Axcella Announces Initiation of EMMPOWER℠ Phase 2 Clinical Trial of AXA1665

• Initial clinical sites activated and patient screening underway
• Potential to improve the standard of care for cirrhotic patients by addressing multiple key drivers of overt hepatic encephalopathy (OHE)

Axcella (Nasdaq: AXLA), a clinical-stage biotechnology company pioneering a new approach to treat complex diseases and improve health using endogenous metabolic modulator (EMM) compositions, today announced that it has activated initial clinical sites and patient screening for its global Phase 2 clinical trial of AXA1665, the company’s multi-targeted oral product candidate for the reduction in risk of recurrent overt hepatic encephalopathy (OHE).

“OHE is a condition that has devastating consequences for patients and families and places a substantial economic burden on the overall healthcare system,” said Andres Duarte-Rojo, M.D., M.S., Ph.D., Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition at the University of Pittsburgh and the trial’s principal investigator. “Given the limitations of today’s standards of care and the lack of clinical development activity beyond ammonia-focused agents, it also is an area in dire need of medical innovation. In prior clinical studies, AXA1665 has demonstrated the potential to have a multifactorial benefit to patients inclusive of improvements in amino acid balancing, ammonia metabolism, muscle function and neurocognition. I look forward to investigating AXA1665’s ability to replicate these findings and reduce OHE events in EMMPOWER.”

Axcella has branded the Phase 2 trial EMMPOWER based on the potential for AXA1665, an EMM composition, to help patients, physicians and other caregivers overcome significant challenges associated with cirrhosis and OHE. This randomized, double-blind, placebo-controlled, multi-center investigation will evaluate the efficacy and safety of AXA1665 in patients who have experienced at least one prior OHE event and have neurocognitive dysfunction at screening. Approximately 150 patients on lactulose ± rifaximin (stratified by rifaximin use) will be randomized 1:1 to receive either 53.8 grams per day of AXA1665 or a calorie-matched placebo in three divided doses for 24 weeks, with a four-week safety follow-up period.

“The initiation of EMMPOWER is an important milestone, ushering in an exciting new era of clinical development for Axcella as we seek to tackle a variety of complex diseases utilizing proprietary, multi-targeted EMM compositions,” said Bill Hinshaw, President and Chief Executive Officer of Axcella.

The EMMPOWER trial will be conducted globally at more than 70 clinical sites with a primary endpoint assessing the proportion of patients with a ≥2 point increase in the psychometric hepatic encephalopathy score (PHES) after the 24-week treatment period. The trial’s key secondary endpoints will focus on the proportion of patients experiencing an OHE breakthrough event and time to first OHE breakthrough event, including time to hospitalization. Other secondary endpoints include changes in physical function, including the liver frailty index, and patient-reported outcomes. Measures of circulating ammonia, amino acid profile, and inflammation-related markers will also be included as endpoints.

“By taking on the core drivers of OHE more comprehensively, we not only see the potential for AXA1665 to improve today’s standard of care, but also to eventually become a first-line treatment option,” said Alison Schecter, M.D., President of R&D at Axcella. “On behalf of the Axcella organization, we would like to express our gratitude to the many patients and dozens of clinical global sites that will be involved in this trial as we seek to transform the OHE treatment paradigm.”

Additional trial information can be found on https://clinicaltrials.gov/ via the identifier NCT04816916.

About AXA1665 and Overt Hepatic Encephalopathy (OHE)

Hepatic encephalopathy (HE), one of the most common complications of cirrhosis, is a condition involving amino acid imbalance, ammonia toxicity and muscle wasting, all of which contribute to diminished brain function. OHE refers to the presence of neurological abnormalities that are clinically apparent and do not require specialized psychometric testing. OHE is well established as a significant cause of morbidity and mortality in the cirrhotic population and is an area that continues to have unmet medical needs.

AXA1665, Axcella’s product candidate for reduction in risk of recurrent OHE, is a composition of eight amino acids and derivatives that is designed to target multiple metabolic pathways intersecting key organ systems, including the liver, muscle and gut. In prior clinical studies, this oral product candidate has been safe, well tolerated and has demonstrated the potential to improve ammonia handling, physical function, amino acid balance and neurocognition with a safe and well tolerated profile. AXA1665 is now in Phase 2 development.

About Endogenous Metabolic Modulators (EMMs)

EMMs are a broad family of naturally occurring molecules, including amino acids, that regulate human metabolism. Axcella is developing a range of novel product candidates that are comprised of multiple EMMs engineered in distinct combinations and ratios to simultaneously impact multiple metabolic pathways to modify the underlying causes of various complex diseases and improve health.

About Axcella’s Clinical Studies

Each of the clinical investigations that the company has completed to date have been conducted as non-investigational new drug application (IND) clinical studies under U.S. Food and Drug Administration regulations and guidance supporting research with food. These studies evaluate product candidates for safety, tolerability and effects on the normal structures and functions in humans, including in individuals with disease. They are not designed or intended to evaluate a product candidate’s ability to diagnose, cure, mitigate, treat or prevent a disease. If Axcella decides to further develop a product candidate as a potential therapeutic, as is the case with AXA1665 and AXA1125, any subsequent clinical studies will be conducted under an IND.

Internet Posting of Information

Axcella uses its website, www.axcellahealth.com, as a means of disclosing material nonpublic information and for complying with its disclosure obligations under Regulation FD. Such disclosures will be included on the company’s website in the “Investors and News” section. Accordingly, investors should monitor this portion of the company’s website, in addition to following its press releases, SEC filings and public conference calls and webcasts.

About Axcella

Axcella is a clinical-stage biotechnology company pioneering a new approach to treat complex diseases and improve health using endogenous metabolic modulator (EMM) compositions. The company’s product candidates are comprised of EMMs and their derivatives that are engineered in distinct combinations and ratios to simultaneously impact multiple biological pathways. Axcella’s pipeline includes lead therapeutic candidates for non-alcoholic steatohepatitis (NASH) and the reduction in risk of overt hepatic encephalopathy (OHE) recurrence. For more information, please visit www.axcellahealth.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding the characteristics, competitive position, and development potential of AXA1665, the potential for AXA1665 to improve upon the standard of care for OHE patients and reduce OHE events, and the company’s ability to address other complex diseases utilizing EMM compositions. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, those related to the potential impact of COVID-19 on the company’s ability to conduct and complete its ongoing or planned clinical studies and IND-enabled clinical trials in a timely manner or at all due to patient or principal investigator recruitment or availability challenges, clinical trial site shutdowns or other interruptions and potential limitations on the quality, completeness and interpretability of data the company is able to collect in its planned clinical trial of AXA1665, other potential impacts of COVID-19 on the company’s our business and financial results, including with respect to the company’s ability to raise additional capital and operational disruptions or delays, changes in law, regulations, or interpretations and enforcement of regulatory guidance, whether data readouts support the company’s clinical trial initiation plans and timing, clinical trial design and target indications for AXA1665, the clinical development and safety profile of AXA1665 and its therapeutic potential, whether and when, if at all, the company’s product candidates will receive approval from the FDA or other comparable regulatory authorities, potential competition from other biopharma companies in the company’s target indications, and other risks identified in the company’s SEC filings, including Axcella’s Annual Report on Form 10-K, Quarterly Report on Form 10-Q and subsequent filings with the SEC. The company cautions you not to place undue reliance on any forward-looking statements, which speak only as of the date they are made. Axcella disclaims any obligation to publicly update or revise any such statements to reflect any change in expectations or in events, conditions or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements. Any forward-looking statements contained in this press release represent the company’s views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. The company explicitly disclaims any obligation to update any forward-looking statements.

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