COBENFY
KarXT; xanomeline and trospium chloride
In the midst of a number of setbacks for emerging schizophrenia treatments (e.g., Acadia Pharmaceuticals Inc’s pimavanserin and Minerva Neurosciences Inc’s roluperidone), the approval of COBENFY represents a transformative moment for schizophrenia treatment. It is the first drug approved with a novel mechanism of action for schizophrenia in more than 30 years. Using a fragment-drug conjugate (FDC) of xanomeline and trospium, COBENFY selectively targets M1 and M4 receptors, rather than the traditional dopamine pathways, using the xanomeline component, while the trospium chloride component is a muscarinic receptor antagonist that does not appreciably cross the blood-brain barrier (BBB) and minimizes cholinergic side effects of xanomeline outside the brain. At present, there is not enough data to make definitive conclusions about COBENFY’s use in psychosis related to Alzheimer’s disease (AD). However, if the results show effectiveness in treating hallucinations and delusions associated with AD psychosis, the drug is anticipated to have strong commercial potential.
About COBENFY
- Karuna Therapeutics (acquired by Bristol Myers Squibb)
- Dual M1/M4 muscarinic acetylcholine receptor agonist
- Twice daily oral administration to treat schizophrenia in adults
- Also in development for schizophrenia patients that have responded inadequately to traditional treatments and for psychosis related to AD
- ~5.4m diagnosed prevalent cases of schizophrenia in the G7 markets in 2024
- ~3.2m diagnosed prevalent cases of psychosis related to AD in the G7 markets in 2024
Why is it a drug to watch?
It can be challenging to find an effective treatment for all individuals with schizophrenia. The fact that all existing drugs target dopamine D2 receptor signaling in the brain limits the treatment choices and makes effective treatment for many even more difficult. The approval of COBENFY adds another option to the schizophrenia armamentarium and represents a significant achievement for Bristol Myers Squibb’s recent re-entry into the field of neuropsychiatry. The company is also launching COBENFY Cares™, a program designed to support patients who have been prescribed COBENFY.
Bristol Myers Squibb acquired COBENFY developer Karuna Therapeutics Inc, which was founded by PureTech Health plc to develop COBENFY, in a deal that closed in March 2024. Muscarinic receptors were linked to schizophrenia in research carried out in the 1980s and 1990s, and xanomeline had previously been taken into phase 2 development in AD and schizophrenia by Eli Lilly and Co but was dropped because of the dose-limiting side effects (e.g., gastrointestinal side effects), likely due to xanomeline activating M1 and M4 receptors in the periphery as well as in the brain. By adding trospium chloride, which does not cross the BBB, M1/M4 receptors in the periphery are likely blocked, overcoming the tolerability issues.
The FDA approval of COBENFY was supported by data from the EMERGENT clinical program, which included three placebo-controlled trials and two open-label studies evaluating long-term safety and tolerability and showed statistically significant reductions in positive schizophrenia symptoms and, to some extent, negative symptoms, with an impressive effect size when compared with placebo:
-
EMERGENT-2 and EMERGENT-3: adult inpatients with schizophrenia
-
COBENFY vs placebo for five weeks
-
Change in total Positive and Negative Syndrome Scale (PANSS) score:
-
EMERGENT-2: -21.2 with COBENFY vs -11.6 with placebo (effect size=0.61)
-
EMERGENT-3: -20.6 with COBENFY vs -12.2 with placebo (effect size=0.60
-
Change in Clinical Global Impression-Severity (CGI-S) score:
-
EMERGENT-2: -1.2 with COBENFY vs -0.7 with placebo
-
EMERGENT-3: -1.1 with COBENFY vs -0.6 with placebo
-
Treatment discontinuation due to adverse events:
-
EMERGENT-2: 7% vs 6% (COBENFY vs placebo)
-
EEMERGENT-3: 6.4% vs. 5.5% (COBENFY vs placebo)
-
Treatment effects were demonstrated as early as two weeks, which could promote its use in the acute hospital setting and continued use in the outpatient setting.
-
The most common AEs in both studies were nausea (19% vs 4%), dyspepsia (18% vs 5%), constipation (17% vs 7%), vomiting (15% vs 1%), hypertension (11% vs 2%), abdominal pain (8% vs 4%), diarrhea (6% vs 2%), tachycardia (5% vs 2%), dizziness (5% vs 2%) and gastroesophageal reflux disease (5% vs <1%).
-
Notably, the rates of somnolence, weight gain and extrapyramidal symptoms (EPS) were similar to those with placebo; these are typical side effects with existing treatments and can be reasons for discontinuing treatments.
-
EMERGENT-4: open-label extension with participants who completed EMERGENT-2 or EMERGENT-3; interim analysis:
-
COBENFY for 52 weeks
-
>75% of participants achieved ≥30% improvement in symptoms
-
Change in total PANSS score: -33.3 points
-
Change in CGI-S score: -1.7 points
-
EMERGENT-5: open-label study with adult outpatients with schizophrenia administered COBENFY for up to 52 weeks.
-
Not associated with weight gain, metabolic dysfunction and extrapyramidal symptoms
In addition, the company is evaluating COBENFY as adjunctive therapy to treat patients with inadequate response to their current atypical antipsychotic treatment in a phase 3 and extension trials, which is anticipated to be used to file an sNDA for COBENFY as adjunctive treatment:
-
ARISE: adults with schizophrenia who have not achieved an adequate response to their current atypical antipsychotic treatment (U.S., Europe, Japan, others)
-
COBENFY vs placebo for six weeks
-
Primary endpoint: change in total PANSS scoreExpected completion: February 2025
Additional phase 3 trials for psychosis related to AD (e.g., hallucinations, compulsiveness, wandering) are underway:
-
ADEPT-1: adults (55 to 90 years old) with AD across the severity spectrum (MMSE: 8-22 inclusive) with psychosis (moderate-to-severe delusions or hallucinations)
-
COBENFY (titrated to a maximum dose) for 12 weeks
-
Responders (≥ 40% decline from baseline in Neuropsychiatric Inventory-Clinician: Hallucinations and Delusions (NPI-C: H+D) score at week 10 or 12 and CGI-C score of “improved” or “very much improved”) randomized to continue COBENFY or placebo for 26 weeks
-
Primary endpoint: time from randomization to relapse
-
Expected completion: October 2026
-
ADEPT-2: adults (55 to 90 years old) with AD across the severity spectrum (MMSE: 8-22 inclusive) with psychosis (moderate-to-severe delusions or hallucinations)
-
COBENFY for 14 weeks
-
Primary endpoint: change in NPI-C: H+D score
-
Expected completion: July 2025
-
ADEPT-3: open-label extension study with participants who completed ADEPT-1 or ADEPT-2
-
COBENFY for 52 weeks
-
Primary endpoint: incidence of treatment-emergent adverse events (TEAEs)
-
Expected completion: April 2026
-
ADEPT-4: randomized, double-blind, placebo-controlled, parallel-group study
-
COBENFY for 14 weeks
-
Primary endpoint: change in NPI-C: H+D score
-
Expected primary completion: October 2026
Review and approval status
September 2023
NDA submitted: U.S. FDA (schizophrenia)
September 2024
NDA approved: U.S. FDA (schizophrenia)
Actual and expected launch:
- 2024: United States (schizophrenia)
- 2026: Mainland China (schizophrenia)
- 2027: United States (AD psychosis), European Union (schizophrenia [inadequate responders])
- 2028: European Union (AD psychosis)
- 2029: Mainland China (AD psychosis)
Patents estimated to expire beginning in 2030
Drug Timeline & Success Rates
Source: Cortellis Competitive Intelligence, Drug Timeline & Success Rates Prediction current as of October 31, 2024
How will COBENFY impact the market for schizophrenia and psychosis related to AD?
- The schizophrenia therapy market is expected to increase from $8.6bn in 2022 to nearly $15.2bn in 2032 (6% CAGR) in the G7 markets, with growth partially driven by the increase in the drug-treated population. Sales of new and emerging therapies are expected to outweigh the impact of generics entering the markets.
- Oral atypical antipsychotics will remain firmly entrenched as the key first-line therapeutic choices for schizophrenia, given physician comfort and familiarity with the efficacy, safety and tolerability of these drug classes and the availability of generics, particularly of therapies heavily used in early lines of treatment (e.g., aripiprazole, risperidone, olanzapine).
- Of the two drugs in novel drug classes launching in the next few years, COBENFY and iclepertin (Boehringer Ingelheim; glycine transporter-1 inhibitor), the latter is forecast to have the greater impact on sales because it will manage cognitive impairment associated with schizophrenia (CIAS), an area of high unmet need and with a high prevalence.
- However, COBENFY will help address the need for drugs with novel MOAs to treat schizophrenia. It is expected to be used as monotherapy as well as adjunctive therapy to antipsychotics in schizophrenic patients with insufficient response to other agents or who experience side effects, and could command up to 9.5% patient share in the U.S. in 2032.
- COBENFY is expected to be used as second- or later-line monotherapy initially because payers are expected to encourage prescriptions of generics first before switching to COBENFY when patients display positive or negative symptoms that respond inadequately to other treatments or cannot tolerate side effects.
- Given its demonstrated two-week onset of action, COBENFY could also be prescribed for hospitalized acutely psychotic individuals with schizophrenia, and treatment could be continued for treatment-responsive patients as outpatients.
- For psychosis related to AD, the unique MOA, specific labeling for psychosis related to AD and potential lack of a boxed warning for mortality risk in older adults could drive COBENFY uptake, but it will compete with entrenched, lower cost atypical antipsychotics.
- The prevalence, diagnosis and treatment rates of AD are increasing, along with population aging.
- The success of COBENFY could encourage continued growth in the muscarinic pipeline, which has recently received heavy investment from large pharma companies with an interest in neuropsychiatric drugs.
What gaps in treatment does COBENFY fill?
Existing schizophrenia treatments, which all target dopamine D2 receptor signaling in the brain, provide some relief from the “positive” symptoms, such as hallucinations and delusions, but have varying efficacy by patient and do not address negative symptoms, such as anhedonia and emotional withdrawal, or disease-related cognitive impairment. In addition, side effects—such as sedation, weight gain and motor effects—are burdensome and can be dose-limiting. The heterogeneous nature of schizophrenia also creates challenges for effective treatment, and 20-30% of individuals with schizophrenia have symptoms that are refractory or resistant to treatment; these patients often are prescribed higher doses or polypharmacy, which increases the risk of side effects and poor compliance. Therefore, a significant need exists for antipsychotics with improved efficacy and a better safety profile. With its novel MOA, COBENFY has the potential to impact the treatment paradigm for schizophrenia.
Psychosis and agitation related to AD are distressing to the patient, increase caregiver burden and are a primary reason for institutionalization. There is a high unmet need for safe, effective therapies for these symptoms, given REXULTI® (Otsuka America Pharmaceutical Inc and Lundbeck) is the only approved drug for this indication. However, physicians often prescribe antipsychotics off-label, as well as other drugs such as hypnotics, despite their modest efficacy and the safety concerns associated with antipsychotic use in older adults with dementia due to an increased incidence of cerebrovascular events.
What hurdles might it need to overcome to reach blockbuster status?
Antipsychotic sales are often limited by poor compliance and adherence; although COBENFY has demonstrated better tolerability than other available antipsychotics, it could still be affected by the schizophrenia-related cognitive dysfunction that can impair adherence with burdensome, frequently administered treatment regimens. Clinicians might also be reluctant to prescribe COBENFY in first-line treatment because of the potentially long adjustment period, competition from the generically available antipsychotics, high treatment discontinuation rates in clinical trials and lack of documented results in individuals with primarily negative symptoms. In addition, the $1,850/month price tag for COBENFY, which is more than the annual cost of most currently available generic antipsychotics, might limit access, particularly as the disabling nature of schizophrenia places many patients in poor economic circumstances, with limited or no insurance coverage and with less-than-optimal healthcare. Launch in Europe and Japan could be delayed by the EMA’s requirement for long-term clinical study results for schizophrenia drug approval and some markets’ lengthy HTA processes and the lack of Japanese sites in the completed phase 3 trials.
