Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jan;11(1):4-16.
doi: 10.1002/acn3.51897. Epub 2023 Sep 10.

Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data

David R Lynch  1   2 , Angie Goldsberry  3 , Christian Rummey  4 , Jennifer Farmer  5 , Sylvia Boesch  6 , Martin B Delatycki  7 , Paola Giunti  8 , J Chad Hoyle  9 , Caterina Mariotti  10 , Katherine D Mathews  11 , Wolfgang Nachbauer  6 , Susan Perlman  12 , S H Subramony  13 , George Wilmot  14 , Theresa Zesiewicz  15 , Lisa Weissfeld  16 , Colin Meyer  3
Affiliations

Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data

David R Lynch et al. Ann Clin Transl Neurol. 2024 Jan.

Abstract

Objective: The natural history of Friedreich ataxia is being investigated in a multi-center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity-matched comparison of data from the open-label MOXIe extension (omaveloxolone) to that from FACOMS.

Methods: MOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis.

Results: Data from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = -3.6; nominal p value = 0.0001).

Interpretation: These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity-matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.

PubMed Disclaimer

Conflict of interest statement

Lynch D receives grants from FARA, the Muscular Dystrophy Association (MDA), the National Institutes of Health (NIH), Reata Pharmaceuticals, and Retrotope. Rummey C reports research and consultancy fees from FARA, The National Ataxia Foundation (NAF), PTC Therapeutics, Reata Pharmaceuticals, Biohaven, Santhera Pharmaceuticals, and Takeda Pharmaceuticals. Boesch S has received fees for consultancy, advisory boards, and/or honoraria from AbbVie, Ipsen, Reata Pharmaceuticals, Merz Pharma, Stada Arzneimittel, and VICO Therapeutics. Delatycki M, Mariotti C, and Mathews K have received funding from Reata Pharmaceuticals during the study. Mathews K reports personal fees for consultancy from VICO Therapeutics; grants from Takeda and FARA. Giunti P has received grants and consultancy fees from Reata Pharmaceuticals, VICO Therapeutics, and consultancy fees from Triplet Therapeutics, and PTC Therapeutics. Nachbauer W reports advisory and speaker honoraria from Reata Pharmaceuticals. Hoyle C has received grants from Reata Pharmaceuticals, Takeda, and FARA during the conduct of the study; personal fees from Reata Pharmaceuticals and Avexis outside the submitted work. Subramony S H reports grants from Reata Pharmaceuticals, Biohaven Pharmaceuticals, Takeda, PTC Therapeutics, Retrotope, Acceleron Pharmaceuticals, NIH, FDA, MDA, Wyck Foundation, FARA, Stealth, Avidity Biosciences, and Fulcrum Therapeutics. Wilmot G has received grant/research support from Reata Pharmaceuticals, Biohaven Pharmaceuticals, NIH, NAF, and FARA. Weissfeld L is an employee of WCG Clinical, Inc. WCG is a paid consultant for Reata Pharmaceuticals. Zesiewicz T has received compensation for serving on the advisory boards of Boston Scientific, Reata Pharmaceuticals, and Steminent Biotherapeutics; has received personal compensation as senior editor for Neurodegenerative Disease Management and as a consultant for Steminent Biotherapeutics; has received royalty payments as co‐inventor of varenicline for treating imbalance (patent number 9,463,190) and non‐ataxic imbalance (patent number 9,782,404); has received research/grant support as principal investigator/investigator for studies from AbbVie; Biogen; Biohaven Pharmaceuticals; Boston Scientific; Bukwang Pharmaceutical Co, Ltd; Cala Health; Cavion; FARA; Houston Methodist Research Institute; NIH (READISCA U01); Retrotope; and Takeda Development Center Americas. Perlman S reports no conflicts or relevant disclosures. Goldsberry A and Meyer C are employees of Reata Pharmaceuticals. Farmer J is an employee of FARA.

Figures

Figure 1
Figure 1
CONSORT diagram of entire study. Omav, omaveloxolone; PBO, placebo.*Completed 12 weeks of treatment. **Completed Week 48 on treatment and had a Week 52 visit.
Figure 2
Figure 2
Diagram of study populations (A), MOXIe extension sets (B), and matching process (C). (A) Study populations. Populations were selected from the FACOMS and MOXIe extension studies. All study populations require a baseline mFARS, at least one post‐baseline mFARS within 3 years after baseline, and values for all propensity score model covariates. For the sensitivity natural history population, baseline mFARS and age were within the range observed in MOXIe extension patients at baseline. (B) MOXIe extension sets of patients. From the extension participants, subjects were further classified as to whether they were on sustained omaveloxolone before starting the extension. (C) Primary analysis populations. The propensity matching process was carried out separately for the three analysis sets.
Figure 3
Figure 3
Change in mFARS from baseline over time. (A) Primary pooled population. (B) Primary placebo‐Omav population. (C) Primary Omav‐Omav population.
See this image and copyright information in PMC

References

    1. Lynch DR, Schadt K, Kichula E, McCormack S, Lin KY. Friedreich ataxia: multidisciplinary clinical care. J Multidiscip Healthcare. 2021;14:1645‐1658. - PMC - PubMed
    1. Puccio H, Koenig M. Friedreich ataxia: a paradigm for mitochondrial diseases. Curr Opin Genet Dev. 2002;12:272‐277. - PubMed
    1. Babady NE, Carelle N, Wells RD, et al. Advancements in the pathophysiology of Friedreich ataxia and new prospects for treatments. Mol Genet Metab. 2007;92:23‐35. - PMC - PubMed
    1. Martelli A, Napierala M, Puccio H. Understanding the genetic and molecular pathogenesis of Friedreich ataxia through animal and cellular models. Dis Model Mech. 2012;5:65‐76. - PMC - PubMed
    1. Puccio H, Anheim M, Tranchant C. Pathophysiological and therapeutic progress in Friedreich ataxia. Neurol (Paris). 2014;170:355‐365. - PubMed

Publication types

Grants and funding