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Discovery & Development Drug Delivery, Drug Discovery

Bringing a New MOA to the Table

Cerevel Therapeutics’ investigational treatment for both schizophrenia and Alzheimer’s disease psychosis passed a phase Ib trial with flying colors – mitigating side effects present in currently existing antipsychotics, while outperforming placebo.

We spoke with Erica Koenig, Vice President of Global Clinical Development at Cerevel Therapeutics, to learn more about emraclidine and the challenges of neuroscience research.

What is emraclidine?

Emraclidine is a highly M4-selective positive allosteric modulator that leverages the muscarinic pathway in development to treat schizophrenia and Alzheimer’s disease psychosis – disease areas that have not seen innovation in decades. It’s administered as a once-daily medication – without the need for titration – and has the potential to reduce psychotic symptoms without affecting the dopamine, serotonin, and/or histamine receptors, which underlie many of the unwanted side effects of current antipsychotics. 

What are the limitations of current drugs for schizophrenia?

Existing therapies primarily work by directly interfering with dopamine, serotonin and histamine receptors to varying degrees. In most cases, these existing therapies result in negative side effects such as weight gain, long-term metabolic effects, and extrapyramidal symptoms. Such side effects are also associated with non-adherence and high relapse rates, creating a vicious cycle of worsening symptoms and disease progression.

Treatment adherence is a primary challenge for people living with schizophrenia. Statistics suggest medication non-adherence is seen in nearly 50 percent of patients with schizophrenia; about one in three patients adjust their treatment dose; and nearly half stop their schizophrenia treatment without any guidance from their healthcare professional. Furthermore, up to 75 percent of those that discontinue their treatment will relapse within 12 to 18 months.

There is significant need for more therapies with novel mechanisms of action in the treatment of schizophrenia, such as the one we are bringing forth in emraclidine. By selectively targeting M4, we believe that emraclidine can change the landscape of schizophrenia treatment by reducing psychotic symptoms without the unwanted side effects of current drugs that often lead to non-adherence. 

What can you tell us about emraclidine’s phase Ib trial? 

The phase Ib trial was a two-part trial designed to assess the safety and tolerability of emraclidine in people living with schizophrenia. The first part was a multiple ascending-dose design to establish safety, tolerability, and appropriate dosing based on pharmacokinetics; the second assessed the safety and tolerability of emraclidine 30 mg once daily and 20 mg twice daily compared with placebo. After this, we released the trial’s subsequent data which showed a significant improvement with emraclidine in the positive and negative syndrome scale (PANSS; the standard assessment for the effectiveness of antipsychotic therapies) total score at six weeks.

Specifically, the 30 mg once daily dose improved the PANSS total score at six weeks by 12.7 points compared with placebo. We were also able to prove that emraclidine was not associated with extrapyramidal side effects and weight gain, and that selectively targeting the M4 receptor resulted in infrequent GI side effects, with rates similar to placebo. 

An additional risk-mitigating step for continued development per FDA guidance relates to blood pressure with chronic dosing in people living with schizophrenia. Our phase I ambulatory blood pressure monitoring trial provided clear evidence that emraclidine does not induce an increase in blood pressure. These results are promising, and we’re advancing emraclidine as a potential option for people living with schizophrenia, with a comprehensive phase II development program underway.

What are the main challenges in drug development within the neuroscience sphere?

The brain is vastly complex and we continue to learn more and more every day about its complex neurocircuitry. We’re spurred on by the unknown and the fact that we could make a real difference in the lives of patients with some of the most devastating neuroscience diseases. Historically, we have seen incredible medical innovations across many disease areas. It’s time for neuroscience to experience the same level of attention and subsequent progress as other fields.

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About the Author
Jamie Irvine

Associate Editor, The Medicine Maker

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