The Last Frontier of Medicine

The Chief Medical Officer of Cerevel Therapeutics shares how the company is applying deep expertise in neurocircuitry, targeted receptor subtype selectivity, and differentiated pharmacology to transform what is possible in neuroscience treatments.

Raymond Sanchez, M.D.

I began my career as a practicing clinician, treating people with some of the most devastating neurological and psychiatric diseases, including schizophrenia. Seeing patients who were unable to work, go to school, or maintain meaningful relationships was challenging, but witnessing some of them get swept away by psychosis into lives of poverty, homelessness, and even death led me to pivot into the life sciences industry. I knew that I wanted to move beyond clinical practice and into the development of new therapies to address the tremendous unmet patient need that I experienced on a daily basis. Ever since, I have proudly worked alongside some of the brightest scientists across the industry to deliver groundbreaking therapies for neuroscience diseases, but there is still work to be done.

The brain represents the last great frontier in medicine, and the need to address neuroscience diseases is one of the most challenging areas of drug discovery and development. Historically, the lack of deep understanding of the intricate functioning of the brain has resulted in too few therapeutic hypotheses being explored, and in turn, a lack of innovation in neuroscience. For years, studies have shown that medicines intended to treat disorders of the central nervous system (CNS) take longer to develop and are rejected at a higher rate than any other category by the U.S. Food and Drug Administration (FDA), leading many researchers and investors to focus their efforts on other conditions.¹

As the global population ages, we are witnessing a growth in mental health challenges – worsened by the COVID-19 pandemic – and the need to address neurological conditions has never been more urgent. Today, we stand at the cusp of a great flourishing of new treatment options – similar to what we have seen in prior decades in oncology, cardiovascular disease, and HIV/AIDS. This neuroscience renaissance provides new reasons to be optimistic, and to ensure this progress continues, we must take a dynamic approach to unlocking treatments that can transform what is possible in neuroscience.

Unlocking new treatment opportunities

In 2018, I was first introduced to Cerevel Therapeutics, a company created to focus specifically on unraveling the mysteries of the brain. The distinctive approach to our broad and diverse pipeline is backed by twenty years of research and investment by Pfizer. Our focus is to truly understand how the brain is wired, pursue novel targets and address specific receptor sub-types to provide enhanced therapies to those in need. I knew that Cerevel had the potential to be a unique enterprise in biopharmaceutical development, and I was proud to join the organization in January of 2019. Since this time, we have continued to take a deliberate and differentiated approach to treating neuroscience diseases in three key ways:

• Targeted neurocircuitry: We unlock new treatment opportunities by precisely identifying and targeting the neurocircuitry that underlies a given neuroscience disease.
• Receptor subtype selectivity: We selectively target only the receptor subtype(s) related to the disease physiology, to minimize undesirable off-target effects while maximizing activity.
• Differentiated pharmacology: We design full and partial agonists, antagonists and allosteric modulators that can precisely fine-tune the receptor pharmacology and neurocircuit activity without over-activation or over-suppression of the endogenous physiologic range.

This three-pronged approach enables us to develop highly specific and dynamic solutions to face challenges the neuroscience industry has attempted to address for years, supporting the underserved needs of patient communities.

Breaking new ground in the treatment of schizophrenia

First, let's look at schizophrenia, a challenging chronic condition that affects the thinking, emotions and behavior of an estimated 24 million people worldwide.² One of the leading theories on its etiology is that the overactivity of dopamine is strongly associated with psychotic symptoms. While current antipsychotics target a direct blockade of dopamine receptors to reduce symptoms, this also leads to significant side effects.

Our team is focused on developing emraclidine for the treatment of both schizophrenia and Alzheimer’s disease psychosis. Emraclidine was rationally designed as a positive allosteric modulator (PAM) that selectively targets the muscarinic acetylcholine 4 receptor subtype (M4) to harness potential anti-psychotic benefit while minimizing the side effects typically associated with pan-muscarinic agonists. Having a well-tolerated therapy is important to both physicians and patients to improve treatment adherence, a significant challenge due to the cyclical nature of the condition. Patients usually require lifelong antipsychotic maintenance, however, studies show that by the sixth month of treatment, 33% to 44% of patients have dropped out, and, by one year, as many as 59% have dropped out.^3,4,5,6 Emraclidine seeks to address this challenge by potentially improving tolerability compared to the current standard of care and hopefully leading to better treatment outcomes.

Advancing treatment of Parkinson’s disease

We are also exploring a next-generation therapeutic to support patients with Parkinson’s disease (PD). Over 10 million individuals are estimated to be affected by PD globally, and these numbers are only expected to grow with our increasingly aging population.⁷ Between 1990 to 2015, the number of people with PD doubled to over 6 million, and this number is projected to double again to over 12 million by 2040.⁸

Patients living with PD lose dopamine-producing neurons, which are believed to drive motor symptoms. Of the two dopamine receptor subtypes, D1/D5 receptors are expressed in a subset of neurons whose function is to modulate signaling from the thalamus to the cortex. This direct motor pathway is responsible for the appropriate initiation of motor activity. Our most advanced therapeutic candidate, tavapadon, is currently in development for the treatment of PD as a monotherapy in early-stage PD and adjunctive treatment to levodopa in late-stage PD. It was designed to selectively target and bind to dopamine D1/D5 receptor subtypes via the direct motor pathway, potentially driving motor benefit while minimizing side effects.

Transforming what is possible in neuroscience

At Cerevel, we are working to bring novel targeted therapies to market that can improve upon what is currently available to patients. Over the years, our team has continuously pushed boundaries and delivered data supporting the thesis of Cerevel. We have delivered positive data readouts for emraclidine for schizophrenia, which was recently published in The Lancet, and for darigabat, a selective GABA_A PAM, for anxiety. We are also committed to seeking new treatment options for Parkinson’s disease, epilepsy and other neuroscience conditions.

While it is difficult to know the true reach of our work, we know that the growing number of people impacted by neurological conditions is staggering. People are not simply seeking treatments, but the ability to be fully present in their own daily lives, unencumbered by their disease. Accordingly, it is not enough to simply focus on the portfolio we have today – we must ensure each new discovery helps us explore new frontiers, push new boundaries and inform the therapies that we develop. Only with this proactive and dynamic approach can we profoundly improve people’s lives.

As a physician, I have witnessed firsthand the need for our industry to do more for patients. This is why, at Cerevel, the patient is at the core of all our endeavors. By unlocking new knowledge, we will find ourselves closer to developing the treatments of tomorrow. Embracing this opportunity ahead of us, we can drive progress, develop next-generation therapies and transform the lives of people living with neuroscience diseases for decades to come.

____________________________

¹ Tufts Center for the Study of Drug Development (CSDD). November 2014. https://www.raps.org/regulatory-focus%E2%84%A2/news-articles/2014/11/report-finds-fda-slow-to-approve-cns-drugs,-but-getting-faster

² World Health Organization. Schizophrenia. 2022. https://www.who.int/news-room/fact-sheets/detail/schizophrenia

³ Peuskens J, Gillain B, De Graeve D, Van Vleymen B, Albert A. Belgian Schizophrenia Outcome Survey-results of a 2-year naturalistic study in patients stabilised on monotherapy with olanzapine, risperidone or haloperidol. Eur Psychiatry. 2009;24:154–163.

⁴ Perkins DO, Johnson JL, Hamer RM, Zipursky RB, Keefe RS, Centorrhino F, et al. Predictors of antipsychotic medication adherence in patients recovering from a first psychotic episode. Schizophr Res. 2006;83:53–63.

⁵ Robinson DG, Woerner MG, Alvir JM, Bilder RM, Hinrichsen GA, Lieberman JA. Predictors of medication discontinuation by patients with first-episode schizophrenia and schizoaffective disorder. Schizophr Res. 2002;57:209–219.

⁶ Perkins DO, Gu H, Weiden PJ, McEvoy JP, Hamer RM, Lieberman JA Comparison of Atypicals in First Episode Study group. Predictors of treatment discontinuation and medication nonadherence in patients recovering from a first episode of schizophrenia, schizophreniform disorder, or schizoaffective disorder: a randomized, double-blind, flexible-dose, multicenter study. J Clin Psychiatry. 2008;69:106–113.

⁷ Parkinson’s Foundation. “Who Has Parkinsons’s”. https://www.parkinson.org/understanding-parkinsons/statistics

⁸ Dorsey ER, Sherer T, Okun MS, Bloem BR. The Emerging Evidence of the Parkinson Pandemic. J Parkinsons Dis. 2018;8(s1):S3-S8. doi: 10.3233/JPD-181474. PMID: 30584159; PMCID: PMC6311367.