Esreboxetine (AXS-14): A Comprehensive Clinical and Regulatory Review for the Management of Fibromyalgia

I. Executive Summary

Esreboxetine, also known under the developmental code AXS-14, is an investigational small molecule drug currently under review for the treatment of fibromyalgia. Chemically, it is the (S,S)-enantiomer of reboxetine and functions as a highly selective and potent norepinephrine reuptake inhibitor (NRI).[1] This specific enantiomeric form is reported to offer enhanced potency and selectivity compared to racemic reboxetine.[1] The therapeutic rationale for Esreboxetine in fibromyalgia is based on the modulation of noradrenergic pathways, which are implicated in endogenous pain inhibition and other symptoms characteristic of the condition.

Clinical development, initially undertaken by Pfizer Inc., demonstrated Esreboxetine's efficacy in Phase 2 and Phase 3 trials, where it met primary endpoints related to pain reduction and overall improvement in fibromyalgia symptoms compared to placebo.[4] Despite these positive outcomes, Pfizer discontinued the program in early 2009, citing a strategic reallocation of resources to higher-potential programs and a perception that Esreboxetine might not offer a meaningful benefit beyond then-current standards of care, rather than any safety concerns.[6]

In January 2020, Axsome Therapeutics acquired the U.S. rights to Esreboxetine, including Pfizer's extensive clinical data package.[4] Axsome has since advanced the compound, now designated AXS-14, and submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the management of fibromyalgia in early 2025.[8] The FDA's decision on the acceptance of this filing is anticipated in the second quarter of 2025.[8]