Topic 2.1. History of examining modifying therapies

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This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.

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2.1 History of examining modifying therapies

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The Clinical Management Guidelines for Friedreich ataxia (‘Guidelines’) are protected by copyright owned by the authors who contributed to their development or said authors’ assignees.

These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.

Guidelines users must seek out the most recent information that might supersede the diagnostic and treatment recommendations contained within these Guidelines and consider local variations in clinical settings, funding and resources that may impact on the implementation of the recommendations set out in these Guidelines.

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These Guidelines are made available as general information only and do not constitute medical advice. These Guidelines are intended to assist qualified healthcare professionals make informed treatment decisions about the care of individuals with Friedreich ataxia. They are not intended as a sole source of guidance in managing issues related to Friedreich ataxia. Rather, they are designed to assist clinicians by providing an evidence-based framework for decision-making.

These Guidelines are not intended to replace clinical judgment and other approaches to diagnosing and managing problems associated with Friedreich ataxia which may be appropriate in specific circumstances. Ultimately, healthcare professionals must make their own treatment decisions on a case-by-case basis, after consultation with their patients, using their clinical judgment, knowledge and expertise.
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2.1 History of examining modifying therapies

George Wilmot, Caterina Mariotti, David Lynch, Geneieve Tai and Massimo Pandolfo

Since 1996, the year of the discovery of the genetic cause of Friedreich ataxia (FRDA), many pharmacological clinical trials have been conducted to explore potential medications and different strategies aimed at ameliorating or preventing cell damage due to reduced frataxin.

The first compounds tested in individuals with FRDA were medications that were already available – either supplements or drugs approved for other indications. Initially, medications used in clinical trials were compounds with antioxidant properties, including vitamin E, co-enzyme Q10 and idebenone. In particular, idebenone was the most tested drug, with numerous clinical trials conducted from 1998 to 2012. Administration of different dosages of idebenone was shown to be safe. However, the results of the most recent Phase III study did not confirm the efficacy of idebenone on neurological symptoms and it is still unclear whether idebenone provides any cardiac benefit (1).

Other compounds tested for their antioxidant and neuroprotective properties are EGb761, an extract of Ginkgo biloba leaves (EGb 761®, Tanaken, Ipsen, France), OX1 (indole-3-propionic acid, IPA) a naturally occurring small molecule, and A0001 or alpha-tocopherol quinone (Penwest-Edison Pharmaceuticals), a co-enzyme Q10 analogue (2, 3). Although these molecules have been demonstrated to improve mitochondrial function in vitro, their efficacy in ameliorating or stabilizing disease progression in individuals with FRDA has not been confirmed.

Pioglitazone hydrochloride (ACTOS®, Takeda Pharmaceuticals) has also been proposed as a potential treatment for FRDA because it was postulated to induce the expression of many enzymes involved in mitochondrial metabolism, including the superoxide dismutases. Pioglitazone is a thiazolidinedione oral antidiabetic agent, which may cause or worsen congestive heart failure and other cardiovascular problems in FRDA (4). Its efficacy in the treatment of FRDA has not been demonstrated (5).

A different therapeutic strategy came from the observation of iron overload in mitochondria of individuals with FRDA (6). The commercially available iron chelator deferiprone (Ferriprox®, Apopharma, Canada) has been tested in a double-blind placebo-controlled trial (sponsored by Apopharma) of 72 individuals with FRDA aged 7 to 35 years (7). The participants assigned to the high-dose arm (60 mg/kg/day) were prematurely discontinued due to worsening of ataxia. Participants receiving 40 mg/kg/day also had worsening Friedreich Ataxia Rating Scale (FARS) and the International Cooperative Ataxia Rating Scale (ICARS) scores, whereas participants receiving 20 mg/kg/day of deferiprone had no significant change in FARS, similar to the placebo-treated individuals. The lack of deterioration in the placebo arm impaired the ability to detect any potential protective effect of deferiprone. However, subgroup analyses in participants with less severe disease suggest a benefit of deferiprone at 20 mg/kg/day on ICARS, FARS, kinetic function, and 9-hole peg test (9HPT). Deferiprone-treated participants receiving 20 or 40 mg/kg/day showed a significant decline in the left ventricular mass index. Higher doses of deferiprone caused systemic iron depletion and anemia; however, only one participant treated with 20 mg/kg/day had to discontinue treatment because of this complication (7). The major risk with deferiprone is the sudden, idiosyncratic development of agranulocytosis, which may occur at any time, even after a few years of treatment. No cases of agranulocytosis occurred during this study, but one participant experienced neutropenia, which resolved upon discontinuation of deferiprone (7). This study suggests that systemic iron depletion is deleterious in people with FRDA, possibly further impairing iron sulfur cluster biogenesis, but a low dose of a membrane penetrant chelator such as deferiprone may be beneficial by removing excess redox-active iron.

An anecdotal observation of an improvement in balance and coordination in patients treated with varenicline (Champix®, Pfizer), an agonist of nicotine receptors, to help quit smoking suggested the potential use of this drug for individuals with FRDA. However, a Phase II pilot study was stopped before completion due to concerns on safety and observations of worsening gait and imbalance. There was also insufficient evidence of efficacy. A complete report detailing study data will be issued shortly.

Other compounds have been tested for their in vitro property of increasing frataxin protein or enhancing frataxin gene transcription in cells from individuals with FRDA. Among these drugs, erythropoietin (EPO) and carbamylated EPO (C-EPO) were also tested in double-blind controlled studies, but neither neuro- nor cardio-protective properties were demonstrated in vivo (8-11).

Another drug tested for its property of increasing both frataxin messenger RNA (mRNA) and protein levels in a variety of cell types, including cells from individuals with FRDA, is the exogenous interferon gamma‐1b (ACTIMMUNE). This drug was administered at different dosages via subcutaneous injection in an open-label study design. The twelve children with FRDA who received the treatment for 12 weeks improved in FARS scores without a clear relationship to changes in frataxin levels (12). The following double-blind placebo-controlled study performed in a much larger series of individuals with FRDA (n = 92) did not demonstrate significant differences between interferon-treated and placebo-control groups after 6 months of treatment. No change was noted in buccal cell or whole blood frataxin levels (13).

Although a great scientific effort has been dedicated to selecting these drugs and testing their efficacy in clinical trials, most of these compounds have been removed from the list of potential therapeutic candidates for FRDA. While there is currently no approved pharmacological treatment for FRDA, research into potential therapeutic agents has nevertheless advanced considerably in the past two decades. There are many other potential therapeutic candidates that have been proposed in the treatment of FRDA that have undergone or are in the process of undergoing clinical trial evaluation.

David Lynch, MD, PhD
Professor of Neurology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

Caterina Mariotti, MD
Neurologist, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Massimo Pandolfo, MD
Professor (Clinical), McGill University, Montreal, Quebec, Canada

Geneieve Tai, BBiomedSc(Hons)
Research Assistant, Murdoch Children’s Research Institute, Parkville, Victoria, Australia.

George Wilmot, MD, PhD
Associate Professor, Department of Neurology, Emory University, Atlanta, Georgia, USA

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These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.

This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.

It is our expectation that going forward individual topics can be updated in real-time in response to new evidence versus a re-evaluation and update of all topics simultaneously.