New adjunctive antidepressant elevates serotonin in Phase I trial

Hormones in the brain concept

Evecxia Therapeutics has reported favourable safety, tolerability, pharmacokinetic, and pharmacodynamic data from a Phase I trial of EVX-101 in healthy volunteers treated with escitalopram.

The company is also planning a Phase II adjunctive EVX-101 trial in patients with major depressive disorder (MDD) responding inadequately to a first-line antidepressant (selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI)).

EVX-101 is a novel, proprietary gastro-retentive, sustained-release tablet formulation of 5-hydroxytryptophan (5-HTP), the natural precursor to serotonin, and low-dose carbidopa.

Administered in addition to a first-line antidepressant, the drug is intended to elevate extracellular serotonin beyond the first-line antidepressant effect, which convergent clinical pharmacology, brain imaging, and neuroanatomical data support would augment antidepressant efficacy.

“Based on the results of the Phase I trial, EVX-101 may offer a novel treatment option for patients not helped by current antidepressant treatment,” remarked Dr George I Papakostas, Professor of Psychiatry at Harvard Medical School and Director of Treatment-Resistant Depression Studies in the Department of Psychiatry at Massachusetts General Hospital in Boston, Massachusetts.

“Of note, patients treated with EVX-101 may not experience some rare but serious side effects associated with adjunctive treatment of MDD patients with atypical antipsychotics.”

Details of the trial

In EVX-101, the 5-HTP dose is fixed at 250mg, while variable levels of carbidopa control 5-HTP plasma exposure levels.

In the multiple ascending dose (MAD) part of the trial, 5-HTP plasma levels increased with each escalation in carbidopa dose. 5-HTP accumulated several-fold over days when EVX-101 was dosed to steady state.

Following repeated BID dosing of EVX-101, even the lowest dose, 0.3125mg carbidopa/250mg 5-HTP, achieved steady-state 5-HTP plasma levels approaching the putative therapeutic 5-HTP target levels of about 100ng/ml. EVX-101, 2.5mg carbidopa/250 mg 5-HTP, reached steady-state 5-HTP plasma levels approaching 300ng/ml.

An acute transient rise in serum cortisol was used as a validated neuroendocrine biomarker of acute elevation in brain extracellular serotonin. In the MAD trial, all doses of EVX-101 produced an increase in serum cortisol, demonstrating that adjunctive EVX-101 elevated extracellular serotonin beyond the effect of the first-line antidepressant.

All adverse events reported were mild or moderate, generally transient, and consistent with the serotonergic pharmacology, with gastrointestinal events the most common.

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