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Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia

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Abstract

Objectives

Friedreich ataxia is (FRDA) an autosomal recessive neurodegenerative disorder associated with intrinsic oxidative damage, suggesting that decreasing lipid peroxidation (LPO) might ameliorate disease progression. The present study tested the ability of RT001, a deuterated form of linoleic acid (D2-LA), to alter disease severity in patients with FRDA in a double-blind placebo-controlled trial.

Methods

Sixty-five subjects were recruited across six sites and received either placebo or active drug for an 11-month study. Subjects were evaluated at 0, 4, 9, and 11 months, with the primary outcome measure being maximum oxygen consumption (MVO2) during cardiopulmonary exercise testing (CPET). A key secondary outcome measure was a composite statistical test using results from the timed 1-min walk (T1MW), peak workload, and MVO2.

Results

Forty-five subjects completed the protocol. RT001 was well tolerated, with no serious adverse events related to drug. Plasma and red blood cell (RBC) membrane levels of D2-LA and its primary metabolite deuterated arachidonic acid (D2-AA) achieved steady-state concentrations by 4 months. No significant changes in MVO2 were observed for RT001 compared to placebo. Similarly, no differences between the groups were found in secondary or exploratory outcome measures. Post hoc evaluations also suggested minimal effects of RT001 at the dosages used in this study.

Interpretations

The results of this study provide no evidence for a significant benefit of RT001 at the dosages tested in this Friedreich ataxia patient population.

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Data availability

Data will not be made publicly available at the present time.

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Acknowledgements

The authors wish to acknowledge the participation of the subjects, the efforts of the site coordinators, and the aid in recruitment from the Friedreich Ataxia Research Alliance.

Funding

The present study was funded by grants to each Institution for Retrotope pharmaceutical. Dr Lynch receives grant money through the Children’s Hospital of Philadelphia from Reata, PTC, Design, FARA, NIH and the FDA. Employment: Drs Midei, Krtolica, Litterman, van der Ploeg, Heerinckx, and Milner are employees of Retrotope, who sponsored the study. Dr Vogel is an employee of Redenlab, who provided speech testing for the study.

Author information

Authors and Affiliations

  1. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    David R. Lynch

  2. Departments of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, 502F Abramson Research Center, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA

    David R. Lynch

  3. Departments of Pediatrics and Neurology, University of Iowa Carver College of Medicine, Iowa City, USA

    Katherine D. Mathews

  4. University of California Los Angeles, Los Angeles, USA

    Susan Perlman & Omid Omidvar

  5. USF Ataxia Research Center, University of South Florida, James A. Haley Veteran’s Hospital, Tampa, FL, USA

    Theresa Zesiewicz

  6. Norman Fixel Center for Neurological Disorders, University of Florida College of Medicine, Gainesville, USA

    Sub Subramony

  7. University of Melbourne, Parkville, Australia

    Adam P. Vogel

  8. Redenlab Inc, Melbourne, Australia

    Adam P. Vogel

  9. Retrotope, Los Altos, CA, USA

    Ana Krtolica, Nadia Litterman, Lex van der Ploeg, Frederic Heerinckx, Peter Milner & Mark Midei

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Contributions

Drs Lynch, Mathews. Perlman, Zesiecz, Vogel, Omidvar and Subramony performed the exams, and supervised data collections at individuals sites. Drs. Krtolica, Litterman, van der Ploeg, Heerinckx, Milner, and Midei designed the experiment, supervised data management at the central site, and performed statistical calculations. Dr. Lynch wrote the initial draft, and all authors provide critical revision.

Corresponding author

Correspondence to David R. Lynch.

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Conflicts of interest

The authors report no other conflicts of interest.

Ethical approval

IRB approval was obtained by the Institutional Review Board at each Institution.

Consent to participate

Written informed consent was obtained from all subjects before initiation of study procedures.

Supplementary Information

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Supplementary file1 (PDF 76 KB)

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Lynch, D.R., Mathews, K.D., Perlman, S. et al. Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia. J Neurol 270, 1615–1623 (2023). https://doi.org/10.1007/s00415-022-11501-4

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