On 8 August, Karuna Therapeutics announced positive topline results from the Phase III EMERGENT-2 trial (NCT04659161) of KarXT (xanomeline + trospium chloride) in acutely psychotic hospitalised adult patients with schizophrenia. KarXT targets the muscarinic acetylcholine receptors and could potentially present a novel mechanism of action (MOA) in the schizophrenia market. If KarXT continues to show success within the EMERGENT trial programme as a monotherapy, as well as in the ongoing ARISE trial (NCT05145413) as an adjunctive to traditional antipsychotics, the drug could have a major competitive edge over current atypical antipsychotics, particularly later-generation products.

The EMERGENT-2 randomised, double-blind, parallel-group, placebo-controlled, multicentre inpatient study demonstrated that KarXT reduced positive and negative symptoms of schizophrenia after five weeks, including a statistically significant 9.6-point reduction in Positive and Negative Syndrome Scale (PANSS) compared with placebo. The trial also showed a statistically significant reduction in PANSS positive and negative subscales. As such, the study’s key primary and secondary endpoints were both achieved. In addition, KarXT was generally well-tolerated, with a side-effect profile consistent with prior trials of KarXT in schizophrenia.

There are three ongoing Phase III trials in the EMERGENT programme to evaluate the acute efficacy and long-term safety of KarXT: EMERGENT-3 (NCT04738123), EMERGENT-4 (NCT04659174), and EMERGENT-5 (NCT04820309). The trials have primary completion dates of this month, next June and next July respectively.

The dopaminergic hypothesis of schizophrenia is the basis of current antipsychotic medication, whereby the majority of antipsychotic drugs target the 5-HT2A and D2 dopamine receptors. In contrast, KarXT is a coformulation of a muscarinic acetylcholine receptor agonist, xanomeline, and peripheral muscarinic acetylcholine antagonist, trospium chloride, and does not directly modulate dopaminergic or serotonergic transmission.

To differentiate KarXT from the marketed atypical antipsychotics, Karuna Therapeutics will need to replicate its findings, confirming that the novel MOA can improve both positive and negative symptoms, while not being associated with common side effects of antipsychotics including weight gain, sedation, and movement disorders. GlobalData forecasts that KarXT will launch as a monotherapy for inpatients with schizophrenia in the US in the third quarter (Q3) of 2024.

But as numerous atypical antipsychotics and their generics dominate the schizophrenia market and are very well-entrenched in the treatment algorithm, it is unlikely that KarXT monotherapy will be used as a first-line treatment option. KarXT could, however, be an option for patients who cannot tolerate the side effects of atypical antipsychotics.

Key opinion leaders (KOLs) interviewed by GlobalData worried that patient uptake of novel monotherapies, such as KarXT, for schizophrenia treatment was likely to be limited by premium prices compared to current antipsychotic treatments and thus restricted reimbursement by payers. In efforts to improve patient uptake, Karuna Therapeutics announced, at the First Annual Needham Virtual Neuroscience Forum in March this year, its aim to submit a new drug application (NDA) for the use of KarXT as a monotherapy, followed closely by a supplemental NDA for the use of KarXT as an adjunctive therapy for the treatment of schizophrenia.

At present, although physicians will occasionally prescribe a second antipsychotic or antidepressant off-label to augment the effects of an antipsychotic, there are no approved combination therapeutic regimens for schizophrenia. In addition, KOLs reported only modest improvements in efficacy and increased side-effect burden with this type of polypharmacy.

If positive results are found in the ongoing Phase III ARISE clinical trial, KarXT could be the first approved adjunctive therapy for the treatment of schizophrenia. ARISE is a six-week, randomised, double-blind, placebo-controlled, multicentre, outpatient study in patients with schizophrenia with an inadequate response to their current atypical antipsychotic treatment. With a primary completion date of November next year, GlobalData forecasts that KarXT will be launched as an adjunctive therapy in the US in Q3 2025.

The strategy of seeking approval as both a monotherapy and an adjunctive therapy in schizophrenia could help Karuna Therapeutics establish itself within the crowded schizophrenia market. In particular, if KarXT can be used in combination with marketed antipsychotics rather than having to compete with them, this could greatly expand market size. In addition, KOLs were hopeful that KarXT as an adjunctive therapy could benefit patients who have a partial response to current antipsychotic medication, a group that accounts for about 30% of total drug-treated cases.

Neurocrine Biosciences’ Ingrezza (valbenazine tosylate) and Acadia Pharmaceuticals’ Nuplazid (pimavanserin tartrate) are two notable late-stage pipeline products that are also being developed as adjunctive therapies for schizophrenia and set to compete with KarXT. But as they both are anticipated to launch in the fourth quarter of 2025 for adjunctive use in patients with inadequately controlled symptoms of schizophrenia, GlobalData expects KarXT to have a first-to-market advantage.