CNM-Au8 is an experimental oral therapy being investigated as a potential disease-modifying treatment for relapsing and progressive forms of multiple sclerosis (MS).
It is being developed by Clene Nanomedicine, which also is testing CNM-Au8 for amyotrophic lateral sclerosis and Parkinson’s disease, two other neurodegenerative disorders.
In MS, the immune system mistakenly launches an inflammatory attack that damages myelin, a fatty sheath that covers nerve fibers and is essential for the efficient conduction of nerve signals. The lost myelin can be replaced by myelin-producing cells called oligodendrocytes, but the inflammation in MS renders the remyelinating process largely inefficient.
CNM-Au8 is an oral liquid suspension of gold nanocrystals designed to increase energy reserves within nerve cells and oligodendrocytes, while helping to remove toxic substances of cellular metabolism. This is expected to help protect neurons and aid in the generation of myelin by oligodendrocytes.
In animal models of demyelination, in which the myelin sheath is damaged in a way that resembles MS, CNM-Au8 treatment resulted in a significantly higher energetic capacity and a greater number of myelinated nerve fibers. It also was associated with a significant recovery of physical abilities in the mice, evaluated using different locomotor and fine motor tests.
CNM-Au8 is a drinkable therapy that is available in a dark red/purple-colored liquid suspension. In MS clinical trials, the therapy is being tested at daily doses ranging from 7.5 to 60 mg.
CNM-Au8 was first tested in a Phase 1 clinical trial (NCT02755870) involving 80 healthy volunteers. Participants were randomly assigned to receive CNM-Au8 — at doses of 15, 30, 60, or 90 mg — or a placebo.
Those in the single-ascending dose group received their assigned treatment once and were followed for 17 days. A multi-ascending dose group, meanwhile, received the therapy daily for 21 days, with participants followed for up to 50 days.
Results showed that CNM-Au8 was safe and well-tolerated. The most common treatment-related adverse events involved the neural and gastrointestinal systems, and were mostly mild in severity. There were no drug-related adverse events deemed serious or leading to treatment discontinuation.
Based on these findings, Clene launched the REPAIR-MS and VISIONARY-MS Phase 2 trials to better understand the safety and efficacy of CNM-Au8 in people with MS.
The REPAIR-MS trial (NCT03993171) was designed to evaluate the bioenergetic and metabolic impact of the gold nanocrystals in people with relapsing forms of MS. The participants all had stable disease over the previous six months. After a four-week screening period, each received one of four doses of CNM-Au8 in a liquid suspension, daily for 12 weeks. The doses were 7.5, 15, 30, or 60 mg.
The study’s main goal was to measure changes in the ratio of two metabolic markers — NAD+ and NADH – that indicate how much energy cells produce. The ratio was measured using 31-phosphorous magnetic resonance spectroscopy (31P-MRS), a noninvasive brain imaging technique.
Combined data from REPAIR-MS and REPAIR-PD (NCT03815916), a similar Phase 2 trial involving people with Parkinson’s disease, demonstrated that patients had a 10.4% increase in their energy metabolism after 12 weeks of treatment. Altogether, these trials involved 24 people: 11 MS patients and 13 with Parkinson’s.
Among the MS patients, the treatment also improved measures of cognition, visual function, dexterity, and walking speed.
The trial is now recruiting adults with progressive forms of MS, including primary progressive MS and non-active secondary progressive MS. The endpoint, or goal, is to determine if CNM-Au8 also can improve energetic capacity in these patients.
A trial called VISIONARY-MS (NCT03536559) sought to test the remyelination potential of CNM-Au8 in people with relapsing forms of MS and chronic damage to the optic nerve, which connects the eye to the brain.
A total of 76 participants with stable disease for at least six months were randomly assigned to receive 15 mg or 30 mg of CNM-Au8, or a placebo, daily for up to 48 weeks, or about one year.
Preliminary blinded data — in which it remained unclear which patients had been assigned to CNM-Au8 or to a placebo — showed significant improvements in low contrast letter acuity (LCLA) scores after 24 weeks. LCLA is an eye exam chart with low contrast between the letters and the background; it assesses visual disability in MS.
There also were significantly higher scores in the modified MS Functional Composite scale, a combined measure of visual acuity, dexterity, walking speed, and cognition. Patients also showed significant improvements in all individual components, except walking speed.
Due to pandemic-related challenges that prevented in-person visits, Clene decided to conclude the VISIONARY-MS trial early. Available data from up to 48 weeks of clinical visits will be used to determine the safety and efficacy of CNM-Au8. Unblinded data from the trial is expected in the second half of 2022.
Patients who complete the VISIONARY-MS trial will have the option to enter an open-label extension study called VISIONMS-LTE (NCT04626921). All participants in this extension will receive the 30 mg dose of CNM-Au8 for another 48 weeks.
The primary goals are to assess long-term safety and changes in LCLA scores. Secondary measures include signal velocity in the optic nerve, changes in brain and lesion volume, and changes in myelin content. The study is expected to conclude in August 2024.
CNM-Au8 has been well-tolerated in MS clinical trials. Most side effects were transient and mild to moderate in severity. No serious adverse events or treatment discontinuations related to the therapy have been reported to date.
The most commonly reported side effects deemed potentially related to treatment include:
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CNM-Au8 is an experimental treatment being tested in multiple sclerosis patients in clinical trials. The oral, drinkable medication is designed to increase energy reserves and help clear toxic substances resulting from the metabolism of nerve cells and oligodendrocytes, the cells that produce the myelin coating that is damaged in MS. This disease-modifying therapy is expected to protect nerve cells and boost myelin production by oligodendrocytes.
Phase 2 trials in CNM-Au8 have shown promising results in adults with relapsing forms of multiple sclerosis. Clene, the therapy’s developer, extended one of these trials to include people in non-active progressive disease. While these trials are expected to conclude in late 2022, Phase 3 trials will be needed to confirm the treatment’s safety and efficacy in these patient populations. Thus, it is still too early to know if or when the medication might be approved by the U.S. Food and Drug Administration.
Clinical trials of CNM-Au8 have excluded patients who are pregnant, breastfeeding, or planning to become pregnant during the studies or within six months after treatment discontinuation. Therefore, it is not known if the treatment is safe for use during pregnancy.
Some patients in clinical trials have seen benefits within about three months. In Phase 2 clinical trials involving individuals with relapsing forms of multiple sclerosis, CNM-Au8 treatment resulted in a significant increase in energy metabolism, as well as significant improvements in vision and physical abilities, within 12 weeks of treatment initiation.
Hair loss and weight gain have not been reported in clinical trials as side effects of CNM-Au8. Patients should talk with their care team if they experience any unexpected side effects during treatment.
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