**Multi-Targeted Therapeutic AXA1665 Advances to Phase 2 Development for Managing Recurrent Hepatic Encephalopathy**

Axcella, a clinical-stage biotech firm developing endogenous metabolic modulator (EMM) compositions, has taken a significant step forward by activating initial trial sites and initiating patient recruitment for the EMMPOWER investigation. This globally distributed Phase 2 study represents a comprehensive approach to addressing overt hepatic encephalopathy (OHE), a severe complication affecting individuals with cirrhosis.

**Understanding the Clinical Challenge**

Hepatic encephalopathy emerges as one of cirrhosis's most debilitating complications, characterized by amino acid imbalances, ammonia accumulation, and progressive muscle wasting that collectively impair cognitive and neurological function. The overt form—OHE—manifests as clinically observable neurological dysfunction without requiring specialized testing. Beyond individual suffering, OHE generates substantial healthcare costs and represents a significant driver of morbidity and mortality in the cirrhotic population. Current standard-of-care approaches remain limited, with existing therapies primarily targeting ammonia metabolism alone, leaving a substantial therapeutic gap.

**The EMMPOWER Trial Framework**

Axcella's investigational product AXA1665 comprises an eight-component amino acid composition engineered to simultaneously influence multiple metabolic pathways across interconnected organ systems—the liver, muscle, and gut microbiota. The EMMPOWER trial will evaluate this multi-targeted strategy through a randomized, double-blind, placebo-controlled design across more than 70 international clinical sites.

The investigation will enroll approximately 150 patients with documented prior OHE episodes and existing neurocognitive impairment while maintaining concurrent lactulose therapy, with or without rifaximin stratification. Participants will receive either 53.8 grams daily of AXA1665 or calorie-matched placebo administered in three divided doses throughout a 24-week treatment window, followed by four weeks of safety monitoring.

**Trial Design and Endpoints**

The primary efficacy measure focuses on the proportion of patients achieving a ≥2 point improvement on the psychometric hepatic encephalopathy score (PHES) following the treatment period. Secondary assessments will track breakthrough OHE events, time to first neurological decompensation requiring hospitalization, and functional metrics including the liver frailty index. Additional evaluation includes circulating ammonia concentrations, amino acid profile normalization, and inflammatory marker reduction.

**Mechanistic Rationale**

Prior clinical investigations have positioned AXA1665 as a compound with multifaceted therapeutic potential. Earlier phase studies demonstrated improvements in ammonia clearance, amino acid rebalancing, muscle function preservation, and neurocognitive performance. By targeting multiple pathogenic mechanisms simultaneously rather than relying on ammonia reduction alone, the EMMPOWER program seeks to establish whether this platform can functionally reset the biochemical abnormalities underlying OHE pathophysiology.

Dr. Andres Duarte-Rojo, principal investigator and hepatology specialist from the University of Pittsburgh, emphasized the clinical necessity: "The existing treatment landscape leaves patients with limited options, and most approved approaches address only single disease mechanisms. AXA1665's multi-targeted architecture represents a conceptual paradigm shift for this severely underserved population."

**Broader Therapeutic Vision**

The EMMPOWER designation reflects Axcella's strategic positioning of EMM-based therapeutics as agents capable of modifying underlying disease drivers across multiple complex conditions. The company's pipeline extends beyond OHE, with parallel development programs targeting non-alcoholic steatohepatitis (NASH) through similar metabolic modulation strategies.

EMMs—naturally occurring molecules including amino acids and metabolic intermediates—function as biological regulators of human metabolism. By engineering distinct EMM combinations in optimized ratios, Axcella seeks to create therapeutics that simultaneously impact several metabolic pathways, effectively treating diseases at their biochemical foundation rather than addressing isolated symptomatic manifestations.

**Regulatory and Clinical Context**

The preceding clinical evaluations supporting AXA1665 were conducted as non-investigational new drug application (IND) studies under FDA guidance for food-related research, evaluating safety, tolerability, and metabolic effects in both healthy and diseased populations. The transition to formal Phase 2 development under an IND represents escalation toward potential therapeutic approval pathways.

This trial advancement signifies meaningful progress in addressing an area characterized by minimal recent pharmaceutical innovation and substantial unmet clinical needs in the hepatology field.