Endogenous treatment for NASH

Axcella reports that AXA1125 performed well in models of NASH and diabetes

Register for free to listen to this article
Listen with Speechify
CAMBRIDGE, Mass.—Axcella Health is using endogenous metabolic modulators, which include amino acids, to impact human disease. These acids, in contrast to synthetic or reengineered molecules, have a known safety profile within the body and have shown a long history of self-proliferation, signaling and differentiation.
Of course, when these classic molecules go awry, diseases can emerge. Axcella harnesses these innate resources, designing unique compositions that work with the body to ameliorate relevant diseases.
Their latest success story joins an already crowded field of non-alcoholic steatohepatitis (NASH) research and treatment. NASH is an advanced fatty liver disease that involves liver inflammation and scarring. The composition in question, AXA1125, has performed positively across metabolism, inflammation and fibrosis, the main fields of interest in NASH. AXA1125 affects multiple pathways at the same time safely, which could potentially mean significant results for large numbers of people. This fruitful multifactorial effect suggests a highly promising new treatment modality for NASH and diabetes.
“What attracted me to Axcella,” says Shreeram Aradhye, the company's executive vice president and chief development officer, “is a modality that works with the body, relying on the body’s own pathways to master regulation by endogenous molecules. There’s an inherent known safety of individual amino acids. Computational biology has enabled us to develop an understanding of how multiple pathways interact with each other and how specific compositions of amino acids in distinct ratios have the possibility of impacting multiple pathways simultaneously.”
AXA1125 began with a known set of amino acids in liver biology, coupled with a deep review of literature and cell data to understand which acids impact key biologies. The company explored reprogramming the pertinent metabolic pathways to reverse the dysregulation found in liver disease, such as insulin resistance and glucose dysregulation, or lipotoxicity. The results proved very positive, significantly reducing inflammatory markers, liver fat content and fibrosis without toxic side effects.
“Given our multifactoral effects across the metabolic informational fibrogenic pathways, in addition to its excellent tolerability profile, we have been better positioned to initiate conversations with the FDA much earlier than we normally would have been,” asserts Manu Chakravathy, senior vice president of clinical development and chief medical officer at Axcella.
NASH is closely correlated with diabetes, as both diseases feature insulin resistance and lipotoxicity, so it is no surprise that AXA1125 showed even stronger results in diabetic subjects. Because the composition reprograms the associated metabolic pathways, the greater the dysregulation, the greater the impact.
According to study consultant Steven Harrison, if the results continue to pan out as these initial findings suggest, AXA1125 has the potential to be a real game-changer. Simply finding an oral insulin desensitizer that doesn't cause weight gain has been a real challenge. AXA1125, according to a recent press release, performed strongly. Fifty-five percent of diabetic subjects saw a relative reduction in MRI-PDFF—a non-invasive, quantitative and accurate measure of liver fat content used to assess treatment response in NASH trials—from baseline of more than 30 percent. They also saw a relative reduction in the liver enzyme ALT of 35 percent.
As obesity rates increase across the globe, so too does the incidence rate of type 2 diabetes. As Axcella embarks on their Phase 2B study, likely in the first half of 2021, one focus will be in the exploration of introducing the therapy in pediatric care to help forestall childhood disease. In addition, that the platform leverages science and already innate amino acids means the signaling molecules can be investigated beyond the liver. The team is exploring how their carefully modulated biologies might benefit muscle atrophy, sickle cell anemia, cirrhosis of the liver and overt hepatic encephalopathy.
“We’re designing multifunctional drugs,” states Aradhye. “We design unique compositions of endogenous modulators to simultaneously target multiple biologies in discovering what is relevant. Because we have long known of the safety of individual compositions, we can do it in an extremely efficient manner. All of our programs have generated human data in under two years.”

Published In:

Subscribe to Newsletter
Subscribe to our eNewsletters

Stay connected with all of the latest from Drug Discovery News.

DDN Magazine May 2024

Latest Issue  

• Volume 20 • Issue 3 • May 2024

May 2024

May 2024 Issue