Clene (CLNN) Study Update summary

Key regulatory guidance and study objectives

• FDA indicated willingness to consider neurofilament light (NfL) as a surrogate endpoint for accelerated approval if data show biomarker changes are reasonably likely to predict clinical benefit, especially survival.

• Multiple face-to-face meetings with the FDA have shaped the study design and statistical analysis plan, with a Type C meeting planned to discuss the totality of biomarker and survival data.

• The program aims to provide confirmatory evidence of clinical benefit, focusing on long-term survival and biomarker substantiation.

Key biomarker findings and clinical relevance

• Statistically significant reductions in NfL and GFAP biomarkers were observed with CNM-Au8 in both the HEALEY ALS Platform Trial and the NIH-sponsored Expanded Access Program, including advanced ALS patients.

• NfL and GFAP are validated biomarkers in ALS, with higher levels predicting faster disease progression and mortality; their reductions were highly concordant and associated with improved survival outcomes.

• In the HEALEY trial, CNM-Au8 showed significant reductions in plasma NfL (p=0.0403) and GFAP (p=0.0401) at 24 weeks compared to placebo.

• The EAP analysis demonstrated significant NfL reduction in all matched participants (p=0.0373) and especially in bulbar-onset ALS (p=0.0049), but not in non-bulbar subgroups.

• Placebo participants who switched to CNM-Au8 showed similar biomarker trajectories as those originally treated, reinforcing the treatment effect.

Expanded Access Program (EAP) and real-world data

• The NIH EAP provided a large, real-world biomarker dataset, including advanced ALS patients often excluded from traditional trials.

• Propensity-matched controls from the Answer ALS dataset were used to ensure robust comparisons.

• Significant biomarker reductions were observed even in sicker, more variable populations, supporting the generalizability of findings.

• The NIH-sponsored EAP enrolled 183 ALS participants at eight US sites.