Clinical Trials

ALS Trial

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.   

More Information

More details of the ALS Trial can be found at here.

And details of the extension study can be found here.

Parkinsons Trial

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.

Parkinson’s disease is a progressive neurodegenerative disorder mainly affecting the motor system.  A hallmark pathological feature of Parkinson’s disease is loss of dopaminergic neurons of the substantia nigra. Neurologic deficits emerge when the availability of dopamine fills below the level required for rapid compensation or when the system is subjected to certain pharmacologic, environmental or physiologic challenges.  While Parkinson’s disease itself is not fatal, disease complications, including fatal falls, aspiration (accidently breathing in food or foreign objects), deep vein thrombosis, and pulmonary embolism, can reduce life expectancy. 

There are likely mechanisms underlying the development of Parkinson’s disease, involving multiple related processes, including mitochondrial dysfunction, oxidative and nitrative stress, microglial activation and inflammation, and aggregation of α-synuclein and impaired autophage. The role of environmental exposure and the contribution of single genetic risk factors remains controversial.  In most cases of Parkinson’s disease, disease onset is probably triggered by a complex interplay of many genetic and non-genetic factors, each of which conveys a minor increase in risk of disease.   Mitochondrial dysfunction and associated molecular pathways appear to represent a bridge between the idiopathic and familial forms of Parkinson’s disease and mitochondrial dysfunction has been widely accepted as a central pathogenic mechanism underlying Parkinson’s disease.

The following findings supported initiation of a clinical study of CuATSM for treatment of Parkinson’s disease:

  • Evidence of copper dysfunction in post-mortem substantia nigra from patients with idiopathic Parkinson’s disease.  Compared with tissues from unaffected controls, SN from Parkinson’s disease 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 Parkinson’s disease;
  • Phase 0 clinical PET imaging studies showing [62Cu]ATSM delivers copper selectively to the striatum in patients with Parkinson’s disease compared with age-matched unaffected controls. Additionally, increased tracer accumulation was correlated with disease severity assessed by the Unified Parkinson Disease Rating Scale (UPDRS) score;
  • Demonstration in four different mouse models of Parkinson’s disease, conducted by Kevin Barnham at the University of Melbourne, that CuATSM treatment enhances dopamine levels in the striatum, reduces toxic forms of α-synuclein in the substantia nigra, and prevents neuronal cell death; and 
  • No findings from preclinical ADME and safety studies that would preclude clinical development. 

Because Parkinson’s disease itself is not fatal, the phase 1 study in Parkinson’s disease was not initiated until the first two dose cohorts in the ALS study had been completed successfully.  The starting dose for the Parkinson’s disease study was a dose that had been shown to be well tolerated in the ALS study.

In August 2017, CMD initiated a phase 1 dose-finding study of CuATSM in patients with early idiopathic Parkinson’s disease (Study CMD-2016-002; clinical trial information: NCT03204929).  Dose cohorts (n=6) are evaluated for safety following administration of daily oral doses for 28 days.  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, serum metals) 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 UPDRS score, cognitive function by the Montral Cognitive Assessments (MoCA) score, constipation by the Wexler Constipation Score, and quality of life by the 39-item Parkinson’s Disease Questionnaire (PDQ-39)) are measured at baseline and after the first and sixth cycle of treatment.  Provided that treatment is well tolerated, dose escalation will continue until 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 Parkinson’s disease. 

More Information

More details of the Parkinsons Trial can be found at here.