Karuna Therapeutics’ KarXT (xanomeline/trospium chloride) still draws expert reservations on whether the dosing combinations could mitigate previously seen cholinergic and gastrointestinal (GI) adverse events (AEs) for the ongoing Phase II schizophrenia trial.

Eli Lilly’s xanomeline had previously been researched in Alzheimer’s disease and schizophrenia by independent researchers and was found to significantly improve behavioural symptoms. 

However, as a single agent, xanomeline’s GI AEs, including nausea, vomiting and diarrhoea, were found to be intolerable in the aforementioned studies, and development in either indication had ceased. Adding trospium, which only acts peripherally and does not cross the blood-brain barrier (BBB), makes sense for ameliorating the side effects without affecting efficacy, experts said, noting they await proof-of-concept of the combination with the Phase II trial. Safety and tolerability are secondary outcome measures, according to the ClinicalTrials.gov website. 

A couple of analysts expressed optimism for a successful trial based on Phase I studies, but experts advised caution as they were being conducted in healthy patients who could better tolerate side effects, despite positive efficacy and safety trends in Phase I trials, and noted those trials were much shorter than the Phase II trial. Additionally, earlier work in Alzheimer’s disease precluded the translation of full confidence into schizophrenia, experts noted. The third-party research in schizophrenia was small, and despite promising early efficacy signals, drawing such Phase II conclusions was premature, experts said. 

KarXT is in a 182-patient Phase II trial (NCT03697252) exploring xanomeline/trospium dosed twice daily, at 200mg/40mg and 250mg/60mg, after a lead-in of 100mg/40mg, according to ClinicalTrials.gov. Topline results are expected in late 2019, according to an 8 August press release.

The press release stated approximately 90% of patients in the Phase II trial have escalated to the highest dose, and the early termination rate was about 20–25%. While a 20-25% dropout rate sounds high, it is premature to conclude the risk-benefit until the reasons for early termination and the efficacy are known, an expert noted. Karuna’s Chief Operating Officer Andrew Miller did not address the dropout rate but said fewer than 5% of patients have de-escalated back to the lower dose.

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By GlobalData

GI AE uncertainties remain

Karuna’s Phase I studies had promising albeit inconclusive trends, but it is unclear whether the trospium component is enough to offset the GI side effects for the Phase II, especially at the highest dose, said Dr Joshua Kantrowitz, assistant professor of clinical psychiatry, Columbia University, New York. The highest dose of KarXT’s Phase II is higher than what had typically been tested in previously published studies, said Dr Anantha Shekhar, associate vice president of research, Indiana University, Indianapolis, who led the first-in-schizophrenia study.

A Phase I multiple ascending dose study explored combinations of 200mg and 250mg xanomeline with 40mg and 80g of trospium, respectively, and side effects were reported in the 40mg trospium group, especially those in the 250mg combination (Brennan et al., Schizophrenia Bulletin, April 2019; 45(Suppl_2): S244–S245). AE rates were about 39% in the 200mg xanomeline group and 33% in the 250mg group, similar to the 34% seen in a previous Phase I study (NCT02831231) that tested a 225mg/40mg xanomeline-trospium combination.

In a 20-patient trial of xanomeline as monotherapy, the GI side effects became apparent at around 200mg onwards, where about 70% of patients experienced AEs, although there were no discontinuations, Shekhar noted (Shekhar et al., Am J Psychiatry, August 2008; 165(8):1033–1039). The results were consistent with Eli Lilly’s trial, which had a 75% AE rate, although that trial also had a 59% rate of discontinuations, he added (Bodick et al., Arch Neurol, April 1997; 54(4):465–473). Finding the right xanemoline/trospium balance can be tricky, but the reduction of AEs to the 30% range from the 70% range in the monotherapy studies was a promising start, said Shekhar and Dr Carol Tamminga, professor of psychiatry, University of Texas Southwestern, Dallas.

However, the Phase I trials were conducted in healthy volunteers and only spanned one week, whereas the Phase II trial is more than five weeks long and is conducted in moderate-to-severe schizophrenia patients, precluding any strong conclusions, said Tamminga. The Phase I trial was in healthy volunteers, who might be able to tolerate GI side effects better, Tamminga said. It is not clear whether there is a meaningful difference between tolerance of GI side effects between healthy volunteers and schizophrenia patients, as there have been few drugs for schizophrenia where GI AEs were prevalent, said Dr Donald Goff, professor of psychiatry, New York University.

Adding trospium makes mechanistic rationale for tackling the AEs, all the experts agreed. Trospium’s peripheral-only action should be able to mitigate xanomeline’s muscarinic receptor agonism-led AEs, while leaving its antipsychotic benefits intact, said an adult psychiatrist and Goff.

All the experts noted KarXT did not seem to have a meaningful risk on heart rate and blood pressure, a known cholinergic side effect with xanomeline, as seen in the Phase I study (Shannon et al, J Pharmacol Exp Ther, April 1994; 269(1):271–281). The 40mg dose of trospium is an approved generic for overactive bladder, but it is not clear if there are any safety downsides to exploring a 60mg combination, Shekhar added.

Three independent safety monitoring reviews have recommended that the trial should proceed without any changes, Miller noted.

Strong effect size, multisymptom potential

Xanomeline demonstrated a highly clinically meaningful improvement in the positive and negative syndrome scale (PANSS) in the 20-patient trial, with a 24-point difference in improvement from placebo (p=0.039), and an effect size of about 0.8, Shekhar said. While that could provide some rough idea of KarXT’s PANSS efficacy, Shekhar and Goff cautioned against inferring too much from a 20-patient trial.

KarXT is using PANSS, amedical scale for measuring symptom severity of patients with schizophrenia,as a primary endpoint in the ongoing Phase II trial, according to ClinicalTrials.gov.

An effect size of 0.8 PANSS improvement is relatively uncommon among currently used antipsychotic drugs, including generic olanzapine and risperidone, said Goff and Tamminga, adding it would be impressive if KarXT achieves that magnitude. Meta-analyses of antipsychotic studies have shown that a typical effect size versus placebo tends to be about 0.46, or a 9.6-point PANSS reduction, experts said (Haddad et al., Ther Adv Psychopharmacol, Nov 2018; 8(11):303–318).

KarXT’s Phase I trials were not powered for efficacy signals, with all efficacy impressions drawing from Shekhar’s trial or Eli Lilly’s AD trial, and thus actual effect size remains to be seen in Phase II, all experts noted. Eli Lilly’s trial showed that 52.9% of AD patients stopped having hallucinations (p=0.008) and 28.6% of patients stopped having delusions (p=0.02) after xanomeline treatment—two symptoms recognized as also being positive symptoms in schizophrenia.

One of the bigger draws of KarXT is that xanomeline also appears to have a benefit on cognitive symptoms, and no antipsychotic has been able to impact both positive symptoms and cognitive symptoms concurrently, all experts said. Shekhar’s trial showed significant (p<0.05) improvements in the list-learning component of the verbal learning test, digit span and story recall components of the working memory tests, as well as the delayed memory component of the visual learning tests. Analyst reports noted the potential cognitive benefit is a potential differentiator from other antipsychotics in the market. If the cognitive benefit is replicated in Phase II and Phase III, this feature would be a game-changer in schizophrenia treatment, the psychiatrist said.

by Shuan Sim in Stockholm

Shuan Sim is a Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.


Related Report:

Cognitive Impairment Associated With Schizophrenia (CIAS) Global Clinical Trials Review, H1, 2019