Ketone ester lowers neurofilament levels in ALS phase 2 trial
- **In a randomized phase 2 trial of patients with amyotrophic lateral sclerosis, D-β-hydroxybutyrate ester reduced the monthly rise in neurofilament light chain compared to placebo in adjusted analysis.
- The treatment was well tolerated but did not significantly improve functional decline or body mass index.**
- In adjusted analysis, the D-β-hydroxybutyrate ester group showed a neurofilament light chain slope of -1.5 pg/mL/month versus +2.8 pg/mL/month in the placebo group, a mean difference of -4.2 pg/mL/month (95% CI -∞ to -1.1, p = 0.014).
- However, a mixed-effect model analysis found no statistically significant difference between groups (mean difference -0.7 pg/mL/month, p = 0.30).
The publication
**In a randomized phase 2 trial of patients with amyotrophic lateral sclerosis, D-β-hydroxybutyrate ester reduced the monthly rise in neurofilament light chain compared to placebo in adjusted analysis. The treatment was well tolerated but did not significantly improve functional decline or body mass index.**
Who the findings apply to
The trial enrolled patients with probable or definite amyotrophic lateral sclerosis who experienced a decline in the ALS functional rating scale revised of at least 0.33 points per month.
Why this matters
The study aimed to address energy deficits in ALS by providing oral ketone bodies as high-energy substrates. Researchers investigated whether this intervention could slow disease progression markers and clinical decline.
What the study found
In adjusted analysis, the D-β-hydroxybutyrate ester group showed a neurofilament light chain slope of -1.5 pg/mL/month versus +2.8 pg/mL/month in the placebo group, a mean difference of -4.2 pg/mL/month (95% CI -∞ to -1.1, p = 0.014). However, a mixed-effect model analysis found no statistically significant difference between groups (mean difference -0.7 pg/mL/month, p = 0.30).
Unadjusted analysis indicated a faster decline in ALS functional rating scale revised scores for the treatment group (-1.4 points/month) compared to placebo (-0.8 points/month, p = 0.020). No significant differences were found between groups regarding clinical endpoints such as ALSFRS-R or BMI in the adjusted analysis.
The intervention was well tolerated with a similar frequency of adverse events across both groups.
What the result does not establish
The authors note that whether effects on neurofilament light chain translate into meaningful clinical benefits requires confirmation in a larger phase 3 trial with extended treatment duration. The study was investigator-initiated and funded by private donation.
Divergent results between adjusted linear regression and mixed-effect models for the primary endpoint introduce uncertainty regarding the robustness of the biomarker finding.
Authors’ conclusion
“Whether the effects on NfL can be confirmed and translated into meaningful clinical effects, remains to be clarified by a larger phase 3 trial with extended treatment duration. βHB was well tolerated. Funding: This was an investigator-initiated study, funded by a private donation.”
Trial registration
| Registered title | Efficacy and Tolerability of Beta Hydroxybutyrate Ester in Patients With Amyotrophic Lateral Sclerosis (ALS) (KETO-ALS) |
|---|---|
| Registry status | Interventional, completed |
| Lead sponsor | University of Ulm |
| Registered size | 81 participants — actual enrolment. The abstract reports: 81 patients |
| Where | 1 site in 1 country (Germany) |
| Registered primary outcome |
Primary endpoint named in the abstract: change of neurofilament light chain (NfL) per month, measured as slope over 6 months. Compare the two: a change of primary endpoint after registration matters. |
- Start: Apr 2022
- Completion: Feb 2025
- Primary completion: Feb 2025
- Paper published: Oct 2026
ClinicalTrials.gov record as held by ENCLAI, last updated May 2024 / May 2026. The registry status may have changed since; the link shows the current record.
Study and sources
Efficacy and tolerability of D-β-hydroxybutyrate ester in patients with amyotrophic lateral sclerosis (KETO-ALS)-a randomised, placebo-controlled, double-blind study
Randomised trial · Phase 2 · EClinicalMedicine · 2026-10-26
Sources and limitations
- PubMed record PMID 42990966 (PubMed / NLM · 2026-11-08)
- Trial registry NCT04820478 (ClinicalTrials.gov · 2026-11-08)
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