Drug Trials Snapshot: COBENFY
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the COBENFY Prescribing Information for all the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
COBENFY (xanomeline tartrate and trospium chloride)
co-BEN-fee
Karuna Therapeutics, Inc., a Bristol Myers Squibb company
Original Approval date: September 26, 2024
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
COBENFY is a combination of xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist, and is used for the treatment of schizophrenia in adults.
How is this drug used?
COBENFY is given as capsules by mouth twice daily.
Who participated in the clinical trials?
The FDA approved COBENFY based on evidence from two clinical trials of 470 adult patients with schizophrenia. The trials were conducted at 39 sites in the United States and Ukraine. There were 425 trial participants from the United States.
The efficacy of COBENFY (which is a measure of how well the drug works) was evaluated in two clinical trials for 470 patients with schizophrenia, and safety was assessed in the two trials in a total of 504 patients with schizophrenia who received at least one dose of COBENFY. The same trials were used to assess efficacy and safety. The number of patients representing efficacy findings differs from the number of patients representing safety findings due to different pools of study participants analyzed for efficacy and safety.
How were the trials designed?
COBENFY was evaluated in two clinical trials of 470 patients with schizophrenia.
In the trials, patients were randomly assigned to receive COBENFY or placebo, and neither patients nor care providers knew which treatment was given during the trial. Symptoms of schizophrenia were measured using a clinician-administered measure of schizophrenia symptoms called the Positive and Negative Syndrome Scale (PANSS). The benefit of COBENFY was assessed in both trials by determining the improvement in schizophrenia symptoms (the difference in PANSS scores before and after five weeks of treatment).
How were the trials designed?
Each trial consisted of a 5-week double-blind treatment period, during which patients with schizophrenia who were currently experiencing symptoms of psychosis (e.g., hearing voices, feeling as though others are out to get them) stayed at the hospital in an inpatient unit. All patients were between 18 to 65 years of age and had a prior diagnosis of schizophrenia with moderate to severe symptoms.
Each patient received either placebo or COBENFY for the entire 5-week period, and neither the patient nor their care providers were aware of the treatment assigned during the trial. Each patient received a starting dose of one 50 mg/20 mg capsule (contains 50 mg of xanomeline and 20 mg of trospium chloride) orally twice daily for at least two days. The dosage was increased to one 100 mg/20 mg capsule (100 mg xanomeline and 20 mg trospium chloride) orally twice daily for at least five days, and, if tolerated, the dosage was increased to one 125 mg/30 mg capsule (125 mg xanomeline and 30 mg trospium chloride) orally twice daily.
Each week patients were asked about their symptoms of schizophrenia and any side effects. At certain visits blood was drawn and a measure of heart function was taken to check for any changes in health. At the end of five weeks of treatment, the patient’s symptoms of schizophrenia were measured and compared to the symptoms reported before starting the trial. Patients receiving placebo were compared to patients receiving COBENFY to determine if COBENFY improves symptoms of schizophrenia.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many male and female patients were enrolled in the clinical trials used to evaluate the efficacy of COBENFY.
Figure 1. Baseline Demographics by Sex, Efficacy Population
Source: Adapted from FDA Review of Clinical Data
Figure 2 summarizes the percentage of patients by race who were enrolled in the clinical trials used to evaluate the efficacy of COBENFY.
Figure 2. Baseline Demographics by Race, Efficacy Population
Source: Adapted from FDA Review of Clinical Data
Figure 3 summarizes the percentage of patients by race who were enrolled in the clinical trials used to evaluate the efficacy of COBENFY.
Figure 3. Baseline Demographics by Race, Efficacy Population
Source: Adapted from FDA Review of Clinical Data
Figure 4 summarizes the percentage of patients by ethnicity who were enrolled in the clinical trials used to evaluate the efficacy of COBENFY.
Figure 4. Baseline Demographics by Ethnicity, Efficacy Population
Source: Adapted from FDA Review of Clinical Data
Who participated in the trials?
Table 1. Trial 1 Baseline Demographics, Efficacy Population
| Demographic | COBENFY N=117 | Placebo N=119 | Total N=236 |
|---|---|---|---|
| Sex, n (%) | |||
| Female | 30 (25.6) | 28 (23.5) | 58 (24.6) |
| Male | 87 (74.4) | 91 (76.5) | 178 (75.4) |
| Age, years | |||
| Mean (SD) | 45.9 (10.4) | 46.1 (10.8) | 46.0 (10.6) |
| Median (min, max) | 48.0 (31, 65) | 47.0 (20, 63) | 47.0 (20, 65) |
| Age group, years, n (%) | |||
| <45 | 45 (38.5) | 55 (46.2) | 100 (42.4) |
| ≥45 | 72 (61.5) | 64 (53.8) | 136 (57.6) |
| Age group ≥65 years, n (%) | |||
| ≥65 | 1 (0.9) | 0 | 1 (0.4) |
| Race, n (%) | |||
| White | 23 (19.7) | 31 (26.1) | 54 (22.9) |
| Black or African American | 91 (77.8) | 86 (72.3) | 177 (75.0) |
| Asian | 2 (1.7) | 0 | 2 (0.8) |
| Other or Not reported | 1 (0.9) | 2 (1.7) | 3 (1.3) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 12 (10.3) | 11 (9.2) | 23 (9.7) |
| Not Hispanic or Latino | 104 (88.9) | 107 (89.9) | 211 (89.4) |
| Not reported | 1 (0.9) | 1 (0.8) | 2 (0.8) |
| Region | |||
| United States | 117 (100) | 119 (100) | 236 (100) |
Source: Adapted from FDA Review of Clinical Data
Abbreviation: SD standard deviation
Table 2. Trial 2 Baseline Demographics, Efficacy Population
| Demographic | COBENFY N=114 | Placebo N=120 | Total N=234 |
|---|---|---|---|
| Sex, n (%) | |||
| Female | 35 (30.7) | 25 (20.8) | 60 (25.6) |
| Male | 79 (69.3) | 95 (79.2) | 174 (74.4) |
| Age, years | |||
| Mean (SD) | 43.7 (11.3) | 42.7 (12.4) | 43.2 (11.9) |
| Median (min, max) | 44.5 (19, 64) | 40.5 (19, 65) | 42.0 (19, 65) |
| Age group, years, n (%) | |||
| <45 | 57 (50.0) | 67 (55.8) | 124 (53.0) |
| ≥45 | 57 (50.0) | 53 (44.2) | 110 (47.0) |
| Age group ≥65 years, n (%) | |||
| ≥65 | 0 | 1 (0.8) | 1 (0.4) |
| Race, n (%) | |||
| Asian | 1 (0.9) | 0 | 1 (0.4) |
| Black or African American | 72 (63.2) | 70 (58.3) | 142 (60.7) |
| White | 41 (36.0) | 50 (41.7) | 91 (38.9) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 17 (14.9) | 11 (9.2) | 28 (12.0) |
| Not Hispanic or Latino | 97 (85.1) | 109 (90.8) | 206 (88.0) |
| Region, n (%) | |||
| United States | 95 (83.3) | 94 (78.3) | 189 (80.8) |
| Ukraine | 19 (16.7) | 26 (21.7) | 45 (19.2) |
Source: Adapted from FDA Review of Clinical Data
Abbreviation: SD standard deviation
What are the benefits of this drug?
In two trials, patients with schizophrenia who were given COBENFY achieved more improvement of schizophrenia symptoms after five weeks of treatment than patients given placebo.
What are the benefits of this drug (results of trials used to assess efficacy)?
In the two trials assessing efficacy of COBENFY, where the primary efficacy endpoint was the change from baseline in the PANSS total score at Week 5, COBENFY resulted in larger reductions than placebo in symptoms of schizophrenia over five weeks of treatment.
Table 3 summarizes efficacy results for the evaluated patients in the clinical trials. The primary efficacy endpoint was the change from baseline in the PANSS total score at the end of the treatment course (Week 5).
Table 3. Change From Baseline in PANSS Total Score at Week 5, Trial 1 and Trial 2, Efficacy Population
| Trial | Treatment Group | N | Mean Baseline Score (SD) | LS Mean Change From Baseline | Placebo-Subtracted Difference (95% CI) |
|---|---|---|---|---|---|
| Trial 1 | COBENFY | 117 | 98.2 (8.9) | -21.2 (1.7) | -9.6 (-13.9, -5.2) |
| Placebo | 119 | 97.7 (9.4) | -11.6 (1.6) | ||
| Trial 2 | COBENFY | 114 | 96.9 (8.8) | -20.6 (1.6) | -8.4 (-12.4, -4.3) |
| Placebo | 120 | 96.5 (8.8) | -12.2 (1.6) |
Source: COBENFY Prescribing Information
Abbreviation: CI, confidence interval; LS, least squares; N, number of participants in the efficacy population; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation; SE, standard error
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: COBENFY worked similarly in both males and females.
- Race: COBENFY worked similarly in White and Black or African American participants. However, the number of participants in other races was limited; therefore, differences in how well COBENFY worked in other races could not be determined.
- Age: Differences in how COBENFY worked in ages older than 65 could not be determined because all participants were adults younger than 65 years old.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Table 4 and Table 5 summarize efficacy results by subgroup based on the mean change from baseline in the PANSS total score. Of note, the comparisons were not powered to determine differences between demographic groups for changes in the PANSS Total Score.
Table 4. PANSS Total Score by Subgroup, Trial 1, Efficacy Population
| Subgroup | Parameter | Treatment Group | N | Mean Baseline Score (SD) | LS Mean Change From Baseline (SE) | Placebo-Subtracted Difference (95% CI) |
|---|---|---|---|---|---|---|
| Sex | Female | COBENFY | 30 | 97.9 (9.1) | -18.8 (3.4) | -9.1 (-18.9, 0.8) |
| Placebo | 28 | 99.4 (8.3) | -9.7 (3.6) | |||
| Male | COBENFY | 87 | 98.4 (8.9) | -21.8 (2.0) | -9.8 (-14.9, -4.7) | |
| Placebo | 91 | 97.2 (9.7) | -12.0 (1.8) | |||
| Race | Black or African American | COBENFY | 91 | 98.5 (8.5) | -23.3 (1.8) | -12.2 (-17.1, -7.2) |
| Placebo | 86 | 98.1 (9.3) | -11.2 (1.8) | |||
| White | COBENFY | 23 | 96.6 (10.6) | -14.4 (4.1) | -1.3 (-11.5, 9.0) | |
| Placebo | 31 | 96.2 (9.7) | -13.2 (3.3) | |||
| Ethnicity | Hispanic or Latino | COBENFY | 12 | 93.3 (9.4) | -17.0 (4.4) | -5.3 (-18.3, 7.7) |
| Placebo | 11 | 95.6 (10.0) | -11.7 (4.3) | |||
| Not Hispanic or Latino | COBENFY | 104 | 98.8 (8.8) | -20.6 (1.8) | -9.1 (-13.7, -4.4) | |
| Placebo | 107 | 97.9 (9.4) | -11.6 (1.7) |
Source: Adapted from FDA Review of Clinical Data
Abbreviation: CI, confidence interval; LS, least squares; N, number of participants in the efficacy population; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation; SE, standard error
Table 5. PANSS Total Score by Subgroup, Trial 2, Efficacy Population
| Subgroup | Parameter | Treatment Group | N | Mean Baseline Score (SD) | LS Mean Change From Baseline (SE) | Placebo-Subtracted Difference (95% CI) |
|---|---|---|---|---|---|---|
| Sex | Female | COBENFY | 35 | 99.4 (8.6) | -21.3 (3.1) | -5.8 (-14.6, 3.0) |
| Placebo | 25 | 97.8 (9.6) | -15.5 (3.2) | |||
| Male | COBENFY | 79 | 95.8 (8.6) | -20.3 (1.9) | -8.4 (-13.2, -3.6) | |
| Placebo | 95 | 96.2 (8.6) | -11.9 (1.9) | |||
| Race | Black or African American | COBENFY | 72 | 96.1 (8.6) | -20.8 (1.9) | -7.9 (-13.2, -2.7) |
| Placebo | 70 | 94.2 (8.0) | -12.9 (1.9) | |||
| White | COBENFY | 41 | 98.2 (9.0) | -18.8 (2.8) | -8.5 (-15.3, -1.8) | |
| Placebo | 50 | 99.8 (8.9) | -10.3 (2.5) | |||
| Ethnicity | Hispanic or Latino | COBENFY | 17 | 95.8 (6.4) | -4.7 (4.7) | 2.3 (-11.9, 16.4) |
| Placebo | 11 | 95.8 (10.2) | -6.9 (6.2) | |||
| Not Hispanic or Latino | COBENFY | 97 | 97.1 (9.11) | -21.8 (1.7) | -9.36 (-13.6, -5.1) | |
| Placebo | 109 | 96.6 (8.7) | -12.4 (1.6) |
Source: Adapted from FDA Review of Clinical Data
Abbreviation: CI, confidence interval; LS, least squares; N, number of participants in the efficacy population; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation; SE, standard error
What are the possible side effects?
The most common side effects seen in the clinical studies were nausea, dyspepsia, constipation, vomiting, high blood pressure, abdominal pain, diarrhea, increased heart rate, dizziness, and heartburn (also known as gastrointestinal reflux disease [GERD]).
What are the possible side effects (results of trials used to assess safety)?
The most common side effects seen in the clinical studies were nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and heartburn (also known as GERD). Other side effects observed in more patients receiving COBENFY as compared to placebo include dry mouth, sleepiness, blurry vision, drooling, dizziness upon standing, cough, and involuntary muscle movements or spasms.
Table 6 summarizes the adverse reactions that occurred in greater than 1% of patients and at a greater rate than placebo in Trials 1 and 2 combined.
Table 6. Safety Results, Trial 1 and Trial 2, Safety Population
| Adverse Reaction | COBENFY N=251 % | Placebo N=253 % |
|---|---|---|
| Nausea | 19 | 4 |
| Dyspepsiaa | 18 | 5 |
| Constipation | 17 | 7 |
| Vomiting | 15 | 1 |
| Hypertensionb | 11 | 2 |
| Abdominal painc | 8 | 4 |
| Diarrhea | 6 | 2 |
| Tachycardiad | 5 | 2 |
| Dizziness | 5 | 2 |
| Gastroesophageal reflux disease | 5 | <1 |
| Dry mouth | 4 | 2 |
| Somnolence | 3 | 2 |
| Vision blurred | 3 | 0 |
| Salivary hypersecretion | 2 | 0 |
| Orthostatic hypotension | 2 | 1 |
| Coughe | 2 | 1 |
| Extrapyramidal symptoms (EPS), non-akathisiaf | 2 | <1 |
| Akathisia | 1.6 | 0.8 |
| Hyperhidrosis | 1.6 | 0 |
| Hot flush | 1.2 | 0 |
| Pruritus | 1.2 | 0 |
| Throat irritation | 1.2 | 0 |
Source: COBENFY Prescribing Information
a Dyspepsia includes dyspepsia and esophageal discomfort
b Hypertension includes hypertension, blood pressure increased, labile hypertension, and orthostatic hypertension
c Abdominal Pain includes abdominal discomfort, abdominal pain upper, abdominal pain, abdominal pain lower, and abdominal tenderness
d Tachycardia includes tachycardia, heart rate increased, and sinus tachycardia
e Cough includes cough and productive cough
f EPS (non-akathisia) includes dyskinesia, drooling, dystonia, extrapyramidal disorder, muscle contraction involuntary, and muscle spasms
Were there any differences in side effects among sex, race, and age?
- Sex: The occurrence of side effects with COBENFY was similar in both males and females, although females reported slightly higher rates of nausea and constipation.
- Race: The occurrence of side effects with COBENFY was similar in White and Black or African American participants, although patients who were White reported slightly higher rates of nausea and vomiting. The number of participants in other races was limited; therefore, differences in how well COBENFY was tolerated in other races could not be determined.
- Age: Differences in side effects for COBENFY in ages older than 65 could not be determined because all participants were adults younger than 65 years old.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Table 7 summarizes the occurrence of adverse reactions by subgroup in the safety population for Trial 1 and Trial 2.
Table 7. Adverse Reactions by Subgroup, Safety Population
| Characteristic | All Patients | All Grades* | Grades 3 to 4* | |||
|---|---|---|---|---|---|---|
| COBENFY N=251 n (%) | Placebo N=253 n (%) | COBENFY N=251 n/Ns (%) | Placebo N=253 n/Ns (%) | COBENFY N=251 n/Ns (%) | Placebo N=253 n/Ns (%) | |
| Sex | ||||||
| Female | 69 (27.5) | 57 (22.5) | 54/69 (78.3) | 30/57 (52.6) | 5/69 (7.2) | 3/57 (5.3) |
| Male | 182 (72.5) | 196 (77.5) | 129/182 (70.9) | 107/196 (54.6) | 15/182 (8.2) | 8/196 (4.1) |
| Age group, years | ||||||
| ≥18 to <30 | 25 (10.0) | 25 (9.9) | 16/25 (64.0) | 11/25 (44.0) | 1/25 (4.0) | 2/25 (8.0) |
| ≥30 to ≤65 | 226 (90.0) | 228 (90.1) | 167/226 (73.9) | 126/228 (55.3) | 19/226 (8.4) | 9/228 (3.9) |
| Race | ||||||
| White | 71 (28.3) | 83 (32.8) | 51/71 (71.8) | 43/83 (51.8) | 5/71 (7.0) | 4/83 (4.8) |
| Black or African American | 176 (70.1) | 166 (65.6) | 128/176 (72.7) | 93/166 (56.0) | 13/176 (7.4) | 7/166 (4.2) |
| Asian | 3 (1.2) | 1 (0.4) | 3/3 (100) | 0/1 (0) | 1/3 (33.3) | 0/1 (0) |
| Other | 1 (0.4) | 2 (0.8) | 1/1 (100) | 1/2 (50.0) | 1/1 (100) | 0/2 (0) |
| Not reported | 0 (0) | 1 (0.4) | 0/0 (NA) | 0/1 (0) | 0/0 (NA) | 0/1 (0) |
| Ethnicity | ||||||
| Hispanic or Latino | 32 (12.7) | 24 (9.5) | 21/32 (65.6) | 12/24 (50.0) | 3/32 (9.4) | 3/24 (12.5) |
| Not Hispanic or Latino | 218 (86.9) | 228 (90.1) | 162/218 (74.3) | 124/228 (54.4) | 17/218 (7.8) | 8/228 (3.5) |
| Not reported | 1 (0.4) | 1 (0.4) | 0/1 (0) | 1/1 (100) | 0/1 (0) | 0/1 (0) |
Source: Adapted from FDA Review of Company data
* “Grades” refer to a five-grade system to indicate the severity of side effects, where grades 1 and 2 are mild/moderate, 3 and 4 are life-threatening/urgent intervention needed, and grade 5 is death.
Abbreviation: N, number of participants in the safety population; n, number with given characteristic; NA, not applicable; Ns, total number in each category
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.