The first clinical trial of copper-ATSM as a potential treatment option for motor neurone disease (MND) started recruiting for Phase 1 in November 2016.
Copper-ATSM therapy was developed in Australia. Its chemical name is diacetylbis(4-methylthiosemicarbazonato) copperII but it is often abbreviated to Cu-ATSM, CuII(atsm) or copper-ATSM. CuATSM is a small artificial molecule able to cross the blood-brain barrier and deliver copper to cells containing damaged mitochondria, the cell compartments responsible for the production of energy. Damaged mitochondria are considered a hallmark of several neurodegenerative disorders, including MND.
Research has shown copper-ATSM can protect motor neurones in the spinal cord, improve MND-like symptoms, and extend the lifespan of mice with a mutated form of SOD1. It is more effective in mutant SOD1 mice than riluzole (the only approved treatment for MND in Australia).
Research to date has been conducted on familial MND animal models. There is no animal model for sporadic MND. However, in 2015 Peter Crouch and colleagues at The University of Melbourne and the Florey Institute found MND-affected tissues obtained from people who died because of sporadic MND had important similarities to mice that responded to copper-ATSM. This suggests that copper-ATSM may have activity in both sporadic and familial MND.
Phase 1 of the study was conducted at two sites in Australia and was completed at the end of 2018. This phase identified a safe dosage of copper-ATSM. This trial was undertaken in patients with sporadic and familial ALS who received CuATSM for six months. The initial reports from this study claimed that the potential therapy slowed disease progression, as well as participants’ cognitive and lung function decline. However, the trial was too small and too short to support those claims. The Phase 1 trial did identify the dosing regimen that should be used for the Phase 2/3 trials, however.
The Phase 2/3 trial evaluated the efficacy and safety of CuATSM. The multicentre, randomised, double-blinded, placebo-controlled study recruited 80 ALS patients at four clinical sites in Australia. The aim is to evaluate efficacy (whether the compound works as intended) and to further evaluate safety. Patients involved in this phase of the trial were randomly assigned Cu-ATSM or a placebo for 6x28 day cycles.
This trial has now been completed and we are currently waiting to hear of the results.
A possible treatment resulting from these studies is many years away. Phase 1 determined a safe dose of copper-ATSM. The Phase 2/3 results are yet to be released.
Motor Neurone Disease Research Australia has invested more than $1.2 million to support three projects that aim to assist developing copper-ATSM as a potential therapeutic. These projects are:
Betty Laidlaw MND Research Grant: Copper malfunction in motor neurone disease: a therapeutic target for sporadic MND
zo-ee MND Research Grant: Proteomic investigation of functional copper deficiency in MND
Jenny Barr Smith MND Collaboration Grant: Drug-specific biomarkers to facilitate clinical translation of CuII(ATSM) as a potential therapeutic for MND,