Axcella Health Submits Prospectus Highlighting EMM-Based Therapies for Complex Diseases

On February 14, 2022, U.S. biotechnology company Axcella Health (NASDAQ: AXLA, hereinafter referred to as “Axcella”) announcedThe FDA has granted Fast Track designation to AXA1125 for the treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis.。

AXA1125 is a multi-targeted oral endogenous metabolic modulator (EMM) with the potential to reduce established markers of hepatic steatosis, inflammation, and fibrosis.

AXA1125 is one of Axcella’s EMMs therapeutic candidates. The recent FDA Fast Track designation undoubtedly underscores the potential of Axcella’s novel therapies in treating complex diseases.

Axcella is a clinical-stage biotechnology company, formerly known as Pronutria Biosciences, which was founded in 2009 by the venture capital firm Flagship Pioneering. In June 2016, Pronutria Biosciences was renamed Axcella Health,to better reflect its mission of promoting cellular health through amino acids, leveraging a systems pharmacology approach。

Axcella has pioneered a novel approach to treating complex diseases using endogenous metabolic modulators (EMMs). EMMs encompass a broad family of molecules, including amino acids and their derivatives. As key regulators and signaling agents in systemic metabolic pathways, EMMs fundamentally influence and regulate metabolism, thereby controlling numerous biological functions.

Complex diseases involve the dysregulation of multiple biological pathways that converge into distinct nodes. Conventional therapies, which employ single-target drugs, can only address individual metabolic or disease nodes,However, EMMs compositions may exert synergistic effects on multiple metabolic pathways associated with health and disease, enabling more effective treatment of complex conditions. Axcella believes that EMMs compositions hold potential applications in the fields of inflammatory diseases, immune disorders, metabolic diseases, mitochondrial diseases, and muscular atrophy.

Comparison of Single-Target Therapy and Axcella Multi-Target Therapy (Source: Axcella Official Website)

Axcella aims to combine its deep understanding of biological pathways with the latest advances in systems biology and machine learning to unlock the full therapeutic potential of EMMs.

Axcella has created a platform that integrates metabolic expertise, relevant reasoning algorithms, proprietary non-clinical systems, advanced analytics, and safety databases to develop EMM candidates.This platform primarily encompasses three processes: data, design, and development.

Axcella’s Proprietary Platform Process (Source: Axcella Official Website)

Leveraging this platform, Axcella is currently developing two therapeutic candidates: AXA1125 and AXA1665, targeting three complex diseases: non-alcoholic steatohepatitis (NASH), Long COVID, and overt hepatic encephalopathy (OHE).

Axcella’s R&D Pipeline (Image source: Axcella official website)

AXA1125 is a multi-targeted oral endogenous metabolic modulator that received FDA Fast Track designation in 2022 for the treatment of NASH with liver fibrosis.

Non-alcoholic fatty liver disease (NAFLD) refers to a group of disorders characterized by excessive fat accumulation in the liver among individuals who consume little or no alcohol.A small subset of patients may progress to a more severe stage, known as non-alcoholic steatohepatitis (NASH). NASH can lead to significant hepatic fibrosis and cirrhosis.

Approximately one-quarter of the global population suffers from non-alcoholic fatty liver disease (NAFLD), which has become a major driver of the accelerated increase in hepatocellular carcinoma (HCC) incidence in the United States, France, and the United Kingdom. Over the next decade, the prevalence of non-alcoholic steatohepatitis (NASH) among individuals with NAFLD is projected to rise to 56%, likely continuing to push up HCC incidence rates.

Axcella’s latest data indicate that AXA1125-associated changes in metabolic profiles can serve as predictive markers for reductions in hepatic fat content in patients with nonalcoholic fatty liver disease (NAFLD). Currently, Axcella is conducting the EMMPACT Phase 2b clinical trial of AXA1125 (NCT04880187)., to evaluate the efficacy and safety of AXA1125 in patients with biopsy-confirmed F2/F3 NASH. The trial enrolled approximately 270 patients. Axcella plans to release interim data in mid-2022.

In addition to NASH, AXA1125 also holds potential for treating patients with Long COVID.

Long COVID (also known as Post-COVID conditions or long-term COVID) refers to a range of new, recurring, or persistent health issues that individuals may experience four weeks or longer after their initial infection with the novel coronavirus (COVID-19).

Long COVID may trigger various combinations of the following symptoms:

Some patients with severe COVID-19 experience prolonged multi-organ dysfunction, adversely affecting vital organs such as the heart, lungs, and kidneys, and may also trigger autoimmune diseases.

The WHO estimates that approximately 10–20% of patients with acute COVID-19 infection experience residual symptoms lasting from weeks to months after infection.

While patients with Long COVID continue to suffer, the medical community is actively investigating the disease’s triggers and treatment options. Growing evidence indicates that SARS-CoV-2 infection impairs mitochondrial function—the “powerhouses of the cell”—manifesting as fatigue and muscle weakness in Long COVID.

Preclinical and clinical study results have demonstrated that AXA1125 has the potential to improve mitochondrial energy and reduce inflammation, thereby providing better therapeutic options for patients with Long COVID.

A Phase 2a clinical trial of AXA1125 for Long COVID (NCT05152849) is currently underway.This is a 28-day, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of AXA1125 in approximately 40 patients with exertional fatigue associated with Long COVID. Axcella plans to complete enrollment for the Phase 2a trial in the first half of 2022 and release the relevant data in mid-2022.

AXA1665 is a multi-targeted oral EMM composition consisting of eight amino acids and derivatives, targeting three key nodes: ammonia toxicity, amino acid imbalance, and muscle atrophy.

Asp and Orn are designed to promote urea cycle function. BCAAs (branched-chain amino acids) are intended to improve amino acid balance and increase protein synthesis. His, Lys, and Thr, along with other amino acids, are used to support protein synthesis and improve muscle function.

Mechanism of Action of AXA1665

AXA1665 for Overt Hepatic Encephalopathy (OHE). Liver cirrhosis is an advanced stage of liver disease, and OHE is one of the most common complications of cirrhosis. It is characterized by impaired brain function due to the accumulation of toxins in the blood, primarily ammonia.

In the United States, the prevalence of cirrhosis is estimated at 633,000 adults, among whom 10% to 14% have overt hepatic encephalopathy (OHE).

Axcella has completed two clinical studies (non-IND) of AXA1665. The results indicate that AXA1665 is generally well-tolerated, demonstrates activity across multiple biologics, and that higher doses of AXA1665 show positive effects on key markers of ammonia metabolism, amino acid balance, and muscle structure and function.

AXA1665 is currently undergoing the EMMPOWER Phase 2 clinical trial, which has enrolled approximately 150 patients with a history of OHE.

To further expand its R&D pipeline and accelerate development progress, Axcella has adopted a dual-pronged strategy of pursuing collaborations and increasing R&D investment.

In October 2019, Axcella partnered with CYTOO, a preclinical drug development company, to leverage CYTOO’s MyoScremm platform to advance the development of novel AXA candidate drugs.

In the first nine months of 2021, Axcella’s R&D expenses amounted to $30.7 million, an increase of $4.3 million year over year, primarily used to support clinical trial activities for two drug candidates in development.

As of December 31, 2020, Axcella’s global intellectual property portfolio comprised 22 patent families, 6 issued U.S. patents, and 283 pending global patent applications.The intellectual property matrix includes trade secrets and trademarks, product candidates (various ingredients and quantities), indications, development platforms, manufacturing processes and technologies, formulations, and other content.

In May 2019, Axcella raised $71.4 million in its initial public offering (IPO), bringing its total funding to over $230 million when combined with the five previous rounds of financing.

Axcella Financing Status

Axcella’s ability to secure such a substantial financing round and complete its initial public offering was due in part to the company’s intrinsic value, and in no small measure to the support of venture capital firm Flagship Pioneering (hereinafter referred to as “Flagship”).

Flagship has participated in nearly every financing round of Axcella, providing substantial financial support. According to data from Qichacha as of March 31, 2021, Flagship had become the largest shareholder of Axcella, holding a 33.3% equity stake.

According to Nasdaq data, as of February 24, 2022, Axcella’s closing price was $1.69, with a market capitalization of approximately $68.5 million.

Product R&D and the company’s rapid growth are inseparable from team support.

Axcella’s leadership team brings extensive experience in biopharmaceuticals, research and development, clinical affairs, and commercialization. Bill Hinshaw, President and Chief Executive Officer of Axcella, joined the company in May 2018. He has approximately 30 years of experience leading commercial, medical, clinical development, strategy, finance, legal, policy, and operations teams within the life sciences industry. Previously, he served as Executive Vice President of Novartis Pharmaceuticals’ U.S. Oncology division, where he spent 15 years and led the launch of more than a dozen products, including Tasigna®, Gleevec®, and Kymriah®. He also served as Head of Novartis Oncology for the Nordic and Central Europe regions, overseeing all functional areas across 33 countries. Mr. Hinshaw holds a Bachelor’s degree in Molecular Biology from the University of Wisconsin.

President and CEO Bill Hinshaw (Image source: Axcella official website)

David Epstein, an Executive Partner at Flagship Pioneering, serves as the Chairman of Axcella. Mr. Epstein previously served as Chief Executive Officer of Novartis Pharmaceuticals and currently holds the position of Executive Chairman at International Flavors & Fragrances (NYSE: IFF), biotechnology company Evelo Biosciences (Nasdaq: EVLO), and biopharmaceutical company Rubius Therapeutics (Nasdaq: RUBY). He holds an MBA in Finance and Marketing from Columbia Business School and a Bachelor of Science in Pharmacy from Rutgers University.

ChairmanDavid Epstein (Image source: Axcella official website)

The Board of Directors boasts a wealth of talent. In addition to Epstein and Hinshaw, it includes seven members with extensive industry experience, such as Dr. Cristina M. Rondinone, Founder of CMR Pharmaceutical Consulting; Greg Behar, CEO of Nestlé Health Science; and Dr. Catherine A. Sohn, Adjunct Professor at the University of California, San Francisco.

Furthermore, Axcella has assembled a scientific advisory team comprising professionals from the medical industry, including a Distinguished Service Professor at Harvard Medical School, the Director of the Sarah W. Stedman Nutrition and Metabolism Center, the Chief Medical Officer of Flagship Pioneering, the CEO of the biotechnology company Kallyope, and a Professor of Human Genetics at the University of Pittsburgh.

References: Huang Daniel Q, ElSerag Hashem B, Loomba Rohit. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention.[J]. Nature reviews. Gastroenterology & hepatology,2020: