Research Pipeline

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, i.e., where or how each 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, research and pre-clinical, take place in the research laboratory, and represent early discovery and development. The stages “Phase 1” through “available to patients” are phases of clinical trials/studies.

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 November 2011. This pipeline 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 – 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

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

Catena® does have conditional approval in Canada. Santhera has informed FARA that they are making every effort to communicate with Canadian physicians and regulatory agencies to ensure that individuals currently taking Catena® continue to have access to the drug until the additional results from both studies are available.

Based on the results presented above 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. Additional clinical trials in Friedreich’s Ataxia are not presently being discussed.

Drug - EPI-A0001
Sponsor: Edison Pharmaceuticals
A phase II study of EPI-A0001 was completed and initial results were announced by Edison Pharmaceuticals in June 2011. EPI-A0001 is alpha-tocopherolquinone is a drug which functions in the mitochondria. 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

Drug – EPI-743
Sponsor: Edison Pharmaceuticals
Edison Pharmaceuticals is advancing another compound, EPI-743, 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. A recent 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.
Publication reference - http://www.sciencedirect.com/science/article/pii/S1096719211003787

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

Ipsen is conducting 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 are recruiting individuals with FA between the ages of 12 - 22 years and who are ambulatory. The completion of the study was recently posted as Oct 2011; results have not yet been made public. More information on the study can be found at http://clinicaltrials.gov/ct2/show/NCT00824512?term=egb761&rank=3

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. There is some evidence 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 has initiated a proof of concept trial in France to explore the effects of Pioglitazone on neurological function in FA patients. The trial is recruiting patients less than 22 years of age. Patients will be treated two years and will undergo clinical exams and testing during two days each six months at the clinical investigation center. This study will be completed in late 2011. Of note, individuals with Type I diabetes and those at risk for congestive heart failure should not take pioglitazone

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 has funded an open-label, pilot study of Resveratrol at the University of Melbourne which began in April 2011 and should be completed in the first half of 2012.

Drug - OX1
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. A larger pharmaceutical company, ViroPharma, recently purchased the licensing rights of OX1 and plan to advance this drug in Friedreich’s ataxia. ViroPharma expects to initiate a phase 2 study within 12 to 18 months after completion of longer term toxicology studies. ViroPharma intends to file for Orphan Drug Designation upon review of the phase 2 proof of concept data. ViroPharma press release

Mitochondrial Radical Quenchers (MRQs) - This is a new bar on our chart. 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

Drug - Deferiprone
Sponsor: Apopharma
Deferiprone, also known as Ferriprox® is an oral iron chelator. Ferriprox® is indicated for the treatment of iron overload in patients with thalassemia major and has been approved in Europe for this indication since 1999 and was recently approved in the US. Redistribution of iron has been proposed as a therapeutic strategy for FA. Specifically, iron chelators that can remove excess iron from the mitochondria where excess free iron can increase oxidative stress/damage.
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

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 an 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.
http://www.ncbi.nlm.nih.gov/pubmed/21506154

Dr. Francesco Sacca at the University Federico II in Naples, Italy is in the process of initiating a follow-on longer term clinical trial of epoetin alfa to look for evidence of efficacy (clinical benefit). The study will test the effect of erythropoietin on exercise capacity, which is reduced in patients with FRDA. 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 is being funded by FARA through the Keith Michael Andrus Memorial Award.

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 provided a grant this year to Stategics for further testing of Epo-mimetics for FA. STATegics’ Press release

Drug - Histone Deacetylase inhibitors (HDACi)
Sponsor: 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 has identified a lead candidate (RG2933) and has filed an IND with the FDA in the United States to begin testing these compounds in humans. The FDA has requested additional toxicology studies which are scheduled for completion in 2011. RepliGen has also made similar request of the European regulatory agency and they were given permission to advance Phase I studies in Europe. Repligen hopes to begin Phase I safety studies in 2011 in Europe (Italy). While work continues on pre-clincal and safety studies of RG2833, RepliGen has also done moved forward with identifying another HDAC inhibitor, a follow-on compound, that they have begun pre-clinical studies in as well. The follow-on compound may offer some advantages over RG2833 in terms of metabolic stability and brain penetration. A recent review article discussing the development of these compounds - http://www.ncbi.nlm.nih.gov/pubmed/21913121

Watch the RepliGen/FARA Webinar recorded July 26, 2011

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 is looking to develop this approach further and, with FARA’s assistance, is seeking a pharmaceutical partner to help do so.

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 different kind of assay that measures genetically influenced increases in frataxin protein. 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. FARA is confident that these research projects will bring new specific lead candidates to our pipeline in the near term.

- Candidates that have been removed from the pipeline –
We know that not all of our drug candidates will lead to safe and effective treatments.
Below are some compounds that were previously on our pipeline but were removed after initial testing.

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

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.