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Friedreich Ataxia Research Update

Presented by

Ronald J. Bartek, President
Friedreich's Ataxia Research Alliance

Dear friends,
Please find below part II of the summary of what was discussed in the Boston ataxia parents' Birds of a Feather group regarding the tremendous progress being made in FA research and the real promise involved in the multiple clinical trials planned to be underway over the next twelve months. In fact, please find below both parts I and II of the summary, because recent meetings with some of the key scientists have permitted a couple of updates of clinical trials in part I, and this will give you a complete (and long) summary in this one message:

Part I

1. Clinical trials - FA scientists and FARA are preparing for clinical trials that show real promise of developing treatments. These trials are to include a number of different drug candidates that operate in different ways with different, mutually reinforcing intended outcomes. Those drug candidates are:

a.Idebenone – Because of a shortage of frataxin protein in their cells, the mitochondria of FA patients produce far less energy and suffer far more oxidative damage. Idebenone might assist in electron transport along the mitochondrial membrane so as to produce more energy and reduce oxidative radicals.

Thanks to many of your families and a totally dedicated NIH team at the NIH National Institute of Neurological Disorders and Stroke (NINDS), the Phase II trial of Idebenone in FA is at its midpoint. The NINDS team, led by Dr. Nick Di Prospero and Nurse Practitioner Angela Baker, completed the initial examination of all 48 participants in the trial as those participants began their 6-month regimen involving 4 doses - 5mg/kg, 15mg/kg, 45mg/kg, and placebo.

Beginning this month, the patients who began the trial last October will begin returning for their second examinations (so, they will have been dosed for six months). That process is to continue until late this summer, when all 48 patients will have been dosed for six months and examined for the second time. The data from this phase II trial will then be analyzed and published. Patients in Europe have begun enrolling for a phase III trial of Idebenone to be conducted by Santhera Pharmaceuticals (the Swiss company that manufactures the Idebenone being used in the NINDS trial). Thomas Meier, Santhera's Chief Scientific Officer, briefed the FA parent and patient groups and said plans are also being made for a Phase III trial of Idebenone in the United States for which patient recruitment might begin as soon as this summer. In both the European and U.S. trials, several clinical centers will be used. The list of centers for the U.S. trial has not yet been finalized, but it appears that the lead investigator will be Dr. Rob Wilson at the University of Pennsylvania in Philadelphia. In these Idebenone trials, the investigators are and will be monitoring participants by using various cardiac and neurological measurements intended to help determine if Idebenone benefits FA patients in terms of such things as heart function, energy level, exercise tolerance, and coordination. FARA has been working closely with the Santhera people for years and continues to do so. The Santhera CEO and Chief Scientific Officer, in fact, briefed the FARA Board of Directors in Boston before the NAF meeting began. Santhera will appeal to FARA for help in preparing for the Phase III Idebenone FA trial being planned for the United States. The FARA president served on the NIH steering committee tasked with preparing the Phase I and Phase II Idebenone trials and it was at the first NIH/FARA international FA conference that Idebenone was first discussed in the FA scientific community (Pierre Rustin briefing the conference on his small trial in France).

b. Mitoquinone (MitoQ) - Because of a shortage of frataxin protein in their cells, the mitochondria of FA patients produce far less energy and suffer far more oxidative damage. MitoQ might help increase energy production and reduce oxidative damage by preventing electrons from escaping from the mitochondrial membrane and forming oxidative radicals.

MitoQ consists of the Idebenone molecule to which has been attached a charged particle called a phosphonium cation that serves to concentrate the molecules at the mitochondria where it is hoped that MitoQ's antioxidant properties will be of most beneficial effect in blocking mitochondrial oxidative damage and preventing cell death. A Phase II clinical trial of MitoQ in FA is planned to begin this year in two locations - Melbourne, Australia, and UCLA. Dr. Martin Delatycki will lead the Melbourne trial and hopes to begin this spring. Dr. Susan Perlman is to lead the UCLA trial and hopes to begin later this year, probably in the fall. FARA helped fund some of the earlier MitoQ work (for example, Michael Murphy's continued development of MitoQ and testing it in FA mice, as well as Martin Delatycki's preparations for a MitoQ clinical trial).

Because Mitochondrial dysfunction underlies a wide range of diseases and because protecting mitochondria from oxidative damage is a promising and innovative therapeutic strategy in such diseases, MitoQ is also being evaluated as a treatment for Parkinson's disease (in phase II clinical trial now in New Zealand) and in other indications, including retinal degeneration, Alzheimer's disease and cardiac ischemia. MitoQ is the lead compound of Antipodean Pharmaceuticals. Updates regarding MitoQ can be found on the Antipodean website at:

c. Erythropoietin (EPO) - Friedreich’s ataxia symptoms result from a shortage of frataxin protein. Increasing the supply of frataxin protein would almost certainly be therapeutic.

You may have read the article published a few months ago by the FARA/SAM-funded team in Austria led by Drs. Barbara Scheiber-Mojdehkar and Brigitte Sturm (see the article summary on the FARA website at http://www.faresearchalliance.org/news/2006-02-07.asp).

This Austrian team, with a two-year grant awarded by FARA and SAM/MDA, demonstrated that EPO is able, in cell cultures derived from FA patients, to elevate frataxin protein levels by two to five fold. The team is now preparing a very short (8-week), small (13 FA patients), open-label (no placebo), "proof of principle" pilot trial of EPO to be conducted in Insbruck, Austria. FARA is in the process of reviewing the plans and protocol for this trial. If the scientific review finds sufficient merit in the proposed pilot trial, FARA will seek to fund the Austrian pilot trial in collaboration with other funding organizations.

FARA is also in discussions with the Austrian team, other European investigators, a drug company and the NIH in regards to preparing a phase II FA trial of EPO that could possibly be conducted in the United States and Europe.

None of these clinical trials would be or will be possible without you. The financial support so many of you have helped assemble, and the participation of your families in these clinical trials truly enable all this exciting progress. With at least five clinical trials being conducted over the next twelve months, we will ALL need to work hard together to redouble our efforts to assemble far more in the way of resources and patient participants. I know we will do that and that we will succeed in developing treatments for FA as a result of these trials. Please do take a look at the first FARA E-Bulletin that Marilyn Downing posted, as it provides some excellent additional information and tells you where to look on the FARA website to register for such E-Bulletins and find the new FARA patient registry very soon. Part II of the research summary coming soon!

Part II

There is one other compound being prepared for a clinical trial being planned for this year. Also, two additional compounds have shown tremendous promise in FA cell cultures and might well lead to clinical trials next year. Finally, we should not lose sight of trials already conducted that seemed to hold out promise of benefit.

a. EPI-A0001—If EPI-A0001 is successful, the FA patients would have more energy, be less fatigued and their cells would not die as a result of programmed cell death (apoptosis).

EPI-A0001: This compound being prepared for a Phase II FA clinical trial later this year is that of Edison Pharmaceuticals as outlined on the FARA website (www.faresearchalliance.org). The compound is referred to as EPI-A0001 and it has shown in cell assays the ability, even at very low concentrations, to increase significantly the amount of energy produced by mitochondria and to reduce significantly the amount of oxidative stress around the mitochondria. In an FA yeast model, the compound improved indirect measures of mitochondrial function more than eight fold. It is believed that EPI-A0001 accomplishes this by assisting substantially in the transport of electrons across the respiratory chain complexes of the mitochondria so that more ATP (the currency of cellular energy) is produced and fewer oxidative radicals are formed. If EPI-A0001 were able to accomplish the same thing in FA patients – increase mitochondrial energy production and reduce oxidative stress – the FA patients would have more energy, be less fatigued and their cells would not die as a result of programmed cell death (apoptosis). EPI-A0001 is derived from plants and should be well tolerated and non-toxic. EPI-A0001 HAS BEEN ACCEPTED INTO AN NIH FAST-TRACK PROGRAM INTENDED TO GREATLY ACCELERATE THE PROCESS of moving a "drug discovery" through "drug development" and into clinical trial.

The program is called NIH RAID (Rapid Access to Interventional Development). The co-applicants for this NIH RAID program were Dr. Rob Wilson of the University of Pennsylvania, Dr. Guy Miller, CEO of Edison, and FARA. The U.S. Food and Drug Administration (FDA) RECENTLY AWARDED THE COMPOUND ORPHAN DRUG STATUS TO EPI-A0001 for treatment of inherited mitochondrial respiratory chain diseases including FA. FARA believes that the FDA's decision will help accelerate the compound's NIH RAID program and that, with the rapid progress already being made in the preclinical preparations of the compound, it should be in a phase II clinical trial before the end of this year. FARA has been sufficiently impressed with the tremendous promise of the Edison compound to have awarded Edison Pharmaceuticals research grants totaling $3,300,000 and invested another $1,100,000 in Edison's preferred stock so as to help launch the company and its intensive effort to get the compound into clinical trial as quickly as possible. Seek A Miracle/MDA, in collaboration with FARA, awarded $100,000 to the initial research grant to Edison. Additional details are available on the FARA website www.faresearchalliance.org).

b. Frataxin protein upregulation – Friedreich’s ataxia symptoms result from a shortage of frataxin protein. Increasing the supply of frataxin protein would almost certainly be therapeutic.
The two compounds not yet targeting clinical trials in 2006 but that have shown exciting capability, in FA cell cultures, of increasing substantially the levels of frataxin protein, are Histone Deacetylase inhibitors (HDAC inhibitors) and small molecules called polyamides. Dr. Joel Gottesfeld of the Scripps Research Institute in La Jolla, California, leads both of these efforts with grants from FARA.

1) HDAC inhibitors Background - DNA, including the FA gene, is wrapped around bundles of proteins. These bundles are called chromatin and they include histone proteins. When the gene in question is to be transcribed (or read), the chromatin bundle has to "de-condense" or "lay out" so the transcription molecule can read the gene's DNA sequence and the gene's protein can be assembled. It appears from Dr. Gottesfeld's important work that the chromatin associated with the FA triplet expansion does not de-condense" properly because the histone proteins there have been deacetylated. Dr. Gottesfeld has modified molecules called Histone Deacetylase inhibitors to optimize their ability to maintain acetylated histone proteins in the chromatin associated with the FA gene's expansion area so that the chromatin can de-condense, the gene can be transcribed properly, and more frataxin protein can be produced. In cell cultures and whole blood from FA patients and siblings, Dr. Gottesfeld's modified HDAC INHIBITORS HAVE NOW SHOWN THE ABILITY TO ELEVATE THE FRATAXIN PROTEIN IN PATIENT SAMPLES TO LEVELS WEEL IN EXCESS OF THOSE IN SAMPLES FROM CARRIER SIBLINGS AND EVEN APPROACHING THOSE LEVELS IN ‘CLEAR’ SIBLINGS. Again, these experiments are being done in cell lines and primary blood cells - not in patients - but the results are extremely encouraging. Dr. Gottesfeld has applied, with FARA as co-applicant, for the NIH Rapid Access to Interventional Development (RAID) program. Especially if that application is successful, Dr. Gottesfeld and FARA are hopeful that the modified HDAC inhibitors could be in an FA clinical trial by early next year. This hope is advanced by the fact that HDAC inhibitors are already being tested in humans for other indications such as cancer and Huntington's disease.

2) Polyamides - Dr. Gottesfeld is collaborating, under several FARA grants, with Dr. Peter Dervan of Caltech, in developing very small molecules called polyamides that are being expressly designed to address the FA triplet expansion mutation (GAA). This project has been focused on optimizing the small molecule for maximum effect on frataxin protein expression. THE CURRENT SMALL MOLECULE DESIGN HAS SHOWN, IN CELL CULTURES AND WHOLE BLOOD FROM FA PATIENTS AND SIBLINGS, THE ABILITY TO ELEVATE FRATAXIN PROTEIN LEVELS IN PATIENT SAMPLES TO LEVELS EQUAL TO OR GREATER THAN THOSE IN CARRIER SIBLINGS. Once again, these experiments are being done in cell lines and primary blood cells – “NOT” in patients - but the results are extremely encouraging. These polyamides are newly designed by Drs. Gottesfeld and Dervan. They have not, therefore, been tested yet in humans for any indication and will require longer to develop, test and prepare for clinical trial. Drs. Gottesfeld, Dervan and FARA are pursuing this effort with maximum speed so that the polyamides might be made available in time to join some of the other drugs above in a therapeutic cocktail of treatment.

c. CoQ10 and Vitamin E – Both CoQ10 and Vitamin E are naturally present in human cells. Supplementing them might help in assisting in electron transport along the mitochondrial membrane (CoQ10’s natural function) and reducing production of oxidative radicals (Vitamin E’s natural function).

As most know, a number of clinical trials in FA have been completed in recent years. Some of those (such as various small trials of Idebenone in other countries and a phase I trial of MitoQ in New Zealand) have been followed by additional trials or plans for additional trials as outlined above. Another trial already completed is that of CoQ10 and Vitamin E in FA patients. This trial was conducted by the fine team in London led by Dr. Mark Cooper. The small, open-label, pilot trial was conducted over a 47-month period during which 10 FA patients were dosed with 400 mg of CoQ10 and 2100 International Units (IU) of Vitamin E per day. The clinical measurements of these 10 patients over that 47-month period were compared with such measurements from 77 other FA patients not participating in the drug trial. The clinical measurements were made using echocardiography and the International Cooperative Ataxia Rating Scale (ICARS). Cardiac and skeletal muscle bioenergetics were assessed using phosphorus P 31 magnetic resonance spectroscopy. RESULTS: There was a significant improvement in cardiac and skeletal muscle bioenergetics that was maintained throughout the 47 months of therapy. Echocardiographic data revealed significantly increased fractional shortening at the 35- and 47-month time points. Comparison with cross-sectional data from the 77 other patients with FA indicated the changes in total ICARS and kinetic scores over the trial period were better than predicted for 7 of the 10 patients, but the posture and gait and hand dexterity scores progressed as predicted. "This therapy resulted in SUSTAINED IMPROVEMENT IN MITOCHONDRIAL ENERGY SYNTHESIS THAT WAS ASSOCIATED WITH A SLOWING OF THE PROGRESSION OF CERTAIN CLINICAL FEATURES AND A SIGNIFICANT IMPROVEMENT IN CARDIAC FUNCTION." (taken from Arch Neurol. 2005 Apr;62(4):621-6, PMID: 15824263 [PubMed - indexed for MEDLINE].

At the present time, I know of no additional clinical trial of CoQ10 and Vitamin E being planned in FA, but FARA will soon be discussing this with the London team. Also, CoQ10 is currently being tested in a significant clinical trial in Parkinson's disease, which shares with FA substantial defects in mitochondrial dysfunction involving electron transport across the respiratory chain complexes of the mitochondria. It is becoming clearer and clearer that the insights being gained in the clinical trials in FA (for example, of CoQ10, Idebenone, MitoQ and EPI-A0001) are likely to shed bright light on potential treatment options for other important diseases. Such benefits for these other diseases, if they continue be promising, could significantly accelerate progress in the drug development and eventually could significantly reduce drug costs for all the disease groups.

The clinical trials and therapeutic approaches outlined above are only those that seem to be nearest the clinic - those for which clinical trials are being planned for this year (2006) or anticipated for next year (with the exception of CoQ10/Vitamin E). WHILE FARA CONTINUES111 TO PUT MAXIMUM EFFORT INTO THESE NEAREST-TERM PROJECTS, WE ARE CONTINUING TO SUPPORT PROJECTS WITH LONGER LEAD TIMES AND ENCOURAGING BASIC SCIENTISTS TO CONTINE TO DEVELOP ADDITIONAL PROMISING APPROACHES.

FARA is confident that the clinical trials outlined above will result in beneficial treatment. However, no one can be certain how effective such treatment will be, so we must continue pushing for additional breakthroughs that could supplement such treatments where necessary.

You can really stay up to date on these exciting research developments by checking back on the FARA website (www.faresearchalliance.org) and by signing up there, if you haven't already, for FARA's new E-Bulletins and E-Updates. You can also sign up there if you are interested in participating in such clinical trials.


A brief note on the question of treatment benefits for FA patients for whom the onset of symptoms was quite some time ago and whose disease progression is more advanced - there is real hope that the treatments we are currently pursuing will have benefit for them, too! The FA scientists explain that FA patients have three categories of cells - healthy cells, sick cells battling for survival, and cells already dead. The scientists also explain that, if the treatments achieved from clinical trials like those above are sufficiently effective in stopping FA in its tracks so as to ensure no additional damage is done by the disease, the healthy cells will remain healthy and many of the sick cells will be rescued. Those two results, alone, will probably lead to SOME reversal of symptoms, though maybe not very much - impossible to define at this point. Furthermore, the scientists say, if no additional damage is done by the disease, the body's natural repair and plasticity mechanisms (currently being overwhelmed by disease damage) will be able to regain some lost ground by establishing new neurological networks and pathways, thus compensating somewhat for cells already dead. Again, the amount of lost ground that might be regained in this way is impossible to determine at this point, but, if we stop FA in its tracks, we will ALL benefit.


We must ALL work together to achieve these exciting results. None of the clinical trials above and none of the treatments and benefits they promise will be possible unless we ALL put our shoulders to the wheel in a collective effort to assemble the financial resources and patient participants needed for the trials and the other research. FARA is leaving no stone unturned in seeking funding collaborators like the NIH, MDA & SAM, NAF, and organizations in Europe and Australia/New Zealand, for example. However, ALL of us need to do whatever we can to help.

Please do remember to register on the FARA website if you are interested in clinical trial participation. Please consider, too, helping assemble the CRITICALLY needed financial resources.

Many have worked hard to raise money to support the research that has led to the wonderful promise of these clinical trials. The clinical trials, though, will be far more expensive than the basic research that enabled them. If everyone helps out, we will get this all-important work done. Mary Caruso (AKA Meir Bode) recently suggested the following: If everyone raises just a little bit, nobody has to raise a lot. "If 500 of us make a commitment to raise $1,000 per year (and you know it can be more than that), that translates to $500,000!!!!! Now, that is a STRONG payback! Alone we can accomplish nothing -- together we can beat the giant!"

You can find good fundraising ideas on the FARA website at http://www.faresearchalliance.org/fundraising/ . You can also request excellent fundraising materials from FARA by sending an email to fara@faresearchalliance.org.

As Mary says, we should all recognize that, acting alone, there is little we can do but, acting together, there is little we can NOT do!

Together, we will stop FA in its tracks!

Best regards, Ron

Ronald J. Bartek, President
Friedreich's Ataxia Research Alliance
2001 Jefferson Davis Hwy., Suite 209
Arlington, Virginia USA 22202
Tel (703) 413-4468, Fax (703) 413-4467
FARA website: http://www.faresearchalliance.org
Email: FARAresearch@yahoo.com