What To Know About Cobenfy, First New FDA-Approved Treatment For Schizophrenia in Decades

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<p>On September 26th, 2024, the FDA <a href="https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia?os&ref=app" target="_blank" rel="noreferrer noopener">announced</a> approval for Cobenfy (xanomeline and trospium chloride) the first novel schizophrenia treatment for adults in over 30 years. </p>
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<p>Early Cobenfy proponents find this new medication exciting because it may diminish some of the <a href="https://medshadow.org/antipsychotic-side-effects/" target="_blank" rel="noreferrer noopener">adverse side effects</a> of currently available drugs. Right now, most antipsychotics that are prescribed for schizophrenia <a href="https://www.mountsinai.org/health-library/report/schizophrenia" target="_blank" rel="noreferrer noopener">work by blocking dopamine</a>, a chemical in the brain thought <a href="https://www.nhs.uk/mental-health/conditions/schizophrenia/symptoms/#:~:text=The%20symptoms%20of%20schizophrenia%20are,often%20appear%20emotionless%20and%20flat" target="_blank" rel="noreferrer noopener">to play a key role</a> in hallucinations and delusions. However, many of these medications <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556563/" target="_blank" rel="noreferrer noopener">are unhelpful when it comes to other</a> life-altering symptoms of schizophrenia, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041437/#:~:text=The%20negative%20symptom%20domain%20consists,(reduced%20experience%20of%20pleasure)." target="_blank" rel="noreferrer noopener">such as</a> a reduced experience of pleasure, decreased motivation, slowed speech, and decreased emotion. They also carry a long list of significant side effects, such as weight gain, metabolic changes, and movement disorders.</p>
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<p>Cobenfy, on the other hand, does not interact with the dopamine system. Instead, the xanomeline in Cobenfy acts as an M1/M4 agonist (stimulator), which means it works to stimulate acetylcholine muscarinic receptors, which are housed throughout the body and in the brain. These receptors <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006961/" target="_blank" rel="noreferrer noopener">have been shown</a> to modulate the brain circuits and physiology that are disrupted by schizophrenia, and are thought to be key drivers of both the psychotic and cognitive symptoms of the condition. (The addition of trospium is designed to minimize <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776782/" target="_blank" rel="noreferrer noopener">the noted adverse effects of xanomeline</a> when used alone, which include slowed heart rate, cardiac arrest, lowered blood pressure, digestive issues, bronchial spasms, and muscle twitching.) </p>
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<p>Additionally and most importantly, clinical trials suggest that Cobenfy may also improve the symptoms traditional antipsychotics can’t seem to touch.</p>
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<h2 class="wp-block-heading">Benefits of Cobenfy</h2>
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<p>Two phase-3 clinical trials are highlighted as evidence of Cobenfy’s efficacy. The <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2823%2902190-6/abstract" target="_blank" rel="noreferrer noopener">first phase-3 trial</a> lasted five weeks and included 251 individuals with schizophrenia based in the U.S. During this trial, individuals taking Cobenfy had statistically significant reductions of schizophrenia symptoms compared to placebo. The <a href="https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2818047" target="_blank" rel="noreferrer noopener">second phase-3 trial</a> also lasted five weeks and included 256 individuals living with schizophrenia from both the U.S and Ukraine. This trial also found statistically significant reductions in symptoms. </p>
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<p>It’s worth noting that both trials were funded by Karuna Therapeutics, which <a href="https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Completes-Acquisition-of-Karuna-Therapeutics-Strengthening-Neuroscience-Portfolio/default.aspx" target="_blank" rel="noreferrer noopener">was acquired</a> by Cobenfy’s manufacturing company Bristol Myers Squibb in March, 2024.</p>
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<p>“Due to its heterogeneous nature, schizophrenia is not a one-size-fits-all condition, and people often find themselves in a cycle of discontinuing and switching therapies,” explains <a href="https://www.segaltrials.com/about/physician-biographies/rishi-kakar/" target="_blank" rel="noreferrer noopener">Rishi Kakar</a>, M.D., chief scientific officer and medical director at Segal Trials and investigator in the EMERGENT program (which conducted the clinical trials), in a <a href="https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-COBENFY-xanomeline-and-trospium-chloride-a-First-In-Class-Muscarinic-Agonist-for-the-Treatment-of-Schizophrenia-in-Adults/default.aspx" target="_blank" rel="noreferrer noopener">press statement</a> put out by Bristol Myers Squibb. “The approval of Cobenfy is a transformative moment in the treatment of schizophrenia because, historically, medicines approved to treat schizophrenia have relied on the same primary pathways in the brain. By leveraging a novel pathway, Cobenfy offers a new option to manage this challenging condition.”</p>
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<h2 class="wp-block-heading">Side Effects of Cobenfy</h2>
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<p>While the evidence around Cobenfy sounds exciting, it’s essential for the public to realize that as with any emergent medication, the long-term effects of this drug are not yet known. In addition to the fact that both trials highlighted in Bristol Myers Squibb’s press release only lasted a combined 10 weeks and included a sample size of only 508 people, the longest this drug has been clinically studied in those with schizophrenia has currently only been <a href="https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-COBENFY-xanomeline-and-trospium-chloride-a-First-In-Class-Muscarinic-Agonist-for-the-Treatment-of-Schizophrenia-in-Adults/default.aspx#:~:text=two%20open%2Dlabel%20studies%20evaluating%20the%20long%2Dterm%20safety%20and%20tolerability%20of%20COBENFY%20for%20up%20to%20one%20year." target="_blank" rel="noreferrer noopener">one year</a>.  </p>
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<p>Research shows that many antipsychotic drugs become most effective at <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9702459/" target="_blank" rel="noreferrer noopener">seven to 12 months</a>, which is much longer than the highlighted clinical studies.</p>
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<p>“Although Cobenfy is being marketed and described by clinicians as a ‘revolutionary’ new treatment for schizophrenia, there are no ‘magic bullets’ for people diagnosed with schizophrenia, and clinicians should exercise caution when prescribing Cobenfy.” notes <a href="https://www.umb.edu/directory/lisacosgrove/" target="_blank" rel="noreferrer noopener">Lisa Cosgrove, Ph.D</a>. a clinical psychologist, professor, and Faculty Fellow at the Applied Ethics Center at the University of Massachusetts, Boston.</p>
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<p>“While the primary outcome measure [of the clinical studies] was the <a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3589309/" target="_blank" rel="noreferrer noopener">Positive and Negative Syndrome Scale (PANSS)</a>,” continues Dr. Cosgrove, “we need data on whether or not Cobenfy improves quality of life, which a PANSS score cannot tell us.”</p>
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<p>Cobenfy also comes with its own set of side effects. <a href="https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia?os&ref=app" target="_blank" rel="noreferrer noopener">According to the FDA</a>, this drug is not recommended for individuals with liver impairment, and there is a risk of liver damage. Because the kidneys do a lot of work when it comes to excreting Cobenfy, this medication is also not recommended for those with moderate to severe renal impairment.</p>
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<p>Cobenfy can also cause <a href="https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-COBENFY-xanomeline-and-trospium-chloride-a-First-In-Class-Muscarinic-Agonist-for-the-Treatment-of-Schizophrenia-in-Adults/default.aspx" target="_blank" rel="noreferrer noopener">urinary retention</a> and should not be given to people who are already living with this condition.</p>
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<p>Other risks, according to Bristol Meyers Squibb, include:</p>
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<li>Decreased gastrointestinal motility (which essentially means a slower digestion process)</li>
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<li>Angioedema (swelling that occurs under the skin) of the face, lips, tongue and larynx </li>
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<li>Issues in people with narrow-angle glaucoma</li>
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<li>Increased heart rate</li>
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<li>Central nervous system issues (such as dizziness, confusion, and hallucinations—which may prove difficult to assess in individuals already dealing with these symptoms due to schizophrenia)</li>
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<p>The most common side effects, listed in percentages in Bristol Meyers Squibbs’ first phase-3 clinical trial, include:</p>
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<li>Constipation (21%)</li>
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<li>Dyspepsia (indigestion) (19%)</li>
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<li>Nausea (19%)</li>
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<li>Headache (14%)</li>
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<li>Vomiting (14%)</li>
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<li>Hypertension (10%)</li>
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<p>Other reported side effects include:</p>
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<li>Abdominal pain</li>
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<li>Diarrhea</li>
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<li>Dizziness</li>
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<li>Gastroesophageal reflux disease</li>
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<h2 class="wp-block-heading">How Much Does Cobenfy Cost?</h2>
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<p>According <a href="https://time.com/7024352/fda-approves-new-schizophrenia-drug-cobenfy/" target="_blank" rel="noreferrer noopener">to a story in <em>Time</em> magazine</a>, representatives at Bristol Myers Squibb note that for individuals without insurance coverage, a monthly supply of Cobenfy will likely cost around $1,850, but “could” be lower for those who are insured.</p>
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<p>Schizophrenia is a chronic mental health disorder that can lead to disability, significantly impacting a person’s quality of life. Its symptoms can also often be highly personalized, meaning one drug or treatment may not work for every affected individual. Due to the side effects of older antipsychotic drugs, <a href="https://www.nature.com/articles/s41537-023-00356-x" target="_blank" rel="noreferrer noopener">medication adherence has remained a real issue</a> when it comes to treating this condition, which is why the FDA’s approval of Cobenfy has been so celebrated by experts. However, no medication—especially one that has only recently been approved—comes without side effects. </p>
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<p>“Before we hype this new drug,” cautions Dr. Cosgrove, “we should wait until we have more data” from ongoing studies assessing both tolerability and long-term safety. </p>
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