The Friedreich’s Ataxia Treatment Pipeline is a visual tool for communicating the progress of research and development on lead therapeutic candidates.
Along the horizontal 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 vertical 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 to begin human studies.
The stages “Phase 1” through “available to patients” are phases of clinical trials/studies.
Nutritional approach Nrf2 activators ALCAR Resveratrol
EPO EPO-mimetics Ubiquitin Competitors TAT Frataxin
HDAC Inhibitors Nicotinamide Interferon gamma RNA-based Approach Epigenetic Approach
Gene Therapy Cardiac Gene Therapy Central Nervous System Gene Therapy
Removed: Pioglitazone Idebenone/Catena Deferiprone Lu AA24493 / cEPO Chantix EGb-761
FARA is supporting the advancement of these treatments with financial resources, advocacy, 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 June 2014, and focuses on drugs that are already in human trials or in preclinical development. It only represents a small sampling of earlier-stage (discovery) research ongoing to identify and develop new potential therapies.
Drug – 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) http://onlinelibrary.wiley.com/doi/10.1002/mds.25058/abstract
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Drug – EPI-743
Sponsor: Edison Pharmaceuticals
News Article: Edison Shedding Light on Energy Production in Diseased Cells
EPI-743, is a “sister” compound to EPI-A0001, which aims to improve mitochondrial function by targeting the enzyme NADPH quinone oxidoreductase 1 (NQO1). EPI-743 works to synchronize energy generation in mitochondria by countering cellular redox stress.
In September 2012 at the USF/FARA Symposium, Drs. Guy Miller and Theresa Zesiewicz announced that they were planning a double-blind, placebo-controlled trial sponsored by Edison Pharmaceuticals Inc. The study will primarily measure the effect of EPI 743 on vision, including contrast and acuity, in FA patients, many of whom experience varying degrees of visual changes. Researchers plan secondarily to evaluate neurologic function using the Functional Assessment Rating Scale.
FARA Press Release - http://www.curefa.org/_pdf/EPI-743_Phase2B_FAclinicalTrial.pdf
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. As of June 2014, all subjects have been enrolled and all have completed the double-blind portion of the study but the open label extension portion is still ongoing. Results are anticipated by early fall 2014. Also, there is a small open label study for FA patients with point mutations ongoing at the University of South Florida.
Of note, in March 2014, Edison announced that FDA granted EPI-743 Fast Track designation. When the FDA grants the Fast Track designation, the Agency encourages early and more frequent meetings and communications with the drug company throughout the drug development and review process to ensure that any questions and issues are resolved quickly. With this status, the drug may also benefit from "rolling review," which permits the drug company to submit completed portions of its application for approval (New Drug Application) for immediate review by the FDA, instead of waiting for the entire application to be completed. These multiple benefits are intended to result in substantially faster drug approval and earlier treatment access by patients.
For more information on the study go to ClinicalTrials.gov - http://www.clinicaltrials.gov/ct2/show/NCT01728064
Phase 2 Study - http://www.clinicaltrials.gov/ct2/show/NCT01728064
FA Point Mutation study - http://www.clinicaltrials.gov/ct2/show/NCT01962363
Edison Press Releases:
FDA Grants Edison Pharmaceuticals' EPI-743 Orphan Status for Friedreich's Ataxia
Edison Pharmaceuticals, Inc. enters into strategic alliance with Dainippon Sumitomo Pharma Co., Ltd.
FDA Awards Fast Track Status to Edison Pharmaceuticals’ EPI-743 for Friedreich’s Ataxia
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Drug – 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. ViroPharma press release
Viropharma launched a Phase 1 trial of VP20629 in adults with FA in September 2013. This trial is ongoing at the Children's Hospital of Philadelphia, Emory University, Univ of CA Los Angeles, Univ. of Iowa. This is 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 are no changes to the ongoing trial. Shire is a larger pharmaceutical company with a known special interest and track record in rare disease. ViroPharma press release - http://ir.viropharma.com/releasedetail.cfm?ReleaseID=806022
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Drug – RTA408
Sponsor: Reata Pharmaceuticals
Early this year Reata Pharmaceuticals contacted FARA about a drug in their pipeline, RTA 408, that they believe could have benefit in FA. RTA 408 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., Dr. Gino Cortopassi, UC Davis and Dr. Pierre Rustin’s group in France) have shown that Nrf2 is paradoxically decreased in cells from FA patients. Nrf2 should be activated when there is mitochondrial dysfunction and oxidative stress so one would expect it to be active in FA however data has shown that it is not. It could be that there is a “vicious cycle” that is causing Nrf2 to be lower in FA and if one could find a way to increase it you could break the cycle. The hypothesis is that increasing Nrf2 could improve mitochondrial function by reducing oxidative stress 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. Working with FARA and several FA Investigators in our Clinical Research Network, Reata is moving very quickly and planning for a Phase 2 clinical trial of RTA 408 to begin during the second half of 2014. They are in the process of completing study design and regulatory filings and we look forward to sharing more details with the FA community later this year.
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Drug – 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.
No further studies have been conducted until now. Dr. Theresa Zesiewicz at the University of South Florida has initiated a long term open label study of ALCAR examining cardiac and neurological measures in adults with FA. This study is open for enrollment. For more information and coordinator contact info, see the study ad: http://www.curefa.org/_pdf/Acetyl-L-CarnitineTrialAtUSF.pdf.
Proceeds from the FARA Energy Ball are funding this study.
For more information on this study go to ClinicalTrials.gov - http://www.clinicaltrials.gov/ct2/show/NCT01921868
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Drug – Resveratrol
University of Melbourne, Australia, Dr. Martin Delatycki
Resveratrol is not a new compound but new to FA. Resveratrol is 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.
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. These interesting clinical findings suggest further studies, such as a placebo controlled trial with additional dose groups.
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Drug/Approach – Deuterated Polyunsaturated Fatty Acids (dPUFAs)
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. http://www.retrotope.com/Technology.html
In 2012, FARA awarded a grant for testing these compounds in established cell models. Results of this work have been published - http://authors.elsevier.com/sd/article/S2213231713000529
In October 2012, Retrotope, Inc 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 anticipates having all the IND-enabling studies complete and manufacturing of enough drug for clinical studies in 2014 and file the IND before the end of the year.
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Drug/Approach – Mitochondrial Radical Quenchers (MRQs)
Dr. Sid Hecht at Arizona State University is designing and testing compounds that target the mitochondrial dysfunction that occurs in FA. FARA provided funding to support Dr. Hecht’s work to design compounds that will perform multiple functions in mitochondria. These compounds are now being tested in various cell and animal models of FA. Dr. Rob Wilson enthusiastically referred to this approach as “Hecht Wizardry” at a recent FA conference.
A recent publication of Dr. Hecht’s work - http://proxy.library.upenn.edu:2069/pubmed/21732153
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Drug/Approach – Nutritional approach
Dr. Robert Wilson at the University of Pennsylvania has identified certain nutritional compounds that can activate PGC1α, which is decreased in frataxin deficient cells. Normally, when there is mitochondrial dysfunction in a cell PGC1α is recruited to try to correct the damage. PGC1α 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 PGC1α through other mechanisms, such as with nutritional compounds.
In 2013, FARA awarded a grant to Dr. Wilson to further develop this therapeutic approach.
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Drug/Approach – Nrf2 activators
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. Dr. Cortopassi is collaborating with Dr. Susan Perlman at UCLA to provide further validation of these therapeutics targets. Ixchel pharma LLC has options on this Intellectual property. In September 2013, Dr. Cortopassi received Orphan Drug designation of dimethyl fumarate for the treatment of Friedreich ataxia. Dimethyl fumarate is a drug that is approved for multiple sclerosis however trials in Friedreich ataxia have not been done so we don’t yet know if there is benefit in treating FA.
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Drug – 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. 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 of the study will complete in mid 2014. This study is being 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
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Drug/Approach – EPO-mimetics
Epo-mimetics - STATegics, a company in Northern CA, specializes in small molecule mimetics of EPO. These compounds provide several potential advantages when compared to rhEPO due to their small size, tissue penetrance and feasibility for oral dosing. The studies to date demonstrate encouraging properties of STATegics’ lead compounds for both neuroprotection and enhancement of frataxin protein levels. FARA has provided grant funding to Stategics for further testing of their compounds in cell and animal models of FA and to further evaluate mechanism of action in FA. STATegics’ Press release
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Drug/Approach – 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. FARA has funded research in the Testi lab to validate the efficacy of these compounds in an animal model of the disease. In addition to FARA funding, Dr. Testi has also received a grant from the European Research Council to support the pre-clinical development of these compounds. Successful compounds might be candidates for future clinical trials.
Scientific Publication - http://hmg.oxfordjournals.org/content/20/7/1253.long
BabelFAmily Interview with Dr. Testi -
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Drug/Approach – TAT-Frataxin
Dr. Mark Payne, who first described the possibility of frataxin replacement therapy via TAT-Frataxin, has been developing this exciting prospect for FA therapy. He makes synthetic frataxin protein and uses 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 - http://hmg.oxfordjournals.org/content/early/2011/11/23/hmg.ddr554.abstract?ct=ct ).
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.
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Drug – Histone Deacetylase inhibitors (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.
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. A new lead candidate that meets a very specific set of criteria has been selected and we look forward to working with RepliGen to get this new candidate advanced as quickly as possible.
Recent review articles discussing the development of these compounds - http://www.ncbi.nlm.nih.gov/pubmed/21913121 and http://www.ncbi.nlm.nih.gov/pubmed/22764181
Watch the RepliGen/FARA Webinar recorded July 26, 2011 -
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 - http://www.chop.edu/service/friedreichs-ataxia-program/friedreichs-ataxia-symposium/
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).
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Drug – 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.
Scientific publications - http://www.ncbi.nlm.nih.gov/pubmed/21483810
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.
The full results have been published and can be accessed at: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60382-2/abstract
Clinicaltrials.gov reference: http://www.clinicaltrials.gov/ct2/show/NCT01589809
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Drug – Interferon gamma
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 - http://hmg.oxfordjournals.org/content/early/2012/03/23/hmg.dds110.abstract
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 IFNɤ in late 2013. This study will evaluate 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 study results are being analyzed and should be published and presented in the fall of 2014.
More info - http://www.clinicaltrials.gov/ct2/show/NCT01965327?term=friedreich+ataxia&rank=11
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Drug - RNA-based approach
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
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Drug - Epigenetic approaches
Epigenetic and RNA-based approaches involve increasing FXN gene transcription. These approaches take advantage of the primary disease causing mutation in the FXN gene, the expanded triplet repeat (GAA ), occurring in a non-coding region (intron 1). This mutation results in blocked or reduced transcription of the FXN gene; however this blockage is not 100%. Individuals with FA have significantly reduced levels of the protein encoded by the FXN gene, frataxin, but not absent protein. Multiple studies have confirmed reduced levels of transcription and frataxin levels in individuals with FA being reduced to 2-10%. Because the mutation is in a non-coding region, frataxin is made when the FXN gene is able to be transcribed.
There are many molecules along with specific DNA and RNA sequences that control gene transcription. FARA has funded several grants to academic scientists to further expand this research and understand the specific “controls” of transcription of the FRDA gene. There are also several companies in early stages of discovery who are developing these approaches.
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Drug/Approach – Gene Therapy
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 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
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Drug/Approach – Cardiac Gene Therapy
Sponsor - AAVLife
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
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Drug/Approach – Central Nervous System Gene Therapy
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
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Drug/Approach – Central Nervous System Gene Therapy
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
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Additional Approaches – High Throughput Screening
Throughout the research pipeline are other early stage research studies that are focused on discovery of new treatments. We believe that we need multiple shots on goal in various areas to ensure successful treatments are delivered to all patients with FA. For example, at the end of the pipeline chart are several red bars that represent research designed to discover new therapeutic candidates. These are primarily high-throughput drug screens. A researcher develops an assay or a test in the laboratory. The assay is specific for function, i.e., improved mitochondrial function, increased expression of frataxin, etc… One such high throughput assay measuring mitochondrial function in an FA model was developed by Dr. Robert Wilson at the University of Pennsylvania and has been used to screen hundreds of thousands of compounds. From this screening, supported by the National Institutes of Health (NIH), a promising structural candidate has been identified. With the additional assistance of a recently awarded FARA grant, Dr. Wilson is working with expert medicinal chemists to optimize this candidate so as to identify 2-5 compounds that are appropriate for testing in animal models of FA and pre-clinical development. Dr. Wilson’s project is so promising that FARA is assisting him in the search for an appropriate pharmaceutical partner for drug development.
Dr. Marek Napierala at M.D. Andersen in Houston has developed a new cell line is a molecular model of FRDA by inserting 560 GAA•TTC repeats into an intron of a GFP reporter minigene. This cell line was optimized for high-throughput screening.
Scientific publication - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577344/
The NIH has recently selected Dr. Napierala’s assay to go through their high throughput screening program just as Dr. Wilson’s did. This allows access to one of the largest drug-compound libraries for testing and also provides additional support through a large database of knowledge on the compounds and assistance with selecting lead candidates from the assay results as well as with the medicinal chemistry needed to optimize such lead compounds.
Dr. Michele Lufino at Oxford University in England has developed an assay that replicates the FXN gene mutation and allows for identification of compounds that can increase FXN transcription. This work has been supported by FARA and our worldwide FA funding partners (Ataxia UK, FARA-Australasia, BabelFAmily, and AISA)
Dr. Lufino’s interview with FARA at the 4th International Scientific Conference, May 2011 - http://www.youtube.com/watch?v=dUrs1ZHLOxw
Dr. Lufino’s Platform presentation, 4th International Friedreich’s Ataxia Scientific Conference, May 5th-7th, 2011, Strasbourg, France. - “Drug screening based on FRDA genomic-reporter fusion vectors identifies two candidate molecules able to up-regulate FXN expression”
Dr. Devin Oglesbee at the Mayo Clinic in Rochester, Minnesota developed a MesoScale Discovery assay for detecting frataxin protein levels in human white blood cells. The development of the assay was funded as a Kyle Bryant Translational Research Award, from FARA. In addition to development for drug screening, this assay is also being used to measure frataxin levels as a clinical test and will further be developed as a newborn screening assay for FA.
Platform presentation, 4th International Friedreich’s Ataxia Scientific Conference, May 5th-7th, 2011, Strasbourg, France. Title: Development and Validation of a High-Throughput, Quantitative, Luminex Immunoassay for Frataxin in Whole Blood or Dried Blood Spots: An Assay for Newborn Screening, Diagnosis, and Treatment Monitoring
Dr. Gino Cortopassi at the University of California, Davis has developed an assay that measures biochemical differences in FA (this work was funded as a Kyle Bryant Translational Research Award from FARA). Dr. Cortopassi has used this assay to screen a library of 1600 drugs already approved for use in humans to find new therapeutic targets for FA. FARA is continuing to support the pre-clinical evaluation of “hits” from Dr. Cortopassi's screening, including testing of compounds in FA mouse models.
FARA is confident that these research projects will bring new specific lead candidates to our pipeline in the near term.
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Below are some compounds that were previously on our pipeline but were removed after initial testing.
Drug – 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.
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.
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Drug – 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) 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.
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Drug – Deferiprone
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 - http://www.curefa.org/conference.html
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Drug – Lu AA24493 carbamylated EPO
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.
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Drug – 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.
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Drug – EGb-761
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
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