Cu(II)ATSM is being developed for treatment of amyotrophic lateral sclerosis (“ALS”), also known as motor neuron disease (“MND”), and Parkinson’s disease.  An overview of the research that has been performed to date, the rationale for why Cu(II)ATSM may be an effective treatment, and development status are summarized briefly below.

A brief history of the research

Cu(II)ATSM was initially developed in Japan as an imaging agent for hypoxic tissues, based on finding that Cu(II)ATSM selectively delivers copper (“Cu”) to hypoxic tissues but not normal tissues.  In 2005, Kevin Barnham, Paul Donnelly and Anthony White at the University of Melbourne began discussing the potential of Cu(II)ATSM to treat neurodegenerative diseases such as ALS/MND and Parkinson’s disease.  Subsequently, they showed that Cu(II)ATSM selectively releases copper (“Cu”) in cells with damaged mitochondrial electron transport chains, which are characteristic of many neurodegenerative diseases, including ALS/MND, Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease. They also showed that Cu(II)ATSM eliminates peroxynitrite, a chemical that inhibits components of the mitochondrial electron transport chain.

Cu(II)ATSM in models of ALS/MND:  In 2008, researchers led by Peter Crouch at the University of Melbourne initiated studies of Cu(II)ATSM in animal models of ALS/MND associated with a mutated form of SOD1. [Although only about 10% of ALS/MND cases are associated with SOD1 mutations, the SOD1 animal models are commonly used to assess potential treatments for ALS/MND as they replicate many of the clinical features of ALS/MND in humans.] In a series of publications starting in 2010, they showed that Cu(II)ATSM treatment was associated with significant improvements in locomotor function and survival in four different models of SOD1-associated ALS/MND.  Notably, in the SOD1 model of ALS/MND, Cu(II)ATSM was more effective than riluzole, the only approved treatment for ALS/MND. Independent studies from researchers in the USA and Europe confirmed the findings from Australia.

Unfortunately, there is no animal model for sporadic ALS/MND. However, in 2015 researchers led by Peter Crouch published their findings of similar alterations in copper homeostasis in spinal cord from animal models of SOD1-associated ALS/MND and in (post-mortem) spinal cord from humans with sporadic ALS/MND. No alterations in copper homeostasis were found in the spinal cords from humans without ALS/MND. These results suggest that using Cu(II)ATSM to therapeutically modulate copper bioavailability in humans with sporadic ALS/MND may attenuate disease symptoms and prolong survival, as was observed with Cu(II)ATSM treatment in animal models of SOD1-associated ALS/MND.

Cu(II)ATSM in models of Parkinson’s disease: Parkinson’s disease is a neurodegenerative disease that is defined by the presence of Lewy bodies, which primarily consist of aggregated a-synuclein, and is accompanied by the loss of monoaminergic neurons, most prominently dopamine-producing neurons within the substantia nigra.  In 2010, researchers led by Kevin Barnham at the University of Melbourne initiated studies of Cu(II)ATSM in four different animal models of Parkinson’s disease.  In a series of publications starting in 2012, they showed that oral administration of Cu(II)ATSM after the onset of toxin-mediated cell death resulted in significant improvements in motor coordination, dopamine metabolism and cognition, reduced levels of a-synuclein dimer, and neuroregeneration (increased number of nigral neurons).  Independent studies from researchers in Japan, USA and Europe confirmed the findings from Australia.

Moving from the laboratory into the clinic

Since licensing commercial rights to Cu(II)ATSM, CMD has developed a formulation of Cu(II)ATSM with improved aqueous solubility and improved oral bioavailability in animals; developed processes for large scale manufacturing of clinical supplies of the Cu(II)ATSM formulation in compliance with Good Manufacturing Practices (“GMP”); completed repeated oral dose toxicology studies in rodents and non-rodents to define target organ toxicities and the starting dose for clinical trials; and completed a panel of tests to show that Cu(II)ATSM has no genotoxic potential at surpa-therapeutic doses.  CMD has announced plans to initiate a dose-finding study of Cu(II)ATSM in patients with ALS/MND in Australia.  Once the trial has been approved by regulatory authorities, details will be posted on