Epicatechin is a flavonoid found in dark chocolate harvested from the cacao tree. What’s that got to do with Duchenne? Epicatechin is one of dozens of flavonoids found in dark chocolate, but it is unique with respect to its effects on muscle and heart. Epicatechin has been demonstrated in animals and humans to increase the production of new mitochondria in heart and muscle (termed “mitochondrial biogenesis”) while concurrently stimulating the regeneration of muscle tissue. The progression of muscle weakness in Duchenne muscular dystrophy is associated with a loss of mitochondria, which power the skeletal muscle. Recent evidence indicates that Epicatechin is acting as a mimic of a newly discovered human hormone released by normal muscles after exercise that may be responsible for mitochondria biogenesis and stronger muscle fibers that occur normally after exercise training. Other closely related flavonoids in chocolate either have no effect or are actually inhibitory to mitochondrial biogenesis. Thus use of extracts of cacao or non-pharmaceutical grade Epicatechin may be ineffective. The current studies in muscular dystrophy are being conducted with pharmaceutical grade Epicatechin, free of any other flavonoids or contaminants. There is a trial in Europe evaluating a related compound, epigallocatechin gallate (EGCG) for its anti-oxidant effects in muscular dystrophy. ECGC has none of the mitochondrial or muscle effects that has been observed for Epicatechin, because it is the wrong shape to mimic the human hormone.
Other effects of Epicatechin is increased plasma levels of the muscle regenerating protein follistatin and a lowering of the protein myostatin responsible for muscle atrophy and fibrosis. Epicatechin also appears to stimulate the production of utrophin, a sarcoglycan that can potentially compensate for missing dystrophin expression.
The net effect of Epicatechin has been shown to be improvement in the function of both heart and muscle in humans and in animal models of muscle disease. Epicatechin represents a new class of therapeutic for muscular dystrophy and well-worth adding to PPMD’s current pipeline.
Advancing the development of Epicatechin
PPMD is planning to work with a small company, Cardero Therapeutics to advance the development of Epicatechin. Cardero is planning to develop a rare, more potent variant of the (-)-Epicatechin found in cacao, called (+)-Epicatechin. Both (-)-Epicatechin and (+)-Epicatechin have been shown to improve skeletal muscle function, decrease cardiac fibrosis, and improve heart function in animal studies. Additionally, (-)-Epicatechin has recently been studied in a small clinical study in Becker muscular dystrophy (Becker) by Dr. Craig McDonald at the University of California Davis and supported by Cardero Therapeutics. Results of this study are being presented publically this Saturday, March 14 at the MDA Scientific meeting in Washington, DC. The non-controlled pilot trial in seven patients yielded encouraging results after 8 weeks of treatment using muscle biopsy measures, plasma biomarkers, and graded exercise tests. According to Dr. McDonald, adults with Becker demonstrated an exercise training-like effect but without the exercise. The ratio of follistatin to myostatin in the blood increased after 8 weeks and plasma B-Type Natriuretic Peptide (BNP) Levels, a marker of heart failure, decreased.
This pilot study was encouraging with no adverse effects and anecdotal reports of benefit, with evidence for improved muscle metabolism in the form of decreased lactate levels during exercise and improved mitochondrial efficiency in making ATP. The study was too short and the patients too few to demonstrate statistically significant changes in muscle performance, but positive trends were observed.
Study in Duchenne muscular dystrophy
Cardero is also planning to conduct a study of (+)-Epicatechin in Duchenne muscular dystrophy (Duchenne), focused on improving the heart and slowing progression of muscle loss in non-ambulatory patients with Duchenne muscular dystrophy. Dr. Craig McDonald will serve as PI of the study and Erik Henricson, MPH from UC Davis is serving as co-investigator. Skeletal muscle measures will also be evaluated using new state of the art clinical outcome measures developed for children and adults who are non-ambulatory. PPMD has agreed to partner with Cardero and other potential partners, to expand the number of individuals in the study. The primary outcome measure is likely to be a novel measure of cardiac function such as speckle tracking echo (STE) derived cardiac strain or an MRI derived strain measure, however these plans have not been finalized.
Secondary outcome measures will include novel measures of upper limb function including the Performance of Upper Limb (PUL) and the Microsoft Kinect quantitative measure of reachable work space. Dr. Jay Han from UC Davis has been developing this measure for the last 7 years with NIH and PPMD support. Using the Kinect, they have the ability to measure ‘reachable work space’ and correlate this measure to activities of daily living such as self-feeding, the ability to shampoo hair, etc. The Kinect measure will be obtained weekly using an in-home version.
Our goals for the study are several and include:
Determine the effect of (+)-Epicatechin on cardiac function in Duchenne and the optimal state–of-the-art cardiac endpoints for use in pivotal trials geared at assessing the benefits of (+)-Epicatechin on heart function;
Confirm the PUL and quantitative reachable work space area (RSA) as rigorous and reproducible measures for upper limb function in Duchenne;
Test the ability to collect quantitative reachable work space data from home in an FDA-compliant fashion using the Microsoft Kinect system; and
Test new state-of-the-art biomarkers of skeletal muscle and heart function using the Somalogics proteomics platform recently identified to yield at least 44 potential blood biomarkers in Duchenne.
Dr. McDonald commented to PPMD that:
“The new partnership between Cardero Therapeutics and PPMD is an exciting development that will allow this trial to begin in the very near future. In addition, I believe the planned trial design for non-ambulatory children and young men with Duchenne represents a model of how future trials will be performed in more severely affected patients.”
It is the hope of Cardero, investigators, and PPMD that the trial will confirm the recently developed ability to rigorously measure upper limb function in Duchenne and use this as a means to encourage companies to include non-ambulatory boys as they design clinical trial protocols.
The study will include two sites including UC Davis Medical Center and a yet to be named site. It is anticipated that at least 40 young men will be recruited for the study but the sample size may expand depending on statistical power considerations. Inclusion criteria will include non-ambulatory boys from 8-18 years. As mentioned above, the study will include MRI of the upper limbs, Cardiac MRI, cardiac echo including speckle tracking echo (STE) derived cardiac strain, PUL, and Kinect reachable work space. There will be a dose finding component to the study using recently discovered pharmacodynamic blood biomarkers such as Follistatin/myostatin ratio. Individuals participating in the study will be given a Microsoft Kinect system and required to provide ‘reachable work space area’ data each week.