Topic 2.3. Therapies under investigation

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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.

Topic Contents

2.3 Therapies under investigation
2.3.1 Drugs available off-label
2.3.2 Drugs not available for other indications

Disclaimer / Intended Use / Funding

Disclaimer
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.

The authors of these Guidelines disclaim all liability for the accuracy or completeness of the Guidelines, and disclaim all warranties, express or implied to their incorrect use.

Intended Use
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.
Guidelines users must not edit or modify the Guidelines in any way – including removing any branding, acknowledgement, authorship or copyright notice.

Funding
The authors of this document gratefully acknowledge the support of the Friedreich Ataxia Research Alliance (FARA). The views and opinions expressed in the Guidelines are solely those of the authors and do not necessarily reflect the official policy or position of FARA.

2.3 Therapies under investigation

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

2.3.1 Drugs available off-label

The current state of research into drugs available off-label as possible therapies for FRDA is summarized in Table 2.1 and details are given below.

Resveratrol

Resveratrol is a naturally occurring antioxidant commonly found in many plants, particularly in the skin of red grapes. Resveratrol has been postulated to have antioxidant and neuroprotective benefits and was found to increase frataxin expression in cell and mouse models of FRDA (48). An open-label, proof-of-principle study of 24 individuals over 12 weeks demonstrated improvement in the FARS, the ICARS, hearing and speech outcome measures, and an oxidative stress marker, plasma F2-isoprostanes, in participants on a high dose of resveratrol (5 g) compared to those on a lower dose (1 g) (49). There was no change in lymphocyte frataxin levels (the primary outcome measure) in either treatment group. Significant gastrointestinal adverse events were reported in the high dose treatment group (49). In light of these findings, a randomized blinded, placebo-controlled crossover study assessing the efficacy and safety of a micronized form of resveratrol is underway (https://clinicaltrials.gov/ct2/show/NCT03933163). This formulation of resveratrol has been shown to be safe and have superior bioavailability with a good adverse event profile (50). The primary objective of this study is to compare the change in the modified FARS (mFARS) score from baseline to 24 weeks following treatment with 2 g/day of micronized resveratrol, to treatment with placebo.

Etravirine

Etravirine is an antiviral drug approved in 2008 by the US Food and Drug Administration (FDA) and is currently in use for the treatment of HIV. Alfedi and colleagues (51) have shown that etravirine increased frataxin protein levels in fibroblasts and lymphoblasts derived from individuals with FRDA by increasing frataxin mRNA translation and restoring the activity of aconitase, the enzyme containing an Fe-S cluster that is decreased from frataxin deficiency and provides some resistance to oxidative stress in these tissues. The levels of frataxin in these cell lines were also found to be comparable to frataxin levels in unaffected carrier cells (51). The team are planning to conduct a small study in individuals in FRDA to explore safety and tolerability, and changes in frataxin levels and other FRDA-specific biomarkers.

Dimethyl fumarate

Dimethyl fumarate (DMF) was identified through a drug discovery program by Cortopassi and colleagues who demonstrated this compound’s ability to induce mitochondrial biogenesis through activation of the Nrf2 pathway in individuals with multiple sclerosis (52, 53). DMF was also found to increase mitochondrial gene expression and function in mice models of FRDA (54). A clinical trial of DMF in individuals with FRDA is planned to investigate safety, tolerability and other outcome measures.

Methylprednisolone

An exploratory study was conducted to determine the safety, tolerability and efficacy of pulse methylprednisolone in 11 individuals with FRDA (19). The 26-week open label study found that methylprednisolone was well tolerated; however, there was no change in the timed 25-foot walk (T25FW) which was the primary outcome measure. The 1-minute walk (1MW) in the pediatric participants demonstrated a modest improvement (p < 0.05). It is suggested that methylprednisolone may be useful in children who are ambulant; however, there are no plans for further studies at this stage (19).

Table 2.1 Summary of possible therapies: drugs available off-label

2.3.2 Drugs not available for other indications

The current state of research into drugs that are not available for other indications as possible therapies for FRDA is summarized in Table 2.2 and details are given below.

Vatiquinone (PTC-743)

PTC-743 (previously EPI-743), or vatiquinone, is a follow-on compound to EPI-A0001. Vatiquinone is an orally absorbed small molecule that readily crosses into the CNS. It works by targeting NADPH quinone oxidoreductase 1 (NQO1). Its mode of action is to synchronize energy generation in mitochondria with the need to counter cellular redox stress (55). Vatiquinone seems to be 1000- to 10,000-fold more potent than co-enzyme Q10 or idebenone in protecting cells subjected to oxidative stress in patient fibroblast assays modelling the effects of mitochondrial disease.

A randomized parallel-arm, double-blind, placebo-controlled study evaluating vatiquinone is currently underway. The study aims to recruit approximately 110 children and young adults with FRDA. The 72-week placebo-controlled phase will be followed by a 24-week open-label extension phase. The primary endpoint is the change from baseline in mFARS, with key secondary endpoints assessing ambulation and activities of daily living (https://clinicaltrials.gov/ct2/show/NCT04577352).

A six-month placebo-controlled study of EPI-743 in 63 adults with FRDA has been conducted (56), with participants receiving placebo, 600 mg/day EPI-743 or 1200 mg/day EPI-743. This was followed by an 18-month open-label extension study where all participants were treated with EPI-743. While the primary endpoint of low contrast visual acuity assessment was not met, an improvement in the neurological examination subscale of the FARS was found in participants administered low-dose EPI-743 when compared to the placebo group (p = 0.047) at 6 months. There were significant improvements in neurological outcomes and treatment was well tolerated (57).

EPI-743 at 1200 mg/day has also been tested in people with FRDA who are compound heterozygous for a FXN GAA repeat expansion and a point mutation in an 18-month open-label study (58). There were significant improvements in neurological function as assessed by the FARS indicating potential benefit in this subgroup of individuals (58).

Omaveloxolone

Omaveloxolone (SKYCLARYS™) has been approved by the U.S. Food and Drug Administration (FDA) and European Commission for the treatment of FA in adults and adolescents aged 16 years and older. The authors of this chapter are in the process of updating this section.

Omaveloxolone was developed by Reata Pharmaceuticals to target activation of Nrf2, which is decreased in cells in individuals with FRDA. In a double-blind, randomized, placebo-controlled, multicenter study of 103 individuals with FRDA, participants aged 16 to 40 years received either placebo or omaveloxolone at 150 mg per day (59). Individuals treated with omaveloxolone experienced a statistically significant, placebo-corrected mean improvement in mFARS, the primary outcome measure, of 2.4 points after 48 weeks of treatment (p = 0.014). This benefit was mostly recorded in patients without pes cavus, a common feature of FRDA associated with more severe disease, suggesting that patients with milder disease benefited the most. Omaveloxolone was reported to be safe and well tolerated (59).

Additional analysis has been conducted on the open-label extension data. Similar slopes in the mFARS were found for the placebo to omaveloxolone group (0.59 points per year) and the omaveloxolone to omaveloxolone group (0.41 points per year). There was no significant difference in the rates of change between groups, demonstrating the disease modifying activity of omaveloxolone (59). The open-label extension study is ongoing with additional data collection and safety monitoring (https://www.clinicaltrials.gov/ct2/show/study/NCT02255435). As of May 2021, Reata has been asked to request a pre-NDA FDA meeting for omaveloxolone for the treatment of FRDA (60).

RT001 (dPUFAs)

RT001 is a deuterated polyunsaturated fatty acid (dPUFA). PUFAs are fatty acids that are essential to the structure and function of lipid membranes. As PUFAs are prone to oxidative damage and can therefore lead to mitochondrial dysfunction, a strategy for strengthening these compounds is to replace hydrogen molecules with deuterium, a hydrogen isotope, creating dPUFAs. This process protects cells from oxidative damage (61).

A Phase I/II randomized, double-blind, comparator-controlled study was conducted by Retrotope in 18 individuals with FRDA (62). Participants were administered either 1.8 or 9.0 g/day of RT001, or an RT001 comparator over 28 days. RT001 was safe and well tolerated over the duration of the study and an improvement in peak workload was found (62).

A subsequent Phase II/III study was launched in 2019. The randomized, double-blind, placebo-controlled trial enrolled 65 individuals aged 12 to 50 years, with peak workload change from baseline to 11 months as the primary outcome measure. Results are anticipated at the end of 2021. (see: https://www.clinicaltrials.gov/ct2/show/NCT04102501)

MIN-102

MIN-102, or leriglitazone, is a metabolite of pioglitazone, which has previously been trialed in FRDA. Like pioglitazone, leriglitazone is a potent agonist of peroxisome proliferator-activated receptor-gamma (PPARγ). MIN-102 has been developed by Minoryx Therapeutics. Pre-clinical studies showed that leriglitazone increased frataxin protein levels in DRG neurons that were frataxin deficient (63). An improvement in motor function deficits in FRDA mouse models was also demonstrated. A Phase 1 clinical study demonstrated that MIN-102 was well tolerated and was able to cross the BBB and engage PPARγ within the CNS much more efficiently that pioglitazone (64).

The Phase 2 FRAMES clinical trial enrolled 39 individuals with FRDA and examined the effects of leriglitazone on biochemical, imaging, neurophysiological, and clinical outcome measures. Topline results were announced in December 2020 (65). PPARγ engagement was demonstrated in all participants, as assessed by the biomarker adiponectin. Furthermore, leriglitazone significantly prevented iron accumulation in the dentate nucleus of individuals receiving treatment compared to placebo (ANCOVA p = 0.05). Numerical differences in favor of leriglitazone were also seen in magnetic resonance spectroscopic analysis of cervical spinal cord and in an upper-limb coordination measure. Leriglitazone was also well tolerated, with peripheral edema the most frequent adverse event. Full results are pending and a further confirmatory study is planned.

CTI-1601 (TAT-frataxin)

CTI-1601 is a delivery system whereby a TAT protein fragment is used to transport synthetic frataxin directly into the mitochondria (33). When tested in mouse models, cardiac function (increased heart rate and improved diastolic function) was improved and mean lifespan in the mice was increased.

The first in-human study of CTI-1601 commenced in November 2019, exploring safety and dosage compared to placebo in individuals with FRDA. Following the completion of the single ascending dose study (https://clinicaltrials.gov/ct2/show/NCT04176991), a multiple ascending dose study began in late 2020 (https://www.clinicaltrials.gov/ct2/show/NCT04519567). Individuals received subcutaneous injections of either CTI-1601 or placebo at increasing dose levels and frequencies over 13 days. Dose-dependent increases in frataxin levels from baseline were demonstrated in buccal cells, skin biopsies and platelets of participants receiving CTI-1601 compared to those receiving placebo. CTI-1601 was generally well tolerated at doses of up to 100 mg/day for 13 days (66). An open label extension study had been planned for commencement in mid-2021. However, as of May 2021, the FDA has placed a hold on the CTI-1601 clinical program due to deaths at the highest dose levels in an ongoing 180-day non-human primate toxicology study. At this stage, additional studies are not permitted to commence until a full report has been submitted to the FDA who will determine when this will be able to occur.

XCUR-FXN

XCUR-FXN is a form of antisense oligonucleotide spherical nucleic acid (SNA) therapy developed by Exicure and is designed to increase the production of frataxin. XCUR-FXN will be delivered through intrathecal injection into the spinal canal to enter the CNS. An investigational new drug (IND) application to the FDA is planned with the first in-human study planned for 2022 (67).

Gene-Tac (Syn-TEFS)

Synthetic transcription elongation factors (Syn-TEFs) are a novel class of compounds comprising programmable DNA binders that target desired genomic loci and ligands that engage transcription elongation machinery. Ansari and colleagues (68) have demonstrated that Syn-TEF was able to restore frataxin levels in cell lines from individuals with FRDA to the levels in control cell lines. The company Design Therapeutics has developed derivatives of the initial molecule with greatly improved pharmacological properties and is planning a first in-human study.

Granulocyte colony stimulating factor (GCSF)

Granulocyte colony stimulating factor (GCSF) is a cytokine which has been tested in humanized mouse models of FRDA together with stem cell factor (SCF) (69). Mice received monthly subcutaneous infusions of both compounds and were assessed with a range of behavioral motor performance tests. Frataxin levels increased after six months of treatment with monthly subcutaneous infusions of GCSF. Improvements in motor coordination and locomotor activity were also demonstrated, as well as an increase in neural stem cell numbers and reduced inflammation, indicating its potential as a possible therapy for FRDA. This research is planned to extend to human cell lines (69).

SHP622 (formerly VP20629 or OX1)

Indole-3-propionic acid (IPA), also called OX1 (and now called SHP622), is a naturally occurring, small molecule that has potent anti-oxidant properties that can protect against neurodegenerative disease. In contrast to the vast majority of antioxidants, OX1 has a rare advantage in that it cannot be metabolized through a pro-oxidant pathway. For these reasons, scientists identified the potential of OX1 for treatment of FRDA. In a recent Phase 1 safety and tolerability study conducted in the Netherlands, OX1 was demonstrated to be safe and well tolerated at all dose levels tested (http://www.clinicaltrials.gov/ct2/show/NCT01898884). There are currently no plans to pursue clinical development.

RG2833

HDAC inhibitors, of which RG2833 is one, are compounds that interfere with histone deacetylases, enzymes that remove a key post-translational modification of histones associated with active transcription. After observing excess deacetylation of histones in the FXN gene of cells from FRDA patients, Joel Gottesfeld of The Scripps Research Institute in La Jolla, California identified a family of benzamide HDAC inhibitors able to overcome the gene silencing effect of the GAA expansion in cellular (70) and animal (31) models of FRDA. These compounds specifically target the class I HDACs, HDAC1 and HDAC3, and have a particular slow ON-slow OFF kinetic that differentiates them from other HDAC inhibitors that are unable to upregulate FXN expression. The company Repligen sponsored a phase I study of RG2833 involving 20 adults with FRDA (71). The study comprised four cohorts: two were open-label in design with single 30 to 120 mg doses, while the other two were randomized, double-blind, placebo-controlled crossover studies. In the latter two cohorts, participants received either a single 180 mg dose or placebo or two 120 mg doses, or a placebo. RG2833 was well tolerated and was found to increase FXN gene expression in peripheral blood mononuclear cells. Despite being well tolerated, potentially toxic metabolites of the compound were detected. Together with poor BBB penetration, this made it unsuitable for further testing. Additional compounds with improved characteristics, developed by Repligen and then by BioMarin, are currently being studied as potential candidates for clinical trials (72, 73).

Nicotinamide

Nicotinamide is a class III HDAC and in high concentrations can cause product inhibition of enzymes that generate it by cleaving NAD (74). Nicotinamide has good bioavailability and has been shown to pass through the BBB (75). In an open-label dose-escalation study, 10 individuals with FRDA were treated with doses of up to 8 g/day of oral nicotinamide. While generally well tolerated, three participants demonstrated abnormal liver function test results after taking high doses of nicotinamide, but this resolved after the dose was reduced. Daily dosing at 3.5 to 6 g demonstrated a significant upregulation of frataxin expression in peripheral blood mononuclear cells (p < 0.0001). However, there were no significant improvements in clinical measures. A randomized, placebo-controlled, double-blinded study investigating the efficacy of high dose nicotinamide in FRDA (NICOFA) over two years is planned (76). It is important to note, however, that high-dose nicotinamide (exceeding 3 gm/day) is considered potentially toxic and should not be used without medical supervision (77).

Table 2.2 Summary of possible therapies: drugs not available for other indications

David Lynch, MD, PhD
Professor of Neurology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Email: lynchd@mail.med.upenn.edu

Caterina Mariotti, MD
Neurologist, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Email: caterina.mariotti@istituto-besta.it

Massimo Pandolfo, MD
Professor (Clinical), McGill University, Montreal, Quebec, Canada
Email: massimo.pandolfo@mcgill.ca

Geneieve Tai, BBiomedSc(Hons)
Research Assistant, Murdoch Children’s Research Institute, Parkville, Victoria, Australia.
Email: geneieve.tai@mcri.edu.au

George Wilmot, MD, PhD
Associate Professor, Department of Neurology, Emory University, Atlanta, Georgia, USA
Email: gwilmot@emory.edu

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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.