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Authors: Arun J. Sanyal, Scharmen Confer, Robert Perry, Joel Neutel, Eric Lawitz, Jasmohan S. Bajaj, Andres Duarte-Rojo, William Comb, Jeff Zhao, Manu V. Chakravarthy*

INSTITUTIONS (ALL): 1. Virginia Commonwealth University, Richmond, VA, United States.
2. Axcella Health Inc., Cambridge, MA, United States.
3. Panax Clinical Research, Miami, FL, United States.
4. Ann Storck Centre, Fort Lauderdale, FL, United States.
5. Orange County Research Centre, Tustin, CA, United States.
6. Texas Liver Institute, San Antonio, TX, United States.
7. Pittsburgh Liver Research Center, Pittsburgh, PA, United States.

Introduction: Overt hepatic encephalopathy (HE) involves systemic metabolic dysregulation, including amino acid (AA) imbalance, elevated ammonia, impaired muscle homeostasis, and cognitive dysfunction. Currently, there are limited interventions that comprehensively address these defects. AXA1665 is an investigational composition of 8 specific AAs that targets the multifactorial dysregulation associated with cirrhosis and HE.

Methods: AXA1665-002 was a randomized, placebo-controlled study to investigate the safety, tolerability and physiological impact of AXA1665 in Child-Pugh A and B subjects. After a 2-wk run-in, subjects were randomized 2:2:1 to receive either 29.4g (low) or 53.8g (high) of AXA1665 or placebo (Pbo) in 3 divided doses/day for 12-wks followed by 4-wks safety follow-up. Study assessed neurocognitive performance, muscle structure/function, markers of nitrogen metabolism, and safety/tolerability.

Results: 60 subjects (mean age 59 years, BW 90kg) with Child-Pugh A (n=56) and B (n=4) were evaluated. At Week 12 (W12), AXA1665 treated arms showed dose-dependent improvements in all 3 neurocognitive tests: Psychometric Hepatic Encephalopathy Score (PHES), Critical Flicker Frequency, and Stroop EncephalApp. Absolute increase in PHES in the AXA1665 high-dose arm (+1.1) was significantly greater vs Pbo (-1.2; p <0.05), and higher proportion of AXA1665 treated subjects (33-57%) vs Pbo (29%) reported a clinically relevant ≥2-point increase in PHES (Figure). Consistent with a largely non-sarcopenic, prefrail population, lean mass (total thigh muscle volume, L3 skeletal muscle index) was unchanged across the 3 arms; however, higher proportion of AXA1665 treated subjects (26-40%) vs Pbo (14%) achieved a ≥0.3 unit decrease in the liver frailty index (Figure), a measurement correlated to enhanced ability to perform activities of daily living. Fasted branched chain AA to aromatic AA (Fischer ratio), a metabolic signature linked to cirrhosis outcomes, increased after AXA1665 dosing starting at W2 and showed significant dose-dependent changes (low: +21%, high: +44%) vs Pbo (-9%; p <0.05) at W12, signifying sustained target engagement. While plasma ammonia levels remained stable over 12-wks in the overall cohort, in those with baseline PHES ≤-4, it was decreased ~7% in both the AXA1665 arms vs a 9% increase in Pbo. Adverse events were infrequent, mild or moderate, mostly unrelated to AXA1665, and there were no clinically significant physical exam/safety laboratory findings.

DDW 2021 Presentation Graphic

Conclusions: AXA1665 was well-tolerated, and induced clinically relevant improvements in neurocognition, physical function and nitrogen metabolism. These multitargeted and coordinated actions support the continued evaluation of AXA1665 as a potential novel treatment to address the complex metabolic dysregulation of cirrhosis-related complications such as overt HE and physical frailty.

DISCLOSURE
The following authors have completed their 2021 DDW disclosure: Arun Sanyal: No Answer. | Scharmen Confer: No Answer. | Robert Perry: No Answer. | Joel Neutel: No Answer. | Eric Lawitz: No Answer. | Jasmohan Bajaj: Disclosure completed | Andres Duarte-Rojo: Disclosure completed | William Comb: No Answer. | Jeff Zhao: No Answer. | Manu Chakravarthy: Disclosure completed