Trial of Oxaloacetate in ALS (TOALS)

Authors

• Katie Lillig, University of Kansas Medical Center
• Andrew Heim, University of Kansas Medical Center
• Jeffrey Statland, University of Kansas Medical Center
• Mazen M. Dimachkie, University of Kansas Medical Center
• Russell H. Swerdlow, University of Kansas Medical Center
• Sachini P. Karunaratne, University of Kansas Cancer Center
• In-Young Choi, University of Kansas Medical Center
• Phil Lee, University of Kansas Medical Center
• Edina Kosa, Kansas City University
• Abdulbaki Agbas, Kansas City University
• Heather M. Wilkins, University of Kansas Medical Center
• Richard J. Barohn, University of Missouri Health CareFollow
• Omar Jawdat, University of Kansas Medical Center

Document Type

Article

Publication Title

RRNMF Neuromuscular Journal

Abstract

Background: Mitochondrial dysfunction is a critical therapeutic target in amyotrophic lateral sclerosis (ALS). Oxaloacetate (OAA) is a promising candidate therapy as it crosses the blood brain barrier, reaches motor neurons, and enhances mitochondrial bioenergetics with positive preclinical data in ALS.

Methods: We conducted a prospective, phase 1B, dose escalation study using a standard 3+3 design to assess the safety profile and determine the maximum tolerated dose. Dose-limiting toxicity (DLT) was defined as any serious adverse event (SAE) requiring hospitalization or any adverse event (AE) attributed to OAA that required discontinuation of the medication. Dosages evaluated started at 1000 mg twice daily in Cohort 1 and if tolerated were escalated by 500mg up to 2500 mg twice daily in the maximal dose Cohort 4. To determine target engagement, we evaluated a panel of mitochondrial biomarkers, platelet TDP-43 levels, and MR spectroscopy of brain glutathione from baseline and at end of treatment.

Results: A total of 19 participants were screened, 18 enrolled, and one patient at the 2500mg BID dose withdrew due to a DLT. OAA was overall well tolerated up to a dose of 2500 mg BID. Among the small sample of participants, no consistent signal of target engagement was observed, although in aggregate post-exposure MRS determined brain glutathione levels increased.

Conclusions: This study supports the safety and tolerability of OAA at doses up to 2500 mg BID in patients with ALS. A future trial would be warranted to confirm maximum tolerated dose, to assess efficacy and further explore target engagement.

DOI

10.17161/rrnmf.v7i1_2026.25121

Publication Date

6-4-2026

Keywords

Amyotrophic Lateral Sclerosis (ALS), Oxaloacetate, Maximum tolerated dose

ISSN

2692-3092

Recommended Citation

Lillig K, Heim A, Statland J, Dimachkie MM, Swerdlow RH, Karunaratne SP, Choi I, Lee P, Kosa E, Agbas A, Wilkins HM, Barohn RJ, Jawdat O. Trial of Oxaloacetate in ALS (TOALS). RRNMF Neuromuscular Journal. 2026; 7(1). doi: 10.17161/rrnmf.v7i1_2026.25121.