Antiseizure Agent EQU-001 Shows Safety, Tolerability, and Preliminary Efficacy in Phase 2 Study

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In addition to showing a tolerable safety profile, EQU-001 resulted in reduced IL-17 and IL-1b plasma levels relative to baseline and limited the ability of peripheral mononuclear cells to secrete additional pro-inflammatory cytokines.

Jacqueline A. French, MD, professor of neurology, NYU Grossman School of Medicine

Jacqueline A. French, MD

Newly announced topline results from a dose-finding, phase 2 clinical trial (NCT05063877) assessing Equilibre’s antiseizure medication EQU-001 showed that the therapy was safe and well tolerated at all tested doses through 60 mg QD. Investigators also observed a dose response trend in reduction of focal seizures, as well as decreases in key biomarkers.1

Conducted in the US and Israel, the EQU-201 study evaluated EQU-001 in doses of 10 mg, 20 mg, 40 mg, and 60 mg once daily relative to placebo in a cohort of 43 individuals with epilepsy with focal seizures. Over the course of a 12-week treatment period, no treatment-related serious adverse events (AEs) were reported, all AEs were grade 1 and 2, and AEs occurred at similar rates to that seen in the placebo group.

"Patients living with epilepsy face the debilitating impact of focal seizures, as well as the debilitating side effects of many available medications,” study investigator Jacqueline A. French, MD, professor of neurology, NYU Grossman School of Medicine, and president of the Epilepsy Study Consortium, said in a statement.1 "There is a great need for new and efficacious medications that are well tolerated by patients with fewer AEs. If in fact EQU-001 is working through a novel anti-inflammatory mechanism, this would mean that the drug is acting directly on disease pathophysiology. I am very excited to see the results of the next study."

The cohort had an average age of 40.4 (±13.14) years, and were on either 1 (9%) 2 (33%), 3 (40%), or 4 (19%) stable background antiseizure medications coming in. The median seizure frequency across all the study groups was 12 per 4 weeks. Although the study was designed to assess safety and tolerability of EQU-001, there was an overall dose response trend in increasing median percent seizure reductions, except for the 40 mg group. In the modified intend-to-treat (mITT) population, the median percent reduction in focal seizures per 28 days was 41.6% (95% CI, –5.6 to 83.5), 7.4% (95% CI, –51.3 to 29.1), 19.9% (95% CI, –33.6 to 50.2), 12.3% (95% CI, –32.1 to 83.1) and 5.8% (95% CI, –110.0 to 36.9) in the 60 mg, 40 mg, 20 mg, 10 mg, and placebo groups, respectively.

In total, 88.6% of patients across all treatment arms and 75% in the placebo arm completed the study, with 37 patients moving on to the open-label extension. One individual in each of the 40 mg and 60 mg treatment arms discontinued the study because of an AE. Patients in the placebo arm also showed higher rates of infections, occurring in 37.5% vs 11% of those on EQU-001 and 0% in the 60 mg treatment arm.

"It's important to note that while many other anti-seizure medications work more directly via modulation of neuronal ion channels to suppress action potentials, EQU-001 has an additional, novel anti-inflammatory effect, which could represent a novel addition to our armamentarium of ASMs," Pavel Klein, MD, director, Mid-Atlantic Epilepsy and Sleep Center, professor of neurology, George Washington University, and study investigator, said in a statement.1

All AEs, including neurological and psychological, occurred less than 10% and were similar between active and placebo arms. Dizziness was found in 8.6% of treated participants, 0% of those in the 60 mg treatment arm, and 25% of patients in the placebo arm. Fatigue occurred in 8.6% of treated participants, 22% of participants in the 60 mg treatment arm, and 25% of those on placebo.

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In terms of efficacy and biomarker analyses, 44.4% (odds ratio [OR], 5.6; 95% CI, 0.47-66.4), 0% (not calculable), 12.5% (OR, 1.0; 95% CI, 0.05-19.4), 25% (OR, 2.3; 95% CI, 0.17-32.6), and 12.5% (reference) of patients in the 60 mg, 40 mg, 20 mg, 10 mg, and placebo arms, respectively, achieved at least a 50% reduction in focal seizures. In the highest dosed arm, EQU-001 significantly decreased secretion of specific key biomarkers such as IL-17 (P <.05), IL-21 (P <.01), IFN-g (P <.01), and tumor necrosis factor alpha (P <.05) after 12 weeks of treatment. This was achieved through limiting the ability of peripheral mononuclear cells (PMBCs) in ex vivo stimulation.

One notable finding showed that patients treated in the 60 mg EQU-001 arm did not have spontaneous secretion of IL-1b and TNF-a, contrasting observations seen in the placebo arm. The plasma levels of IL-17 and IL-1b were significantly reduced in the highest dose group compared with pre-dose levels (P <.01). Additionally, compared with placebo, all dosed groups showed significant decreases in plasma levels of IL-17 (P <.05) and IL-1b (P <.01) at the end of the treatment period.

Equilibre noted that it is currently implementing a 300 patient, multicenter study to assess the 20 mg and 60 mg dose arms of EQU-001 vs placebo. The trial, named EQU-202, has received study-may-proceed guidance from the FDA, approval from the Ministry of Health of the State of Israel, with first randomization anticipated for February 2023. Additionally, there is expected to be additional data released in the future regarding the ongoing open-label extension of EQU-201.

REFERENCES
1. Equilibre Biopharmaceuticals announces positive topline results from phase 2 clinical trial of EQU-001 (NCT05063877) for safety, tolerability, and preliminary efficacy as adjunctive therapy for focal seizures in adults with epilepsy. News release. Equilibre Biopharmaceuticals. January 30, 2023. Accessed January 31, 2023. https://www.biospace.com/article/releases/equilibre-biopharmaceuticals-announces-positive-topline-results-from-phase-2-clinical-trial-of-equ-001-nct05063877-for-safety-tolerability-and-preliminary-efficacy-as-adjunctive-therapy-for-focal-seizures-in-adults-with-epilepsy/
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