Research identifies ways CNM-Au8 can effectively reach the brain

Clene anticipates filing new drug application with FDA later this year

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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When investigational amyotrophic lateral sclerosis (ALS) therapy CNM-Au8 reaches the bloodstream, it attracts a layer of proteins called a corona to its surface that help it more easily reach the brain and last longer in circulation, according to recent research.

Developer Clene Nanomedicine says the findings are consistent with previous clinical and preclinical research indicating the oral treatment can reach the brain and exert its biological effects there.

“These new data show that the corona composition of the CNM-Au8 nanocrystals contribute further favorable drug properties to our neuroprotective agent, consistent with what we are seeing in our preclinical and clinical studies,” Mark Mortenson, chief science officer of Clene, said in a company press release.

The new research was published in a study, “Protein Corona Composition of Gold Nanocatalysts,” in ACS Pharmacology & Translational Science. Three of the study authors work at Clene.

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Clene seeking accelerated approval of CNM-Au8

At the end of last year, the company started talking with the U.S. Food and Drug Administration (FDA) about plans to seek approval of CNM-Au8 for ALS under the agency’s accelerated approval pathway.

In those discussions, the FDA indicated initial findings showing that a biomarker of nerve damage called neurofilament light chain (NfL) was reduced with the oral therapy in Phase 2 clinical trials were not enough to support such an approval.

The company is now preparing more recent data to address the agency’s questions, and plans to submit it to prompt accelerated approval discussions still this year.

“Having held our initial discussion with the FDA … we have a clear understanding of the additional data required to support an accelerated approval pathway filing for CNM-Au8,” Rob Etherington, Clene’s president and CEO, said in a separate press release.

“We believe that we can provide additional supportive evidence to advance discussions with the FDA with the potential to file [a new drug application] later this year,” Etherington added.

The CEO noted such evidence will likely include biomarker data, as well as new findings related to clinical function and survival among ALS patients.

Indeed, accumulating evidence from clinical trials and compassionate use programs suggest CNM-Au8 can extend survival and delay clinical worsening among ALS patients.

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CNM-Au8 is an oral liquid suspension of gold nanoparticles

CNM-Au8 is an oral liquid suspension of gold nanoparticles that’s believed to slow ALS progression by supporting the energetic needs of nerve cells and protecting them against types of damage that contribute to the disease.

When nanoparticles reach the bloodstream, they become coated in a layer of proteins and other molecules, together called a corona. The properties of this corona can substantially influence the effects of the nanoparticles in the body.

Findings from the recent study showed when CNM-Au8 was exposed to human blood in the lab, a corona formed that was specifically enriched with apolipoproteins. These proteins are known to bind to the selective blood-brain barrier (BBB) and facilitate the transport of substances into the central nervous system (CNS), or the brain and spinal cord.

The BBB is a cellular layer that seeks to prevent potentially harmful substances circulating in the bloodstream from entering the CNS. It is a major hurdle when developing brain-targeted medications, as many are unable to breach the barrier.

“Our research underlines that these engineered gold nanocrystals … can form a distinct protein corona that facilitates access to brain tissue,” said Morteza Mahmoudi, PhD, of the Michigan State University College of Human Medicine and the study’s senior author.

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Corona lacked proteins capable of producing immune reaction

Moreover, the corona notably lacked proteins capable of producing immune responses in the body. In addition to causing inflammation, such reactions could cause the nanoparticles to be degraded and removed from circulation more quickly.

Taken together, these properties of the corona are critical for ensuring CNM-Au8’s “enhanced stability, prolonged circulation in the bloodstream, and improved ability to cross the BBB,” the researchers wrote.

According to Clene’s chief development officer and a study author, Michael Hotchkin, the findings are “notably consistent” with findings from clinical trials of CNM-Au8 in people with ALS, multiple sclerosis, and Parkinson’s disease.

“Across 500+ years of patient exposure in multiple Phase 2 clinical trials and expanded access programs, CNM-Au8 treatment has been shown to be safe and well-tolerated,” Hotchkin said.

“These prior clinical results are further enriched by the findings from this work explaining how the protein corona forms around CNM-Au8 once in the bloodstream, and how this corona preferentially aids access through the blood-brain barrier to support CNM-Au8’s activity in the brain,” he added.