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.
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 has been updated as of March 2020 and focuses on drugs that are already in preclinical development or have advanced to human clinical trial.
Currently in the Research Pipeline:
Sponsor: Reata Pharmaceuticals
Omaveloxolone, aka Omav 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 and also these compounds have been shown to have protection against diseases involving inflammation (there is some limited data and evidence that FA has some inflammatory aspects). Also, Reata has shown in numerous preclinical studies that their compounds increase the number of mitochondria, improve mitochondrial efficiency, and boost energy production by mitochondria – all would potentially be beneficial in FA patients.
Current Stage of Development
Part 2 of MOXIe is a randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of 150mg omaveloxone in individuals with FA over 48 weeks. The trial has completed enrollment of >100 individuals with FA ages 16-40 years who are able to perform 10-15 minutes of exercise on a recumbent exercise bike during 2018 at the following sites: Children's Hospital of Philadelphia, University of Florida, Ohio State University, University of Iowa, University of South Florida, Emory University, University of California Los Angeles, Murdoch Children's Research Institute (Melbourne, Australia), and Medical University Innsbruck (Innsbruck, Austria), University College London (United Kingdom) and Neurological Institute Carlo Besta (Milan, Italy).
Topline results of this trial were reported by Reata in a press release (link below), October 2019. Part 2 of the MOXIe Phase 2 met its primary endpoint of change in the modified Friedreich’s Ataxia Rating Scale (mFARS) relative to placebo after 48 weeks of treatment. Individuals with FA treated with omaveloxolone (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.
Reata has said that based on these positive results they will open discussions with regulatory authorities and look to proceed with the submission of regulatory filings for marketing approval in the United States and internationally.
There is now an open-label extension study ongoing with additional data collection and safety monitoring (this extension study only enrolled participants from the prior MOXIe studies).
Clinicaltrials.gov Reference - clinicaltrials.gov/ct2/show/NCT02255435
Background & History
Working with FARA and several FA Investigators in our Clinical Research Network, Reata has planned and launched a Phase 2/3 clinical trial of RTA 408 (MOXIe). MOXIe is a two-part, randomized, placebo-controlled Phase 2/3 Study of the Safety, Efficacy, and Pharmacodynamics of RTA 408 in the Treatment of Friedreich's Ataxia). Part 1 of the study was a randomized, placebo-controlled, double-blind, dose-escalation study to evaluate the safety of multiple doses of RTA 408 in patients with Friedreich's ataxia. Part 1 was completed in May 2017. Omaveloxolone was found to be well-tolerated and safe with mild adverse events. At doses of 80-160mg/day there were pharmacodynamics changes suggestive of Nrf2 activation which inform dosing for the Part 2 efficacy study. 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.
News/ Press Releases
October 14, 2019 - Reata Announces Positive Topline Results from the MOXIe Registrational Trial of Omaveloxolone in Patients with Friedreich's Ataxia
August 14, 2017 - FDA Confirms That Use of mFARS as Primary Endpoint in Part 2 of the MOXIe Trial Can Support Approval of Omaveloxolone in Friedreich's Ataxia
June 22, 2017 - Reata Pharmaceuticals, Inc. Receives Orphan Drug Designation for Omaveloxolone for the Treatment of Friedreich's Ataxia
June 1, 2017 - Reata Pharmaceuticals, Inc. Announces Positive Data From Part One of Moxie Trial of Omaveloxolone for Friedreich's Ataxia
January 2020 - The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich's Ataxia
October 2019 - Targeting NRF2 for the Treatment of Friedreich's Ataxia: A Comparison Among Drugs
October 2019 - Orphan Drugs In Development For The Treatment Of Friedreich's Ataxia: Focus On Omaveloxolone
November 10, 2018 - MOXIe Part 1 trial results - Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia
July 17, 2018 - Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models
Sponsor: PTC Therapeutics
PTC-743 (previously EPI-743), 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.
In March 2020, PTC announced that plans to continue development of PTC-743 in FA with a potential registrational trial of PTC743 in patients with Friedreich Ataxia (FA) expected to begin in 3Q 2020.
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 - http://www.clinicaltrials.gov/ct2/show/NCT01728064
FA Point Mutation study - http://www.clinicaltrials.gov/ct2/show/NCT01962363
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
February 4, 2014 - FDA Grants Edison Pharmaceuticals' EPI-743 Orphan Status for Friedreich's Ataxia
March 17, 2014 - FDA Awards Fast Track Status to Edison Pharmaceuticals' EPI-743 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)
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 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 is enrolling individuals with FA who are ages 12 - 50 yrs, able to walk at least 25-feet within 1 minute, with or without an assistive device. For more information on the study click the link below.
Trial Recruitment Notice http://www.curefa.org/clinical-trials/clinical-trials-active-enrolling/rt001-006-trial-10-31-2019
Clinicaltrials.gov Reference - https://www.clinicaltrials.gov/ct2/show/NCT04102501
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
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
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
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.
Clinicaltrials.gov Reference - https://www.clinicaltrials.gov/ct2/show/NCT02660112
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 clinicaltrials.gov 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
Sponsor: Minoryx Therapeutics
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. MIN-102 is already being tested in another rare, CNS disease, adrenomyeloneuropathy.
Current Stage of Development
Minoryx Therapeutics initiated a phase 2 clinical trial of their compound MIN-102 in FA patients in 2019. This is a randomized, double-blind, placebo-controlled study evaluating the effects of MIN-102 on biochemical, imaging, neurophysiological, and clinical markers in individuals with FA. The study is being conducted at 4 sites in Europe (Spain, France, Belgium and Germany), enrollment is complete (36 subjects), treatment and evaluation is ongoing for 48 weeks. The study should be completed and results reported near the end of 2020.
Clinicaltrials.gov Reference - https://www.clinicaltrials.gov/ct2/show/NCT03917225
Background and History
Several research studies in both animal and cell models have identified that the peroxisome-proliferator activator receptor gamma (PPARγ)/PPARγ coactivator 1 alpha (Pgc1a) pathway is dysregulated when there is frataxin deficiency thus making this pathway a potential therapeutic target. Drs. Pandolfo and Coppola first reported this in 2009, when they conducted an unbiased genomic screen looking for metabolic pathways that were altered in a frataxin deficient mouse model of FA.
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.
News/ Press Releases
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
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
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 partnered with Dr. Francesco Sacca at the University Federico II in Naples, Italy to plan a clinical trial 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. Further details will be released later in 2019 when the trial is ready to begin. FARA is providing funding support for this clinical study.
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
Sponsor: Chondrial 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 has formed a company, Chondrial Therapeutics, to further develop this approach and begin preclinical studies, and is seeking a pharmaceutical partner.
Current Stage of Development
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.
Trial Recruitment Notice http://www.curefa.org/clinical-trials/clinical-trials-active-enrolling/clin-1601-101-chondrial-therapeutics-phase-i-study-of-cti-1601-a-frataxin-replacement-therapy
Clinicaltrials.gov Reference - https://www.clinicaltrials.gov/ct2/show/NCT04176991
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
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
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.
Results of this research were published in May 2017 in Neuropharmacology - http://www.sciencedirect.com/science/article/pii/S0028390817302174
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.
2017 - http://www.cell.com/cell-reports/fulltext/S2211-1247%2817%2930149-3
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.
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:
- 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.
- 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.
Scientific Publication - Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia
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.
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.
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
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
Press release - http://investors.biomarin.com/2017-10-18-BioMarin-Highlights-Breadth-of-Innovative-Development-Pipeline-at-R-D-Day-on-October-18th-in-New-York
Recent review articles discussing the development of these compounds including results from a Phase 1 study in FA patients:
Watch the HDAC inhibitor update from RepliGen at the CHOP symposium Oct 2012 - includes information on the first clinical trial of HDAC inhibitors (RG2833) in FA patients in Italy and the follow-on compound RG3250 - https://www.youtube.com/watch?v=bkITGdPbfzo&list=PLUv9oht3hC6SLm2iD5kNrwuk5yaNSOewc&index=8
Sponsor: Jupiter Orphan Therapeutics, Jupiter, FL & Murdoch Children's Research Institute, Melbourne, Australia
Resveratrol is a naturally occuring compound found in the skin of red grapes. Resveratrol has been under intense 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. 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.
Background & History
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.
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. IND-enabling studies, manufacturing and plans for a Phase 2 clinical trial are underway with Murdoch Children's Research Institute in Melbourne, Australia.
News/ Press Releases
Press release - http://www.curefa.org/pdf/sci-news/JOT-MurdochPR-01-12-2016.pdf
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.
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.
Current Stage of Development
Clinicaltrials.gov reference - http://www.clinicaltrials.gov/ct2/show/NCT01589809
Background & History
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 - http://www.orpha.net/consor/cgi-bin/ResearchTrials_Networks.php?lng=EN&data_id=119998&title=NICOFA---Nicotinamide-for-the-treatment-of-Friedreich-ataxia&search=Disease_Search_Simple
Scientific publication - http://www.ncbi.nlm.nih.gov/pubmed/21483810
The full results have been published and can be accessed at: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60382-2/abstract
RaNA is focused on increasing frataxin through increasing expression of the gene with a novel approach that we are excited to add to the pipeline. In FA we know that the gene is silenced and therefore individuals don't make enough frataxin. Many FA scientists and pharmaceutical partners are working to understand why the gene is silenced and how to un-silence it.
RaNA is focused on the epigenetics (other inherited factors, such as RNA targets) that influence expression of the FXN gene. Their strategy has identified novel non-coding RNA (ncRNA) potentially responsible for directing the localized epigenetic silencing of the FXN gene.
"Degrading this ncRNA led to at least partial heterochromatin reversal and FXN mRNA and protein level upregulation to therapeutically significant levels." These results were recently presented at the American Society for Human Genetics meeting in Boston, MA, October 2013. http://www.ashg.org/2013meeting/abstracts/fulltext/f130123048.htm
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” (under Lead Candidates). This grant award allowed for some of the early testing in animal models.
Current Stage of Development
Design Therapeutics announced in March 2020 press release that they have a lead candidate for FA that they are advancing to IND-enabling studies.
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.
News/ Press Releases
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
Significant advances in gene replacement therapy are opening new opportunities to explore this approach to treatment options. FARA is funding several groups who are evaluating different approaches to gene replacement therapy using different viral vectors and targeting different organs affected in FA.
In addition, during 2014 there was significant growth in industry interest in gene therapy both in the formation of new companies and well-known established pharmas launching gene therapy programs.
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 and profound results that demonstrate complete prevention and correction of cardiomyopathy in the FA cardiac knock-out mouse model at the FARA/USF symposium. FARA is funding 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 - http://www.ustream.tv/recorded/25228853
In April 2014, Dr. Puccio's gene therapy research was published in Nature Medicine. http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3510.html
Dr. Ernest Giralt at the Institute for Research in Biomedicine (IRB) and Dr. Javier Diaz Nido at the "Centro de Biología Molecular Severo Ochoa" (CBMSO) launched a gene-therapy project to treat Friedreich's ataxia in late 2013. Dr. Giralt is an international expert on the design of transporters, such as nanoparticles, that can carry drugs or other molecules, such as DNA, into the brain and thus overcome the blood-brain barrier.
The unique quality of the project is that the idea for it came from those affected by the disease, patients and relatives, who, in their endeavors to find a cure got in touch with basic research groups in order to start a long-term project. The GENEFA Platform, in close collaboration with FEDAES and the BabelFAmily, started fund-raising efforts in May 2013. In early 2014, FARA joined this international effort and has provided funding for the project.
This project aims to generate modified viral vectors and viral-free synthetic nanoparticles for highly efficient DNA delivery into the nervous system in order to facilitate gene therapy for Friedreich's ataxia (FA). These gene delivery nanosystems will cross the blood-brain barrier (BBB) thanks to novel peptides able to carry cargoes through the BBB (which are referred to as BBB-shuttles). Synthetic nanoparticles are highly advantageous as delivery vehicles since they are very simple to prepare and scale-up and have generally less pro-inflammatory effects than viral particles. This project will compare the gene transfer efficiency and therapeutic activity of the different nanosystems in suitable human cell and mouse models to find the most promising candidate for further development.
Press Release - http://www.curefa.org/_pdf/FARA-PressRelease01-28-2014.pdf
In April 2014 it was announced that a new company, AAVLife, was formed, based on Dr. Puccio's very encouraging work treating the cardiac disease of FA in the mouse model. AAVLife has been founded with a clear commitment to the rapid development of a gene-therapy program focused on treating the life-threatening cardiac condition suffered by FA patients. FARA has been collaborating closely with the founders of AAVLife since the middle of 2013 and appreciates their dedication to treating the cardiac disease which causes premature mortality in FA. AAVLife announced successful series A financing, licensing of rAAVrh10 vector from RegenX, and is presently working on the large animal studies to translate Dr. Puccio's mouse studies to clinical studies in individuals with FA.
Press release - http://www.curefa.org/_pdf/FARA-PressRelease04-06-2014.pdf
Sponsor - Agilis Biotherapeutics
Agilis Biotherapeutics, LLC is a synthetic biology-based company focused on developing best-in-class DNA-based therapeutics to improve and save the lives of people affected by serious and life-threatening rare diseases. Through an Exclusive Channel Collaboration with Intrexon (NYSE:XON), a leader in synthetic biology, Agilis has initiated its lead program for Friedreich's ataxia (FA). Agilis leverage Intrexon's UltraVector® gene engineering platform and other technologies to develop therapeutic candidates to treat the pathologies associated with FA. Agilis believes that engineered DNA-based therapeutics have great potential to target underlying disease mechanisms more effectively and aims to provide transformational medicines for patients and families suffering from these debilitating disorders.
For more information, please visit www.agilisbio.com
Sponsor - Voyager Therapeutics
In February 2014, a new gene therapy company, Voyager Therapeutics, was launched with a focus on FA and a few other neurodegenerative diseases. Voyager is backed by Third Rock Ventures and just recently announced licensing terms in which REGENX has granted Voyager 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 have had the opportunity to participate in discussions with many of Voyager's founders since early 2013 and appreciate their interest and commitment to developing a gene therapy approach for the neurological symptoms of FA.
Press release - http://www.curefa.org/_pdf/FARA-PressRelease02-12-2014.pdf
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.
Candidates below are not presently on the pipeline displayed aboveThese compounds have been previously tested in animal or cellular models of FA or in prior human clinical trials
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.
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 ClinicalTrials.gov - http://www.clinicaltrials.gov/ct2/show/NCT01921868
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.
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, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813973/pdf/pone.0192779.pdf 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 clinicaltrials.gov - https://www.clinicaltrials.gov/ct2/show/NCT02705547 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 clinicaltrials.gov study posting.
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 - http://www.ncbi.nlm.nih.gov/pubmed/17379741
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 - http://www.ncbi.nlm.nih.gov/pubmed/20865357
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 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 http://clinicaltrials.gov/ct2/show/NCT00824512?term=egb761&rank=3
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) http://onlinelibrary.wiley.com/doi/10.1002/mds.25058/abstract
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. http://www.ncbi.nlm.nih.gov/pubmed/18759345
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).
ClinicalTrials.gov reference: http://www.clinicaltrials.gov/ct2/show/NCT01493973
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) http://archneur.ama-assn.org/cgi/content/full/67/8/941
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) http://www.ncbi.nlm.nih.gov/pubmed/21779958
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) http://www.ncbi.nlm.nih.gov/pubmed/21392622
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.
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: https://www.ncbi.nlm.nih.gov/pubmed/25552656
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.
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:
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:
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.
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).
Clinicaltrials.gov Reference https://www.clinicaltrials.gov/ct2/show/NCT02424435
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.
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.
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.
Clinicaltrials.gov reference - http://www.clinicaltrials.gov/ct2/show/NCT00811681
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.
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. \
Clinicaltrials.gov reference: http://www.clinicaltrials.gov/ct2/show/NCT01898884
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 clinicaltrials.gov (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 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.
Clinicaltrials.gov Reference https://www.clinicaltrials.gov/ct2/show/NCT03214588
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 Clinicaltrials.gov (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.
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.