CNM-Au8 Improved Brain’s Energetic Profile in Parkinson’s Patients
CNM-Au8, an experimental oral treatment by Clene Nanomedicine, was safe and led to improvements in the brain’s energetic profile — thought to protect against cell death — in adults with Parkinson’s disease, according to data from the Phase 2 clinical trial REPAIR-PD.
“In addition to achieving its primary [goal], the [REPAIR-PD] study reinforced our lead candidate CNM-Au8’s central nervous system target engagement, as well as its ability to significantly rebalance brain [energetic] metabolites, both of which have implications across most neurodegenerative diseases,” Rob Etherington, Clene’s CEO, said in a press release.
The central nervous system (CNS) comprises the brain and spinal cord, and metabolites are intermediate or end products of metabolism.
Robert Glanzman, MD, Clene’s chief medical officer, said: “We see CNM-Au8’s impact on brain bioenergetics as a breakthrough in the way Parkinson’s will be treated.”
These findings, supporting CNM-Au8’s further development in Phase 2b and 3 trials, were shared by Glanzman through a poster presentation at the International Parkinson and Movement Disorder Society (MDS) Virtual Congress 2021, which took place Sept. 17–22.
Parkinson’s disease is characterized by the progressive loss of neurons that produce dopamine, a major brain chemical messenger that supports nerve cell communication. Nerve cells are particularly susceptible to energetic deficiencies because they require large amounts of energy to function.
Problems in mitochondria, the cell’s powerhouses, as well as oxidative stress, have been associated with several neurodegenerative diseases, including Parkinson’s. Oxidative stress is an imbalance between the production of harmful free radicals — that occurs mostly in mitochondria — and cells’ ability to detoxify them.
CNM-Au8 is a stable suspension of pure gold nanocrystals designed to increase energy production. Specifically, it works by boosting the conversion of one molecule to another — nicotinamide adenine dinucleotide (NADH) to its oxidized form (NAD+) — replenishing NAD+ pool used by cells to produce ATP, their main “energy currency.”
Notably, the NAD+/NADH ratio has been shown to decline with age by about 0.5% per decade, and a ratio decline has been implicated in Parkinson’s disease.
In addition, CNM-Au8 has antioxidant properties that may help protect cells against oxidative stress.
By restoring energy balance and reducing oxidative stress, the therapy is expected to prevent nerve cell death and slow disease progression in Parkinson’s patients.
Promising data in cellular and animal models, showing that CNM-Au8 prolonged the survival of dopamine-producing neurons and improved motor function, supported the launch of the pilot Phase 2 REPAIR-PD trial (NCT03815916).
Initiated in 2019, the study was designed to evaluate CNM-Au8’s safety, pharmacokinetics, pharmacodynamics, and CNS metabolic effects in up to 30 adults, ages 30 to 80, diagnosed with Parkinson’s disease within the past three years.
Pharmacokinetics refers to the therapy’s movement into, through, and out of the body, while pharmacodynamics concerns its effects on the body.
REPAIR-PD enrolled 13 patients (six women and seven men) at the University of Texas Southwestern Medical Center, and its currently not recruiting more patients. However, according to Clene, the trial may reopen and enroll new patient dosing groups, depending on discussions with trial investigators.
Participants, with a mean age of 65.9 years and all on dopaminergic therapy, drank two ounces of CNM-Au8 daily each morning for 12 weeks (about three months).
The trial’s main goal was to assess changes in the NAD+/NADH ratio, reflecting the brain’s bioenergetic potential, while secondary goals included level changes in total NAD+ and NADH, as well as other bioenergetic metabolites, or critical markers of brain energy production capacity.
The brain levels of these molecules were measured using a new imaging technique called 31P-Magnetic Resonance Spectroscopy.
Consistent with the study’s interim data from six patients, results from the 13 participants showed that three months of treatment with CNM-Au8 improved the brain’s energetic profile of Parkinson’s patients.
“There was a trend in increased NAD+/NADH ratio, which was driven by both increased NAD+ and decreased NADH,” Glanzman said in the poster presentation, adding that these changes did not reach statistical significance due to a higher-than-expected variability between patients’ responses.
Notably, when combining data from REPAIR-PD and REPAIR-MS (NCT03993171) — a similar Phase 2 trial in 11 people with multiple sclerosis (MS) — CNM-Au8 treatment resulted in a significant, 10% increase in the NAD+/NADH ratio.
This “corresponds to a reversal of approximately 20 decades of normal aging based on an anticipated decline of 0.5% per decade, a significant result,” Glanzman said in the release.
In the REPAIR-PD study, the therapy also led to a rebalancing of brain energy production markers, such as beta-ATP and phosphorylation potential, “showing that CNM-Au8 has a profound normalization [effect] on bioenergetic capacity in the brain of Parkinson’s patients,” Glanzman added.
CNM-Au8 was generally safe, with few reports of adverse side effects, which were temporary and mild in severity. There were no reports of serious events or abnormalities in lab results.
Also, after three months of treatment, Parkinson’s patients showed no clinical worsening, as assessed with the MDS-Unified Parkinson’s Disease Rating Scale.
These findings “demonstrated target engagement with CNM-Au8 in the brains of patients with Parkinson’s disease, supporting further development in Phase 2 and Phase 3 clinical trials,” Glanzman said.