine, and/or functional unblinding worked for consistent results vs placebo with Cobenfy. 

It may take longer than anticipated to have several muscarinic modulators in the market for schizophrenia and beyond. Questions are raised whether M1 and M4 stimulation is superior to stimulation of only one of the muscarinic receptors, whether agonism is more powerful than a PAM mechanism, whether expectation bias worked against showing efficacy vs placebo with emraclidine and/or functional unblinding worked for consistent results vs placebo with Cobenfy. It will likely take longer than anticipated to have several muscarinic modulators in the market for SCZ and beyond. 

Dr Kunovac –

Importance to Science: 4
Importance to the Molecule: 7
Importance to the Medication Class: 4 

In light of the limited information provided (detailed study design, entry criteria, evolution throughout the study), it is assumed that the compound was not effective in reducing symptoms associated with schizophrenia. In the absence of an active control, it is not possible to determine if the studies are considered "failed" or negative." Therefore, the impact on science and the therapeutic class is limited. However, the impact on the specific molecule is significant as it clearly indicates that further investment is unlikely. 

This update quite negatively impacts how we should think about the molecule. It is unlikely that further investment would be attractive following these equivocal findings. The jury is still out on how this will impact the medication class, as it is difficult to generalize these findings to the entire class. The impact is minimal in the CNS therapeutic area. It is significant in schizophrenia, as it underlines the large heterogeneity among patients diagnosed with schizophrenia and the risk associated with drug development in this diagnosis. This update confirms the significant and urgent need to segment populations with a large heterogeneity in neuroscience. The impact on the antipsychotics market will be minimal as antipsychotics are widely used in different diagnoses and not limited to schizophrenia. 

Dr Mattingly – 

Importance to Science: 7 
Importance to the Molecule: 9 
Importance to the Medication Class: 7

The emraclidine EMPOWER 1 and 2 trials failed to separate from placebo in both phase 2 six-week schizophrenia trials. All doses—10, 15, and 30 mg per day—failed to separate from placebo on the PANSS total score at 6 weeks. As an M4 selective allosteric modulator, there was a great deal of hope that this molecule would offer a once-daily muscarinic agent for schizophrenia.  

The medication was well tolerated with minimal gastrointestinal side effects. Remaining questions include: Were the negative efficacy results due to being an allosteric modulator? Were the negative results specific to this molecule, or do they extend more broadly to the M4 class? Will M4 medications prove effective in other disease states (ie, cognition, neurodegeneration) and more broadly? Are M1/M4 modulators more effective than M4 selective molecules? On the positive side, emraclidine appeared safe with few gastrointestinal side effects.