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When investigational <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) therapy <a href="https://alsnewstoday.com/cnm-au8/">CNM-Au8</a> 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 <a href="https://clene.com/">Clene Nanomedicine</a> 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 <a href="https://www.globenewswire.com/news-release/2024/03/15/2847014/0/en/Clene-Announces-Peer-Reviewed-Publication-Characterizing-the-Protein-Corona-of-the-Investigational-Neurodegenerative-Disease-Drug-CNM-Au8.html">company press release</a>.
The new research was published in a study, “<a href="https://pubs.acs.org/doi/10.1021/acsptsci.4c00028">Protein Corona Composition of Gold Nanocatalysts</a>,” in ACS Pharmacology &amp; Translational Science. Three of the study authors work at Clene.
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<h3>Clene seeking accelerated approval of CNM-Au8</h3>
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 <a href="https://alsnewstoday.com/news/auto-draft-2/">not enough to support such an approval</a>.
The company is now preparing more recent data to address the agency&#8217;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 <a href="https://www.globenewswire.com/en/news-release/2024/03/13/2845345/0/en/Clene-Reports-Full-Year-2023-Financial-Results-and-Recent-Operating-Highlights.html">separate press release</a>.
“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 <a href="https://alsnewstoday.com/news/cnm-au8-use-extends-als-survival-compassionate-use-studies/">compassionate use programs</a> suggest CNM-Au8 can <a href="https://alsnewstoday.com/news/long-term-survival-benefit-seen-cnm-au8-healey-als-analyses-trial/">extend survival</a> and <a href="https://alsnewstoday.com/news/cnm-au8-delayed-clinical-worsening-als-patients-healey-trial/">delay clinical worsening</a> among ALS patients.
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<h3>CNM-Au8 is an oral liquid suspension of gold nanoparticles</h3>
CNM-Au8 is an oral liquid suspension of gold nanoparticles that&#8217;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&#8217;s senior author.
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<h3>Corona lacked proteins capable of producing immune reaction</h3>
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&#8217;s &#8220;enhanced stability, prolonged circulation in the bloodstream, and improved ability to cross the BBB,&#8221; 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, <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a>, and <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson’s disease</a>.
“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.

Research identifies ways CNM-Au8 can effectively reach the brain

Treatment with <a href="https://alsnewstoday.com/cnm-au8/">CNM-Au8</a> significantly delayed clinical worsening in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to new exploratory analyses from the therapy&#8217;s arm of the HEALEY ALS platform trial.
The experimental therapy, from <a href="https://clene.com/">Clene Nanomedicine</a>, had previously been found to reduce the risk of death by more than 90% during the six-month trial.
Clene&#8217;s announcement of the new analyses comes on the heels of the latest data from the <a href="https://clinicaltrials.gov/ct2/show/NCT04098406">RESCUE-ALS Phase 2 trial (NCT04098406)</a> and its <a href="https://clinicaltrials.gov/ct2/show/NCT05299658">open-label extension part (NCT05299658)</a>. These studies demonstrated that a longer time on CNM-Au8 was associated with significantly <a href="https://alsnewstoday.com/news/slower-progression-experimental-als-treatment-cnm-au8/">slower disease progression</a> compared with a nine-month treatment delay.
The new findings are &#8220;highly encouraging,&#8221; Rob Etherington, Clene&#8217;s CEO, said in a <a href="https://www.globenewswire.com/news-release/2023/03/09/2623829/0/en/CNM-Au8-Associated-With-Delayed-Time-to-Key-Clinical-Progression-Events-at-Six-Months-Supporting-a-Survival-Benefit-in-the-Healey-ALS-Platform-Trial.html">company press release</a>, adding, &#8220;When supported by a confirmatory trial, this would give people living with ALS longer periods of independence, which are precious to them and their families.&#8221;
Etherington noted that the company will discuss the findings with the U.S. Food and Drug Administration, with the goal of identifying a path toward regulatory approval. Meanwhile, plans for a Phase 3 trial of CNM-Au8, called RESTORE-ALS, are underway.
[recommended-reading id=79748]
<h3>Therapy previously found to reduce risk of death more than 90%</h3>
CNM-Au8 is an oral liquid suspension of gold nanocrystals. It&#8217;s expected to support the energetic needs of nerve cells, protecting them against oxidative stress, a type of cellular damage implicated in ALS.
The novel <a href="https://clinicaltrials.gov/ct2/show/NCT04297683?term=HEALEY+ALS&amp;draw=2&amp;rank=1">HEALEY platform trial (NCT04297683)</a> is the first clinical study designed to simultaneously test several ALS treatment candidates — an approach expected to cut costs and accelerate the development of new therapies.
Adults with ALS who&#8217;ve had symptom onset within the last three years are screened through the trial&#8217;s master protocol. If found eligible, they are randomly assigned to one of the trial&#8217;s arms that is accepting new participants. <a href="https://clinicaltrials.gov/ct2/show/NCT04297683?term=HEALEY+ALS&amp;draw=2&amp;rank=1#contacts">Recruitment</a> is ongoing at dozens of sites in the U.S.
The <a href="https://clinicaltrials.gov/ct2/show/NCT04414345">CNM-Au8 trial arm (NCT04414345)</a> enrolled 161 patients who were randomly assigned to receive oral CNM-Au8 (30 mg or 60 mg) or a placebo, given daily for 24 weeks or about six months. Because HEALEY uses a shared placebo group, it allows 75% of participants in each arm to be given each investigational treatment.
The trial did not meet its main goal of slowing functional declines, as assessed by changes in the ALS Functional Rating Scale Revised (ALSFRS-R) scores. Nor did it demonstrate benefit in a joint assessment of survival and disease progression or measures of lung function.
Still, exploratory analyses showed that CNM-Au8 at its 30 mg dose reduced the risk of death, and the combined risk of death and need for permanently assisted ventilation, by more than 90% after six months.
Now the new analyses show that 30 mg of CNM-Au8 also significantly reduced the risk of overall clinical worsening by 74%. This measure assesses the risk of death, breathing tube placement, need for assisted ventilation for more than 22 hours a day, or feeding tube placement.
Individually, the risk of each of these measures also decreased with the experimental treatment.
In particular, the risk of feeding tube placement and the risk of death or permanent ventilation assistance were both significantly reduced — by 74% and 98%, respectively. Other, non-significant risk reductions also were observed for death (95%), assisted ventilation (63%), ALS-related hospitalizations (84%), and all-cause hospitalizations (69%).
Analyses taking into account patients&#8217; blood levels of neurofilament light chain, a biomarker of nerve cell damage, led to similar reductions, Clene noted.
Additionally, the treatment was found to be well tolerated, with no significant safety issues reported.
After completing the six-month trial, participants could join an open-label extension phase, in which all are receiving the 30 mg dose of CNM-Au8.
[quote align=&#8221;center&#8221;]When supported by a confirmatory trial, this would give people living with ALS longer periods of independence, which are precious to them and their families.[/quote]
Additional analyses from the HEALEY trial are planned, including an examination of disease progression biomarkers, as well as assessments of clinical worsening and survival in the extension phase. Overall, these findings will inform the design of future trials, according to Clene.
The benefits of the treatment identified thus far &#8220;could prove to be profoundly beneficial to people living with ALS and their families,” said Merit Cudkowicz, MD, the principal investigator of the HEALEY study. Cudkowicz also is the director of the Sean M. Healey &amp; AMG Center for ALS, and chief of the department of neurology at Massachusetts General Hospital in Boston.
“We hope to see these results persist and strengthen over an even longer-term follow-up period for patients who have entered the open-label portion of the trial, and for those individuals who will participate in Clene’s next ALS clinical trial,” Cudkowicz said.
James Berry, MD, the co-lead investigator for the CNM-Au8 trial arm, said the new results &#8220;provide ample rationale to continue its development in a Phase 3 ALS trial.&#8221;
&#8220;We would like to thank the hundreds of people living with ALS and their loved ones and caregivers, who have dedicated themselves to participation in this trial, and we look forward to learning more about the impact of CNM-Au8 on ALS progression in the future,” Berry added.

Tag: Clene Nanomedicine

Research identifies ways CNM-Au8 can effectively reach the brain

CNM-Au8 found to delay clinical worsening in ALS HEALEY trial