NfL changes may help predict treatment benefit in ALS
Post hoc analyses link NfL declines or stability with better survival, function
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- NfL changes may help predict clinical benefit with CNM-Au8 in ALS, with lower or stable levels linked to better survival and function.
- In post hoc analyses, CNM-Au8-treated patients whose NfL declined or remained stable had better outcomes than concurrently randomized controls.
- Clene plans to include the NfL findings in its application seeking accelerated approval of CNM-Au8 for ALS.
New analyses of data from two Phase 2 clinical trials and observational studies suggest that changes in blood levels of neurofilament light chain (NfL), a biomarker of nerve damage, may help predict which people with amyotrophic lateral sclerosis (ALS) are more likely to experience clinical benefits with Clene’s experimental therapy CNM-Au8.
The findings, which Clene plans to include in an application seeking accelerated approval of CNM-Au8, could support the use of NfL as a potential surrogate endpoint, or a measure expected to predict the therapy’s clinical benefit. The application is expected to be submitted later this year.
Accelerated approval may hinge on NfL findings
Accelerated approval allows the U.S. Food and Drug Administration (FDA) to approve certain therapies based on a measure that is reasonably likely to predict clinical benefit, rather than waiting for direct evidence of that benefit. Clene is seeking accelerated approval of CNM-Au8 based on clinical data showing that treatment can reduce NfL levels and that NfL reductions are associated with better outcomes.
According to the company, the new analyses were conducted to address questions raised by the FDA during a meeting earlier this year, when the agency said NfL could potentially serve as a “reasonably likely” surrogate endpoint to support accelerated approval.
“Observing the NfL biomarker-to-clinical-benefit relationship replicated in two independent trials, and NfL’s prognostic value confirmed in more than 2,000 patients who never received CNM-Au8, is exactly the kind of evidence that gives us confidence in what we’re submitting to the FDA,” Rob Etherington, president and CEO of Clene, said in a company press release.
NfL is a structural protein in nerve fibers that is released into surrounding fluids and the blood when nerve cells are damaged. In ALS, which is marked by the gradual degeneration and death of nerve cells that control movement, blood NfL levels can provide information about how the disease is likely to progress.
CNM-Au8, an oral suspension of gold nanocrystals, was tested in an arm (NCT04414345) of the HEALEY ALS platform trial (NCT04297683), which is evaluating several potential ALS therapies simultaneously to accelerate treatment development. CNM-Au8 did not meet the trial arm’s main goal of significantly slowing functional decline compared with placebo.
Earlier analyses pointed to survival, clinical benefits
However, exploratory analyses suggested that the 30 mg dose of CNM-Au8 was associated with a reduced risk of death or clinical worsening after six months. Long-term analyses spanning the main trial and its open-label extension also suggested survival benefits with the experimental therapy, and biomarker data showed that many ALS patients given CNM-Au8 had decreases or stable NfL levels.
The new biomarker analyses were post hoc and exploratory. Researchers compared data from patients given CNM-Au8 with concurrently randomized controls — patients given a placebo or other investigational therapies that did not meet their primary endpoints in other HEALEY arms. After 12 months of follow-up, patients given 30 mg CNM-Au8 had a 74% lower risk of death than controls.
Further analyses showed that survival outcomes with CNM-Au8 tracked closely with NfL levels. Among patients whose NfL levels declined or remained stable while on CNM-Au8, the risk of death was 38% lower than in concurrently randomized controls over the full follow-up period, which extended to about four years. In patients whose NfL increased while on CNM-Au8, survival outcomes did not clearly differ from controls over the same follow-up period. Measures of function showed a similar pattern.
An analysis of more than 2,000 ALS patients enrolled in observational studies who had never received CNM-Au8 also found a significant association between changes in NfL and survival: a 10% decline in NfL was associated with a 6% to 10% lower risk of death.
Pretreatment factors may help identify NfL responders
In another FDA-requested analysis, researchers used pretreatment characteristics alone to classify patients into two groups: those predicted to have NfL levels decline or remain stable, and those predicted to have NfL levels increase.
Results showed that patients predicted to have NfL levels decline or remain stable had a 41% lower risk of death with CNM-Au8 than controls who were also predicted to have the same NfL response. No significant difference was observed between CNM-Au8 and controls among patients predicted to have an increase in NfL.
“ALS is a heterogeneous disease, and it matters that a biomarker signal, NfL decline or stabilization, marks the patients in whom CNM-Au8 appears to be providing the greatest benefit. In the HEALEY analyses, we were able to go a step further: using pre-treatment characteristics alone, we could identify the patients likely to show NfL response, and the treatment benefit was concentrated in exactly that group,” said Ben Greenberg, MD, head of medical at Clene.
Clene said a similar relationship between NfL response and survival was reported in an earlier Phase 2 study called RESCUE-ALS (NCT04098406).
“HEALEY and RESCUE-ALS were designed differently and enrolled under different criteria, and in both, the patients whose NfL responded to CNM-Au8 lived substantially longer, strengthening our New Drug Application planned for filing early Q4,” Etherington said.
If the FDA grants accelerated approval to CNM-Au8, Clene would be required to submit additional evidence verifying that the therapy provides clinical benefit. The company is planning a Phase 3 study called RESTORE-ALS to confirm CNM-Au8’s benefit in people with ALS.
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