Science and Clinical Program

The Science of 3K3A-APC in Amyotrophic Lateral Sclerosis (‘ALS’)

ZZ Biotech ALS ProgramIn 2009, researchers in Professor Zlokovic’s lab demonstrated in mutant mice superoxide dismutase-1 (SOD1) mice that administration of APC or 3K3A-APC after disease onset slows ALS disease progression and extends survival.

In 2014, researchers at Professor Zlokovic’s lab were able to show that blood brain barrier breakdown contributes to early motor-neuron degeneration in ALS mice and that restoring BBB integrity via 3K3A-APC during an early disease phase retards the disease process.

In 2019, researchers at the University of Southern California demonstrated that Induced Motor Neurons (iMNs) from C9ORF72 and several sporadic ALS patients share two common defects – impaired autophagosome formation and aberrant accumulation of glutamate receptors. It was shown that 3K3A-APC treatment lowers C9ORF72 dipeptide-repeat protein (DPR) levels, restores nuclear TDP-43 localization, and rescues the survival of both C9ORF72 and sporadic ALS iMNs; and that 3K3A-APC also lowers glutamate receptor levels and rescues proteostasis in vivo in C9ORF72 gain- and loss-of-function mouse models.

A Phase 2 Trial of 3K3A-APC in ALS 2021

Professor Dominic Rowe at Macquarie University Hospital runs the largest motor neuron diseases clinic in Australia. As Principal Investigator, Professor Rowe is currently conducting a Phase 2 clinical trial (NCT05039268) of 3K3A-APC in ALS looking at several biomarkers of disease activity. The trial started in December 2021 and is testing an escalating acute dose regimen of 3K3A-APC in patients to determine safety and tolerability. A further endpoint is PET imaging to determine whether microglial activation can be modulated with imaging at baseline, day 3, day 7 and day 14. Other biomarkers of microglial/monocyte activation are being assayed.

No trial thus far has attempted to use an acute therapeutic regimen to attenuate microglia activation, with in vivo assessment of end organ penetration and efficacy. This study should answer the question whether microglia activation is a major pathogenic contributor to ALS.