A D V E R T I S E M E N T F E A T U R E
A D V E R T I S E R R E TA I N S S O L E R E S P O N S I B I L I T Y F O R C O N T E N T
Axial Therapeuticsaxialtx.com
Harnessing the gut–brain axis todevelop CNS therapeuticsAxial Therapeutics focuses on the gut–brain axis to develop therapeutics to mitigate centralnervous system disorders and conditions. The company has built a pipeline of novel smallmolecules with lead programs in autism spectrum disorder and Parkinson’s disease.
Axial Therapeutics is a clinical-stage biopharmaceu-tical company harnessing the gut–brain axis (G–BA)to develop safe and effective therapies for patientsimpacted by central nervous system (CNS) disor-ders and conditions. Using its ‘omics’ platform, thecompany has built a deep pipeline of gut-restrictedsmall molecules based on pioneering research fromits cofounder, Sarkis Mazmanian, and his lab at theCalifornia Institute of Technology. Axial’s pipelinehas significant potential for mitigating underlyingdisease pathology and resulting symptoms.
“Targeting diseases believed to be of CNS originvia the gut microbiome is a disruptive concept,”said David Donabedian, CEO and cofounder ofAxial. “There’s a growing body of evidence aboutthe G–BA, and our ‘omics’ platform allows us to seeconstellations where others only see stars, puttingus at the forefront of scientific research validatingthe G–BA in CNS diseases and developing innova-tive, safe and effective therapies.”
Axial’s lead programs include AB-2004, a gut-restricted, first-in-class compound poised to firstredefine the treatment of irritability in children withautism spectrum disorder (ASD), and AB-4166, anoral compound that reduces gastrointestinal (GI)symptoms, i.e., colonic dyskinesia in patients withParkinson’s disease (PD). Other programs in preclinicaldevelopment include additional small molecules for PD,a rare CNS disorder, and most recently oncology (Fig. 1).
The gut–brain axis in CNS diseaseAxial has developed a unique platform that com-bines the study of human samples and experimentalapproaches with proprietary in vivo models to estab-lish the role of the gut microbiome in diseases to iden-tify novel G–BA-specific targets. Once a novel targetis validated, Axial designs and develops new chemicalentities. The Axial approach has two distinct and criti-cal advantages over other approaches. By targetingthe gut microbiome, the challenge of crossing theblood–brain barrier is eliminated. Additionally, thegut-restricted therapies minimize systemic exposure,resulting in exceptional safety profiles.
Studies have revealed profound differencesbetween the gut microbiomes of children withASD and those of typically developing children.These differences result in altered concentrationprofiles of certain bacteria-derived metabolites,including levels of so-called neuroactive microbialmetabolites (NMMs) that are produced in the gut,but reach the brain, altering neuronal networks andactively contribute to ASD and other CNS disorders.
Axial’s AB-2004 is designed to remove NMMslinked to ASD-associated behaviors with high affinityand selectivity. The compound effectively removes theNMMs in the gut, limiting their impact on the brain.
In a phase 1b/2a open-label clinical trial of malesaged 12 to 17 with ASD, AB-2004 exhibited a favor-able safety profile with no drug-related adverseevents. Importantly, levels of key NMMs, includ-ing 4-ethylphenylsulfate (4-EPS), p-cresol sulfate(p-CS) and indoxyl sulfate (IS) were substantiallyreduced in plasma and urine. With >�90% adher-ence to the dosing regimen, significant improve-ments in subjects with high irritability and highanxiety scores were observed.
Axial has initiated activities for a pediatric phase2b randomized, double-blind, placebo-controlledstudy for irritability associated with ASD. Thecompany plans to file an IND in the last quarter of2020 and seek US Food and Drug Administrationbreakthrough/fast-track therapy designation.
A gut–amyloid link in Parkinson’s diseaseParkinson’s disease is a neurodegenerative disor-der characterized by motor impairment resultingfrom damage to the dopaminergic neurons of thesubstantia nigra and the formation of α-synucleininclusion bodies (Lewy pathology) in several otherbrain regions. Certain gut bacteria produce amy-loids that accelerate α-synuclein propagation fromthe gut to the brain. In preclinical PD models, the
bacterial amyloid CsgA, the major curli subunit,induces α-synucleinopathy and a PD phenotype.
Small molecules developed by Axial block CsgAaggregation resulting in reduced α-synucleinopathyand overall motor improvement. In a small studywith PD subjects exhibiting elevated bacterialamyloid levels and GI symptoms, AB-4166 dem-onstrated improvements in GI symptoms such asconstipation and a reduction in colonic dyskinesiawhile maintaining a strong safety profile. A newmore potent chemical entity, AB-5006, is in latestage preclinical development.
Axial is seeking collaborators interested in lever-aging its omics platform to identify new targets andadvance the development of its pipeline.
“Not long ago, neuroscientists would never havebelieved that a therapeutic targeting the gut and notthe brain, could have an impact on CNS disorders andconditions,” said Donabedian. “With our platformand groundbreaking approach, we look forward tobringing new treatments to the market and improv-ing the lives of patients and families worldwide.”
Immunesystem
Metabolites ‘Leaky gut’Proteinaggregates
Inflammatorysignals
Gut microbiota
Neurotransmitters
Neurodegeneration
Neuroinflammation
Neuroplasticity
PD AB-5006Oncology AB-6000 series
Mast cellEnteroendocrine cell
Enteric nervous system→ vagus nerve Peripheral
circulation
ASD/Rare CNSAB-2004, AB-2000 series
PDAB-4166,AB-5006
Fig. 1 | Harnessing the gut–brain axis to treat CNS disorders. Axial’s therapies target specific processesincluding the enteric nervous system, the immune system and neuroactive microbial metabolites (NMMs) inperipheral circulation. ASD, autism spectrum disorder; CNS, central nervous system; PD, Parkinson’s disease.
David H. Donabedian, Cofounder & CEOAxial TherapeuticsWaltham, MA, USATel: +1-781-701-8468Email: [email protected]
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www.nature.com/biopharmdeal | December 2020 | B13
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