Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Friedreich ataxia (FA) is a progressive neurodegenerative disease that leads to limb ataxia, scoliosis, cardiac hypertrophy, and diabetes.1,2 Currently, there are no disease-modifying therapeutic strategies to treat FA. There are, however, many agents undergoing clinical development.1
Trials on Antioxidants and Nrf2 Inducers
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that activates the expression of antioxidant enzymes and is involved in the regulation of mitochondrial biogenesis.3 This signaling pathway is also impaired in FA.4
Omaveloxolone (also known as RTA-408) is a molecule able to activate Nrf2, and its activity is being studied in the phase 2 clinical trial MOXIe (NCT02255435), sponsored by Reata Pharmaceuticals.4 MOXIe is a 2-part study in which the safety, efficacy, and pharmacodynamics of omaveloxolone are being assessed. The first part of the trial is a randomized, placebo-controlled, double-blind, dose-escalation study, and the second part is a randomized, placebo-controlled, double-blind, parallel-group study for determining the safety and efficacy of the Nrf2 inducer at 150 mg. MOXIe has enrolled 172 participants thus far and is expected to be completed by December 2024.4 Results from the trial have shown that omaveloxolone significantly improved neurological function compared to placebo and that it was generally safe and well tolerated.5
An extension study is expected to allow the evaluation of the long-term safety and tolerability of 150 mg of omaveloxolone in patients with FA who completed either part 1 or part 2 of the study.4
EPI-743, or vatiquinone, is an investigational therapy that inhibits 15-lipoxygenase, an enzyme involved in oxidative stress and inflammation. Different studies have shown that this agent has an impact on neurological and neuromuscular symptoms related to FA as well as a favorable safety profile.6 The MOVE-FA phase 2/3 clinical trial (NCT04577352) is currently ongoing and is a placebo-controlled, parallel-arm study that is evaluating vatiquinone in about 110 children and young patients with FA over an 18-month period.6,7 The long-term safety of vatiquinone will be assessed in a phase 3 trial involving patients exposed to vatiquinone in the MOVE-FA study. This trial is not yet recruiting (NCT05515536).8
There is also a phase 2 clinical trial currently recruiting participants that will study the pharmacokinetics and safety of vatiquinone in patients under 7 years of age (NCT05485987).9 In addition, a phase 3 trial is recruiting to assess the safety of vatiquinone in participants with inherited mitochondrial disease who had prior exposure to vatiquinone (NCT05218655).10
Another antioxidant agent in clinical development is resveratrol. A double-blind, placebo-controlled, randomized phase 2 clinical trial is currently ongoing to assess the potential benefits of micronized resveratrol in reducing ataxia symptoms after 24 weeks of treatment (NCT03933163).11
Read more about FA therapies
Trials on Agents That Increase Frataxin Expression
Friedreich ataxia results from defects in the frataxin (FXN) gene, leading to decreased frataxin protein levels.1 Several ongoing trials are assessing a restoration of these levels as a means of therapy.
Nicotinamide is a histone deacetylase (HDAC) inhibitor that can increase the histone acetylation of FXN and increase frataxin levels.1 A recent study by Libri et al has demonstrated that nicotinamide can help restore frataxin levels in patients with FA.12 A phase 2 clinical trial, NICOFA (NCT03761511), will be evaluating the safety and efficacy of nicotinamide in patients with FA. This trial is not yet recruiting and aims to enroll 225 participants. It is expected to be completed by December 2025.13
Intelence® (etravirine), an antiviral drug used for the treatment of human immunodeficiency virus (HIV), has also been shown to increase frataxin levels in vitro and in vivo. A phase 2 clinical trial is currently ongoing to determine the safety and efficacy of the drug in patients with FA (NCT04273165).14
Read more about FA experimental therapies
Gene Therapy Clinical Studies
A phase 1/2 clinical trial is currently recruiting to evaluate the safety and tolerability of 2 ascending doses of LX2006 (AAVrh.10hFXN) in patients with FA who present with cardiomyopathy (NCT05445323).15 LX2006 is an investigational adeno-associated virus (AAV) vector therapy that is intravenously administered for the delivery of FXN to cardiac cells over a 52-week period. LX2006 is expected to restore frataxin levels and improve mitochondrial activity. The long-term safety and efficacy of the therapy will be studied for 4 years after treatment.15
DT-216 is an investigational small molecule that activates the transcription of the FXN gene, restoring frataxin levels. It is a GeneTAC™ gene-targeted chimera small molecule that targets the GAA repeat expansion mutation in the FXN gene, restoring its expression.16,17 Recently, initial results from a single-ascending dose phase 1 clinical trial (NCT05285540) have reported that DT-216 was well tolerated and that the levels of frataxin messenger RNA were increased.16-18 The study is continuing in multiple ascending doses of DT-216.16
CTI-1601 is a recombinant fusion protein designed to deliver human frataxin into the mitochondria of patients with FA.19 Following single- and multiple-ascending dose phase 1 clinical trials, a phase 2 study is currently recruiting to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneous CTI-1601 in patients with FA over 28 days (NCT05579691).20
Read more about FA genetics
1. Zesiewicz TA, Hancock J, Ghanekar SD, Kuo SH, Dohse CA, Vega J. Emerging therapies in Friedreich’s ataxia. Expert Rev Neurother. 2020;20(12):1215-1228. doi:10.1080/14737175.2020.1821654
2. Lynch DR, Schadt K, Kichula E, McCormack S, Lin KY. Friedreich ataxia: multidisciplinary clinical care. J Multidiscip Healthc. 2021;14:1645-1658. doi:10.2147/JMDH.S292945
3. Rodríguez LR, Lapeña T, Calap-Quintana P, Moltó MD, Gonzalez-Cabo P, Navarro Langa JA. Antioxidant therapies and oxidative stress in Friedreich’s ataxia: the right path or just a diversion? Antioxidants (Basel). 2020;9(8):664. doi:10.3390/antiox9080664
4. RTA 408 capsules in patients with Friedreich’s ataxia – MOXIe. ClinicalTrials.gov. October 2, 2014. Updated December 6, 2022. Accessed January 25, 2023.
5. Lynch DR, Chin MP, Delatycki MB, et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe study). Ann Neurol. 2021;89(2):212-225. doi:10.1002/ana.25934
6. PTC Therapeutics announces initiation of global phase 3 clinical trial to evaluate vatiquinone in Friedreich ataxia. News release. PTC Therapeutics, Inc; November 30, 2020.
7. A study to assess the efficacy and safety of vatiquinone for the treatment of participants with Friedreich ataxia (MOVE-FA). ClinicalTrials.gov. October 6, 2020. Updated December 15, 2022. Accessed January 25, 2023.
8. A study to assess the safety and efficacy of vatiquinone in participants with Friedreich ataxia. ClinicalTrials.gov. August 25, 2022. Updated October 24, 2022. Accessed January 25, 2023.
9. A study of vatiquinone for the treatment of participants with Friedreich ataxia. ClinicalTrials.gov. August 3, 2022. Updated November 8, 2022. Accessed January 25, 2023.
10. A safety study for previously treated vatiquinone (PTC743) participants with inherited mitochondrial disease. ClinicalTrials.gov. February 1, 2022. Updated October 24, 2022. Accessed January 25, 2023.
11. Micronised resveratrol as a treatment for Friedreich ataxia. ClinicalTrials.gov. May 1, 2019. Updated December 8, 2022. Accessed January 25, 2023.
12. Libri V, Yandim C, Athanasopoulos S, et al. Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich’s ataxia: an exploratory, open-label, dose-escalation study. Lancet. 2014;384(9942):504-513. doi:10.1016/S0140-6736(14)60382-2
13. Study of the efficacy and safety of nicotinamide in patients with Friedreich ataxia (NICOFA). ClinicalTrials.gov. December 3, 2018. Updated October 26, 2022. Accessed January 25, 2023.
14. Safety and efficacy of etravirine in Friedreich ataxia patients (FAEST1). ClinicalTrials.gov. February 17, 2020. Updated March 31, 2022. Accessed January 25, 2023.
15. Gene therapy for cardiomyopathy associated with Friedreich’s ataxia. ClinicalTrials.gov. July 6, 2022. Updated December 5, 2022. Accessed January 25, 2023.
16. Design Therapeutics reports positive data from single-ascending dose trial of DT-216 for the treatment of Friedreich ataxia and portfolio progress. News release. Design Therapeutics, Inc; December 7, 2022.
17. Design Therapeutics announce positive data from Friedreich’s ataxia trial. Ataxia UK. December 16, 2022. Accessed January 25, 2023.
18. Study to evaluate DT-216 in adult patients with Friedreich ataxia. ClinicalTrials.gov. March 17, 2022. Updated April 12, 2022. Accessed January 25, 2023.
19. Larimar Therapeutics provides update on CTI-1601 clinical program. News release. Larimar Therapeutics, Inc; February 14, 2022.20. A double-blind, placebo-controlled, dose exploration study of CTI-1601 in adult subjects with Friedreich’s ataxia. ClinicalTrials.gov. October 14, 2022. Accessed January 25, 2023.
Reviewed by Kyle Habet, MD, on 1/23/2023.