CuATSM is a small synthetic molecule that contains copper. CuATSM was initially developed in Japan as an imaging agent for hypoxic tissues, based on finding that CuATSM selectively delivers copper 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 CuATSM to treat neurodegenerative diseases. Subsequently, they showed that CuATSM selectively releases copper 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 CuATSM eliminates peroxynitrite, a chemical that inhibits components of the mitochondrial electron transport chain. CMD licensed commercial rights to CuATSM for treatment of neurodegenerative diseases from the University of Melbourne.
ALS is a rare degenerative disorder of the large motor neurons that supply voluntary muscles. The effect clinically is progressive muscle weakness leading to death; patients usually die from respiratory failure within 3 years of symptoms onset.
Although there are likely multiple mechanisms involved in ALS pathogenesis, results from various postmortem and biochemical studies indicate that oxidative stress and mitochondrial dysfunction are the most probably and principle molecular mechanisms of motor neuron degeneration in all forms of ALS. Mitochondrial dysfunction associated with oxidative damage is observed in nearly all cases of ALS.
The following findings supported initiation of a clinical study of CuATSM for treatment of ALS:
- Evidence of copper dysfunction in post-mortem spinal cord and motor cortex from patients with idiopathic ALS. Compared with tissues from unaffected controls, spinal cord/motor cortex from ALS patients showed a significant decrease in copper content, and decreased activity of major cuproenzymes, including ceruloplasmin, superoxide dismutase-1 (SOD1), and cytochrome C oxidase. Similar findings have been reported in mouse models of SOD1-related ALS;
- Phase 0 clinical PET imaging studies showing [62Cu]ATSM delivers copper selectively to motor neuron related areas in patients with ALS compared with age-matched unaffected controls. Additionally, increased tracer accumulation was correlated with disease severity assessed by the ALS Functional Rating Scale-Revised (ASLFRS-R);
- Demonstration by three independent laboratories—Peter Crouch at the University of Melbourne, Joe Beckman at Oregon State University, and Fernando Vieira at the ALS Therapy Development Institute– that CuATSM treatment significantly improved locomotor function and prolonged survival in mouse models of SOD1-related ALS. Importantly, the ALS Therapy Development Institute reported that their finding of CuATSM efficacy in an aggressive mouse model of ALS was the first time in over 15 years of testing over 100 potential drugs that they have been able to reproduce published reports of efficacy using rigorously controlled testing methods; and
- No findings from preclinical ADME and safety studies that would preclude clinical development.
In October 2016, CMD initiated a first-in-man (at therapeutic doses) phase 1 dose-finding and pharmacokinetic (PK) study of CuATSM in patients with both sporadic and familial ALS (Study CMD-2016-001; clinical trial information: NCT02870634). Dose cohorts (n=6) are evaluated for PK and safety following administration of a single oral doses, followed by a 28-day repeated daily dose safety study. Patients whom the investigator considers are benefitting from treatment may continue to receive up to six 28-day cycles of treatment. Safety assessments (physical exam, vital signs, hematology, serum chemistry) are performed at baseline, once weekly during the first 28-day cycle of treatment, and after each subsequent cycle of treatment. Efficacy assessments (disease severity for ALSFRS-R score, respiratory function by forced vital capacity (FVC) and sniff nasal pressure (SNP), cognitive function by the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS), and quality of life by the ALS Specific Quality of Life (ALSSQOL-R) score) are measured at baseline and after the first and sixth cycle of treatment. Provided that treatment is well tolerated, dose escalation will continue until ALS patients show plasma levels equivalent to those seen in mice given 30 mg/kg/day, a dose level that showed significant treatment benefits in mouse models of ALS.
At the MNDA meeting in Boston in December 2017, CMD presented interim safety results for the first three dose cohorts. Based on PK findings for the first four dose cohorts, completed shortly after the MNDA meeting, CMD expects to complete the dose-finding phase of the study in March 2018.