VISIONARY-MS Trial Reports CNM-Au8 Improves Vision and Cognition in Multiple Sclerosis

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Over 144 weeks of treatment, patients on CNM-Au8 demonstrated sustained improvements in low contrast vision, working memory, and information processing speed.

Benjamin Greenberg, MD, vice chair of clinical & translational research at UT Southwestern Medical Center

Benjamin Greenberg, MD

Newly announced data from the long-term extension (LTE) phase of the pivotal VISIONARY-MS trial (NCT03536559) showed that treatment with investigational CNM-Au8 (Clene Nanomedicine) resulted in improved progressive vision and cognition in patients with relapsing multiple sclerosis (MS). Full results of the LTE will be presented at the upcoming ninth annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum.1

After completing the double-blind, placebo-controlled portion of the study, 55 of 69 eligible participants continued on 30 mg of CNM-Au8 for up to an additional 96 weeks. After 144 total weeks of treatment, investigators observed a least-square mean improvement of 8.70 (SE, 1.88; 95% CI, 5.0-12.4; P <.0001) letters on low contrast visual acuity (LCLA) change across both eyes. Cognition, assessed through the symbol digit modality test (SDMT), showed least-square mean changes of +8.03 (SE, 1.52; 95% CI, 5.01-11.0; P <.0001) vs the original randomization baseline.

“These observed long-term clinical improvements for participants with stable disease, over and above background immunomodulatory disease modifying therapy, are unprecedented,” study investigator Michael Barnett, PhD, MBBS, FRACP, a senior academic at the University of Sydney, said in a statement.1 “The data show clear overall improvements in vision and cognition for participants treated for nearly three years from randomization. Importantly, these results were robust and consistent.

He added, "positive impacts on disease progression and the potential to at least partially reverse established disability, if confirmed in a larger study, represent a major therapeutic leap for patients with MS."

In comparison with the end of the 48-week double-blind period, results at week 144 showed a LCLA least-square mean difference of +4.0 (SE, 1.67; 95% CI, 0.72-7.30; P = .017) letters for those who continued on with CNM-Au8. On SDMT, investigators reported least-square mean difference of +3.11 (SE, 1.3; 95% CI, 0.55-5.68; P = .018) vs the end of the double-blind period. Between both assessments, patients showed sustained improvement by up to 38 letters across both eyes, as well as gains in working memory and information processing speed by up to 35 points.

Similar to the double-blind period, the agent demonstrated a safe and tolerable profile, with no serious adverse events related to treatment and no significant findings observed. Notably, improvements seen on timed 25-foot walk test and 9-hole peg test at 48 weeks were maintained through the LTE.

"Despite tremendous advances in immunotherapies for MS, there is a significant unmet need for treatments to prevent neurodegeneration and create opportunities for clinical improvement," Benjamin Greenberg, MD, vice chair of clinical & translational research at UT Southwestern Medical Center, said in a statement.1 "Years have been spent investigating neuroprotective therapies for multiple sclerosis and other neurodegenerative diseases. These data continue to build a strong case in favor of pursuing CNM-Au8 in upcoming Phase 3 studies."

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CNM-Au8, an oral suspension of gold nanocrystals, previously met its primary and secondary end points in VISIONARY-MS, with results read out in August 2022. On LCLA, the primary end point, Clene reported a least-square mean treatment difference of 3.13 (95% CI, –0.08 to 6.33; P = .056) compared with placebo in the clinically affected eye over 48 weeks. Mean change in modified Multiple Sclerosis Functional Composite (mMSFC) scores, a secondary end point, showed a least-square mean difference of 0.28 (95% CI, 2.83-23.94; P = .0207) with CNM-Au8.2

The study featured patients with stable MS with a history of chronic visual impairment (who are allowed disease-modifying therapy) in a 1:1:1 fashion to CNM-Au8 in doses of 15 mg/day or 30 mg/day, or placebo. Its execution was halted because of operational challenges related to COVID-19, enrolling 73 of 150 anticipated participants, thus the threshold for significance was set at P = .10 prior to database lock.

Additional secondary outcomes originally reported included the LS mean difference in mMSFC average rank score (LS mean difference, 13.38; 95% CI, 2.83-23.94; P = .0138) and the time to first repeated clinical improvement to Week 48 (treatment: 45%; placebo: 29%; P = .3991). As well, CNM-Au8 showed favorable signs of consistent improvement across a variety of paraclinical biomarkers— multifocal visual evoked potentials (mfVEP) amplitude and latency, and optical coherence tomography—and MRI end points—magnetization transfer ratio and diffusion tensor imaging metrics.

At the 2023 American Academy of Neurology Annual Meeting, Barnett sat down with NeurologyLive® to discuss the VISIONARY-MS trial results and how CNM-Au8 would fit in the treatment landscape if approved. In the link below, he discussed patients who need a combination of therapeutics to effectively manage their disease, as well as whether data from the study identified which patients may be best suited for this approach.

REFERENCES
1. Clene Reports Significant Improvement in Vision and Cognition With CNM-Au8® Treatment in VISIONARY-MS Trial Long-Term Open Label Extension. News release. Clene Nanomedicine. January 8, 2024. Accessed January 8, 2024. https://finance.yahoo.com/news/clene-reports-significant-improvement-vision-120000893.html

2. Clene Reports Positive Topline Results for CNM-Au8® in the Phase 2 VISIONARY-MS Trial in Multiple Sclerosis. News release. Clene Nanomedicine. August 15, 2022. Accessed January 8, 2024. https://www.globenewswire.com/news-release/2022/08/15/2498070/0/en/Clene-Reports-Positive-Topline-Results-for-CNM-Au8-in-the-Phase-2-VISIONARY-MS-Trial-in-Multiple-Sclerosis.html

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