The US Food & Drug Administration (FDA) has accepted a New Drug Application (NDA) for KarXT (xanomeline-trospium) for the treatment of schizophrenia in adults. Xanomeline-trospium a novel pharmacological compound to be considered for the treatment of schizophrenia. 

Schizophrenia is a disease of diverse aetiology, involving numerous neurotransmitters (e.g., dopamine, 5-hydroxytryptamine [5-HT], and acetylcholine), which results in a variety of symptoms. It is characterised by positive and negative symptoms and cognitive impairment. The positive symptoms are hallucinations, delusions, and disorganised thoughts. Negative symptoms are a blunted affect, apathy, and anhedonia. Cognitive impairments include alterations in memory, learning, and attention. 

Pharmacological treatment of schizophrenia has mainly been modulating the activity of dopamine and 5-HT. The older antipsychotics are readily available and inexpensive. They have significant adverse effects including dry mouth, constipation, difficulty urinating, impotence and movement disorders. 

Rather than dopamine blockade, xanomeline-trospium focuses on muscarinic receptors to indirectly modulate dopamine signalling. Xanomeline-trospium is a muscarinic antipsychotic, a dual M1/M4 muscarinic acetylcholine receptor agonist. (It has partial agonist pharmacology at the M₂, M₃ and M₅ receptors.) The messengers in the brain called acetylcholine are responsible for communication between nerve cells. Muscarinic receptors are the ports for these messages. Xanomeline acts like a key, unlocking these receptors and amplifying the acetylcholine signal. This may mediate cognitive, positive, and negative symptoms of schizophrenia. 

Xanomeline-trospium has adverse events including cholinergic characteristics and were categorised as mild to moderately severe. The most common side effects of this combination included constipation, dry mouth, and nausea. The rates of discontinuation due to treatment-related adverse events were low and showed similarity between xanomeline-trospium and placebo in all trials. Xanomeline-trospium also did not exhibit the typical adverse events that are commonly associated with currently available antipsychotic medications, such as alterations in metabolic function, weight gain, drowsiness, and extrapyramidal symptoms. 

Xanomeline-trospium demonstrated a significant and clinically relevant reduction in the total score on the Positive and Negative Syndrome Scale (PANSS) when compared to placebo. PANSS is a rating scale that measures symptoms of schizophrenia. Xanomeline-trospium also exhibited reductions in both positive and negative symptoms of schizophrenia, as assessed through the PANSS positive, PANSS negative, and PANSS negative Marder factor subscales—the secondary endpoints across all 3 trials. 

Xanomeline, was also used Alzheimer’s disease research. It is an M1 and M4 agonist and considered to be useful in treating neurodegenerative disorders by enhancing cholinergic transmission promoting acetylcholine. Acetylcholine is essential for memory and learning. It may be useful in other dementia disease and addiction, as trials in these areas are on-going. 

Xanomeline development in Alzheimer’s disease was stopped in 1998, due to the severe cholinergic adverse effects. Then xanomeline was explored with trospium. Trospium is a peripheral cholinergic antagonist, used to treat side effects from medication used for treatment of schizophrenia.   Trospium is expected to reduce the adverse effects of xanomeline. This combination is promising in the treatment of schizophrenia.  

It is estimated that the one-third of patients who do not respond to existing drugs might benefit from xanomeline since it acts through a different mechanism. The negative symptoms of schizophrenia have been difficult to treat pharmacologically and xanomeline-trospium may improve both positive and negative symptoms. 

All looking very positive. Let’s see how things progress, the FDA decision is anticipated in September 2024.