Biomarker data insufficient to support CNM-Au8’s approval: FDA

Developer plans to show FDA supplemental data in early 2024

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by Steve Bryson, PhD |

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Early data from Phase 2 programs showing that CNM-Au8, an oral therapy candidate for amyotrophic lateral sclerosis (ALS), induced significant reductions in a nerve damage biomarker but did not meet the criteria for accelerated approval at this time, the U.S. Food and Drug Administration (FDA) concluded.

Despite the FDA’s decision at a recent meeting, Clene Nanomedicine, the therapy’s developer, released promising new data from the long-term extension study of the HEALEY ALS platform trial (NCT04297683).

Results showed CNM-Au8 significantly reduced the blood levels of the nerve damage biomarker neurofilament light chain (NfL) by 16% after about 18 months, decreased the risk of long-term all-cause mortality by 60%, and reduced the risk of clinical worsening in the highest-risk participants.

Clene plans to provide the FDA with supplemental data in the first half of 2024. The data package will include additional long-term clinical evidence and biomarker results, data on CNM-Au8’s mechanism of action and its connection to NfL reduction, as well as the association between lower NfL and improved clinical outcomes, including prolonged survival.

“As we continue to analyze the data from our Phase 2 clinical program, we believe the evidence supports that CNM-Au8 treatment improved survival in people living with ALS,” Benjamin Greenberg, MD, Clene’s head of medical, said in a company press release. “We are also encouraged that the recently disclosed long-term NfL biomarker decreases are consistent with delayed clinical time-to-event outcomes.”

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Candidate therapy aims to support health of motor neurons

CNM-Au8 is an oral liquid suspension of gold nanocrystals that aims to support the health of motor neurons, nerve cells that control voluntary muscle movement which progressively die in people with ALS.

The therapy has been granted orphan drug status by the FDA for ALS, a designation that provides incentives to accelerate CNM-Au8’s clinical development and regulatory review.

In addition to an arm of the HEALEY trial, which simultaneously tested several ALS treatment candidates against a shared placebo group, the therapy is being evaluated in the Phase 2 RESCUE-ALS trial (NCT04098406) and its open-label extension (OLE) study (NCT05299658). So far, study data show that CNM-Au8 is safe, slows ALS progression, and extends patient survival.

During the initial six months of treatment in the HEALEY trial, CNM-Au8 was associated with a 10% relative reduction in NfL compared with a placebo.

Newly released data from HEALEY’s 12-month OLE study showed the 30 mg dose of CNM-Au8 reduced NfL levels by 16% after 76 weeks, or about 18 months, relative to those initially assigned to a placebo. Similar results were found when data was combined from both doses tested (30 mg and 60 mg).

A long-term survival analysis of HEALEY OLE data compared patients originally assigned CNM-Au8 in the main study compared with those given a placebo. While those on a placebo eventually switched to CNM-Au8 in the OLE, the researchers employed a statistical model that estimated their survival had they remained on a placebo during the OLE period. The data showed a 60% reduction in the risk of all-cause mortality in patients given CNM-Au8 for the entire period.

Studying relationship between NfL, worsening ALS

To investigate the relationship between NfL and the incidence of ALS worsening, Clene pooled data from the HEALEY ALS platform and the RESCUE-ALS trials. Participants were classified based on NfL levels before receiving CNM-Au8 (baseline). ALS worsening events included death, needing a breathing or feeding tube, or the initiation of permanent assisted ventilation.

Analyses showed CNM-Au8 significantly delayed these worsening events in the group of patients with the highest baseline NfL levels, indicating greatest nerve cell damage. In these patients, the risk of such events was reduced by 75%.

At the same time, there also were significant extensions in the time to death or the initiation of permanent assisted ventilation, and a reduction in all-cause mortality.

The company plans to launch a Phase 3 study to confirm these findings in 2024.

Meanwhile, the National Institutes of Health (NIH) has recently awarded about $45.1 million toward an expanded access program (EAP) of CNM-Au8. Referred to as compassionate use, this program will join two other CNM-Au8 EAP programs to provide CNM-Au8 to U.S. patients who are not eligible for these clinical trials.

“Clene is committed to people living with ALS,” said Rob Etherington, CEO of Clene. “We presently support two ongoing CNM-Au8 compassionate use (expanded access) programs and are shortly commencing a third compassionate use program that is supported by a $45.1M grant from the National Institutes of Health.

“In addition, we anticipate launching the Phase 3 ALS confirmatory study in 2024. Importantly, we also plan to submit new information to the FDA for further discussions on the totality of evidence in order to advance the accelerated development of CNM-Au8 for the treatment of ALS.”

Clene also is testing CNM-Au8 for the treatment of multiple sclerosis and Parkinson’s disease, two other neurodegenerative disorders.