Newron Pharmaceuticals S.p.A. has announced what it says are ‘very exciting new results’ from the first 100 randomized patients who have completed one year of treatment in its study of evenamide as an add-on to an antipsychotic (excluding clozapine) in patients with moderate to severe treatment-resistant schizophrenia (TRS) not responding to their current antipsychotic medication.
Results from these same 100 patients in the international, randomized, open label, rater-blinded study at six weeks and six months have been reported previously.
Results in patients completing one year of treatment with evenamide provide further new evidence of the sustained efficacy of evenamide as an add-on to antipsychotics (excluding clozapine) in TRS patients, by demonstrating substantially greater benefit at one year than noted at the six-week and six-month datapoints.
The efficacy results, based on changes over baseline at one year in the Positive and Negative Syndrome Scale (PANSS), showed more than a 50% increase over the statistically significant benefit noted at the six-week datapoint. Also, the proportion of patients experiencing a clinically meaningful PANSS improvement (responders) at one year was almost three times higher than the proportion responding at week six (16%).
In addition, the mean change for the severity of illness (as measured by Clinical Global Impression of Severity (CGI-S)) showed a statistically significant improvement at one year compared to baseline. The proportion of patients who experienced highly meaningful (at least two categories) improvement in the severity of disease as assessed by the CGI-S more than doubled compared to the proportion of patients improving at week six (10%).
The proportion of patients experiencing clinically meaningful improvement (i.e., patients rated at least ‘much improved’) on the Clinical Global Impression of Change (CGI-C) increased by an additional 10% at one year from the proportion at week six (27%). Further evidence of the progressive benefit over time was evident from the growing proportion of patients rated ‘very much improved’ at one year.
New pathways for treatment
Jean-Pierre Lindenmayer, director of research, Psychopharmacology Research Unit – Nathan Kline Institute for Psychiatric Research at Manhattan Psychiatric Center, said: “Clozapine is the treatment of choice for the management of treatment-resistant schizophrenia (TRS). However, more than half of patients with TRS do not respond to clozapine, which makes it extremely urgent to find new and effective treatments for TRS.
“These phase II, open-label data of evenamide in patients with TRS, obtained with blinded raters, are very promising. The pattern of improvement is particularly unusual as it occurs gradually over a year and is sustained. We rarely see such a pattern of improvement with current treatments. In addition, the mechanism of action of evenamide appears to be completely novel, which may open up new pathways for treatment for TRS. Of course, these results need to be confirmed by a planned randomized, placebo-controlled study in TRS patients.”
The interim results are based on the first 100 patients randomized to receive evenamide (7.5, 15 or 30 mg bid) in study 014. Ninety of these entered the long-term treatment period (study 015) and 77 of these reached the 52-week endpoint. Most of the first 100 patients were randomized to receive either the 7.5 or 15 mg bid doses, as patients were initially randomized to treatment with these doses before an Independent Safety Monitoring Board reviewed the safety data from the first 50 patients completing the trial and agreed with the initiation of the randomization to the 30 mg bid dose.
The addition of evenamide to the current antipsychotic medication continued to be well tolerated, only two patients discontinued for adverse events (flu-like symptoms and headache) after one year of treatment.
Better than expected results
Ravi Anand, Newron’s chief medical officer, said: “These striking results, at the end of one year, from the first 100 patients randomized to this study are markedly better than could have been expected. While recognizing this study has no control arm, such statistically significant, clinically meaningful improvements over baseline in key efficacy measures after one year are, to our knowledge, unprecedented in patients with diagnosed treatment-resistant schizophrenia.
“We are particularly struck by data suggesting there is a continued improvement over time in these measures. We eagerly await the full results from the trial, which will include six- and twelve-month data from many more patients on the higher 30 mg dose. These results validate the role of this glutamate release inhibitor in repairing disturbed neural connectivity in a treatment-refractory patient population and should help us to expedite the start of our placebo-controlled Phase III study in patients with TRS that we plan in 2023.”
The enrollment of patients in study 014 has been completed, with 161 subjects randomized. Newron anticipates announcing the full results from the study in March 2023. The extension study 015 is ongoing and is expected to provide results of evenamide treatment for up to one year from all patients by Q1 2024.
Newron expects to initiate a potentially pivotal, multinational, randomized, placebo-controlled trial in patients with TRS (study 003) in 2023, as part of its ongoing phase II/III development plan for evenamide. The first potentially pivotal study of this development program, study 008A, with evenamide as add-on therapy in patients with chronic schizophrenia experiencing inadequate response to their current antipsychotics (but not diagnosed as having TRS), is enrolling patients, and results are expected in 2023.
Newron continues its dialogue with industry partners around potential future collaboration opportunities for the development of evenamide.
About Newron’s evenamide
Newron’s evenamide, an orally available new chemical entity, specifically blocks voltage-gated sodium channels (VGSCs) and is devoid of biological activity at >130 other CNS targets. It normalizes glutamate release induced by aberrant sodium channel activity (veratridine-stimulated), without affecting basal glutamate levels, due to inhibition of VGSCs.
Combinations of ineffective doses of evenamide and other APs, including clozapine, were associated with benefit in animal models of psychosis, suggesting synergies in mechanisms that may provide benefit in patients who are poor responders to current APs, including clozapine.