PracticeUpdate Conference Series - SSIEM 2018

Epicatechin Improves Several Measures of Friedreich’s Ataxia Treatment with epicatechinwas safe and tolerable over 24 weeks and resulted in neurological improvement.

T reatment with epicatechin was safe and tolerable over 24 weeks and resulted in neurological improve- ment of total Friedreich's Ataxia Rating Scale score, 8-m timed walk, nine-hole peg test, and a reduction in left ventricu- lar myocardial mass index in a subset of patients. This outcome of a phase II open-label, single-center trial was reported at SSIEM 2018. Marc Patterson, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues evaluated the safety and efficacy of epicatechin for 24 weeks in 10 subjects with Friedreich’s ataxia. Participants 10 to 50 years of age with a confirmed diagnosis of Friedreich’s ataxia, disease duration ≤7 years, and affected cardiac/neurological systems took epicatechin 75 mg daily orally. The dose was escalated to 150 g daily after 3 months in subjects not showing improvement. Primary endpoints were safety and efficacy according to neurological, cardiac, and metabolic evaluations before and after treatment. Secondary endpoints included frataxin upregulation and urine F2-isoprostane reduction before and after treatment. A total of 10 patients completed all safety and efficacy measurements, except for 1 patient who did not complete the Friedreich's Ataxia Rating Scale and 8-m time walk after 24 weeks. Epicatechin was safe and tolerable, without clinically significant side effects but with a transient increase in the frequency of migraine. No subjects discontinued the study. Improvement in Friedreich's Ataxia Rating Scale score was observed in

50% of subjects, by a mean of 5.5 (range 2–8) points and in the 8-m walk in 30% of subjects by a mean of 2.2 s (range 2.2–2.3). In the nine-hole peg test, improvement was seen after 24 weeks in 50% of subjects by a mean of 4.2 s (range 1–9) in the right hand and 5.4 s (range 3–7) in the left hand. A reduction was seen in MRI-derived left ventricular myocardial mass index by >10% in 6 subjects at 12 weeks and in one additional subject at 24 weeks (70%). Left ventricular myocardial mass index showed slight worsening after 24 weeks in the 6 subjects. No improvement in secondary endpoints was observed. Dr. Pa t t e r son exp l a i ned t ha t Friedreich’s ataxia is a rare, progressive neurodegenerative disease caused by mutations in the gene encoding for the frataxin protein, important for normal functioning of mitochondria. Friedreich’s ataxia is clinically characterized by progressive ataxia (lack of voluntary muscle coordination), dysarthria (speech impairment), areflexia, and progressive motor weakness. Patients also develop hypertrophic cardiomyopathy and diabetes. Symptoms appear in childhood and worsen progressively through adulthood. Friedreich’s ataxia commonly fatal in mid-adulthood. Neuropathologically, Friedreich’s ataxia involves degeneration of the dentate nuclei in the cerebellum and sensory and motor tracts of the spinal cord. No therapies are available for Friedreich’s ataxia. Medications can only treat symptoms and address disease- associated cardiovascular, neurological, or motor dysfunction. Epicatechin is a flavonoid that confers similar health benefits to exercise.

Observations suggest a signaling mechanism that may induce mitochondrial biogenesis in mitochondria-depleted muscle fibers and neurons as well as induction of antioxidant enzymes. Epicatechin has been shown to improve mitochondrial function in various models of cardiac and neuromuscular diseases. A study reported a reduction in oxidative stress and some restoration of new mitochondria formation of in senile mice. On the basis of these promising results in mice, an initial, proof-of-concept study was implemented in humans. Following 7 days of epicatechin treatment, significant positive effects were observed in circulating follistatin/myostatin plasma levels and grip strength. Thus, epicatechin is the first compound ever noted, to favorably modulate both regulators of muscle growth and suggest increases in strength. In a small phase I study in 2014, epicatechin was found to help improve mitochondrial enzyme function and plasma levels of frataxin. These changes, in turn, may help reduce the risk of cardiovascular and neurodegenerative disease and improve skeletal muscle structure and strength. Dr. Patterson concluded that treatment with epicatechin was safe and tolerable over 24 weeks and resulted in neurological improvement of total Friedreich's Ataxia Rating Scale score, 8-m timed walk, nine-hole peg test, and a reduction in left ventricular myocardial mass index in a subset of patients. Further studies of epicatechin are warranted for Friedreich’s ataxia. www.practiceupdate.com/c/73327 Epicatechin is not registered in Australia by the TGA therefore the efficacy and safety of this product has not been established.

PRACTICEUPDATE CONFERENCE SERIES • SSIEM 2018 14