What Is KarXT?
KarXT, also known by the investigational brand name COBENFY KarXT, is a medication that combines two active compounds: xanomeline and trospium chloride. It is currently under investigation for its potential effects on various neurological and psychiatric conditions. While the specific mechanism of action is complex, studies involving KarXT have included assessments of episodic memory tasks and brain activity using PET scans.
KarXT is being studied as a potential treatment for conditions such as schizophrenia, psychosis associated with Alzheimer's disease, and irritability linked to autism spectrum disorder. Research into KarXT began with the first trial on 2022-08-23, and studies are ongoing, with the latest trial projected to conclude on 2026-05-06. Across 25 trials, KarXT has involved a total enrollment of approximately 15,200 participants.
Uses and Conditions Under Study
KarXT is currently being investigated across a range of neurological and psychiatric conditions. The majority of studies focus on severe mental health disorders and neurodegenerative conditions.
- Schizophrenia and Related Psychiatric Disorders: KarXT is most extensively studied for schizophrenia, with 7 trials specifically addressing this condition. An additional trial investigates broader psychiatric disorders. Schizophrenia is a chronic brain disorder that affects how a person thinks, feels, and behaves, and KarXT is being explored for its potential to manage symptoms.
- Alzheimer's Disease and Associated Psychosis: A significant number of trials, totaling 8 studies, are dedicated to Alzheimer's disease. These include trials for Alzheimer's disease itself (5 trials) and specifically for psychosis associated with Alzheimer's disease (3 trials). Alzheimer's disease is a progressive neurological disorder that causes the brain to shrink and brain cells to die, leading to memory loss and cognitive decline, and psychosis can be a distressing symptom.
- Irritability Associated With Autism Spectrum Disorder: KarXT is also under investigation in 2 trials for irritability associated with autism spectrum disorder. Autism spectrum disorder is a developmental disability that can cause significant social, communication, and behavioral challenges, including episodes of irritability.
- Memory Disorders: Studies are exploring KarXT for conditions affecting memory, including 1 trial for memory disorder and 1 trial for memory loss. These trials aim to assess KarXT's impact on cognitive functions, potentially building on observations from studies involving episodic memory tasks.
- Epilepsy: KarXT is being studied in 1 trial for epilepsy, a neurological disorder characterized by unpredictable seizures. This research explores its potential role in managing seizure activity or related neurological symptoms.
Beyond therapeutic uses, KarXT has also been administered to healthy volunteers in 2 trials. These studies typically assess the drug's safety, how it moves through the body (pharmacokinetics), and how the body reacts to it, rather than treating a specific condition.
Dosing
KarXT has been studied in various dosage forms and strengths across its clinical trials. The medication is primarily composed of xanomeline and trospium chloride, and these components are often specified in the dosing regimens.
Commonly studied strengths of KarXT include:
- Xanomeline 50 mg and trospium chloride 20 mg (also referred to as COBENFY KarXT (50/20 mg))
- Xanomeline 100 mg and trospium chloride 20 mg
- Xanomeline 125 mg and trospium chloride 30 mg
These doses have been investigated for conditions such as schizophrenia and autism-related irritability. Some studies have also explored KarXT in combination with an additional component, referred to as the KarX-EC Arm or KarXT+KarX-EC, or as an adjuvant therapy.
Administration methods vary by study, with some trials specifying doses to be taken on particular days or at specific times, such as 2 hours prior to an episodic memory task. Researchers have also assessed the impact of taking KarXT on an empty stomach versus with food to understand how food affects its absorption. The precise dosing schedule and whether KarXT is taken alone or as an adjuvant are determined by the specific clinical trial protocol.
Side Effects
The most common side effect reported by patients taking KarXT was nausea, affecting 9% of patients compared to 4% of those on placebo. Other common side effects included:
- Vomiting: 7% of patients taking KarXT experienced vomiting, compared to 2% on placebo.
- Dry mouth: 6% of patients taking KarXT experienced dry mouth, compared to 1% on placebo.
- Constipation: 6% of patients taking KarXT experienced constipation, compared to 2% on placebo.
- Headache: 10% of patients taking KarXT experienced headache, compared to 8% on placebo.
- Dyspepsia (indigestion): 3% of patients taking KarXT experienced dyspepsia, compared to 1% on placebo.
- Dizziness: 3% of patients taking KarXT experienced dizziness, compared to 1% on placebo.
- Somnolence (drowsiness): 2% of patients taking KarXT experienced somnolence, compared to 1% on placebo.
These side effects were generally mild to moderate in severity and typically resolved over time. A small percentage of patients (6% on KarXT vs. 3% on placebo) discontinued treatment due to side effects.
Clinical Trial Results
Clinical trials have evaluated KarXT for the treatment of schizophrenia in adults. The effectiveness of KarXT was primarily measured by changes in the Positive and Negative Syndrome Scale (PANSS) total score and the Clinical Global Impression – Severity (CGI-S) score. Lower scores on both scales indicate an improvement in symptoms.
Short-Term Efficacy Trials
Two key 5-week, placebo-controlled studies demonstrated the efficacy of KarXT. In these studies, patients received either KarXT or a placebo.
In the first study (NCT04012003), KarXT significantly improved symptoms of schizophrenia:
- Patients treated with KarXT experienced an average reduction of 8.4 points in their PANSS total score, compared to a 3.2-point reduction for those on placebo. This difference of 5.2 points was statistically significant (p<0.0001).
- For positive symptoms (e.g., hallucinations, delusions), KarXT led to an average reduction of 2.7 points on the PANSS Positive Symptom Subscale, compared to 1.2 points for placebo (p=0.0003).
- Patients on KarXT also showed an average improvement of 0.3 points on the CGI-S score, compared to 0.1 points for placebo (p=0.0006), indicating a greater overall improvement in illness severity.
The second study (NCT04012016) further supported these findings:
- Patients receiving KarXT showed an average reduction of 9.6 points in their PANSS total score, compared to a 6.0-point reduction for those on placebo. This 3.6-point difference was statistically significant (p=0.0029).
- On the PANSS Positive Symptom Subscale, KarXT resulted in an average reduction of 3.1 points, compared to 2.0 points for placebo (p=0.0029).
- An average improvement of 0.4 points on the CGI-S score was observed in patients on KarXT, compared to 0.2 points for placebo (p=0.0023).
Long-Term Safety and Efficacy
A long-term, open-label safety study (NCT04153123) involving 755 patients evaluated KarXT over 52 weeks. This study showed sustained symptom improvement and generally favorable long-term tolerability:
- Patients experienced an average reduction of 20.6 points in their PANSS total score by Week 52, suggesting continued improvement in symptoms over time.
- The average CGI-S score improved by 1.0 point at Week 52, indicating a sustained reduction in overall illness severity.
- Regarding metabolic parameters, patients experienced an average weight reduction of 0.7 kg, a systolic blood pressure reduction of 1.2 mmHg, a diastolic blood pressure reduction of 1.0 mmHg, and a heart rate reduction of 2.3 bpm at Week 52.
Currently Recruiting Trials
Several clinical trials are actively recruiting participants to further evaluate KarXT for a range of conditions. These studies aim to understand the drug's safety, effectiveness, and long-term impact across different patient populations.
- For individuals with schizophrenia, multiple Phase 3 studies are underway. NCT07288567, the EMERGENT TEEN study, is evaluating KarXT's efficacy and safety in adolescents, targeting an enrollment of 166 participants. Another Phase 3 study, NCT06882785, is assessing KarXT in acutely psychotic Japanese adults with schizophrenia, aiming for 250 participants. A long-term safety and tolerability study, NCT07424404, is also recruiting adolescents with schizophrenia and autism-related irritability, with a goal of 400 participants. Additionally, NCT07061288 is a Phase 1 study exploring the dose levels, safety, and drug levels of a single KarXT intramuscular injection in 48 participants with schizophrenia. A large real-world study, NCT07379827, is describing treatment patterns, effectiveness, and adverse events of KarXT in 1500 adults with schizophrenia.
- Several Phase 3 trials are investigating KarXT for symptoms associated with Alzheimer's Disease. For psychosis associated with Alzheimer's Disease, studies include NCT06947941 (targeting 325 participants), NCT06585787 (targeting 406 participants), NCT06126224 (targeting 500 participants), and NCT05511363 (targeting 410 participants). An open-label extension study, NCT05980949, is assessing the long-term safety and tolerability of KarXT in 800 participants with psychosis associated with Alzheimer's Disease. For agitation in Alzheimer's Disease, NCT06937229 is a long-term efficacy and safety study aiming for 600 participants. Two studies, NCT06976203 and NCT06976216, are evaluating KarXT's efficacy and safety for cognitive impairment in Alzheimer's Disease, each targeting 586 participants.
- For Bipolar-I Disorder, three Phase 3 studies are recruiting. NCT06951711 and NCT06951698 are both evaluating the efficacy and safety of KarXT for manic episodes, each aiming to enroll 274 participants. An open-label extension study, NCT06929273, is assessing the long-term safety of KarXT for manic episodes in 450 participants.
- Finally, NCT07118215 is a Phase 1 study involving 60 healthy adult volunteers to evaluate the effects of KarXT on the drug levels of other medications like midazolam, fexofenadine, and digoxin.
Where to Participate
Clinical trials for KarXT are widely accessible across the United States, with a substantial geographic reach. There are currently 479 study sites located in 227 cities across 37 states. Participants interested in joining a trial can find locations in major metropolitan areas and beyond.
The top recruiting locations include:
- Miami, Florida (82 sites)
- Hialeah, Florida (19 sites)
- Tampa, Florida (16 sites)
- Houston, Texas (12 sites)
- Orlando, Florida (12 sites)
- Miami Lakes, Florida (12 sites)
- Atlanta, Georgia (10 sites)
- Homestead, Florida (10 sites)
- Chicago, Illinois (10 sites)
- Anaheim, California (9 sites)
Eligibility for these studies is broad, welcoming participants of all genders. The age range for enrollment is from 5 to 90 years, and some studies are open to healthy volunteers, as well as children and adolescents.
Development Timeline
The development journey for KarXT began with its first clinical trial on August 23, 2022, and continues with studies projected until May 2026. Initially, the drug was explored for conditions such as IBS-C and hyperphosphatemia. However, the development pipeline quickly expanded into a significant focus on neuropsychiatric and neurological disorders.
Over time, the scope of investigation broadened to include Alzheimer's Disease and its associated symptoms like psychosis, agitation, and cognitive impairment. Studies also began for conditions such as Irritability Associated With Autism Spectrum Disorder, Epilepsy, Memory Disorder, Memory Loss, Psychiatric Disorders, Psychosis, Schizoaffective Disorder, Schizophrenia, Agitation, Seizures, and Bipolar-I Disorder with mania or mixed features. The drug's development has been primarily driven by Bristol Myers Squibb and Karuna Therapeutics, Inc., a Bristol Myers Squibb company, who have sponsored the majority of the 25 total trials conducted to date.
The program has progressed through various phases, with the majority of studies, 17, now in Phase 3, indicating advanced stages of clinical evaluation. This progression reflects a strategic expansion of KarXT's potential applications, moving from initial metabolic indications to a comprehensive exploration of its role in addressing complex neurological and psychiatric conditions.