The Friedreich's Ataxia Treatment Pipeline is a visual tool for communicating the progress of research and development on lead therapeutic candidates.

Along the vertical axis lead candidates are grouped based on mechanism of action or approach to treatment, e.g., where or how each drug might work in the cell, technological approach, or problem being addressed. The horizontal axis indicates the stage of the research - where the candidate is in development.

The first two stages, discovery and pre-clinical, take place in the research laboratory, and represent early discovery and development. The IND stage is an important milestone - this is when there is a regulatory filing with the United States Food and Drug Administration (FDA) to begin human studies. The stages “Phase 1” through “Phase 3” are phases of clinical trials/studies, when a drug is tested in individuals for safety and efficacy. With sufficient evidence proving a drug benefit, a new drug application (NDA) can be filed with the FDA. Once an NDA is approved, the drug then becomes available to individuals in their pharmacies.

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FARA is supporting the advancement of these treatments with financial resources, advocacy, patient engagement and/or fostered collaboration. FARA believes that there is merit in each of these approaches and that effective treatment will come in the form of a "cocktail approach" - a combination of two or more therapies.

This pipeline focuses on drugs that are already in preclinical development or have advanced to human clinical trials and it along with the descriptions below are updated regularly as new information becomes available.


Currently on the Research Pipeline:

+ SKYCLARYS (omaveloxolone)

Sponsor: Biogen
Please note Biogen acquired Reata Pharmaceuticals in September 2023. Click here to read the full press release.

Omaveloxolone, aka omav, brand name SKYCLARYS™, is one of a class of drugs that Reata has developed to target the activation of a transcriptional factor Nrf2. Nrf2 is a therapeutic target in FA. Several researchers (e.g., Gino Cortopassi, UC Davis, Paola Giunti, UCL, and Pierre Rustin France) have shown that Nrf2 is paradoxically decreased in cells from FA patients.

The hypothesis is that increasing Nrf2 could improve mitochondrial function by reducing oxidative stress and preventing lipid peroxidation. Reata and FA investigators have shown in numerous preclinical studies that omav and other Nrf2 activator compounds increase the number of mitochondria, improve mitochondrial efficiency, boost energy production by mitochondria, and reduce lipid peroxidation - all would potentially be beneficial in FA patients.

This video briefly explains the mechanism of action of omav:

Drug Product Manufacturing Update
Reata reported in a press release dated June 27, 2023 that the United States Food and Drug Administration (FDA) has approved the Prior Approval Supplement (PAS) to update the drug substance specification for SKYCLARYS® (omaveloxolone), the first and only FDA approved drug for the treatment of Friedreich’s ataxia in adults and adolescents aged 16 years and older. With the approval of the PAS, SKYCLARYS is now available to patients with Friedreich’s ataxia in the United States. Click here to read the full press release.

Current Stage of Development
Reata Pharmaceuticals announced on February 28, 2023, that the United States Food & Drug Administration (FDA) has approved their New Drug Application (NDA) for SKYCLARYS™ (aka omaveloxolone or omav) in FA for people 16 years of age and older. This marks a milestone for the FA community- the first approved treatment for FA. Please see the press releases from Reata and FARA posted here:

Reata - Reata Pharmaceuticals Announces FDA Approval of SKYCLARYS™ (Omaveloxolone), the First and Only Drug Indicated for Patients with Friedreich’s Ataxia

FARA - First Medication to Treat Friedreich’s Ataxia Approved on Rare Disease Day!

The FA community played a major role in achieving this milestone. The MOXIe Part 2 results provided evidence that omav positively affected neurological function in a dose dependent manner. Omav was also safe and well tolerated. The longer-term open-label extension study, where individuals with FA were taking omav for 3 years, showed a >50% slowing of progression compared to closely matched individuals in the FA natural history study.

This video has a brief history of the development of omav for FA:

Access to SKYCLARYS™ is a multi-step process from prescription to delivery of medication to patient. There are things patients and their families can do to accelerate the process. Please review these helpful resources (FAQs) . Reata is also providing resources to patients through the Reata REACH program.

Europe Marketing Authorization Application Update
On February 12, 2024, Biogen announced that the European Commission (EC) had authorized SKYCLARYS® (omaveloxolone) for the treatment of Friedreich’s ataxia (FA) in adults and adolescents aged 16 years and older. SKYCLARYS is the first treatment approved within the European Union for FA. Click here to read the full press release.

Pediatric Studies in FA
In May 2023, Reata also addressed the plans for pediatric studies (ages below 16) for omav. In the US, Reata plans to request a meeting with FDA to discuss possible label expansion for pediatric patients in Q2 2023, and they plan to conduct a single dose PK study in children in the US in Q4 2023. They indicated that this study could be completed quickly, and it would inform the necessary dose for a larger study required for label extensions to include pediatric patients. In the EU, they received a positive opinion on their pediatric plan from the Pediatric Committee and have submitted a request for scientific advice seeking additional input on a study protocol design. They indicated that after receiving feedback from both agencies they would be able to finalize plans for an additional pediatric study.

The full webcast and press release from May 10, 2023 can be found here: Reata Pharmaceuticals Inc. - Investors - Events & Presentations

Preclinical Studies
As noted above, several research labs have demonstrated in both human FA cell models and mouse FA models that Nrf2 is downregulated. In addition, treatment of FA cell and animal models with omav has demonstrated activation of Nrf2 and improvements in the mitochondrial function. Studies have shown that treatment with omav reduced pathologic levels of oxidative stress, restored antioxidative response, restored complex 1 activity, decreased lipid peroxidation, and decreased mitochondrial reactive oxygen species (ROS). In cellular assays, omav prevented cell death following pro-oxidant challenge. See this reference for the primary paper to learn more about these studies - July 17, 2018 - Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models.

In more recent studies, treatment with omav demonstrated positive impact on cardiac and neurological deficits in mouse models.
November 2022 - Nrf2 agonist omaveloxolone improves cardiac function in mouse model of Friedreich’s ataxia (Figueroa et al 2022)
November 2022 - Nrf2 agonist omaveloxolone improves cardiac function in mice with Friedreich’s ataxia (Figueroa et al 2022)

Omav also showed antiapoptotic, antioxidative stress, anti-inflammatory, and myelin-preserving effects on cultured retinal ganglion cell (RGC) survival.
September 2021 - The Effects of Two Nrf2 Activators, Bardoxolone Methyl and Omaveloxolone, on Retinal Ganglion Cell Survival during Ischemic Optic Neuropathy. Chien JY, Chou YY, Ciou JW, Liu FY, Huang SP.Antioxidants (Basel). 2021 Sep 15;10(9):1466. doi: 10.3390/antiox10091466.

Clinical Studies
Summary of trials conducted

Working with FARA and several FA Investigators in our Collaborative Clinical Research Network (CCRN), Reata conducted a two-part, randomized, placebo-controlled Phase 2/3 Study of the Safety, Efficacy, and Pharmacodynamics of omav). Part 1 of the study was a randomized, placebo-controlled, double-blind, dose-escalation study. Part 2 of the study was conducted to establish the longer-term effectiveness of omav. Finally, Reata also conducted an open label extension study. People who participated in MOXIe part 1 or 2 were able to take omav and continue to be followed for assessment of both efficacy and safety.

Key trial results

The primary endpoint in MOXIei part2 was change from baseline in mFARS at Week 48. Individuals with FA treated with omav demonstrated a statistically significant, placebo-corrected 2.40 point improvement in mFARS after 48 weeks of treatment (p=0.014). Improvements were observed in all prespecified subgroups and populations. All subsections of mFARS favored omav. Omav also significantly improved activities of daily living and other efficacy measures and omav was generally well tolerated in patients with FA.

A Post hoc Delayed-Start Analysis compared mFARS scores at the end of MOXIe part 2 with those at 72 weeks in the open-label extension period (up to 144 weeks) for patients initially randomized to omav versus those initially randomized to placebo. Those in the placebo control group continued to perform worse, i.e., they did not catch up to those people that had previously been taking omav in MOXIe part 2. In addition, the data show similar slopes in changes in mFARS for the placebo-omaveloxolone group when compared to the omaveloxolone-to-omaveloxolone group with no significant difference between the rate of change over 72 weeks. Because the placebo-omav group does not catch up to the omav-omav group, the drug is unlikely to be providing simply symptomatic benefit. The groups also show a similar rate of progression during the open label extension, which is consistent with disease-modifying activity of the drug.

Finally, a post hoc Propensity - Matched-Based Analysis was conducted using data from the open label extension study and external natural history data from FACOMS as a comparator. In the Primary Pooled Population (136 patients in each group) by Year 3, patients in the FA-COMS matched set progressed 6.6 points on mFARS whereas patients treated with omaveloxolone in MOXIe Extension progressed 3 points on mFARS (difference =-3.6; nominal p value =0.0001). Thus, progression in mFARS was slowed by 55% with omaveloxolone treatment.

Below are detailed descriptions of each part of the MOXIe study.

MOXIe Part 1 was a study designed to test the safety and potential efficacy of different doses of omav in FA. This study was needed to establish a safe dose of omav that was then used in Part 2, the larger, longer study designed to test if the drug improved symptoms of FA. The MOXIe Part 1 results provided evidence that omav positively affected the expression of specific genes, as well as neurological function in a dose dependent manner. Omav was also safe and well tolerated. These results were reported in June 2017 and again in Sept 2017 - click HERE for a webinar with Dr. Colin Meyer and FARA reviewing Part 1 study results and plan for Part 2.

+ Details MOXIe Part 1: Randomized, placebo-controlled, double-blind, dose escalation study to evaluate the safety of omav at various doses, designed to identify optimal dose for use in Part 2.
  • 69 individuals enrolled and randomized 3 to 1 (drug to placebo) and studied for 12 weeks.
  • Cohorts of 8 individuals studied at doses ranging from 2.5-300mg.
  • Results2:
    • Omav dose-dependently increased Nrf2 target genes ferritin and GGT
    • Omav improved neurological function, as assessed by mFARS
    • Dose-dependent trends observed and optimal dose identified for Part 2
    • Omav had a favorable safety profile in patients with FA in MOXIe Part 1

MOXIe Part 2 was designed to establish the effectiveness of omav as well as the longer-term effects on safety and tolerability. Again, omav was generally well tolerated. In addition, when compared to the placebo group, patients receiving omav showed improvement in both mFARS as well as in assessments of activities of daily living and other clinical endpoints.
+ Details MOXIe Part 2: Randomized, placebo-controlled, double-blind, parallel-group study to evaluate the safety and efficacy of 150 mg omav in FA patients.
  • The primary endpoint was change from baseline in mFARS at Week 48.
  • 103 individuals with FA, ages 16-40 years, enrolled and randomized 1 to 1 (drug and placebo) and studied for 48 weeks
  • Results3:
    • Individuals with FA treated with omav (150 mg/day) demonstrated a statistically significant, placebo-corrected 2.40 point improvement in mFARS after 48 weeks of treatment (p=0.014). The mFARS is a physician-assessed neurological rating scale used to measure FA disease progression. Improvements were observed in all prespecified subgroups and populations. All subsections of mFARS favored omav.
    • Omav also significantly improved activities of daily living and other efficacy measures.
    • Omav was generally well tolerated in patients with FA.

The MOXIe open-label extension (OLE) study allowed previously enrolled patients who completed MOXIe Parts 1 and 2 to enter into a new study where they would be getting omav at 150 mg once daily (no placebo). Patients were not unblinded to study treatment in Part 1 or Part 2 upon entering the extension study. This study is still ongoing, however much of the data has been made available. The goal of the OLE is to demonstrate longer-term safety and efficacy.
+ Details MOXIe Part 3/Open Label Extension (OLE) – Baseline-Controlled Study - The baseline-controlled study was designed to help assess the strength and certainty of the positive primary endpoint findings in MOXIe Part 2.
  • Results:
    • Individuals with FA treated with omav (150 mg/day) demonstrated a statistically significant, placebo-corrected 2.40 point improvement in mFARS after 48 weeks of treatment (p=0.014). The mFARS is a physician-assessed neurological rating scale used to measure FA disease progression. Improvements were observed in all prespecified subgroups and populations. All subsections of mFARS favored omav.
    • Patients served as their own controls to assess changes in mFARS and included patients considered treatment-naïve prior to initiation of omav treatment in MOXIe Part 3 OLE (i.e., MOXIe Part 1 patients and MOXIe Part 2 placebo patients). All treated populations showed reversal of disease course and improvement P-value for primary analysis is 0.0022.

MOXIe Part3/Open Label Extension (OLE) – Delayed Start Analysis – This analysis is done to give insight into whether a drug has a disease modifying effect or a symptomatic effect. MFARS scores at the end of MOXIe part 2 were compared to those at 72 week in the OLE for patients initially randomized to omav vs those randomized to placebo.
+ Details
  • Results:
    • The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (-2.17 ± 1.09 points) was preserved after 72 weeks in the extension (-2.91 ± 1.44 points). In addition, the data show similar slopes in changes in mFARS for the placebo-omaveloxolone group (0.59 points per year) when compared to the omaveloxolone-to-omaveloxolone group (0.41points per year) with no significant difference between the rate of change over 72 weeks. These data demonstration that both groups show a similar rate of progression during the open label extension is consistent with disease-modifying activity of the drug. In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks.

MOXIe Part 3/ Open Label Extension (OLE) – Propensity Matched Control Study – This analysis was performed to understand the long-term benefits of omav. All individuals enrolled in the MOXIe OLE who had at least one post-baseline assessment were matched to FA-COMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline mFARS score, and baseline gait score.
+ Details FACOMS is a prospective, longitudinal natural history study that has enrolled >1000 individuals with FA with annual clinical visits conducted using similar assessments to those collected in the MOXIe studies including mFARS.
  • Results:
    • In the Primary Pooled Population (136 patients in each group) by Year 3, patients in the FA-COMS 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). Thus, progression in mFARS was slowed by 55% with omaveloxolone treatment.
Here is a link to the publication with the results of this analysis.

News/Press Releases


February 2023 - Omaveloxolone: an activator of Nrf2 for the treatment of Friedreich ataxia. Profeta V, McIntyre K, Wells M, Park C, Lynch DR.Expert Opin Investig Drugs. 2023 Jan;32(1):5-16. doi: 10.1080/13543784.2023.2173063. Epub 2023 Feb 8.
November 2022 - Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension. Lynch DR, Chin MP, Boesch S, Delatycki MB, Giunti P, Goldsberry A, Hoyle JC, Mariotti C, Mathews KD, Nachbauer W, O'Grady M, Perlman S, Subramony SH, Wilmot G, Zesiewicz T, Meyer CJ.Mov Disord. 2022 Nov 29. doi: 10.1002/mds.29286

November 2022 - Nrf2 agonist omaveloxolone improves cardiac function in mouse model of Friedreich’s ataxia Franciso Figueroa, Lili Salinas, Clarie B Montgomery, Phung N Thai, Nipavan Chiamvimonvat, Gino Cortopassi, Elena N Dedkova - ICAR abstract 2022

November 2022 - Nrf2 agonist omaveloxolone improves cardiac function in mice with Friedreich’s ataxia Franciso Figueroa, Lili Salinas, Clarie B Montgomery, Phung N Thai, Nipavan Chiamvimonvat, Gino Cortopassi, Elena N Dedkova - AHA abstract 2022

August 2022 - Direct utility of natural history data in analysis of clinical trials: Propensity match-based analysis of Omaveloxolone in Friedreich ataxia using the FA-COMS dataset David R Lynch, Angie Goldsberry, Christian Rummey, Jennifer Farmer, Sylvia Boesch, Martin B. Delatycki, Paola Giunti, J. Chad Hoyle, Caterina Mariotti, Katherine D. Mathews, Wolfgang Nachbauer, Susan Perlman, S.H. Subramony, George Wilmot, Theresa Zesiewicz, Lisa Weissfeld, Colin Meyer medRxiv 2022.08.12.22278684; doi:

February 2022 - Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study) Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC, Boesch S, Nachbauer W, Mariotti C, Mathews KD, Giunti P, Wilmot G, Zesiewicz T, Perlman S, Goldsberry A, O'Grady M, Meyer CJ.Ann Neurol. 2021 Feb;89(2):212-225. doi: 10.1002/ana.25934. Epub 2020 Nov 5.PMID: 33068037
September 2021 - The Effects of Two Nrf2 Activators, Bardoxolone Methyl and Omaveloxolone, on Retinal Ganglion Cell Survival during Ischemic Optic Neuropathy. Chien JY, Chou YY, Ciou JW, Liu FY, Huang SP.Antioxidants (Basel). 2021 Sep 15;10(9):1466. doi: 10.3390/antiox10091466

April 2021 - Omaveloxolone: potential new agent for Friedreich ataxia. Lynch DR, Johnson J.Neurodegener Dis Manag. 2021 Apr;11(2):91-98. doi: 10.2217/nmt-2020-0057. Epub 2021 Jan 12.PMID: 33430645

+ Vatiquinone (PTC-743) 15 LO inhibitor

Sponsor: PTC Therapeutics

Vatiquinone (PTC-743) 15 LO inhibitor, is a follow-on or "sister" compound to EPI-A0001, which aims to improve mitochondrial and cellular function by targeting 15-lipooxygenase the key enzyme regulator of a pathway of inflammation, oxidative stress and cell death (known as ferroptosis), which has been implicated in CNS disease, including models of Friedreich's ataxia. Vatiquinone has been granted Orphan Drug Designation and Fast Track Designation for FA by the U.S. Food and Drug Administration (FDA).

Current Stage of Development
PTC initiated a registration-directed Phase 3 trial, MOVE-FA study, evaluating Vatiquinone in children and young adults with Friedreich ataxia (FA) in January 2021. The Phase 3 MOVE-FA trial is an 18-month parallel arm, placebo-controlled study evaluating Vatiquinone versus placebo in children and young adults with FA. The primary endpoint is the change from baseline in mFARS, with key secondary endpoints assessing ambulation and activities of daily living. As of November 2021, the study has completed enrollment with >140 subjects enrolled across 14 sites in 9 different countries.

PTC Therapeutics would like to express their gratitude to the Friedreich ataxia community, patients, and families. We appreciate the commitment and dedication of those who are participating in, or considered participating in, the MOVE-FA study. PTC remains focused on those who are impacted by this condition and values the partnership of the community.

May 23, 2023 – PTC reported topline results from the MOVE-FA trial of vatiquinone in patients with FA. The study did not meet its primary endpoint of statistically significant change in mFARS score at 72 weeks in the primary analysis population (all patients enrolled, ages 7-21yrs, N=123). However, vatiquinone treatment did demonstrate significant benefit on key secondary endpoints that are clinically significant to individuals with FA.  There was significant improvement in the patient reported outcome measure of fatigue, the Modified Fatigue Scale (nominal p value of 0.025). The vatiquinone treated group demonstrated less decline in the upright stability of mFARS (measures standing and walking) compared to the placebo group (p<0.021). The study experienced a higher number of early withdrawals, mostly due to COVID-related issues, so there was an additional prespecified analysis with the population of subjects who completed all visits through week 72 (n=96).  In the population of subjects that completed the study protocol, significance was reached in the mFARS endpoint (p <0.05), upright stability subscale of mFARS (p<0.026), and modified fatigue rating scale (p<0.042). The placebo corrected difference in mFARS was 2.31, which represents a 75% slowing in disease progression over 72 weeks. PTC stated that they will discuss the potential path to registration with FDA and EMA based on these results, the unmet need in children with FA and the favorable safety data for vatiquinone.

Background & History
Several publications in 2012 report on open-label clinical studies of EPI-743 in mitochondrial diseases, such as Leigh syndrome and Leber Hereditary Optic Neuropathy. In both studies, there was evidence that patients receiving EPI-743 had clinical improvements and no adverse events were observed. An earlier publication reports on experience in treating 14 patients with various mitochondrial conditions with EPI-743. This open-label study reports "EPI-743 has modified disease progression in > 90% of patients in this open-label study as assessed by clinical, quality-of-life, and non-invasive brain imaging parameters" and controlled trials to follow-up these findings.

January 2013, Edison Pharmaceuticals announced the launch of a Phase 2 clinical trial of EPI-743 in adults with FA. There are three sites - University of South Florida, Children's Hospital of Philadelphia and University of California Los Angeles. Subjects were recruited through the FARA Patient Registry, all subjects were enrolled by the fall of 2013. March 2014, Edison announced that FDA granted EPI-743 Fast Track designation. In September 2016, study investigators reported the results of the EPI-743 phase 2 trial at the FA educational symposium. A total of 63 subjects were enrolled in the trial. EPI-743 was found to be safe and well-tolerated over the entire 24 months study period. There were no significant differences between EPI-743 treatment groups and placebo at 6 months on the primary endpoint, a measure of vision; however, there was a trend towards improvement in neurological function as assessed by the FARS neuro scale. In the analysis of the entire 24-month trial there was suggested evidence of a significant improvement in neurological function based on the FARS score in EPI-743 treated subjects when compared to an age, sex and disease-severity matched natural history cohort followed as part of the Friedreich's Ataxia-Clinical Outcomes Measures Study (FA-COMS). Results of this clinical trial have been published and can be accessed here.

Also, in 2016 results were reported from the open-label study of EPI-743 in FA patients with point mutations and can be accessed here.

Phase 2 EPI-743 Clinical trial - An Open-Label Study to Evaluate Pharmacokinetics, Safety, and Efficacy of Vatiquinone in Children With Friedreich Ataxia Younger Than 7 Years of Age

Phase 2 EPI-743 Clinical trial -  

FA Point Mutation study -

In early 2017, Edison Pharmaceuticals announced name change to BioElectron Technology Corporation.

In late 2019, PTC Therapeutics acquired assets from BioElectron Technology Corporation which included EPI-743.

News/Press Releases
May 23, 2023 - PTC Therapeutics Announces Topline Results Vatiquinone Move FA

November 30, 2020 - PTC Therapeutics Announces Initiation of Global Phase 3 Clinical Trial to Evaluate Vatiquinone in Friedreich Ataxia

March 17, 2014 - FDA Awards Fast Track Status to Edison Pharmaceuticals' EPI-743 for Friedreich's Ataxia

February 4, 2014 - FDA Grants Edison Pharmaceuticals' EPI-743 Orphan Status for Friedreich's Ataxia

October 2019 - Targeting NRF2 for the Treatment of Friedreich's Ataxia: A Comparison Among Drugs

August 2018 - Double-blind, randomized and controlled trial of EPI-743 in Friedreich's ataxia

April 2016 - EPI-743 for Friedreichs Ataxia Patients with Point Mutations (P5.388)

+ Elamipretide

Sponsor: Children's Hospital of Philadelphia

Elamipretide is a peptide compound being developed by Stealth Therapeutics. It targets the inner mitochondrial membrane where it binds reversibly to cardiolipin. In preclinical or clinical studies, elamipretide increases mitochondrial respiration, improves electron transport chain function and ATP production and reduces formation of pathogenic ROS levels. Functional benefit is achieved through improvement of ATP production and interruption and potential reversal of damaging oxidative stress.

Current Stage of Development
The Children’s Hospital of Philadelphia (CHOP) is recruiting patients with Friedreich ataxia (FRDA) in the United States for a Phase 1/2 clinical trial studying the safety and effects of Elamipretide in the treatment of advanced stage FRDA symptoms, specifically vision loss and cardiac disease in both adults and older children. This study will include up to 18 patients to be enrolled at the Children’s Hospital of Philadelphia.

Clinical Trial
FRDA Investigator Initiated Study (IIS) With Elamipretide (ELViS-FA) -

News/Press Releases
March 28, 2022 - Stealth BioTherapeutics Receives Orphan Drug Designation from FDA for Elamipretide for the Treatment of Friedreich's Ataxia

+ NAD+ and Exercise in FA (ExRx in FA)

Sponsor: Children's Hospital of Philadelphia

There is a critical knowledge gap regarding the best ways to intervene to increase aerobic capacity (VO2max on exercise testing) in FA. Exercise is the most potent known stimulus for increasing muscle mass and mitochondrial oxidative phosphorylation (OXPHOS) capacity, increasing VO2max, and increasing insulin sensitivity (Si); however, it has not been studied in FA. One adaptation seen in exercised muscles is an increase in muscle nicotinamide adenine dinucleotide (NAD+), a cofactor required for glycolytic and mitochondrial adenosine triphosphate (ATP) production. In skeletal- and cardiac muscle-specific frataxin (FXN) knock-out animals, NAD+ precursors rescued cardiac function to near-normal, additionally highlighting its translational potential in FA. Nicotinamide riboside (NR) is a NAD+ precursor currently available as a dietary supplement (Tru Niagen ®, ChromaDex, Irvine CA) that is expected to be safe and well-tolerated in adults and children. The central hypothesis of this study is that exercise + NR will increase skeletal muscle mitochondrial OXPHOS and increase muscle mass to increase VO2max in FA. The investigators expect that exercise + NR will also increase Si in this cohort.

Current Stage of Development
Recruiting for randomized, placebo-controlled trial with a 2x2 factorial design testing the effects of an NAD+ precursor (NR) and exercise

Clinical Trial

July 2017 - Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model

+ MIB-626

Sponsor: Metro International Biotech, LLC

Defects in mitochondrial bioenergics are thought the be part of the pathological processes that reduce heart function in FA. Loss of frataxin leading to cardiac hypertrophy is associated with inhibition of the NAD(+)-dependent SIRT3 deacetylase. Increasing mitochondrial NAD(+)/NADH in vitro restores mitochondrial function.

Current Stage of Development
An open label, phase 2 trial, with the primary objective of testing the safety and tolerability of short-term therapy with a nicotinamide adenine dinucleotide (NAD+) precursor (MIB-626) in adults with Friedreich's Ataxia (FA) without overt heart failure and with a left ventricular ejection fraction ≥ 40%. A key secondary objective is to test the effects of MIB-626 on cardiac and skeletal muscle bioenergetics. Outcome measures of cardiac 31-Phosphorus-Magnetic Resonance Spectroscopy (MRS) to measure the Phosphocreatine(PCr)/Adenosine triphosphate (ATP)- γ ratio before and after treatment with MIB-626. In addition, if time permits, we will use proton (1H)-MRS to measure skeletal muscle nicotinamide adenine dinucleotide (NAD+) before and after treatment.

Clinical Trials
Phase 2 open label with 10 patients -

November 2016 - Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders

July 2017 - Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model

March 2012 - Friedreich's ataxia reveals a mechanism for coordinate regulation of oxidative metabolism via feedback inhibition of the SIRT3 deacetylase

+ Leriglitazone

Sponsor: Minoryx Therapeutics

Leriglitazone, also known as MIN-102, is an orally bioavailable selective PPAR gamma agonist that is one of the metabolites of pioglitazone and has been shown to have improved access to the central nervous system and better safety profile. In the phase 1 clinical study MIN-102 was well tolerated and it was confirmed that the compound is able to cross the blood brain barrier and engage PPAR gamma within the CNS at an equivalent level as in preclinical studies. Such level of PPAR gamma engagement in the CNS is well above what can be achieved with pioglitazone in humans. Leriglitazone is being tested in FA as well as another rare, CNS disease, x-linked adrenoleukodystrophy (X-ALD).

Current Stage of Development
Minoryx Therapeutics reported initial results of a phase 2 clinical trial of their compound MIN-102, leriglitazone, in FA patients in December 2020, press release. Full publication of all the results became available November 2022 (reference below). This was a randomized, double-blind, placebo-controlled study evaluating the effects of leriglitazone on biochemical, imaging, neurophysiological, and clinical markers in individuals with FA. The study was conducted at 4 sites in Europe (Spain, France, Belgium and Germany). 39 individuals with Friedreich's ataxia were enrolled, with 32 completing the study. There was no difference between the treatment group and placebo group in the primary endpoint (change in cervical spinal cord as measured by MRI). There was some evidence of improvement in the treatment group on some of the secondary endpoints. The treatment group had less accumulation of iron in the dentate nucleus as measured by QSM compared to placebo group and a measure of upper limb function worsened in the placebo group but not the treated group, however this difference was not statistically significant. Treatment with leriglitazone resulted in PPARg engagement, within the target range, in all patients as assessed by the relevant biomarker (adiponectin). Leriglitazone was well tolerated with some anticipated adverse events (side-effects) known to drugs with this mechanism of action, specifically edema and weight gain. Minoryx has indicated interest in continuing to advance the program and plan to meet with regulatory agencies, FDA and EMA to discuss the design of a confirmatory study in FA.

Minoryx announced in September of 2022 that the EMA had accepted for review the Marketing Authorization Application (MAA) for leriglitazone as a treatment for adult males with x-linked adrenoleukodystrophy. It is likely that future studies in FA are delayed due to ongoing development and regulatory activities for leriglitazone in X-ALD.

Clinical Trials Reference -

Background and History
The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcriptional factor playing a key role in mitochondrial function and biogenesis, fatty acid storage, energy metabolism, and antioxidant defence. Several research studies in both animal and cell models have shown that the PPARγ/PPARγ coactivator 1 alpha (PGC-1α) pathway is dysregulated when there is frataxin deficiency, thus contributing to Friedreich ataxia (FRDA) pathogenesis and supporting the PPARγ pathway as a potential therapeutic target.

Dr. Pandolfo and colleagues also did further research showing that activation of the Pgc1a pathway with a drug called Pioglitazone reversed some of cellular abnormalities observed in the brain and spinal cord of the frataxin deficient mouse model.

More recently, Dr. Lynch and colleagues further described that changes in the Pgc1a pathway are observed in the cerebellum of frataxin deficient mice and likely contributing to a mitochondrial phenotype (deficiency and loss of mitochondria).

Based on this evidence, upregulation of the Pgc1a pathway has emerged as a therapeutic target for FA. There are drugs that have been approved that specifically activate this pathway but some of them have had concerning side effects that have limited use.

In December 2020, preclinical studies of MIN-102 ( leriglitazone) were published that demonstrate rescue of phenotypic features in cellular and animal models of FRDA. In frataxin-deficient dorsal root ganglia (DRG) neurons, leriglitazone increased frataxin protein levels, reduced neurite degeneration and α-fodrin cleavage mediated by calpain and caspase 3, and increased survival. Leriglitazone also restored mitochondrial membrane potential and partially reversed decreased levels of mitochondrial Na+/Ca2+ exchanger (NCLX), resulting in an improvement of mitochondrial functions and calcium homeostasis. In frataxin-deficient primary neonatal cardiomyocytes, leriglitazone prevented lipid droplet accumulation without increases in frataxin levels. Furthermore, leriglitazone improved motor function deficit in YG8sR mice, a FRDA mouse model. In agreement with the role of PPARγ in mitochondrial biogenesis, leriglitazone significantly increased markers of mitochondrial biogenesis in FRDA patient cells. The results observed in these preclinical models reinforced the different tissue requirement in FRDA and the pleiotropic effects of leriglitazone that could be a promising therapy for FRDA.

News/Press Releases
September 14, 2022 - Minoryx’s Marketing Authorization Application for its lead candidate leriglitazone valediated by EMA for orphan indication X-linked Adrenoleukodystrophy (X-ALD)

December 15, 2020 - Minoryx's clinical candidate leriglitazone shows clinical benefit in a proof of concept Phase 2 study in Friedreich's ataxia

November 13, 2019 - Minoryx Therapeutics receives Orphan Drug Designation from the European Commission for leriglitazone in the treatment of Friedreich's Ataxia

October 18, 2019 - Minoryx Therapeutics completes enrollment in FRAMES phase 2 trial with leriglitazone in Friedreich's Ataxia  

October 17, 2019 - Minoryx Therapeutics receives FDA Orphan Drug Designation for leriglitazone in Friedreich's Ataxia

June 4, 2019 - Minoryx Therapeutics announces first patient dosed in the FRAMES phase 2 trial in Friedreich's Ataxia

February 27, 2019 - Minoryx Therapeutics receives approval from Spanish Regulatory Agency to initiate phase 2 study in Friedreich's Ataxia

December 2022 - Efficacy and Safety of Leriglitazone in Patients with Friedreich Ataxia

December 2020 - PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia

November 2017 - Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

April 2010 - PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreich's Ataxia

April 2009 - Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich's ataxia

+ Dimethyl Fumarate

Dr. Gino Cortopassi at the University of California Davis and other groups have observed that Nrf2 (Nuclear factor (erythroid-derived 2)-like 2, a protein that is critical in a pathway to protecting the cell from oxidative stress) is paradoxically decreased. Specifically, Dr. Cortopassi's group has shown that Nrf2 protein is decreased in frataxin deficient cells and FA mouse models. Through a drug discovery program that screened a library of clinically-approved drugs the group has identified several compounds that act as Nrf2 activators and rescue biochemical and cellular deficits related to frataxin deficiency. Ixchel pharma LLC has options on this Intellectual property.

One of the compounds identified though the screen was dimethyl fumurate (a drug that has been approved for treatment of multiple sclerosis and psoriasis). Dr. Cortopassi and colleagues have shown that dimethyl fumurate can induce mitochondrial biogenesis in multiple sclerosis patients and that this is via activation of Nrf2 pathway. Thus this group hypothesizes that other mitochondrial conditions, like FA, that have impairments of Nrf2 activation and loss of mitochondria might benefit from treatment with dimethyl fumarate.

Current Stage of Development
Ixchel Pharma under Dr. Cortopassi's leadership has developed a new compound based of their findings and work studying dimethyl fumarate (DMF). Ixchel has a patented prodrug technology delivers bioactive monomethyl fumarate molecules with superior pharmacokinetics (PK) to other marketed prodrugs. Ixchel is actively looking for licensing and development partners.

Dr. Francesco Sacca at the University Federico II in Naples, Italy has planned a clinical trial to further study DMF in individuals with FA. This clinical trial will investigate if dimethyl fumarate activates Nrf2 pathway, increases mitochondrial number (biogenesis), increases frataxin transcription and/or protein and will evaluate safety, tolerability and other clinical endpoints. The initiation of this study has been delayed due to COVID-19 but anticipated start is mid-2021. FARA is providing funding support for this clinical study.

January 2021 - Dimethyl fumarate dose-dependently increases mitochondrial gene expression and function in muscle and brain of Friedreich's ataxia model mice

October 2019 - Potential biomarker identification for Friedreich's ataxia using overlapping gene expression patterns in patient cells and mouse dorsal root ganglion

June 2019 - Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich's Ataxia

April 2017 - Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans

November 2013 - Frataxin deficiency leads to defects in expression of antioxidants and Nrf2 expression in dorsal root ganglia of the Friedreich's ataxia YG8R mouse model

+ CTI-1601, frataxin replacement

Sponsor: Larimar Therapeutics

Dr. Mark Payne, who first described the possibility of frataxin replacement therapy via TAT-Frataxin, has been developing this exciting prospect for FA therapy. Synthetic frataxin protein is partnered with a unique delivery system (a protein fragment called a Trans-Activator of Transcription or TAT) to get the frataxin protein to the mitochondria. Dr. Payne has tested TAT-frataxin in the FA mice and demonstrated proof of principle and compelling results. (See publication below.)

Dr. Payne's approach increases the life span and weight of FA mice and improves their cardiac function.

Dr. Payne formed a company, Chondrial Therapeutics, to further develop this approach and generate preclinical data. Chondrial is now Larimar Therapeutics and clinical trials of CTI-1601 are in progress.

Current Stage of Development
February 12, 2024 – Larimar Therapeutics, Inc. announced top-line data from the four-week, placebo-controlled Phase 2 dose exploration study of nomlabofusp (CTI-1601) in FA. This completes the dose exploration study. Nomlabofusp was generally well tolerated. Dose dependent increases in frataxin were seen in the evaluated tissues (skin and buccal cells). The press release provides detailed information on the changes in frataxin levels. Briefly, skin cells showed a mean increase in frataxin levels of 2.81mg in the 25 mg cohort (33% of healthy volunteer frataxin levels) and 5.57 pg/mg in the 50mg cohort (59% of healthy volunteer frataxin levels) at 14 days of dosing, with slightly lower levels at 28 days of dosing. Note that doses are given every day from day 1-14 and every other day from day 15-28. The majority of patients also showed increases in buccal cell frataxin levels, but these data were more variable. This may be due to the faster turnover rate of buccal cells vs skin cells and due to the lower level of frataxin in the buccal cells.

There were no severe adverse events in the 50mg cohort. One person in the 25mg cohort had an allergic reaction that resolved with standard treatment. This allergic reaction was reported as a severe adverse event and this person withdrew from the study. Other mild to moderate injection site reactions were reported. The final phase 2 data are expected to be presented at a conference in the second half of 2024.

Larimar is now in discussions with the FDA about a possible submission of a biologics license application (BLA) for accelerated approval in the later part of 2025, using changes in frataxin levels as the basis of the submission. In addition, the open label extension trial (OLE) for the 25mg cohort is underway with interim results expected in Q4 2024. These results will add to the safety data for nomlabofusp and will be submitted to the FDA.

In 2021, the FDA placed a clinical hold on the CTI-1601 clinical program following the Company's notification to the FDA of mortalities which occurred at the highest dose levels in a 180-day non-human primate (NHP) toxicology study. In 2022, following additional data provided by Larimar, the FDA lifted its full clinical hold on the CTI-1601 program and imposed a partial hold to allow the dose exploration study. Data from the dose exploration study and data from the OLE may potentially address the FDA’s concern and allow it to remove the current partial clinical hold.

The plans for both a pediatric study and a global double-blind, placebo control study were briefly discussed on Larimar’s February 12, 2024 Investor Call. A confirmatory study must be underway at the time of the submission of the application for accelerated approval for the FDA to consider granting accelerated approval for nomlabofusp.

July 25, 2023 - Larimar Therapeutics, Inc. announced that the U.S. Food and Drug Administration (FDA) has cleared the Company’s four-week, placebo-controlled, Phase 2 dose exploration trial of CTI-1601 in patients with Friedreich's ataxia (FA) to proceed to a 50 mg cohort in which participants will be dosed daily for the first 14 days, and then every other day until day 28. In addition, Larimar’s open label extension (OLE) trial was also cleared for initiation by the FDA. Participants in the OLE will receive 25 mg of CTI-1601 daily. CTI-1601 is a novel protein replacement therapy designed to deliver frataxin to the mitochondria of patients with FA who have low levels of frataxin.
Participants who complete treatment in the Phase 2 dose exploration trial, or who previously completed a prior clinical trial of CTI-1601, are eligible to screen for Larimar’s OLE trial. Participants in the OLE trial will receive subcutaneous injections of 25 mg of CTI-1601 administered daily. The trial is expected to begin in Q1 2024 with interim data expected in Q4 2024.
Click here to read the full press release or watch the webcast update.

May 15, 2023 – Larimar announced preliminary data from the Phase 2 four-week placebo-controlled, 25mg dose exploration trial of CTI-1601 showing increases in frataxin levels in individuals with FA. Participants in the trial (n=13) were randomized to receive subcutaneous injections of 25 mg CTI-1601 (n=9) or placebo (n=4) daily for 14 days and then every-other-day thereafter until day 28. Data from the cohort indicate CTI-1601 was generally well tolerated and showed increases in frataxin (FXN) levels from baseline compared to placebo in all evaluated tissues (skin and buccal cells) at day 14. One patient had an allergic reaction, most likely to the drug, which resolved with standard treatment. About half of those receiving placebo and all of those receiving CTI-1601 had a mild to moderate injection site reaction that resolved in 24 hours. Steady state levels of the drug were achieved by day 14. Larimar has submitted the data to FDA for review and has a meeting scheduled with the Agency for later this quarter to discuss the information needed to gain clearance to initiate a 50 mg cohort in the Phase 2 trial. Larimar expects to provide an update on the next steps for the CTI-1601 program in the third quarter of 2023, after it has received feedback from the upcoming FDA meeting. The update is also expected to include plans for upcoming trials, including the open label extension trial (JIVE), which would be open to participants in the SAD, MAD and four-week dose exploration studies; and MAD trial in patients 2-17 years of age; and the global double-blinded, placebo-controlled pivotal trial. 

September 14, 2022 - Larimar announced that the FDA has cleared the initiation of the 25 mg cohort of a Phase 2, four-week, placebo-controlled, dose exploration trial of CTI-1601 in FA patients. In a written communication to Larimar, the FDA indicated it was lifting its full clinical hold on the CTI-1601 program and imposing a partial hold. The design of the upcoming Phase 2 trial is identical to the design proposed by Larimar, with the exception of a requirement for the FDA to review data from the 25 mg cohort prior to escalating the dose in the second cohort. Larimar expects to begin the Phase 2 trial in Q4 2022, with top-line data expected in 2H 2023.

August 2022 - Larimar announced that it has received meeting minutes from the FDA following a recent Type C Meeting. The purpose of the Type C Meeting was to obtain FDA feedback on the information needed to resolve CTI-1601's current clinical hold in full or in part, as well as to discuss a proposed change in CTI-1601’s clinical development plan. The proposed change is to introduce a Phase 2 dose exploration study to precede initiation of an open label extension study. The Phase 2, four-week dose exploration study in FA patients would start at the lower dose levels tested in the Company’s Phase 1 multiple-ascending dose clinical trial. This study will provide data on extended dosing of lower doses of CTI-1601, including additional data on safety and tolerability as well as whether lower doses for longer periods of time can increase frataxin levels while maintaining acceptable exposures. The Company plans to submit a complete response to the CTI-1601 clinical hold in the third quarter of 2022.

February 2022 - Larimar announced that it has received feedback from the U.S. Food and Drug Administration (FDA) regarding the clinical hold on the company's CTI-1601 program. FDA stated it is maintaining its clinical hold at this time and that additional data is needed to resolve the clinical hold. Larimar is further analyzing previously completed studies and is evaluating if additional studies are warranted. The Company also intends to engage FDA to determine how best to provide these data.

August 2021 - the Company reported completion of the 180-day NHP toxicology study discussed below. The Company is currently collecting and analyzing data from the study. While there is no way to predict the FDA's response or whether they will require additional data or testing before lifting the clinical hold on CTI-1601 in full or in part, the Company expects to initiate its Jive open-label extension and pediatric MAD trials in the first half of next year.

May 25, 2021 - the United States Food and Drug Administration (FDA) placed a clinical hold on the CTI-1601 clinical program following the Company's notification to the FDA of mortalities which occurred at the highest dose levels in an ongoing 180-day non-human primate (NHP) toxicology study, which is designed to support extended dosing of patients with CTI-1601. In the clinical hold letter, the FDA stated that it needs a full study report from the ongoing NHP study and Larimar may not initiate additional clinical trials until the company has submitted the report and received notification from the FDA that additional clinical trials may commence. At the time of the notice, the Company had no interventional clinical trials with patients enrolled or enrolling.

May 2021 - Larimar shared top line data from the Phase 1 placebo controlled single and multiple ascending dose (SAD and MAD) studies of CTI-1601. The key findings were that CTI-1601 was generally well tolerated at doses up to 100mg administered daily for 13 days and frataxin levels measured in buccal cells, skin and blood were increased more than 2 fold into the range of phenotypically normal heterozygous carriers in the 50mg and 100mg dose groups. As the safety and pharmacokinetic data met the criteria for moving forward, the company states that these data represent a proof of concept and a critical step forward in CTI-1601's development as a frataxin replacement therapy for patients with FA. This is the first time a frataxin replacement therapeutic approach has been tried in FA patients.

Patients who completed the single ascending dose (SAD) and/or MAD clinical trials are eligible to screen for an open-label extension clinical trial, the Jive study, which Larimar expects to initiate in the first half of 2022. Larimar also expects to initiate a MAD clinical trial in patients under 18 years of age in the first half of 2022. Patients completing this pediatric trial will also be eligible to screen for the Jive study.

November 2020 - Larimar completed the single ascending dose (SAD) study of CTI-1601 in FA patients. The multiple ascending dose (MAD) study began enrollment in late 2020.

May 2020 - Chondrial Therapeutics did a reverse merger with Zafgen, Inc. The combined, publicly traded clinical-stage biotechnology company began operating under the name Larimar Therapeutics, Inc.

November 2019 - Chondrial Therapeutics begins a first-in-human study of CTI-1601, Single Ascending Dose Study of CTI-1601 versus Placebo in Subjects with FA. As a phase 1 study the primary goals of the study are to evaluate safety and dose, beginning with single doses. Cohorts of 6-8 of individuals with FA will be enrolled and evaluated a specific dose levels. The study is enrolling individuals with FA who are 18 yrs and older who are able to go the distance of 25 feet with or without an assistive device or pushing oneself using a manual wheelchair. This study requires a 4 night/5 day stay at the study site.

Clinical Trials Reference -

Background & History
January 13, 2016 - Chondrial Therapeutics announced that the company's lead drug candidate for the treatment of Friedreich's Ataxia (FA), TAT-Frataxin (TAT-FXN) has been accepted for further development by Therapeutics for Rare and Neglected Diseases (TRND) program researchers at the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health. This support from the TRND program provides Chondrial with access to additional expertise and resources to complete IND-enabling studies and advance the program to Phase 1 human studies.

February 2017 - Chondrial Therapeutics announced that it secured up to $22.6 million in Series A financing led by Deerfield Management. Also, Chondrial expects to file an Investigational New Drug (IND) application for CTI-1601 (TAT-FXN) with the U.S. Food and Drug Administration (FDA) and, upon acceptance of the IND by the FDA, initiate Phase 1 clinical trials of the compound.

August 2017 - Chondrial Therapeutics announces that it has received Orphan Drug Designation for CTI-1601, a novel investigational therapy for FA. In this press release Chondrial reports that the IND-enabling studies are ongoing.

News/Press Releases
February 12, 2024 - Larimar Therapeutics Reports Positive Top-line Data from Phase 2 Dose Exploration Study from 25 mg and 50 mg Cohorts of Nomlabofusp in Patients with Friedreich’s Ataxia

July 15, 2023 - Larimar Therapeutics Receives FDA Clearance to Proceed to 50 mg Cohort in CTI-1601’s Phase 2 Friedreich's Ataxia Trial and to Initiate Open Label Extension Trial

May 15, 2023 - Larimar Therapeutics Reports Preliminary Top-line Data from Phase 2 Trial’s 25mg Cohort Showing Increases in Frataxin Levels in Patients with FA and Q1 2023 Financial Results

September 14, 2022 - Larimar Therapeutics Announces FDA Clearance to Initiate the 25 mg Cohort of a Phase 2 Dose Exploration Trial of CTI-1601 in Friedreich’s Ataxia Patients

August 11, 2022 - Larimar Therapeutics Provides Updates on CTI-1601 Clinical Program Following a Type C Meeting with the U.S. Food and Drug Administration and Reports Second Quarter 2022 Operating and Financial Results

February 14, 2022 - Larimar Therapeutics Provides Update on CTI-1601 Clinical Program

August 12, 2021 - Larimar Therapeutics Reports Second Quarter 2021 Operating and Financial Results

May 25, 2021 - Larimar Therapeutics Reports FDA Clinical Hold on CTI-1601 and Termination of Recently Announced Private Placement Financing

May 21, 2021 - Larimar Therapeutics Announces $95 Million Private Placement Financing

May 20, 2021 - Larimar Therapeutics Receives European Medicines Agency Priority Medicines (PRIME) Designation for CTI-1601 in Friedreich's Ataxia

May 11, 2021 - Larimar Therapeutics Reports Positive Topline Phase 1 Clinical Trial Data Showing Dose-Dependent Increases in Frataxin Levels in Patients with Friedreich's Ataxia

May 10, 2021 - Larimar Therapeutics Reports First Quarter 2021 Operating and Financial Results

December 8, 2020 - Larimar Therapeutics Announces Completion of Dosing of the Single Ascending Dose Clinical Trial in Friedreich's Ataxia Patients and Provides Program Update

July 28, 2020 - Larimar Therapeutics Announces Positive Opinion on Orphan Drug Designation Received from the European Medicines Agency for CTI-1601 for the Treatment of Friedreich's Ataxia

July 20, 2020 - Larimar Therapeutics Announces Dosing of Patients in Third Cohort of Phase 1 SAD Trial of CTI-1601 for Treatment of Friedreich's Ataxia

May 29, 2020 - Chondrial Therapeutics and Zafgen Complete Merger and Begin Operating as Larimar Therapeutics

December 18, 2019 - Chondrial Therapeutics Announces Dosing of First Patients in Phase 1 Clinical Program of CTI-1601 for Treatment of Friedreich's Ataxia

December 18, 2019 - Zafgen and Chondrial Therapeutics Announce Definitive Merger Agreement

August 3, 2017 - Chondrial Announces FDA Orphan Drug Designation for CTI-1601, a Novel Investigational Technology for the Treatment of Friedreich's Ataxia

February 1, 2017 - Chondrial Therapeutics Secures Up to $22.6 Million in Series A Financing and Licenses Novel Technology for the Treatment of Friedreich's Ataxia

January 13, 2016 - Chondrial Therapeutics Announces Development Milestone

November 2011 - A TAT-Frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich's ataxia mouse model

+ Etravirine

Dr. Roberto Testi, University of Rome - Fratagene

Etravirine (Brand name: Intelence) - Dr. Roberto Testi and his team at the University of Rome and Fratagene recently reported results of a drug screening study. They developed a cell-based assay to conduct a high-throughput screening of 853 FDA-approved drugs in search of drugs that could increase frataxin protein levels in the assay. Among the potentially interesting drugs identified as apparently able to increase frataxin protein levels in the cell-based assay, the team focused on Etravirine for the next step. The team then introduced the drug to some fibroblasts (skin cells) and lymphoblasts (blood cells) derived from FA patients. In those cells, it seemed able to increase frataxin protein levels to some extent and restore activity of an iron-sulphur-cluster-containing enzyme, aconitase, that is decreased with frataxin deficiency. Etravirine appeared also able to protect FA patient-derived cells from oxidative stress. Initial studies to clarify the mechanism of action, also indicated that Etravirine might be able to increase the translation of frataxin messenger RNA (mRNA) into frataxin protein.

The team reported to the FA patient community at a recent meeting but has not yet published the fact that it then gave the drug orally to one of FA mouse models. In those mice, the drug appeared to increase frataxin protein levels to some extent in skeletal muscle and heart.

Current Stage of Development
Dr. Andrea Martinuzzi at the IRCCS Eugenio Medea is conducting a Phase 2 trial of Etravirine in individuals with FA. This is an an open-label, phase 2 clinical trial aimed at assessing the safety and efficacy of Etravirine in FA. Two doses of Etravirine will be evaluated over 4 months. The primary efficacy endpoint will be represented changes in peak VO2 as measured by incremental cycle ergometer exercise test. Secondary endpoints will include maximal workload, SARA score, cardiac measures, Frataxin protein levels in peripheral blood mononuclear cells and molecular analysis of Frataxin mRNA translation efficiency.

As of August 2022, recruitment is completed, 35 participants. The study should to be completed by January 2023 and results are expected by spring 2023.

Clinical Trials reference -

Background & History
Etravirine is an antiviral drug approved in 2008 by the FDA for the life-long treatment of patients who are affected by HIV and are resistant to other anti-HIV drugs. In 2018, that approval was extended to children as young as 2 years of age and affected by HIV. Etravirine's ability to cross the blood-brain barrier into the central nervous system has not been established.

Given these initial data and that this is an approved drug for another indication, there has been significant interest in the FA community to identify opportunities to advance further studies. However, these are very early-stage results and are accompanied by some words of caution as well as the need to develop a solid plan for advancing this potential therapeutic approach in the most expeditious and effective way possible.

The words of caution (from this same team of FA scientists and others of our FARA scientific advisors):

The experiments to date in cell lines were in a limited number of cells and from tissues (skin and blood) that are not affected by FA. The experiment in the mice was limited in scope and details are not yet published or available. There are safety concerns and side-effects of all drugs, including Etravirine, and while there have been studies to characterize the safety concerns in HIV-patients we don't know if and how those safety concerns and side-effects apply when used in a different population for a different purpose. Also, the current prescribing dose is for the indication in treating HIV patients and we don't know if that dose is sufficient or appropriate for increasing frataxin levels in FA patients. Thus, there are important pre-clinical and clinical questions that remain unanswered.

These same scientists, though, are committed to pursuing this opportunity in the most effective manner possible so as not to squander the opportunity by moving into full-scale clinical trials prematurely before we are able to confirm and expand the early-stage data in additional FA cells and animal models, and to understand more about the mechanism of action as well as such important factors as the optimum dose, biomarkers that might be helpful in monitoring drug effect, endpoints that might be optimal in measuring progress - all extremely important in assessing the path forward, identifying the best drug candidate to advance and, for that candidate, designing a clinical trial with the best chance of success.

With the promising early-stage results, these words of caution and their knowledge of what needs to be done to prepare for an effective clinical trial in FA, our scientists have quickly developed the following plan of immediate action:

  1. Dr. Testi and his team and collaborators will conduct a short, small study in FA patients looking at safety and tolerability, changes in frataxin levels as well as other (peripheral) biomarkers that might help identify the mechanism of action of the drug. They also plan to test the efficacy of Etravirine and its analogues in a three-dimensional cardiac model of the disease, developed from FA Induced Pluripotent Stem cells. This team's investigation of Etravirine's mechanism of action in increasing the translation of mRNA into frataxin protein could be extremely helpful. It could unveil general mechanisms that regulate frataxin expression and potentially lead to the identification of additional therapeutic targets. The team will also investigate various Etravirine analogues with the aim of identifying similar drugs with increased activity.
  2. Other scientists in the community will look to do additional testing in FA mouse models and cell models in order to assemble additional data of the drugs effect in various cell-types.
So, you can see how this combination of prompt, well designed studies by these scientists is an excellent way to proceed. If the resulting data are good enough, they will help identify the most promising drug candidate and inform the design of a larger clinical trial with a sound basis for human dose selection, biomarkers to be monitored and endpoints/clinical outcome measures to be used.

Scientific Publication January 2019 - Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia

January 2019 - Etravirine in Friedreich's ataxia: Lessons from HIV?

+ DT-216, Gene-TAC

Sponsor: Design Therapeutics

Design Therapeutics is advancing a novel approach to activate transcription of the FXN gene and restore production of frataxin protein. This approach is based on work from Dr. Aseem Ansari's lab with development of compounds called synthetic transcription elongation factors. In 2019, FARA awarded the Kyle Bryant Translational Research Award to Design Therapeutics for their research proposal “Advancing Syn-TEFs as a therapeutic candidate for FA”. This grant award allowed for some of the early testing in animal models. Design Therapeutics built on this early work to develop a next generation molecule they call gene targeting chimera or Gene-Tac.

Current Stage of Development
In August 2023, Design announced the initial data from the multiple ascending dose (MAD) study. Exploratory analyses demonstrated that DT-216 treatment achieved a statistically significant and dose-related increase in frataxin (FXN) mRNA levels in skeletal muscle (p < 0.05). DT-216 was generally well-tolerated. However, injection site reactions, called thrombophlebitis, were associated with the formulation excipients, and observed across dose cohorts. This led to the decision to re-formulate DT-216. Design has chosen and tested a formulation containing different excipients. DT-216 in this new formulation must now undergo additional preclinical testing and a new IND must be filed. The new MAD study is expected to take place in the first half of 2024, with a Phase 2 study to start in 2025.

While FXN mRNA was increased in those receiving DT-216, muscle FXN protein levels were variable, even within a person when measured a few days apart. FXN mRNA transiently increased in Peripheral blood mononuclear cells (PBMCs). The data on FXN protein changes in PBMCs was not yet available.

Clinical Trials
Phase 1 trials with DT-216 are currently open

Background & History
Dr. Aseem Ansari reported in 2017 a novel class of compounds called synthetic transcription elongation factors (Syn-TEFs). These compounds "incorporate two distinct chemical moieties: (i) programmable DNA binders that target desired genomic loci and (ii) ligands that engage the transcription elongation machinery". Polyamides are used as the DNA binders, in this case selected for specificity to the GAA repeat, and they are tethered to JQ1 which regulates RNA polymerase II pausing to promote transcription elongation. They demonstrated that SynTEF1 could restore FXN expression in FA patient- derived cell lines to the level observed in healthy cells.

Prior to beginning clinical trials, Design Therapeutics presented an Informational Webinar on DT-216 and completed IND-enabling studies with DT-1216 that supported initiation of clinical trials in the first half of 2022. The preclinical data showed the FA GeneTAC was well tolerated and achieved concentrations needed to restore frataxin (FXN) gene expression.

The Investigational New Drug Application (IND) for DT-216 was cleared by the FDA in Feb 2022 and the company initiated a Phase 1 clinical trial of DT-216 to assess the safety, tolerability, pharmacokinetics, and frataxin (FXN) levels in patients with FA in March 2022

The company also received scientific advice from the European Medicines Agency consistent with the favorable feedback previously received from the FDA, supporting the development plan for its DT-216.

In December 2022, Design reported on the initial results from the single-ascending dose (SAD) Phase 1 clinical trial of DT-216 in patients with FA. The single dose study results showed that DT-216 was generally well-tolerated and able to generate a greater than two-fold increase in FXN mRNA in the cohort with the highest response.

The development of DT-216 for the treatment of patients with FA was granted Fast Track designation by the U.S. Food and Drug Administration (FDA).

News/Press Releases
August 14, 2023 - Design Therapeutics Provides Pipeline Update and Reports Second Quarter 2023 Financial Results

December 7, 2022 - Design Therapeutics Reports Positive Data from Single-Ascending Dose Trial of DT-216 for the Treatment of Friedreich Ataxia and Portfolio Progress

March 30, 2022 - Design Therapeutics Completes Dosing in First Patient Cohort of Phase 1 Trial of DT-216 GeneTAC™ Molecule for the Treatment of Friedreich Ataxia

February 28, 2022 - Design Therapeutics Announces FDA Clearance of Investigational New Drug Application for First GeneTAC™ Molecule for Friedreich Ataxia.

August 9, 2021 - Design Therapeutics Reports GeneTAC™ Portfolio Progress and Second Quarter 2021 Results

March, 2021 - Design Therapeutics Announces Closing of Initial Public Offering and Full Exercise of Underwriters’ Option to Purchase Additional Shares

January 27, 2021 - Design Therapeutics Secures $125 Million in Series B Financing to Advance Pipeline of Genomic Medicines for Nucleotide Repeat Expansion Disorders

March 20, 2020 - Design Therapeutics Launches with $45 Million to Develop a New Class of Disease- Modifying Therapies for Serious Degenerative Disorders

Dec 2017 - Synthetic Transcription Elongation Factors License Transcription Across Repressive Chromatin

+ Oligonucleotides

Nucleic acids are the building blocks of DNA and RNA. Oligonucleotides are chemically synthesized short DNA or RNA molecules that can be designed and used as drugs when targeting specific regions of DNA or RNA to regulate or control transcription or translation of DNA or mRNA. Antisense oligonucleotides (ASOs) are single strands of DNA or RNA that are complementary to a chosen sequence and often used to prevent translation of an mRNA into protein, however, ASOs can also be designed to specific targets that can increase expression of a gene.

FARA is funding research in Dr. David Corey's lab at UT Southwestern where he has been testing ASOs and other oligonucleotides called gapmers that target the GAA repeat in the frataxin gene or mRNA as a way to activate or produce more frataxin protein.

FARA is also funding research in Dr. Jonathan Watt's lab at University of Massachusetts where they are improving the chemistry of oligonucleotides so that are able to reach more specific regions in the brain and the periphery (eg., heart). In addition the Watt's lab is trying to identify novel (non-GAA repeat) targets within the frataxin gene where oligonucleotides could be designed to activate frataxin expression.

June 2020 - Progress towards drug discovery for Friedreich's Ataxia: Identifying synthetic oligonucleotides that more potently activate expression of human frataxin protein

February 2018 - Activation of Frataxin Protein Expression by Antisense Oligonucleotides Targeting the Mutant Expanded Repeat

February 2016 - Activating frataxin expression by repeat-targeted nucleic acids

+ LX2006

Sponsor: Lexeo Therapeutics

In 2018, Ron Crystal, Professor and Chairman of the department of Genetic Medicine Department at Weill Cornell Medicine, founded Lexeo with National Institutes of Health small business grants. In January, 2021, the company raised a $85 million Series A to develop 18 preclinical and clinical programs, including a lead program for cardiomyopathy in FA.

In March, 2021, LEXEO announced completion of a license of all intellectual property rights and pre-clinical data associated with Adverum Biotechnologies’ investigational Friedreich's ataxia program.

In February 2022, Lexeo announced approval of their Investigational New Drug (IND) application for LX2006, an AAV-based gene therapy candidate for Friedreich’s Ataxia cardiomyopathy.

In June 2023, Lexeo announced the completion of the first dose cohort and the dosing of the first patient in the second dose cohort in SUNRISE-FA, a Phase 1/2 clinical trial of LX2006 in patients with Friedreich’s ataxia (FA) cardiomyopathy.
Initial data from the first two cohorts, including myocardial protein expression and biomarkers measuring serum and cardiac structure and function is expected in the first half of 2024

Current Stage of Clinical Development
The U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for LX2006. LX2006 is an AAV-based gene therapy candidate designed to intravenously deliver a functional frataxin gene, for the treatment of Friedreich's ataxia cardiomyopathy (FA cardiomyopathy).

LEXEO initiated an open-label, dose-escalation Phase 1/2 clinical trial of LX2006 in patients with FA cardiomyopathy in the July 2022.

FARA, LEXEO Therapeutics, and Weill-Cornell Medical College hosted an informational webinar on Gene Therapy for the Heart in FA on June 27, 2022. The presenters were Dr. Jay Barth, Chief Medical Officer, LEXEO Therapeutics and Dr. Ronald Crystal, Weill-Cornell Medical College; and the session was moderated by FARA.

This webinar provided information on an investigational gene therapy for the treatment of the cardiac manifestations of FA, including details on two clinical trials. Summary Slides and FAQs from the Cornell/ LEXEO community webinar can be accessed here -

News/Press Releases
June 13, 2023 - LEXEO Announces Completion of First Cohort and Dosing in Second Cohort in SUNRISE-FA, a Phase 1/2 Clinical Trial of LX2006 for the Treatment of Friedreich’s Ataxia Cardiomyopathy

February 16, 2022 - LEXEO Announces FDA Clearance of IND Application for LX2006 for Friedreich's Ataxia Cardiomyopathy

September 9, 2021 - LEXEO Therapeutics Closes $100 Million Series B Financing

June 30, 2021 - LEXEO Therapeutics Receives Rare Pediatric Disease Designation and Orphan Drug Designation for LX2006

March 2, 2021 - LEXEO Therapeutics Announces License Agreement and Consolidation of Pre-clinical Data Package

January 2021 - LEXEO Therapeutics Launches with $85 Million Series A Financing to Develop Gene Therapies

August 2020 - Stress-Induced Mouse Model of the Cardiac Manifestations of Friedreich's Ataxia Corrected by AAV-mediated Gene Therapy

+ AAVrh.10hFXN, cardiac

Sponsor: Ron Crystal, Weill Medical College of Cornell University

In 2020, Ron Crystal received a grant from NHLBI/NIH to carry out a phase IA/IB clinical study of AAVrh.10hFXN (a serotype rh.10 adeno-associated virus coding for human frataxin) to treat cardiac manifestations of FA. The drug is administered intravenously. This is a phase 1, open label, dose escalation study with a total of 10 participants.

Current Stage of Clinical Development
AAVrh.10hFXN, the therapeutic gene transfer vector used in the study, is a nonhuman primate-derived serotype rh.10 capsid with a constitutive promoter driving the normal human frataxin cDNA. AAVrh.10hFXN is administered intravenously, a vector and route which in experimental animal models effectively delivers genes to the heart. Based on preclinical efficacy data in two murine models, intravenous AAVrh.10hFXN reverses the consequences of FA cardiomyopathy. The study began recruiting in March, 2022.

Clinical Trials
Phase IA Study of AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich's Ataxia reference -

August 2020 - Stress-Induced Mouse Model of the Cardiac Manifestations of Friedreich's Ataxia Corrected by AAV-mediated Gene Therapy

+ Gene Replacement and Editing

Significant advances in gene replacement therapy and ability to edit genes have garnered much interest as a treatment approach for FA. There are several characteristics of FA that make it a favorable candidate for gene replacement therapy or gene editing approaches:

  • >95% of individuals with FA have the same single gene mutation (GAA repeat expansion). Reducing the number of expansions by gene editing may results in normal expression of the gene
  • The mutation in the gene leads to gene silencing and thus a reduction of the frataxin protein, thus there are not abnormal or toxic proteins to remove
  • Individuals with FA do make some frataxin protein, just not enough, and therefore it is less likely that they will have an immune response to replacing frataxin
  • Individuals who are carriers for FA (one abnormal copy of the gene) only make 50% of normal frataxin and have no symptoms so even modest increases in frataxin are anticipated to be therapeutic
  • Newer generations of viral vectors, adeno-associated viruses, have improved safety profiles and have favorable affinity for the tissues most affected in FA (brain, spinal cord, heart, muscle)
FARA has been funding research to evaluate various approaches to gene replacement therapy using different viral vectors and targeting different organs affected in FA. FARA has also funded gene editing projects.

There has also been significant interest and investment from biotech and pharma. Below we have provided brief summaries of companies with programs in FA.

Background & History
In September 2012 at the FARA/USF symposium, Dr. Hélène Puccio from the Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC) in Strasbourg, France presented early data on a gene therapy approach that uses a specific adeno-associated virus (AAV) that targets both heart cells and specific types of neurons. Dr. Puccio shared her exciting results that demonstrate complete prevention and correction of cardiomyopathy in the FA cardiac knock-out mouse model. FARA has funded continued work in Dr. Puccio's laboratory to evaluate gene therapy using AAV targeting the nervous system in mouse models and to continue pre-clinical development of her cardiac gene therapy approach.

Dr. Puccio's presentation -

April 2014 - Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia or

October 2014 - An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models

August 2018 - Rapid and Complete Reversal of Sensory Ataxia by Gene Therapy in a Novel Model of Friedreich Ataxia

April 2019 - Correction of half the cardiomyocytes fully rescue Friedreich ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms

August 2020 - Stress-Induced Mouse Model of the Cardiac Manifestations of Friedreich's Ataxia Corrected by AAV-mediated Gene Therapy

September 2020 - High Levels of Frataxin Overexpression Lead to Mitochondrial and Cardiac Toxicity in Mouse Models

Gene Therapy

Sponsor - AAVantiBio

Co-founded by Barry Byrne, M.D., Ph.D., and Manuela Corti, P.T., Ph.D., of University of Florida's Powell Gene Therapy Center and the MDA Care Center at UF Health, AavantiBio's lead program is in Friedreich's Ataxia (FA). Using innovative gene transfer and gene editing technologies, the company has a vision to extend to a broader spectrum of genetic diseases. Alexander “Bo” Cumbo, a seasoned biopharmaceutical executive, is Chief Executive Officer and President. Mr. Cumbo joined the Company after eight years at Sarepta, where he served as Chief Commercial Officer and Executive Vice President. A private financing round includes a $15 million equity investment from Sarepta.

On September 30, 2022, Solid Biosciences Inc. (Nasdaq: SLDB), a life sciences company focused on therapies for Duchenne muscular dystrophy (Duchenne), and AavantiBio, Inc, announced that the companies have entered into a definitive merger agreement whereby Solid will acquire AavantiBio, including its pipeline assets and net cash. The combined company will focus on advancing a portfolio of neuromuscular and cardiac programs, led by SGT-003, a differentiated gene transfer candidate, for the treatment of Duchenne. Additional pipeline programs include AVB-202, a gene transfer candidate for the treatment of Friedreich’s ataxia, AVB-401 for BAG3 mediated dilated cardiomyopathy, and additional assets for the treatment of undisclosed cardiac diseases. Bo Cumbo, the current Chief Executive Officer of AavantiBio, will assume the role of President and CEO of Solid Biosciences.

News/Press Releases
September 30, 2022 - Solid Biosciences Announces Acquisition of AavantiBio and Concurrent $75 Million Private Placement

February 2022 - AavantiBio Announces Formation of Scientific Advisory Board

April 2021 - AavantiBio and Catalent Announce Partnership to Support Development and Manufacturing of Gene Therapies for Rare Genetic Diseases

October 2020 - Gene Therapy Company AavantiBio Launches with $107 Million Series A Financing from Perceptive Advisors, Bain Capital Life Sciences, RA Capital Management and Sarepta Therapeutics

Sponsor - Lacerta Therapeutics

Lacerta was founded by University of Florida faculty. It is a preclinical stage biotechnology company with an AAV capsid technology platform and a proprietary scalable manufacturing platform. The platform uses proprietary methodologies to enhance both naturally occurring and engineered AAV capsids to improve tissue tropism and provide immune escape profiles. The manufacturing technology, OneBac platform, uses a baculovirus expression system to infect cells derived from the Spodoptera frugiperda larval moth. Using a chemically defined medium, the system provides a platform to deliver superior yields and purification of infectious AAV for use in gene therapy applications.

Lacerta is advancing a pre-clinical FA program that uses a proprietary capsid to deliver an enhanced copy of the FXN gene to the central nervous system and heart.

Sarepta formed a partnership and made an equity investment in Lacerta (Series A) in 2018. Lacerta announced a second partnership with UCB in 2020.

Sponsor - Novartis Gene Therapies (formerly Avexis)

Previously acquired by Novartis, AveXis was renamed Novartis Gene Therapies in Sept 2020. As Novartis Gene Therapies, the division is responsible for the research, development, manufacturing and commercialization of the next wave of AAV-based innovative gene therapies. Novartis Gene Therapies will also provide manufacturing support for gene therapy work conducted by other Novartis units. Dave Lennon, previously president of AveXis, is the president of Novartis Gene Therapies and reports into Vas Narasimhan, CEO of Novartis. In 2019, AveXis announced a partnership with the Novartis Institutes of Biomedical Research to apply the AAV- platform to Friedreich's ataxia.

Communications to the community
February 2022, Novartis shared this statement with the FA Community and FARA.
Novartis Gene Therapies had been developing a therapeutic approach for Friedreich’s ataxia. One candidate, OAV401, is an investigational AAV9-based gene therapy. The journey to bring new therapies from the lab to patients is complex and our team works with a sense of urgency, a need for flexibility and innovation, and an ability to accept challenges in a developing field of science. In this context, we have made the difficult decision to retire development of the OAV401 gene therapy program for Friedreich’s ataxia. However, we remain fully committed to innovative approaches, such as gene therapy, and are actively pursuing multiple pathways to harness this therapeutic platform.

Unfortunately, the totality of the pre-clinical data for OAV401 does not support a path forward for this development candidate to human clinical trials. More specifically, data generated from a recent biodistribution study revealed that adequate gene expression was not achieved in the specific cells and tissues believed to be necessary for potential therapeutic benefit in patients with Friedreich's ataxia.

These data are complementary, not contradictory, to the research we have presented previously. The prior data demonstrated that OAV401 reached the brain. These more detailed findings, however, indicate that AAV9 does not distribute to the specific brain regions or cells that we believe would be necessary for therapeutic benefit in patients with Friedreich's ataxia.

We have made this data available to enhance the knowledge in the field of AAV9 gene therapy for neurologic conditions. The title of this paper is “Intrathecal sc-AAV9-CBGFP: Systemic Distribution Predominates Following Single-Dose Administration in Cynomolgus Macaques,” and it is posted on bioRxiv ahead of peer-reviewed publication, expected later in 2022.

We recognize this update is especially disappointing to the Friedreich's ataxia patient community. We highly value our collaboration with the community and recognize that this partnership has significantly advanced the scientific understanding of the potential impact gene therapy could have for patients and families and has contributed to the development of potential clinical programs. We will continue to partner with the Friedreich’s ataxia community as we explore therapeutic options for this and other diseases.

February 9, 2021, Novartis Gene Therapies, shared this FA Community statement with FARA.
Dear Friedreich's Ataxia Community,

We at Novartis Gene Therapies hope that you and your families have had a good start to 2021, and we would like to begin the year together by expressing that we deeply appreciate your collaboration and partnership and providing you with an update on our OAV401 program for Friedreich's ataxia (FA).

In recent months, we have been working closely with the FDA to progress OAV401 toward an Investigational New Drug (IND) application. Today, we are pleased to let you know that we expect to submit an IND by the end of 2021. An active IND will allow us to initiate the clinical investigation of OAV401 for the treatment of FA.

In other breaking news, our application for Orphan Drug Designation for OAV401 was granted by the FDA. Orphan Drug Designation is intended to facilitate and expedite drug development for rare diseases or conditions for which there are no current treatments available. We are pleased by this recognition from the FDA that we have provided sufficient scientific justification to support the clinical investigation of OAV401 for the treatment of FA.

Our FA advocacy partners are strong allies who have deepened our understanding of FA and the FA community as we advance our work on promising science with transformative potential for FA. We look forward to continuing to collaborate closely with them and the FA community broadly and commit to providing you with updates on a regular basis as we have more information available to share.

The Novartis Gene Therapies OAV401 Development Team

News/Press Releases
September 2020 - AveXis renamed Novartis Gene Therapies, signifying the growing importance of gene therapy to Novartis corporate strategy

November 2021 - Intrathecal sc-AAV9-CB-GFP: Systemic Distribution Predominates Following Single-Dose Administration in Cynomolgus Macaques

Sponsor - PTC Therapeutics (formerly Agilis Biotherapeutics program)

PTC acquired the Agilis in July of 2018 with plans to advance the gene therapy programs, including one in FA. PTC is a global, public biopharmaceutical company focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to patients with rare disorders. The gene therapy program at PTC, GT-FA, is a recombinant, adeno-associated virus, containing the transgene that encodes for the protein frataxin (FXN) that is currently being developed for the treatment of Friedreich ataxia (FA). The goal of this therapy is to increase the amount of frataxin levels in the central nervous system. By restoring the level of FXN, GT-FA has the potential to improve both physical and cognitive abilities in patients with FA, including the improvement of balance, sensory capability, strength, cognition and coordination. Currently, there are no therapies available that address the underlying issue of FA. GT-FA is in pre-clinical development and has been associated with the restoration of FXN levels in multiple models of disease.

In May, 2023 PTC announced the discontinuation of preclinical and early research programs in gene therapy as part of a strategic portfolio prioritization. The discontinued gene therapy programs include preclinical stage programs in Friedreich ataxia and Angelman syndrome as well as several other programs targeting rare CNS and ophthalmological disorders of high unmet medical need at various stages of preclinical development. Chief Executive Officer Dr. Matthew Klein was quoted as stating "Where possible, we will work to ensure that the discontinued gene therapy programs can be developed by other parties so that the therapies have the potential to benefit patients." 

News/Press Releases
May 23, 2023 - PTC Therapeutics Announces Strategic Pipeline Prioritization

July 2018 - PTC Therapeutics to Acquire Agilis Biotherapeutics

Sponsor - Pfizer

Pfizer is currently in the pre-clinical stages of developing a potential gene therapies to treat FA. They have sponsored work to develop better biomarkers which may help scientists run studies faster and more efficiently.

In July, 2019 RegenxBio announced a license deal with Pfizer for a gene therapy for Friedreich's ataxia. Under the terms of the deal, RegenxBio granted Pfizer a non-exclusive global license, with rights to sublicense, RegenxBio's NAV AAV9 vector. In return, Pfizer is paying RegenxBio an upfront payment, various milestones and royalties on net sales. No financial details were disclosed.

In 2016, Pfizer acquired Bamboo Therapeutics, providing Pfizer with a clinical and several pre-clinical assets in rare diseases, as well as an advanced recombinant Adeno-Associated Virus (rAAV) vector design and production technology, and a fully functional Phase I/II gene therapy manufacturing facility that Bamboo acquired from the University of North Carolina. Bamboo's portfolio includes potential best-in-class rAAV-based gene therapies in neuromuscular, with a pre-clinical asset for Duchenne Muscular Dystrophy (DMD); and central nervous system, with pre-clinical assets for Friedreich's Ataxia and Canavan disease, and a Phase I asset for Giant Axonal Neuropathy.

News/Press Releases
May 2020 - Uncovering new biomarker to better understand Friedreich's Ataxia

July 2019 - RegenxBio and Pfizer Partner on Gene Therapy for Friedreich's Ataxia

August 2016 - Pfizer Aims To Become Industry Leader In Gene Therapy With Acquisition Of Bamboo Therapeutics, Inc.

Sponsor - Takeda

In 2019 Takeda signed an agreement with Durham, NC-based StrideBio for preclinical gene therapy candidates. The agreement included three targets, only one of which was disclosed: Friedreich's Ataxia (FA). StrideBio is leveraging its expertise in adeno-associated viral (AAV) capsid development to generate some leads that Takeda can then take into clinical development and, ideally, commercialization.

News/Press Releases
March 2019 - StrideBio and Takeda Sign Collaboration and License Agreement to Advance Novel Gene Therapies for Neurological Diseases

Sponsor - Voyager Therapeutics and Neurocrine

Voyager has a preclinical stage program for FA, VX-FXN0, that is part of a strategic partnership with Neurocrine Biosciences. The agreement calls for Neurocrine to fund the development through the Phase 1 clinical trial of VY-FXN01. After the data readout of the Phase 1 trial, Voyager has various options to co-commercialize.

In February 2014, Voyager Therapeutics was launched with a focus on FA and a few other neurodegenerative diseases. Voyager is backed by Third Rock Ventures and has a non-exclusive worldwide license, as well as sublicensing rights, to REGENX's NAV vectors for the treatment of ALS, FA and HD. FARA leadership had the opportunity to participate in discussions with many of Voyager's founders since early 2013 and appreciates their interest and commitment to developing a gene therapy approach for the neurological symptoms of FA.

News/Press Releases
January 2019 - Neurocrine Biosciences and Voyager Therapeutics Form Strategic Development And Commercialization Collaboration For Parkinson's Disease And Friedreich's Ataxia

February 2014 - Voyager Therapeutics, a new gene therapy company focused on CNS diseases, including Friedreich's Ataxia (FA), is launched

Gene Editing in FA

Sponsor - CRISPR

CRISPR Therapeutics (NASDAQ:CRSP), a genome editing company focused on creating transformative medicine for serious diseases, received the Kyle Bryant Translational Research Award from FARA. The grant was awarded to fund research on in vivo CRISPR/Cas9-based gene-editing approaches to treat FA in collaboration with Dr. Marek Napierala at University of Alabama at Birmingham.

News/Press Releases
June 2021 - CRISPR Therapeutics and Capsida Biotherapeutics Announce Strategic Collaboration to Develop Gene-Edited Therapies for Amyotrophic Lateral Sclerosis and Friedreich's Ataxia

Sponsor - prime medicine

prime medicine (NASDAQ CM: PRME) is a biotechnology company delivering a new class of differentiated one-time curative genetic therapies. prime medicine uses Prime Editing, a next-generation gene editing approach to address the genetic cause of disease and potentially provide patients with long-lasting cures. In January 2023, prime medicine announced that new preclinical data provided proof-of-concept for Prime Editing’s ability to achieve restoration of genetic function in Friedreich’s ataxia models.

News/Press Releases
January 9, 2023 - prime medicine announces recent progress and highlights 2023 strategic priorities


Candidates below are not presently on the pipeline displayed above

These compounds have been previously tested in animal or cellular models of FA or in prior human clinical trials

+ Resveratrol

Sponsors: Jupiter Orphan Therapeutics, Jupiter, FL & Murdoch Children's Research Institute (MCRI), Melbourne, Australia

Resveratrol is a naturally occurring compound found in the skin of red grapes. Resveratrol has been under investigation as a compound that could improve mitochondrial function and some studies suggest increased longevity, lowering glucose levels and anti-cancer activity. Researchers in Australia found that resveratrol also increased frataxin levels in laboratory studies.

Investigators at MCRI in Melbourne, Australia were evaluating the therapeutic potential of resveratrol in clinical trials.

Jupiter Orphan Therapeutics is a company developing a novel formulation of resveratrol to improve the absorption and pharmacokinetic properties.

Current Stage of Development
The results of the Phase 2 study were presented at the International Congress for Ataxia Research (ICAR) in November 2022. Martin Delatycki, Murdoch Children’s Research Institute, the Principal Investigator of the study, stated that the study was negative, meaning reseveratrol provided no benefit relative to placebo.

A Phase 2 study, Micronised Resveratrol as a Treatment for FA, was held at 3 sites in Australia. In August 2021, at an FA community webinar, Dr. Delatycki reported that enrollment for the study was complete however the treatment phase extended into 2022. The study was a double-blinded, placebo-controlled randomised 2-period crossover trial of 2g/day of micronised resveratrol in FA over 24 weeks. The study enrolled 40 patients, >16 yrs of age with FA, from 3 sites. The primary outcome measure was the change in modified Friedreich Ataxia Rating Scale (mFARS) score from baseline to 24 weeks.

Clinical Trials reference -

Background & History
FARA funded an open-label, pilot study of Resveratrol at the University of Melbourne which began in April 2011. At the American Academy of Neurology in April and FARA's Clinical Research Conference in June 2013 the study team reported the results.

The primary objective of the study was to evaluate the safety, tolerability and efficacy of two different doses of resveratrol (1g and 5g). 27 subjects were enrolled and 24 completed the treatment for 12 weeks. Subjects were compared to baseline on primary and secondary outcome measures after the 12 weeks. The primary outcome measure of lymphocyte frataxin levels did not show a difference in either treatment group. Some of the secondary outcome measures, such as neurological rating scales and speech measures showed improvement in the high dose group however this should be interpreted with caution as there was no placebo group. The high dose group that received 5 grams of resveratrol per day had significant gastrointestinal adverse events including diarrhea, loose stools and abdominal pain. It is encouraging that there were dose-dependent clinical improvements however with dose-limiting adverse events it will be challenging to advance, unless new formulation or delivery strategies are developed. The full results have been published, link is provided below.

January 12, 2016 - Jupiter and Murdoch announce a partnership to further advance development and testing of resveratrol as a treatment for FA. The product, JOT101, will be a novel proprietary formulation developed by JOT utilizing the active ingredient of resveratrol. A new formulation that can more effectively deliver resveratrol and reduce side effects is necessary to fully evaluate the potential efficacy of resveratrol. (see Press Release below)

June 2, 2016 - Jupiter Orphan Therapeutics provided the FA community with an update on their work to develop, JOTROL™, an authentic resveratrol, in a proprietary, optimized and controlled delivery system. They shared data demonstrating improved bioavailability in animals which should result lower resveratrol dosing to achieve efficacy.

News/Press Releases
February 23, 2022 - Jupiter Neurosciences, Inc. Announces Completion of Phase I Safety Trial with Enhanced Resveratrol Product, JOTROL™

August 2017 - Jupiter Orphan Therapeutics Receives Orphan Drug Designation for it Trans-Resveratrol Product JOTROL for Treatment of FA

January 2016 - Jupiter Orphan Therapeutics, Inc. Enters into a Global Licensing Agreement with Murdoch Children's Research Institute

April 2015 - An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels

+ ALCAR (Acetyl-L-Carnitine)

Acetyl-L-Carnitine or ALCAR is a naturally occurring compound made in the body and available as a supplement. L-carnitine transports fatty acids to the mitochondria for breakdown and is also known to have an important role in glucose metabolism. ALCAR has been studied as a supplement in many diseases, including cardiovascular disease, diabetes, neurodegenerative disorder and Friedreich's ataxia. Early studies showed that the drug was well tolerated and that there were some modest objective benefits.

Related publications:

Dr. Theresa Zesiewicz at the University of South Florida initiated a long term open label study of ALCAR examining cardiac and neurological measures in adults with FA. Proceeds from the FARA Energy Ball funded this study.

For more information on this study go to -

+ BMN 290 / HDACi

Sponsor: BioMarin (formerly RepliGen)

HDAC inhibitors are a class of compounds that interfere with the histone deactylase that functions to keep the DNA of a gene tightly coiled so as to silence that gene's expression of its protein. Dr. Joel Gottesfeld of The Scripps Research Institute in La Jolla, California first described the potential use of these compounds in FA to overcome the gene silencing effect of the predominant genetic mutation that causes FA. Dr. Gottesfeld and RepliGen are working together to design novel HDAC inhibitors that act at the DNA/gene level and increase frataxin protein production in cells from FA patients and in FA animal models. The Repligen Corporation has licensed these HDAC inhibitors from Scripps for the purposes of advancing them through preclinical development and clinical trials in FA. Repligen and Dr. Gottesfeld are working very closely together, with support from FARA, MDA and GoFAR, and with the FA mouse-model investigators so as to develop the very best HDAC inhibitor for FA.

Current Stage of Development
October 2017 - BioMarin announces that they have selected BMN 290, a selective chromatin modulation therapy, for the treatment of FA. BMN 290 is a second generation compound derived from a compound acquired by Repligen. BMN 290 was selected because it has been shown to increase frataxin more than two-fold and the compound penetrates the central nervous system and cardiac tissue. BioMarin plans to file an Investigational New Drug (IND) application with FDA for BMN 290 in the second half of 2018.

Background & History
RepliGen identified a lead candidate (RG2833) and has been working on development of new follow-on candidates (RG3250). RG2833 completed a Phase 1 clinical trial in FA patients in Torino, Italy in April, 2013. This trial was designed to study dose and safety. There were four cohorts of subjects who were given single escalating doses of the drug and monitored with various blood and biophysical tests. In the third and fourth cohorts, which were the highest dose levels, the treatment was well tolerated and there was an increase in frataxin mRNA (a measure of frataxin gene expression). These results are significant in that it provides proof of principle that an HDAC inhibitor delivered orally (in a pill) can increase frataxin gene expression measured in blood from subjects. RG2833 is not going to continue forward to further clinical trials with longer term exposure because there are metabolites formed as the compound is broken down in the body that can be harmful. However, over the past two years RepliGen has been developing follow-on compounds have better access to the central nervous system, better metabolic stability, and increase frataxin similarly to RG2833.

In January 2014, Repligen announced that BioMarin had acquired the HDAC inhibitor program. This is very encouraging since BioMarin is a leader in developing therapies for rare, inherited conditions and Repligen was no longer in a position to advance the program. BioMarin is continuing the work that Repligen started to identify a new lead candidate with improved characteristics over RG2833 (the previous candidate that went through Phase 1 studies).

April 2017 - Working in close collaboration with Dr. Joel Gottesfeld of The Scripps Research Institute and Dr. Sanjay Bidichandani at the University of Oklahoma, the BioMarin HDACi team has identified a new generation of compounds with significantly improved potency and brain exposure and reduced levels of harmful metabolites. Additional preclinical profiling, including evaluation in patient samples to be supplied by FARA, will be conducted to help chart a course towards potential regulatory studies.

News/Press Releases
October 2017 - BioMarin Highlights Breadth of Innovative Development Pipeline at R&D Day on October 18th in New York

October 2014 - Epigenetic therapy for Friedreich ataxia

October 2012 - HDAC inhibitor update from RepliGen at the CHOP symposium includes information on the first clinical trial of HDAC inhibitors (RG2833) in FA patients in Italy and the follow-on compound RG3250

September 2012 - Rationale for the development of 2-aminobenzamide histone deacetylase inhibitors as therapeutics for Friedreich ataxia.

2011 - Evaluation of histone deacetylase inhibitors as therapeutics for neurodegenerative diseases.

+ Calcitriol (Vitamin D3)

Sponsor: Berta Alemany, Institut d'Investigació Biomèdica de Girona

The IRBLleida (Institut de Recerca Biomèdica de Lleida Fundació Dr. Pifarré) research group published a paper (Delaspre et al 2020) that showed calcitriol can increase the production of frataxin in cell models. The group evaluated both frataxin as well as other cellular readouts related to frataxin deficiency. The mechanism by which calcitriol could increase frataxin is not known. No in vivo or animal model data is available.

Current Stage of Development
An open label pilot study has been planned and estimated to begin in September 2021 to evaluate the effects of calcitriol in a small cohort (20) of individuals with FA. The study proposed to treat and monitor individuals for 12 months. Outcome measures of neurological function and blood frataxin levels will be assessed throughout the study.

Clinical Trials
Pilot Trial About the Effects of Calcitriol's Treatment in the Neurological Function and Frataxin's Level in Friedreich's Ataxia Patients -

Britti E, Delaspre F, Sanz-Alcázar A, Medina-Carbonero M, Llovera M, Purroy R, Mincheva-Tasheva S, Tamarit J, Ros J. Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia. Biochem J. 2021 Jan 15;478(1):1-20. doi: 10.1042/BCJ20200331.

+ CAT-4001

Catabasis is developing CAT-4001 as a potential treatment for neurodegenerative diseases such as Friedreich's ataxia (FA) and amyotrophic lateral sclerosis (ALS). CAT-4001 is a small molecule that activates Nrf2 and inhibits NF-kB, two pathways that have been implicated in FA and ALS. Catabasis has shown that CAT-4001 modulates the Nrf2 and NF-kB pathways in both cellular assays and animal models.  FARA awarded a research grant to Catabasis, the 2015 Kyle Bryant Translational Research Award, to facilitate pre-clinical testing of CAT-4001 in cell and animal models of FA. Testing of CAT-4001 in cellular and animal models of FA did not support advancement to clinical development.

+ Crestor

Sponsor: Children's Hospital of Philadelphia/University of Pennsylvania

Recent work at the University of Pennsylvania, Center of Excellence in Friedreich Ataxia, has discovered that serum ApoA-1 protein levels are lower in people with FRDA when compared with control levels. These results are published, ApoA-1 is the main protein found in high-density lipoprotein (HDL) cholesterol and individuals with FRDA frequently have low HDL levels. Investigators have designed and initiated a study to assess if administration of HMG-CoA reductase inhibitors (drugs known to increase ApoA-1 such as Crestor) for 3 months alters ApoA-1 protein levels in FRDA. Although the significance of ApoA-1 levels among FRDA patients is currently unknown, this study is proposed as an exploratory study to further examine this protein.  For more information on the clinical study visit - Results from this open-label single-site pilot study of Rosuvastatin in 12 adults with FA revealed that treatment with Rosuvastatin significantly lowered LDL levels but had modest effects on HDL, serum APOA1 levels and frataxin. Interestingly, Rosuvastatin did alter fatty acid metabolism in platelets suggesting that the intervention did have a pharmacodynamics affect on the pathway and confirming the role of HMG-CoA reductase in fatty acid metabolism. Rosuvastatin was well-tolerated in the majority of the subjects, but three subjects discontinued their participation early due to adverse events including elevations in creatinine kinase, liver function enzymes and muscle cramping. There is no data to suggest that treatment with rosuvastatin will impact other clinical features of FA. As this drug is approved and available for treatment of hypercholesterolemia no further studies were initiated. These results were presented at the CHOP FA Symposium in Oct 2018 and will be posted to study posting.

+ Cytokine Mediated Therapy - GCSF

Sponsor: University of Bristol

Granulocyte colony stimulating factor' (GCSF) is a new therapeutic candidate that we have added under stem cell approaches. This is based on research out of the University of Bristol, Experimental studies undertaken within Dr Wilkins' laboratory indicate that bone marrow stem cells protect nerve cells and induce repair of the nervous system. They have recently completed a major study of a mouse model of FA in which the bone marrow stem cell mobilizing drug, GCSF, protected mice from neurological damage. These are drugs that are used in clinical practice that activate stem cells within the bone marrow and induce them to circulate around the body. The Bristol researchers were recently awarded a new research grant from Ataxia UK and FARA to continue this research in human cell lines and a small pilot trial in FA patients.

+ Deferiprone

Sponsor: Apopharma

Deferiprone, also known as Ferriprox®, is an oral iron chelator. Excess free iron in the mitochondria can increase oxidative stress/damage. Iron chelators can remove this excess iron, reducing oxidative stress. This redistribution of excess iron has been proposed as a therapeutic strategy for FA. Since 1999, Ferriprox® has been approved in Europe for the treatment of iron overload in patients with thalassemia major. It was recently approved for this indication in the US. Deferiprone has been evaluated in small open-label studies and recently in a larger double blind placebo controlled trial.

An open-label study was conducted in 13 adolescent patients. Subjects were treated for six months with 20-30 mg/kg/d deferiprone. 4 subjects were withdrawn due to side effects, and 9 completed the study. 1 of the 4 subjects had agranulocytosis, and the others experienced muscular-skeletal pain, dizziness or Guillain-Barre syndrome which resolved after discontinuation of deferiprone. MRI to assess iron in the dentate nucleus (R2*) and neurologic rating scales were performed at the beginning of the study and at the end. A significant reduction in R2* was observed in 8 of the 9 subjects; the one person who did not show a significant decrease in R2* had an initially low value. It was also observed in the study that there was a modest improvement in neurologic function as measured by the ICARS. Specifically, there was a decrease in ICARS (8.5 +/- 4.5 pts).
Boddaert N, et al., Blood 110 (1), 2007 -

Another open-label study was conducted in 20 individuals with FA, ages 8-25, for 11months to assess the combined therapy of Idebenone and deferiprone. Subjects were evaluated with neurological rating scales (ICARS) and MRI to assess brain iron deposits in the dentate nucleus. All subjects were on a steady dose of idebenone (20mg/kg/d) prior to the start of the study and were maintained on this dose throughout the study. Deferiprone was administered at a dose of 20 mg/kg/day/12 h. One subject was withdrawn after 6 months due to severe neutropenia; another subject had mild neutropenia but was able to complete the study. No significant differences were observed in total ICARS when comparing baseline to the end of the study. Of note, this was interpreted as a stabilization of neurologic function as the progression rate of FA demonstrated in other studies is about 4.4-5 points per year. Echocardiographic measures showed a significant reduction of left ventricular and intra-ventricular wall thickness. MRI T2* values in the dentate nucleus showed a statistically significant reduction in iron. Velasco-Sanchez D. et al., Cerebellum 2010 -

A double-blind, randomized, placebo-controlled trial was conducted to assess safety, tolerability and efficacy of multiple doses of deferiprone. A total of 80 patients with Friedreich's ataxia were targeted for enrollment. Study results have only been orally reported at the 4th International FA Scientific Conference, Strasbourg, FR, May 2011. 72 patients were randomized to receive 10 mg/kg BID (21-deferiprone; 5-placebo), 20 mg/kg BID (20-deferiprone; 6-placebo) or 30 mg/kg BID (14-deferiprone; 6-placebo). The high dose arm of the study (30mg/kg/bid) had to be prematurely terminated due to an increase in adverse neurologic events. "There were no significant differences in baseline to end-of-study changes in non-cardiac scores (each deferiprone-treated group vs control group) except for a significant increase in FARS, ICARS and ADL in the 20 mg/kg BID deferiprone group. Improvements in posture, gait and kinetic function were observed in some patients treated with deferiprone, most notably in patients with mild disease. Deferiprone at 10 mg/kg BID and 20 mg/kg BID was associated with a -20.6 (26.5) and -17.6 (21.5) decrease in LV Mass index, respectively. Deferiprone at 30 mg/kg BID was associated with worsening ataxia in some patients, which improved upon discontinuation of the drug. Low serum ferritin levels occurred in 29% and 45% of subjects in the 10 mg/kg BID and 20 mg/kg BID groups, respectively. There was one case of neutropenia that resolved on drug withdrawal." 2011 4th International FA Conference Abstracts - Scientific Conference

+ EGb-761

Sponsor: Ipsen

EGb 761 is an extract of Ginkgo biloba leaves that has antioxidant properties as a free radical scavenger and is being developed by Ipsen under the name Tanakan®. This drug was initially developed to treat symptoms of age-related cognitive impairment and neurosensorial disorders such as vertigo, tinnitus, hearing loss, and retinal disorders.

Ipsen conducted a clinical trial of EGb761 in France - "A Phase II, Randomised, Double Blind Study Assessing the Efficacy of EGb761 120mg Bid Versus Placebo in Patients Suffering From Friedreich Ataxia" They recruited 22 individuals with FA between the ages of 12 - 22 years and who are ambulatory.

In April 2013, Ipsen posted results of the study. Unfortunately, the due to the small number of subjects the investigators were not able to do complete statistical analysis of all the outcome measures. The primary outcome measure was a biochemical measure based on exercise - creatine rephosphorylation rate post exercise measured using Phosphorus 31 Nuclear Magnetic Resonance (P-31 NMR) spectroscopy. There were no differences between the treatment and placebo group on this measure.

More information on the study can be found at

+ EPI-A0001

Sponsor: Edison Pharmaceuticals

EPI-A0001 is alpha-tocopherolquinone, a drug which functions in the mitochondria.

A phase II study of EPI-A0001 was completed and initial results were announced by Edison Pharmaceuticals in June 2011. The primary endpoint of insulin resistence did not show statistically significant improvement; however there was significant improvement in neurological function as assessed by the Friedreich's Ataxia Rating Scale (FARS). This was a double-blind placebo-controlled trial with three arms: placebo, low dose, and high dose EPI-A0001. The improvement in the FARS was statistically significant in both the high and low dose groups in comparison to placebo. There were no differences in the rates of drug-related adverse events between the placebo group and each of the drug-treated groups. These encouraging results will need to be followed up with another study.  Edison Press Release
(Lynch et al., Movement Disorders, 2012)

+ Epicatechin

Sponsor: Epirium Bio (formerly Cardero Therapeutics)

Epirium Bio is developing compounds that promote mitochondrial biogenesis (the making of new mitochondria). They report discovery of a previously unknown hormonal pathway that appears to regulate mitochondrial biogenesis. "Among the distinctive properties of this hormonal pathway is the generation of new, functional mitochondria, coupled with restoring the structure and function of previously atrophic tissue, particularly that of neuromuscular and central nervous systems. The coupling of these pathways mimics a physiological process that can be seen in response to physical exercise and that is essential for the proper functioning of organs."

Current Stage of Development
In December of 2019, the company announced funding that would allow them to advance their lead candidate into clinical development for Becker Musculary Dystrophy and other indications, of which Friedreich's Ataxia is being considered.

Clinical Trials Reference -

Background and History
Cardero Therapeutics identified the natural compound ‘(+)-epicatechin', a rare flavonoid that mimics the novel human hormone, improves mitochondrial function in different models of cardiac disease and neuromuscular disease.

Based on studies demonstrating safety and tolerability in healthy volunteers and encouraging findings individuals with neuromuscular disease (Becker Muscular Dystrophy), Cardero and investigators at the Mayo Clinic ran a pilot study in individuals with Friedreich ataxia in 2016-2017. This was an open-label study for 24-weeks to evaluate the safety and effectiveness of synthetically produced (+) Epicatechin in treating patients who have Friedreich's Ataxia. Some results are posted on site (See link above) and more detailed results are being prepared for publication.

News/Press Releases
December 18, 2019 - Epirium Raises $85 Million in Series A Financing to Advance Unique Scientific Platform Focused on Restoration of Tissue Bioenergetics and Function

+ EPO-mimetics

Sponsor: STATegics, Inc.

Epo-mimetics - STATegics, Inc., a company in South San Francisco, CA, specializes in the discovery and development of small molecule modulators of cytokine receptors. Lead compounds include potent and selective activators of the tissue protective erythropoietin receptor, a potential target for treatment of FA. STATegics received grant funding from FARA to investigate these compounds in cellular and animal models of FA and to investigate cellular mechanisms linking receptor activation to increases in frataxin.

Current Stage of Development
STATegics is now planning to launch preclinical PK-PD studies with a lead compound.

May 2017 - Erythropoietin and small molecule agonists of the tissue-protective erythropoietin receptor increase FXN expression in neuronal cells in vitro and in Fxn-deficient KIKO mice in vivo

+ Erythropoietin (EPO)

EPO is a hormone produced in our bodies and is also an approved drug used to increase red blood cells. It is commonly used in dialysis and cancer patients as well as in patients just prior to surgery in which loss of blood is anticipated. Austrian researchers Drs. Scheiber-Mojdehkar and Sturm found that EPO increases frataxin levels in cellular models and in a promising proof-of-principle study in FA patients (see article). The mechanism is still not understood, but these researchers have concluded that EPO does not appear to affect frataxin levels directly by increasing genetic transcription. Based on these initial results there has been interest in conducting larger more definitive trials of EPO and testing of newer EPO-like compounds that might have fewer side effects.

The Austrian group conducted open-label pilot trials. The longest was a 6 month study with 8 adults with FA who received 2.000 IU rhuEPO thrice a week subcutaneously. Clinical outcome measures included Ataxia Rating Scales along with frataxin levels, and indicators for oxidative stress were assessed. Hematological parameters were monitored biweekly. Scores in Ataxia Rating Scales such as FARS (P = 0.0063) and SARA (P = 0.0045) improved significantly. Frataxin levels increased (P = 0.017) while indicators of oxidative stress such as urine 8-OHdG (P = 0.012) and peroxide levels decreased (P = 0.028). Increases in hematocrit requiring phlebotomies occurred in 4 of 8 patients. The investigators concluded that there was evidence for clinical improvement together with a persistent increase of frataxin levels and a reduction of oxidative stress parameters in patients with FRDA receiving chronic treatment with rhuEPO; however safety monitoring with regular blood cell counts and parameters of iron metabolism is a potential limitation of this approach.
Boesch S et al, Mov Disord. 2008 Oct 15;23(13):1940-4.

To further explore the optimum dosing of EPO, an Italian group of investigators did a short trial of larger- single doses of epo and studied the effect on frataxin and hematocrit levels. They found that "Epoetin alfa had no acute effect on frataxin, whereas a delayed and sustained increase in frataxin was evident at 3 months after the first dose (+35%; P < 0.05), and up to 6 months after the second dose (+54%; P < 0.001). The treatment was well tolerated and did not affect hematocrit, cardiac function, and neurological scale." Sacca et al., Mov Disord 2011 Mar;26(4):739-42.

Dr. Francesco Sacca at the University Federico II in Naples, Italy has launched a new clinical trial that will test the effect of erythropoietin on exercise capacity, which is reduced in patients with FRDA. The title is Efficacy Study of Epoetin Alfa in Friedreich Ataxia (FRIEMAX). Additional objectives of the study will be the drug's safety and tolerability, and its effect on frataxin, blood vessel reactivity, heart functional indexes and disease progression.

This study began in early 2013 and Dr. Sacca reports that all subjects have been enrolled and the treatment phase was completed late 2014. The results are being analyzed and should be reported in early 2015. This study was funded by FARA through the Keith Michael Andrus Memorial Award and AISA (Associazione Italiana per la lotta alle Sindromi Atassiche). reference:

+ Idebenone / Catena

Sponsor: Santhera Pharmaceuticals

"Catena is a small molecule optimized to facilitate the transport of electrons within mitochondria, and contributes to maintaining correct electron balance, which is necessary for the production of cellular energy." - Santhera

Catena® has conditional approval as a treatment for Friedreich Ataxia in Canada, but it is not approved in the United States or other countries. Studies of Idebenone continue in FA and other mitochondrial and neurological diseases. Below is a summary of the most recent clinical trials ongoing and completed in FA. A Phase IIIb Double-Blind, Randomized, Placebo-Controlled Study of Patient Reported Outcomes in Friedreich's Ataxia Patients After Withdrawal From Treatment With Idebenone has just been completed. This study is also known as PROTI and was open to individuals who completed the MICONOS study. The objective of the PROTI study is to establish whether patients can correctly determine which treatment assignment (placebo or idebenone) they received during the randomised phase of the trial, and identify any potential changes on symptoms or activities. Results are pending.

Phase III - IONIA study and 12-month open label extension study (IONIA-E)

On May 19, 2009 Santhera announced that the phase III trial of Idebenone (Catena®) in the United States did not demonstrate benefit at the level of statistical significance. The study did demonstrate that the drug was safe and well-tolerated and that the individuals who received Idebenone improved their scores more than those on placebo. However, the benefit did not reach statistical significance. "Patients who received idebenone improved by 2.5 points on mean ICARS score compared with baseline, while patients in the placebo group improved by 1.3 points. Patients who took idebenone also improved by 1.6 points on the FARS, while patients taking placebo declined by 0.6 points." (Lynch et al, Arch Neurol 2010)

After the Phase III IONIA study 68 patients were enrolled into an open-label extension study where patients received 1350/2250 mg/day idebenone for 12 months (IONIA-E). Changes in ICARS and FARS were recorded during the total of 18 months combined study period. Results were reported in May 2011 at the 4th International FA Scientific Conference in Strasbourg FR. "Patients who received idebenone 1350/2250 mg/day significantly improved in neurological function over the 18 month combined observational period (change in ICARS: -3.02 ± 1.22, p=0.014). Patients who had been on placebo or 450/900 mg/day idebenone for the 6 month IONIA study and who only received idebenone 1350/2250 mg/day for the 12 month of IONIA-E did not deteriorate over the combined 18-month period, which may also be therapeutically relevant for a progressive disease. The improvement in neurological function over time was best seen when the posture & stance subscore was excluded from the analysis."
(Meier et al, J Neurol, 2011)

A third publication was also released in 2011 from the IONIA study looking at cardiac changes via echocardiogram during the 6 month study. ECG abnormalities were found in 90% of the subjects. On echocardiogram, 81.4% of the total cohort had left ventricular (LV) hypertrophy, as measured by increased LV mass index-Dubois, and the mean ejection fraction (EF) was 56.9%. Left ventricular mass index, posterior wall thickness, EF, and ECG parameters were not significantly improved by treatment with idebenone. This study did not provide evidence of benefit in this cohort over a 6-month treatment period.
(Lagerdrost et at., Am Heart J, 2011)

Phase III - MICONOS (Mitochondrial Protection with Idebenone In Cardiac Or Neurological Outcome Study)

On May 20, 2010 Santhera announced that the phase III trial of Idebenone in Europe (MICONOS) did not reach primary or secondary endpoints which were neurological rating scales (ICARS and FARS). This was a 12 month placebo controlled trial in adults with FA.

"A meta-analysis of Santhera's three Phase II and III studies including 344 patients of all age groups and disease stages showed trends for improvement on Catena®/Sovrima® in the mean change in ICARS score in the combined mid- and high dose groups compared to placebo (p=0.083) as well as in the high dose group compared to placebo (p=0.088). Similarly, a larger proportion of patients improved by at least 2.5 ICARS points over a six months treatment period in the Catena®/Sovrima dose groups (placebo: 30.4%; mid-dose group 39.1%; high dose group 41.9%) and comparison with placebo showed a trend in favor of the combined mid and high dose groups (p=0.10) and the high dose group (p=0.098)." - Santhera May 20, 2010

While data from several studies show modest improvements in FA patients, these improvements have not been reproducible or statistically significant in some cases so it is unlikely that Catena® will be approved as a treatment for FA in the United States. However, non-pharmaceutical grade Idebenone is available in the United States as a nutriceutical/supplement through several online sources. Idebenone continues to be studied in other mitochondrial and neurodegenerative diseases.

+ Incretin analogs

Universite Libre de Bruxelles, Brussels, Belgium - Drs. Miriam Cnop, Mariana Igoillo-Esteve and Massimo Pandolfo

Research on the diabetes associated with FA lead this research team to discover that incretin analogs are protective for frataxin-deficient ß-cells.Publication:
Incretins are gut hormones that control blood sugar levels. Stable hormone analogs have been developed in recent years to treat diabetes. Unexpectedly, they observed that these drugs induce frataxin expression in pancreatic ß-cells. In 2014, FARA awarded the Phillip Bennett and Kyle Bryant Translational Research Award to Drs. Miriam Cnop, Mariana Igoillo-Esteve and Massimo Pandolfo at the Universite Libre de Bruxelles, Brussels, Belgium. This award allowed the team to further evaluate a new treatment approach in FA cell models. The aim of this preclinical project was to evaluate the potential of incretin analogs to induce frataxin and prevent or improve cell dysfunction. The team tested this in neuronal cells generated from induced pluripotent stem cells from FA patients. Based on the results, the team launched a small pilot trial of incretin analogs in a few individuals with FA at their University hospital in Belgium. The results of the pre-clinical and clinical studies are complete and being prepared for publication. There are no further clinical development plans at this time.

+ Interferon gamma

Sponsor: Horizon Pharma

Dr. Roberto Testi at the University of Rome "Tor Vergata" published a study in March 2012 that showed that Interferon gamma increases frataxin levels in both cell and animal models of Friedreich ataxia. The data in the report suggest that frataxin is increased by increased transcription of the FXN gene.

Scientific Publication - Dr. Testi

Interferon gamma (Actimmune) is a drug that is approved for treatment of other rare diseases - chronic granulomatous disease (CGD) and severe, malignant osteopetrosis.

Dr. Testi is doing a pilot study of interferon gamma in FA patients. This study will evaluate the safety and tolerability of multiple doses of interferon gamma in individuals with FA, and they will also be looking to see if there is a change in frataxin levels in patients. This study should be completed later in 2014.

In addition, Dr. David Lynch, Principal Investigator of the Collaborative Clinical Research Network in FA Initiated an open-label study of IFN? in late 2013. This study evaluated safety, tolerability and efficacy in children with FA. The study was fully enrolled and the treatment phase was completed in April 2014. FARA funded funding this study and Vidara Pharmaceuticals generously donated study drug.

The full results were presented at the CHOP symposium in October 2014 and were just published in Acta Neurologica. In summary, while there was no significant change in frataxin levels across the group when you look at the individual data in certain tissues (buccal cells) there is a lot of "noise" - levels spiking up and down which is something that does not normally occur. More intriguing, was the clinical data obtained from the study which showed a significant improvement in neurological function measured by the Friedreich Ataxia Rating Scale (FARS). It is important to note that this study did not have a control or placebo group, and it was an open label pilot study so we cannot draw firm conclusions about the efficacy of the drug in treating FA. However, these results are supportive of the need for further investigation. Horizon Pharma, the company that sells Actimmune™ (interferon gamma) in the United States is committed to moving forward.

CHOP Open Label Study information:

Scientific Publication - Dr. Lynch reference

Press release (Horizon)

In April 2015, Horizon Pharma announced that they were granted Fast Track Designation from the FDA for ACTIMMUNE® (interferon gamma-1b) in the treatment of Friedreich's ataxia (FA). This Fast Track Designation can be very helpful in shortening the timeline to approval of the drug for FA if the results of the clinical trial are favorable.

In June 2015, Horizon announced the initiation of a Phase 3 Safety, Tolerability and Efficacy of ACTIMMUNE® Dose Escalation in Friedreich's Ataxia study ("STEADFAST") of ACTIMMUNE (interferon gamma-1b) for the treatment of people with Friedreich's Ataxia (FA). This study is currently enrolling subjects (individuals with FA, ages 10-25 years) - link to FARA page with study announcements.

For more information about STEADFAST:

Active Clinical Trials page for Actimmune

FARA Press Release: Horizon Pharma plc Initiates Phase 3 Trial of ACTIMMUNE(R) (interferon gamma-1b) for the Treatment of People With Friedreich's Ataxia reference

Press release (Horizon)

+ Lu AA24493 carbamylated EPO

Sponsor: Lundbeck

A phase II study of a compound called Lu AA24493 or cEPO, a novel carbamylated form of human erythropoietin (EPO), was initiated in Germany, Austria and Italy. This modified form of EPO (cEPO) is thought to have fewer haematopoietic effects (so would not increase red blood cells) but to maintain the tissue-protective effect (possibly by increasing frataxin protein levels). The primary objective of the study is to evaluate the safety and tolerability in patients with Friedreich's ataxia. This study concluded in 2011 and the company announced in a press release that based on the trial results that they were discontinuing the program in FA. No specific trial results have been released.

+ Methylprednisolone

Sponsor: Children's Hospital of Philadelphia, FA Center of Excellence

A secondary inflammatory response has been proposed to be present in FA, as revealed in autopsy studies and in the alteration of immune pathways in microarray analysis. Inflammation in FA raises the possibility of a therapeutic benefit from anti-inflammatory steroid treatment, as inflammation may directly underlie multiple complications of FA including cardiomyopathy. In support of this theory are clinical observations and patient self-reports of improvement of ataxia symptoms following the prescription of steroids for indications other than the primary FA diagnosis.

Current Stage of Development
There is no further development planned at this time.

In November of 2019, results of a small open label pilot study were published (link to paper is below). Methylprednisolone was found to be well-tolerated however the efficacy outcomes were mostly unchanged except for a modest improvement in the pediatric cohort for 1-minute walk (P<.05).

Clinical Trials Reference

Background and History
Based on clinical observations and growing evidence of inflammation in FA, Dr. David Lynch at the Children's Hospital of Philadelphia conducted a small exploratory study. This was an open-label study to explore safety, tolerability and efficacy of methylprednisolone treatment in 11 individuals with FA. In addition, the study explored if methylprednisolone had any effects on biomarkers associated with FA. This study was completed and the results published (see below).

November 2019 - Open-label Pilot Study of Oral Methylprednisolone for the Treatment of Patients With Friedreich Ataxia

January 2016 - Friedreich Ataxia and nephrotic syndrome: a series of two patients.

+ Nicotinamide

Dr. Richard Festenstein at the Imperial College in London, England has been studying transcriptional control of the FXN gene. Specifically, his laboratory has been working to understand regulation of gene expression and how to increase gene transcription as a therapeutic target in FA.

Dr. Festenstein has proposed Nicotinamide, is also known as vitamin B3, as a potential therapeutic compound for increasing frataxin gene expression. An open-label pilot study, evaluating dosage, safety and biochemical and clinical outcomes in individuals with FA was launched in London, England in 2012.

Current Stage of Development
In 2017 a multinational study was approved and funded by the European Union, E-Rare-3 Project. NICOFA, Nicotinamide for the treatment of Friedreich ataxia will be a randomized, placebo- controlled and double-blinded study evaluating the efficacy of high-dose nicotinamide in FA over 2 years. Study sites are planned for Germany, Spain, Austria, Italy and France.

Orphanet posting - NICOFA : Nicotinamide for the treatment of Friedreich ataxia reference -

Background & History
An open-label pilot study, evaluating dosage, safety and biochemical and clinical outcomes in individuals with FA was launched in London, England in 2012.

The investigators report from the study that at higher doses (>3.5 grams per day of nicotinamide) there were issues with tolerability (e.g.,nausea) and safety (elevated liver enzymes), but at lower doses the drug was well tolerated. An increase in frataxin protein was observed with single oral dosing in a Phase 1 portion of the study, and a sustained increase in frataxin gene expression and protein with daily dosing over eight weeks was observed in the Phase 2 portion of the study. No clinical benefit or improvement was observed. The study authors emphasize that these results are preliminary and not adequate to support the use of nicotinamide as a treatment for FA, but do suggest that further studies should be considered.

Oct 2019 - Protocol of a randomized, double-blind, placebo-controlled, parallel-group, multicentre study of the efficacy and safety of nicotinamide in patients with Friedreich ataxia (NICOFA)

April 2014 - Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study

March 2011 - H3 lysine 4 is acetylated at active gene promoters and is regulated by H3 lysine 4 methylation.

+ Nutritional approach

Dr. Robert Wilson at the University of Pennsylvania has identified certain nutritional compounds that can activate PGC1a, which is decreased in frataxin deficient cells. Normally, when there is mitochondrial dysfunction in a cell PGC1a is recruited to try to correct the damage. PGC1a is a special type of protein that recruits and controls expression of other genes involved in energy metabolism. Dr. Wilson at the CHOP symposium in Oct 2013 talked about trying to break a vicious cycle as a therapeutic approach which includes trying to increase PGC1a through other mechanisms, such as with nutritional compounds.

In 2013, FARA awarded a grant to Dr. Wilson to further develop this therapeutic approach.

+ Pioglitazone

Hôpital Robert Debré, France

Dr. Pierre Rustin has proposed investigation of Pioglitazone, a prescription drug commonly used in the treatment of type II diabetes, as a potential treatment for FA. In addition to working through insulin pathways, pioglitazone, a well known PPAR y (peroxysome proliferators-activated receptor y) ligand induces the expression of many enzymes involved in mitochondrial metabolism, including the superoxide dismutases. This agent may be therapeutic by counteracting the disabled recruitment of antioxidant enzymes in FA patients. Other research groups have reported on this pathway being paradoxically downregulated in FA and hypothesize that if this pathway could be upregulated in FA patients that it may increase frataxin. Also, there is some evidence in the scientific literature that Pioglitazone acts on neurodegeneration in human cells and animal models, so it appears a promising agent to be tested in Friedreich ataxia.

Dr. Rustin initiated a proof of concept trial in France to explore the effects of Pioglitazone on neurological function in FA patients. The trial recruited patients less than 22 years of age. Patients were treated for two years and underwent clinical exams and testing at six month intervals during the study. This study was expected to be completed by 2012 and results are anticipated by March 2013. Of note, individuals with Type I diabetes and those at risk for congestive heart failure should not take pioglitazone. reference -

The pioglitazone trial has been completed but results have not been published as of June 2014. This candidate has been removed from the pipeline chart because the study has been completed and it is unlikely there will be future studies of pioglitazone due its known side effects in individuals at risk for congestive heart failure. However, we still recognize that compounds promote mitochondrial biogenesis and/or target the PGC 1 alpha pathway are of interest in new therapeutic development.

+ RT001 (dPUFAs)

Sponsor: Retrotope

dPUFAS - Fatty acids are an essential source of fuel for the body, especially the heart and muscle. There are different forms of fatty acids - saturated and unsaturated. Polyunsaturated fatty acids (PUFAs) are known as good fats and are essential to cells in the nervous system, specifically the mitochondrial membrane. It has been shown the PUFAs are susceptible to oxidative damage, and it is hypothesized that this oxidative damage can lead to mitochondrial dysfunction, especially in neurological diseases.

The strategy here is to stabilize the PUFAs and protect the cells from this oxidative damage. One approach to stabilizing the PUFAs is to create mimetics (very similar chemical substitutes) of PUFAs.

Deuterated compounds are those that have hydrogen molecules replaced by deuterium. Deuterium is a stable isotope of hydrogen. Substituting deuterium for hydrogen molecules in PUFAs is one approach being evaluated by Retrotope.

Current Stage of Development
In February 2022, FARA was notified by Retrotope that the recently completed Phase 2/3 trial of RT001 in FA did not successfully meet its endpoints.

In October 2019, Retrotope launched a Phase 2/3 study in FA, A Study to Assess Efficacy, Long Term Safety and Tolerability of RT001 in Subjects with FA. This is a double-blind, placebo controlled trial that is designed to study the impact of RT001 on neurological and cardiac symptoms and safety over 11 months of treatment. The study enrolled 65 individuals who are ages 12-50 yrs and the primary outcome measure is peak workload change from baseline to 11 months using cardiopulmonary exercise testing (CPET). There are also secondary outcome measures to further assess neurological outcomes and fatigue. Results are anticipated near the end of 2021.

Clinical Trials
Trial Recruitment Notice Reference -

Background & History
In 2012, FARA awarded a grant for testing these compounds in established cell models. Results of this work have been published and can be accessed below.

In October 2012, Retrotope had an introductory (pre-IND) meeting with the FDA. At that meeting, the FDA provided clear information and guidance on the requirements for Retrotope's Investigational New Drug (IND) Application for a Phase Ib trial of Retrotope's first drug in the orphan indication, Friedreich ataxia. FARA awarded a grant to Retrotope in 2013 to assist with the manufacturing of drug product and toxicology studies required for IND filing with the FDA.

Retrotope filed their IND with FDA in 2015 and announced enrollment of a Phase 1b/2a study of RT001. A 28-day, first-in-human, randomized, double-blind, controlled, ascending dose study of orally dosed RT001 to evaluate the safety, tolerability, pharmacokinetics (PK), disease state, and exploratory endpoints in patients with Friedreich's ataxia (FA) in August 2015. FARA provided a grant to Retrotope to support participant travel for the study.

June 2016 - Retrotope announced that FDA granted Orphan Drug Designation for RT001 in FA.

September 2016 - Retrotope, along with Dr. Theresa Zesiewicz, study Principal Investigator, announced and presented results (at the annual USF symposium, Understanding Energy for A Cure) of this first-in-human study of RT001. "The trial, a randomized, double-blind, comparator controlled, two-dose study of RT001 in 18 FA patients for 28 days, met all of its primary safety, tolerability and pharmacodynamics (PK) goals. While biological activity was not a primary goal of the study, a number of clinically important activity measures were tested, found to be highly correlated to well-studied disease severity scales and showed multiple, unexpected, robust signals of drug effect at one or more doses."

In 2018, a full report of the results was published and can be accessed below.

Based on the Phase 1b/2a study findings Retrotope is advancing the clinical development of the program in addition, RT001 is being evaluated in other neurodegenerative diseases.

News/Press Releases
February 25, 2021 - Retrotope Granted Rare Pediatric Disease Designation from FDA for Lead Development Candidate, RT001, in Two Life-Threatening Neurodegenerative Indications

January 9, 2020 - Retrotope Expands its Drug Pipeline with the First Dosing of RT001 in patients with Friedreich's ataxia (FA)

April 18, 2018 - Retrotope Announces Peer-Reviewed Publication of Positive Phase 1b/2a Findings for RT001 in Friedreich's Ataxia

September 15, 2016 - Retrotope announces Phase I/II Clinical Trial Results of RT001 in Treatment of Friedreich's ataxia

June 1, 2016 - US FDA Grants Orphan Drug Designation for Retrotope's RT001 in the treatment of Friedreich's ataxia

August 17, 2015 - Retrotope announces open enrollment for Friedreich's ataxia clinical trial

September 2020 - Plasma and Red Blood Cell Membrane Accretion and Pharmacokinetics of RT001 (bis-Allylic 11,11-D2-Linoleic Acid Ethyl Ester) during Long Term Dosing in Patients

July 2018 - Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia

2013 - Insights into the role of oxidative stress in the pathology of Friedreich ataxia using peroxidation resistant polyunsaturated fatty acids

+ SHP622 (formally VP20629 or OX1)

Sponsor: Shire (formerly initiated by ViroPharma)

OXIGON™ (OX1). OX1 (indole-3-propionic acid) is a naturally occurring small molecular weight drug compound that prevents oxidative stress by a combination of hydroxyl radical scavenging activity and metal chelation. Phase I studies in healthy adults were completed in 2010. The drug was found to be safe and well-tolerated, and the pharmacokinetics revealed that the drug was rapidly absorbed and distributed in the body after oral administration. This drug was licensed to Viropharma, who launched a Phase 1 trial of VP20629 in adults with FA in September 2013. This trial was conducted at the Children's Hospital of Philadelphia, Emory University, Univ of CA Los Angeles, Univ. of Iowa, and University of south Florida. This is was a single and multiple dose safety study. \ reference:

In November 2013, Shire announced an acquisition of ViroPharma. At this time there were no changes to the ongoing trial. Shire is a larger pharmaceutical company with a known special interest and track record in rare disease.

July 2015 the final cohort of the Phase 1 study is complete and enrollment is closed.

October 2016 - results were posted to (see link above). It appears that the drug was safe and well-tolerated. There were no measures supportive of efficacy. At present there are no plans to continue clinical development.

+ TAK-831

Sponsor: Takeda

TAK-831 is a new investigational medicine being advanced by Takeda. TAK-831 increaseses D-serine, an amino acid that activates specific receptors in the brain that may be important to motor functioning and signaling of neurons.

Current Stage of Development
There is no further development planned at this time.

Clinical Trials Reference

Background and History
Based on studies in FA mouse model studies there was preliminary evidence that TAK-831 might provide symptomatic benefit to neurological and motor function. It was these studies in the mouse model that lead to a clinical trial of TAK-831 in individuals with FA.

A Phase 2 clinical trial of TAK-831 evaluated efficacy, safety and tolerability in 65 individuals with FA, ages 18-55. Multiple US sites participated in the study including Children's Hospital of Philadelphia, Ohio State University, University of Iowa, University of Florida, University of South Florida and University of California Los Angeles. In addition to safety and tolerability this study evaluated exam upper limb function and manual dexterity using the nine-hole pegboard test as well as other neurological and performance assessments. While TAK-831 was found to be safe and well-tolerated it did not demonstrate efficacy based on primary and key secondary endpoints. Results were presented at the International Ataxia Research Conference, Washington, DC, November 2019 and full report is available on (link above).

Even though this study was negative there were several new learnings about clinical outcome measures (9HPT and speech assessments) that were valuable and can be carried forward to future trials.

June 2021 - Results of a randomized double-blind study evaluating luvadaxistat in adults with Friedreich ataxia

+ Ubiquitin Competitors

Dr. Roberto Testi at the University of Rome has been studying how the frataxin protein is degraded. Once understanding how the protein is degraded in the cell, he launched a drug discovery effort to identify a set of small drug-like molecules that prevent frataxin degradation and increase levels of active frataxin in cells derived from Friedreich's Ataxia patients. In early 2017, Dr. Testi announced that he has formed a company, Fratagene Therapeutics, to further advance these FA drug discovery efforts and his group has further identified an important target in the degradation of the frataxin, RNF126, an enzyme whose inhibition leads to an increase in frataxin levels in the cell of patients.

News/Press Releases
Press Release - Rare Disease Day 2017 - Friedreich ataxia: Researchers from Fratagene Therapeutics and the University of Rome "Tor Vergata" identify a new therapeutic target

February 2017 - E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting Its Degradation: Identification of a Potential Therapeutic Target for Friedreich Ataxia

January 2011 - Preventing the ubiquitin-proteasome-dependent degradation of frataxin, the protein defective in Friedreich's ataxia

+ Varenicline (Chantix®)

Sponsor: FARA (Drug provided for the trial by Pfizer)

Dr. Theresa Zesiewicz of the University of South Florida noticed that the uncoordinated movements (ataxia) and balance problems in a patient with fragile X tremor /ataxia syndrome improved greatly after he started Chantix® in an attempt to quit smoking. The symptoms worsened when the medication was discontinued. Dr. Zesiewicz found similar results when treating patients with other types of ataxia, including Friedreich's ataxia, and several of her case reports have been published in medical journals. A Phase II pilot study, sponsored by the Friedreich's Ataxia Research Alliance (FARA), began in June 2009 to investigate whether varenicline (Chantix®) improves neurological symptoms, such as balance, coordination, and sensory perception, all of which are significantly impaired in patients with FA.

This study also evaluated the safety of Chantix® in patients with FA. The double blind, randomized, placebo-controlled pilot study was led by principal investigator Dr. Zesiewicz, at the University of South Florida College of Medicine, and co-investigator Dr. David Lynch, at Children's Hospital of Philadelphia. In early 2010, the study was stopped as a result of concerns regarding safety and intolerability and insufficient evidence of efficacy. Twenty six subjects had been enrolled into the trial. The primary concern among those who were withdrawn was a worsening of gait and imbalance. The study team is analyzing the study data and will issue a complete report, which we are confident will provide important details and insights.

In addition, the initial case reports on which this pilot study was based opened an exciting new avenue of research investigating neurotransmission and improvement of nervous system function in Friedreich's ataxia. We believe that further basic investigation of this area will lead to new studies in the future that will provide hope for a variety of methods of improvement of nervous system function in Friedreich's ataxia.


Sponsor: Exicure

We are shocked and disappointed to read the findings of an internal investigation at Exicure and the subsequent indefinite suspension of their Friedreich's ataxia program, as outlined in the press release below.

Exicure, Inc. Announces Results of Internal Investigation and Implementation of Strategic Measures to Reduce Cash Burn and Prioritize Pipeline Focus

In all aspects of the research process, the integrity of data is of utmost importance. We remain committed to the development of a deep and diverse treatment pipeline for FA-one that is based on sound data and that fosters multiple approaches to therapy.

Exicure is a clinical stage biotechnology company with a proprietary spherical nucleic acid (SNA) technology that advances delivery of oligonucleotides. SNAs are nanostructures consisting of nucleic acids in a spherical configuration, around a nanoparticle core. The SNAs technology allows for delivery of multiple oligonucleotides against multiple targets.

Exicure is developing an oligonucleotide-based SNA therapeutic that focuses on increasing frataxin gene expression and frataxin protein in FA.

Current Stage of Development
This program is in IND-enabling studies to support a future IND filing.

Background & History
Exicure initiated IND-enabling studies for XCUR-FXN in late 2020, expecting to file an IND for XCUR-FXN in FA in the fourth quarter of 2021. First-in-Patient Phase 1b clinical trial for XCUR-FXN in FA are planned for the first half of 2022. Exicure is closely with FARA in the design and site selection of the Phase 1b clinical trial. The Phase 1b clinical trial is designed to demonstrate safety and characterize pharmacokinetic properties of multiple ascending doses of XCUR-FXN in FA patients and inform Phase 2/3 dose selection. The study plan includes examination of multiple biomarkers, including brain imaging and measurements of frataxin levels in patient cerebrospinal fluid (CSF), to provide rapid read-out for target engagement and pharmacodynamic (PD) effects. One or more exploratory endpoints, such as modified Friedreich's Ataxia Rating Scale (mFARS), may also be included to prepare for a subsequent pivotal clinical trial. More background information and pre-clinical data can be found in the corporate presentation shared August 5, 2021, link below.

News/Press Releases
Dec 10, 2021 - Exicure, Inc. Announces Results of Internal Investigation and Implementation of Strategic Measures to Reduce Cash Burn and Prioritize Pipeline Focus

August 12, 2021 - Exicure, Inc. Reports Second Quarter 2021 Financial Results and Corporate Progress

July 8, 2021 - Exicure Announces Upcoming Neuroscience Pipeline Update at Virtual R&D Day

May 12, 2021 - Exicure, Inc. Reports First Quarter 2021 Financial Results and Corporate ProgressJan 4, 2021 - Exicure Announces Agenda for Upcoming Neuroscience Pipeline Update at Virtual R&D Day

Dec 28, 2020 - Exicure Provides Neuroscience Pipeline Update at Virtual R&D Day

Dec 16, 2019 - Exicure Announces First Neurological Development Program in Friedreich's Ataxia and Expands Scientific Advisory Board

Presentations and Publications
August 5, 2021 - Corporate Presentation with pre-clinical data on XCUR-FXN