Trial of Oxaloacetate in ALS (TOALS)
DOI:
https://doi.org/10.17161/rrnmf.v7i1_2026.25121Keywords:
Amyotrophic Lateral Sclerosis (ALS), Oxaloacetate, Maximum tolerated doseAbstract
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.
Downloads
References
References
1. Rowland, L.P. and N.A. Shneider, Amyotrophic lateral sclerosis. N Engl J Med, 2001. 344(22): p. 1688–700.
2. Statland, J.M., et al., Patterns of Weakness, Classification of Motor Neuron Disease, and Clinical Diagnosis of Sporadic Amyotrophic Lateral Sclerosis. Neurol Clin, 2015. 33(4): p. 735–48.
3. Bowling, A.C., et al., Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem, 1993. 61(6): p. 2322–5.
4. Fujita, K., et al., Decreased cytochrome c oxidase activity but unchanged superoxide dismutase and glutathione peroxidase activities in the spinal cords of patients with amyotrophic lateral sclerosis. J Neurosci Res, 1996. 45(3): p. 276–81.
5. Vielhaber, S., et al., Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain, 2000. 123 ( Pt 7): p. 1339–48.
6. Wiedemann, F.R., et al., Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis. J Neurol Sci, 1998. 156(1): p. 65–72.
7. Swerdlow, R.H., Treating neurodegeneration by modifying mitochondria: potential solutions to a "complex" problem. Antioxid Redox Signal, 2007. 9(10): p. 1591–603.
8. Swerdlow, R.H., The Neurodegenerative Mitochondriopathies. J Alzheimers Dis, 2009.
9. Swerdlow, R.H., et al., Role of mitochondria in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord, 2000. 1(3): p. 185–90.
10. Wilkins, H.M., et al., Oxaloacetate enhances neuronal cell bioenergetic fluxes and infrastructure. J Neurochem, 2016. 137(1): p. 76–87.
11. Swerdlow RH, L.K., Khosla SK, Nashatizadeh M, Pahwa R., A Pilot Study of Oxaloacetate 100 mg Capsules in Parkinson’s Disease Patients. J Parkinsons Dis Alzheimer Dis, 2016. 3(2): p. 4.
12. Tungtur, S.K., et al., Oxaloacetate treatment preserves motor function in SOD1G93A mice and normalizes select neuroinflammation-related parameters in the spinal cord. Scientific Reports, 2021. 11(1): p. 11051.
13. Brooks, B.R., et al., El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord, 2000. 1(5): p. 293–9.
14. Hauger, B.M., et al., A blood based mitochondrial functional index biomarker for Alzheimer's disease. Alzheimers Dement, 2025. 21(12): p. e71061.
15. Kemna, R.E., et al., Mitochondrial blood-based biomarker is related to cardiorespiratory fitness and aging in a sex-dependent manner. Alzheimers Dement (N Y), 2025. 11(4): p. e70163.
16. Luthi-Carter, R., et al., Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols. Sci Rep, 2024. 14(1): p. 21837.
17. Sage, J.M., et al., Use of Capillary Electrophoresis Immunoassay to Search for Potential Biomarkers of Amyotrophic Lateral Sclerosis in Human Platelets. J Vis Exp, 2020(156).
18. Choi, I.Y., et al., Lower levels of glutathione in the brains of secondary progressive multiple sclerosis patients measured by 1H magnetic resonance chemical shift imaging at 3 T. Mult Scler, 2011. 17(3): p. 289–96.
19. Choi, I.Y. and P. Lee, Doubly selective multiple quantum chemical shift imaging and T(1) relaxation time measurement of glutathione (GSH) in the human brain in vivo. NMR Biomed, 2013. 26(1): p. 28–34.
20. Ferrante, R.J., et al., Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem, 1997. 69(5): p. 2064–74.
21. Choi, I.Y., et al., Longitudinal changes of cerebral glutathione (GSH) levels associated with the clinical course of disease progression in patients with secondary progressive multiple sclerosis. Mult Scler, 2017. 23(7): p. 956–962.
22. Choi, I.Y., et al., In vivo evidence of oxidative stress in brains of patients with progressive multiple sclerosis. Mult Scler, 2018. 24(8): p. 1029–1038.
23. Wilkins, H.M., et al., Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. Hum Mol Genet, 2014. 23(24): p. 6528–41.
24. Vidoni, E.D., et al., Safety and target engagement profile of two oxaloacetate doses in Alzheimer's patients. Alzheimers Dement, 2021. 17(1): p. 7–17.
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Katie Lillig, Richard J. Barohn, MD, Heather M. Wilkins, PhD, Abdulbaki Agbas, PhD, Edina Kosa, Phil Lee, PhD, In-Young Choi, PhD, Sachini Karunaratne, PhD, Russell H. Swerdlow, MD, Mazen M. Dimachkie, MD, Jeffrey Statland, MD, Andrew Heim, Omar Jawdat, MD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
