In another exciting presentation at the CHDI meetings, Guy Miller, MD, PhD the CEO of Edison Pharmaceuticals gave information on EPI 743, a compound that has been developed for rare childhood mitochondrial diseases. The Huntington's community first heard about Edison's CoQ10 analogues, which were described as more potent and much more highly absorbed into brain than naturally occurring CoQ10. Now one of these compounds has been tested and shown benefit in children with 2 different types of genetic mitochondrial diseases, suggesting that EPI-743 function may be more broad than CoQ10.

EPI-743 may be much more than just a potent CoQ10. It appears that this drug either works at more than one part of the electron transport chain -- or that it might act as a beneficial "parallel circuit" around several defects in this mitochondrial energy system.

What is the Mitochondrial Electric Transport Chain (ETC)? ETC is set of chemical reactions that occur in mitochondria that in turn moves high energy electrons down the cell path that produces energy molecules. Scientists split ETC in to 4 major electron carrier reactions: Complex 1, Complex 2, etc., that act in a sequential process similar to a series electrical circuit. In a series circuit, if one part of the process malfunctions -- similar to the old fashioned (series circuit) Christmas tree lights -- the entire process is affected; all the lights go out.

The series circuit Christmas tree light problem has been corrected by incorporating electrical parallel circuits -- so that if one light burns out, the broken light is bypassed using a parallel circuit. There is evidence from genetic mitochondrial ETC diseases that EPI-43 may be acting like a parallel circuit.

EPI-743 for Childhood Mitochondrial Diseases: In new clinical findings, Dr. Miller reported impressive positive results for EPI-743 when given to a small number of children with inherited (Complex 1 and 4) respiratory chain diseases of the mitochondria under an IND approved by the US Food and Drug Administration. These diseases are caused by gene defects that interfere with mitochondrial energy production and metabolic control. As consequence, these children suffer progressive brain and multi-system damage and frequently are highly disabled and/or die in childhood.

After the 90-180 days of receiving EPI-743, subjects -- which included children with 2 different mitochondrial diseases with defects known to occur at different complexes in the electron transport chain -- had gradual and consistent improvement in clinical and biomarker indices of function. In fact, MRI brain scans showed that prior damage in the brain, which was thought to be irreversible had undergone significant normalization.

Might the success in inherited respiratory chain disease of mitochondria in children extend to Huntington's disease? This drug is clearly beneficial in select inherited respiratory chain diseases of the mitochondria where the energy defect is more clearly defined than is the case for HD. In addition the HD process is more complex, involving many more cell systems than energy alone. Even if EPI-743 completely repaired the energy defect in HD, would it be enough to make a difference in HD?

In partial answer to the question of the drug's usefulness in HD, Dr. Miller presented data showing that EPI-743 prolongs survival of HD mouse-model striatal cells in culture in a dose dependent manner. This means survival of the HD cells improved with higher doses -- even approaching 100% survival. In preliminary data not presented at the meeting, Edison has shown improvements in an animal model of neurodegenerative and aging disease .

EPA-743 for Huntington's disease: What characteristics learned about this drug for inherited mitochondrial disease might be useful for HD?
  • CoQ10 has shown some promise for HD. The NIH is presently funding 2-Care a clinical trial to test benefit of large dose CoQ10
  • EPI-743 is an engineered CoQ10 analog whose function may be more broad -- because it appears to be beneficial at different points of ETC -- than naturally occurring CoQ10
  • EPI-743 is over 1,000 more effective than CoQ10
  • EPI-743, unlike CoQ10 gets into the brain -- the critical target in HD
  • In the lab, EPI-743 protects HD cells.
  • There have been no significant adverse events observed in children receiving EPI-743 for over 6-months.
  • Biomarker and clinical results in these studies may have direct application for HD.

How soon might it be tried in HD people? As part of his presentation Dr. Miller suggested that EPI-743 might go to development as early as late 2010 with first HD human clinical testing in early 2011. Then during the question and answer period following the presentation, a member of the audience asked the poignant question whether Edison might consider a compassionate use trial for children with Juvenile HD just as they had done for children with mitochondrial disease? Though he did not directly answer this question, Dr. Miller confirmed that this is in line with the company's current thinking, and that with HD experts enrollment criteria could be developed.

Author's comments/questions: What more evidence is needed before EPI-743 goes to trial for HD? Is the dose used in the inherited respiratory chain disease of the mitochondria trial the best one to try for HD? How can best dose be determined? And practically speaking who will bear the cost of an HD clinical trial? At present Edison, which is a small biotech pharmaceutical company would not be able to afford this cost without obtaining more capital funds.

Let's hope they find funding soon . . .