Progression Rate of MSA Under EGCG Supplementation as Anti-Aggregation-Approach
Progression Rate of MSA Under EGCG Supplementation as Anti-Aggregation-Approach
MSA is a rapidly progressive disorder with an average survival time of about 7 years after
 the first clinical manifestation. No potent symptomatic treatment is currently available. A
 disease-modifying therapy does not exist either. The growing understanding in recent years of
 the underlying pathological mechanisms of the disease allows the development of new treatment
 options that have a modifying effect on the disease progression. Therefore, treatments are
 urgently required that effect the central underlying pathological mechanism, which appears to
 be the intracellular aggregation of toxic oligomers of α-synuclein.

 EGCG, a polyphenol found in green tea, has shown to inhibit the formation of toxic
 α-synuclein oligomers in vitro and has shown to transform α-synuclein-oligomers in non-toxic
 oligomer species. There is also evidence for a neuroprotective effect in MPTP-mouse models of
 PD and is an antioxidant and iron chelator. There are currently 63 clinical studies
 (http://clinicaltrial.gov) in which EGCG was applied for various indications, such as
 Multiple Sclerosis, various forms of cancer and Huntington's disease. All of which have shown
 good tolerability and safety with the applied doses of EGCG of up to 1200 mg per day,
 demonstrating the safety of the drug under controlled clinical conditions (see 5.3.1 for
 hepatotoxicity in uncontrolled conditions).

 These data provide a solid rationale for testing in a clinical trial if supplementation of
 EGCG can interfere with the core disease mechanism in MSA and consequently retard the
 clinical progression of the MSA-related disability.
5 Introduction Multiple System Atrophy (MSA) is a slowly progressing neurodegenerative
 disease that is characterized by i) a hypokinetic movement disorder which defines MSA of the
 parkinsonian type (MSA-P) or by ii) cerebellar symptoms which define MSA of the cerebellar
 type (MSA-C). In both types the movement disorder can be accompanied by vegetative symptoms
 such as orthostatic hypotension. In contrast to Parkinson's disease (PD), the effect of
 dopaminergic medication on the parkinsonian symptoms is very limited. In spite of several
 efforts, no disease modifying therapy has been identified so far. Several lines of evidence
 including epidemiological, in vitro, and in vivo data, suggest that Epigallocatechin gallate
 (EGCG) might be able to delay disease progression of MSA by modifying several aspects in the
 pathogenesis of MSA such as protein aggregation, oxidative stress and iron accumulation.
 Therefore, this study is designed to investigate the influence of EGCG on disease progression
 in patients with MSA. To assess the effect on disease progression, clinical evaluation and
 MR-imaging will be applied in a bi-center, prospective, placebo-controlled, double-blind
 randomized phase III trial. The primary outcome measure will be the change in motor symptoms
 from V1 to V7 measured by the UMSARS-ME comparing placebo- vs. verum-treated patients. The
 secondary efficacy endpoint will be the change from V1 to V7 in the total UMSARS score, in
 the CGI score and in MRI parameters (global and regional atrophy / iron deposition) comparing
 placebo- vs. verum-treated patients.

 5.1 Background The disease: MSA is a synucleinopathy that is suitable for various reasons as
 a model disease to investigate disease-modifying effects in α-synuclein (aSyn)-dependent
 neurodegeneration. The disease progression is more rapid compared to PD and therefore allows
 the observation of clinically relevant effects in shorter observation periods. As no potent
 symptomatic treatment of MSA is currently available, the influence of symptomatic active
 substances on clinical data is limited and placebo can be used as comparator. This solves the
 potential ethical problem of having to deprive patients of such symptomatic treatment during
 the study and underlines the high medical need for a symptomatic treatment. Another important
 argument for neuroprotection studies in MSA is that in three independent studies EMSA,
 NNIPPS, MEMSA a very similar disease progression was observed over a defined period of time,
 which enables a precise power analysis with sample sizes and follow-up periods that are
 suitable for an investigator initiated trial (IIT).

 The therapeutic target: An increasing amount of data suggests that toxic oligomers from
 misfolded, disease-specific proteins play a potentially important role in the neuronal cell
 death in neurodegenerative diseases. Specifically in MSA, oligomeric aSyn aggregate species
 appear to be crucially involved in the pathogenetic mechanisms.

 The pharmacological compound: Epidemiological data suggest that ingredients in tea may be
 neuroprotective for synucleinopathies in man. Regular consumption of tea reduces the risk of
 contracting PD by about 50%. Also for MSA, a clear trend in the sense of a positive effect of
 tea consumption on the risk of disease development was observed (OR = 0.5, 95% CI: 0.22-1.5,
 p = 0.09). EGCG, a polyphenol that is for example found in green tea, inhibits the formation
 of toxic aSyn oligomers in vitro and transforms aSyn oligomers by direct interaction in
 alternative, non-toxic oligomer species. Furthermore, EGCG shows a neuroprotective effect in
 the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) mouse model of PD. In addition, EGCG
 is an antioxidant and an iron chelator and therefore has more potential beneficial effects on
 synucleinopathies.

 The pharmacokinetic properties of EGCG were tested in humans in the serum and in rodents in
 serum and organs, including the brain in detail. It was found that repeated oral application
 of doses of EGCG result in a significant increase in serum levels in healthy adults compared
 to a single dose. The proposed daily dose of 1200 mg of EGCG is comparable to about 15 to 30
 cups of green tea (depending on the mode of preparation) (Prof. F. Paul, Berlin, pers.
 comm.). Animal experiments in rodents have shown that after a single i.v. dose of EGCG, the
 substance is found in the brain in significant quantities.

 5.2 Trial Rationale MSA is a rapidly progressive disorder with an average survival time of
 about 7 years after the first clinical manifestation. No potent symptomatic treatment is
 currently available. A disease-modifying therapy does not exist either. The growing
 understanding in recent years of the underlying pathological mechanisms of the disease allows
 the development of new treatment options that have a modifying effect on the disease
 progression. Therefore, treatments are urgently required that effect the central underlying
 pathological mechanism, which appears to be the intracellular aggregation of toxic oligomers
 of aSyn.

 EGCG, a polyphenol found in green tea, has shown to inhibit the formation of toxic aSyn
 oligomers in vitro and has shown to transform aSyn-oligomers in non-toxic oligomer species.
 There is also evidence for a neuroprotective effect in MPTP-mouse models of PD and is an
 antioxidant and iron chelator. There are currently 63 clinical studies in which EGCG was
 applied for various indications, such as Multiple Sclerosis, various forms of cancer and
 Huntington's disease. All of which have shown good tolerability and safety with the applied
 doses of EGCG of up to 1200 mg per day, demonstrating the safety of the drug under controlled
 clinical conditions.

 These data provide a solid rationale for testing in a clinical trial if supplementation of
 EGCG can interfere with the core disease mechanism in MSA and consequently retard the
 clinical progression of the MSA-related disability.

 5.3 Side effects and Risk Benefit Assessment 5.3.1 Side effects In all clinical trials
 investigating the oral intake of green tea/EGCG in various doses and pharmacological forms,
 EGCG has shown a good safety and tolerability in daily doses of up to 1200 mg over a period
 of 6 months. Side effects that have been reported after application of EGCG were usually mild
 and did not occur more often than under placebo (flatulence, headache, nausea, vertigo,
 abdominal cramps and muscle pain). Other reported side effects (arterial hypertension,
 palpitations, headache, polyuria, tremor, sleep disorders, nausea/vomiting) are due to the
 caffeine part in green tea and are not due to EGCG, as all studies using pure EGCG have not
 reported such side effects.

 No relevant or persistent changes in the extensive clinical serum tests have been found so
 far; also no influence on vital parameters have been reported after using EGCG. Only minimal
 and transient changes of the blood pressure, echocardiography, liver function tests and serum
 lipids have been reported. In a study of Chow et al. healthy subjects were given 800 mg EGCG
 or Polyphenon E (a mixture of several green tea extracts with a 50-75%share of EGCG) once
 daily or 400 mg twice daily versus placebo over a period of 4 weeks. Only mild side effects
 occurred in several subjects (flatulence, abdominal pain, nausea, headache, dizziness and
 muscle pain) that were not occurring more often than under placebo.

 The SuniMS study, NCT ID: 00525668, recorded no SUSAR in 120 patients with
 remitting-relapsing MS, who were administered 800 mg Sunphenon/ EGCG per day. They also were
 able to show an excellent tolerability. Only 15 patients showed mild, clinically
 insignificant elevations of liver function tests, which are not necessarily caused by the
 study medication. The ongoing SUPREMES study, NCT ID: 00799, has so far not recorded any
 SUSAR in 60 patients with progressive MS who have been on up to 1200 mg EGCG/day for up to 48
 months.

 In a study by Chen et al a significant protective effect of orally applied EGCG could be
 demonstrated in mice with a toxic liver failure caused by tetrachlorohydrocarbons. Otherwise,
 single cases of hepatotoxicity following application of various forms of green tea
 polyphenols are known. In the period between 1999 and 2008, 34 such case reports have been
 published, 29 of which have shown a positive de-challenge and 7 have shown a positive
 re-challenge. The clinical and pathological symptoms included mild elevations of liver
 function tests, cholestasis, cholangitis, hepatocellular inflammation and hepatocellular
 necrosis. The symptoms were usually completely reversible after stopping the medication. One
 patient died of liver failure. Signs of liver toxicity were recorded between day 9 up to 5
 months after beginning a therapy with doses of 187,5 -468,75mg EGCG/day).

 The withdrawal of a green tea extract in Spain and France (Exolise®) a couple of years ago
 needs to be mentioned. After application of this medication some cases of severe
 hepatotoxicity were reported. Symptoms like icterus, massive elevation of transaminases
 occurred not later than 12 weeks after beginning the treatment with the extract in capsules
 and were completely reversible few weeks after stopping the medication. The exact underlying
 mechanisms have not been completely worked out. Possibly these are due to a SAE that is
 specific for Exolise®, and is connected with the manufacturing process (hydro-alcoholic
 extraction techniques). For this reason, only the distribution of Exolise® has been stopped
 by the respective authorities, but not the distribution of other green tea extracts (see also
 the following publications by the WHO):
 www.who.int/entity/medicines/publications/restrictedpharm2005.pdf It has not yet been found
 out which parts of the polyphenols and their metabolites are responsible for the hepatotoxic
 effects. Even though in most cases mixtures of green tea and polyphenols have been
 administered it is suspected, that EGCG as a main component of the green tea extracts shows
 hepatotoxic potential. In favor of this hypothesis is the fact, that there have been reports
 of elevated transaminases under treatment with EGCG in man and interactions with other
 substances. EGCG is known to bind to α- and β-estrogene receptors and increases 17
 β-estradiol-induced reactions in mice. EGCG is a known inhibitor of the
 Catechol-O-methyltransferase (COMT) that catalyses the degradation of exogenous and
 endogenous substances.

 It is suspected, that for the biotransformation of green tea catechines, COMT plays an
 important role. COMT polymorphisms with low activity of COMT could result in elevated plasma
 levels of toxic EGCG metabolites.

 The cytotoxicity of EGCG in hepatocytes seems to be low in vitro and only doses that are
 higher by a multiple compared to the doses used in clinical studies lead to liver necrosis in
 animal models. Also, the extremely low bioavailability in man has to be considered.

 On the basis of all recent studies using green tea extract and EGCG there are no reports of
 persistent and severe influence on the physiological systems (blood circulation, respiratory
 system, central nervous system and urinary tract). Still there are singular case reports of
 hepatotoxic effects in the context of intake of green tea extracts/ EGCG.

 As a conclusion, all data are in favor of a good tolerability of the substance. For further
 details see the investigator's brochure (Polyphenon E).

 5.3.2 Risk Benefit Assessment The reported data suggest a safe pharmacological profile apart
 from individual cases of hepatotoxicity which can be controlled for by routine serum liver
 parameters. The preclinical data suggest a molecular mode of action for EGCG which appears to
 target core pathological mechanisms active in MSA. In absence of any effective symptomatic,
 protective or curative intervention in this devastating disorder, the risk benefit evaluation
 justifies the conduct of the proposed clinical trial.
Inclusion Criteria:

 1. "clinical possible" or "clinical probable" MSA (Gilman et al., Neurology, 2008
 26;71:670-6)

 2. Hoehn & Yahr stage I - III

 3. A stable regimen for at least 1 month prior to V1 and willingness / no fore-seeable
 need to change the regimen throughout the 52 week follow-up pe-riod for

 1. drugs acting against Parkinsonism (e.g. Levodopa, Dopamine-Agonists, Amantadine
 and MAO-B-Inhibitors)

 2. drugs acting against autonomic dysfunction (e.g. ephedrin, midodrin,
 fludrucortison, octreotide, desmopresin, oxybutinine)

 3. antidepressant and antidementive drugs.

 4. No regular consumption of EGCG, green tea, or more than two cups of black tea per day

 5. Capability and willingness to give written informed consent indicating that the
 subject has been informed of and understood all aspects pertinent to the study

 6. Capability and willingness to comply with the procedures of the study

 7. Contraception by adequate contraceptive methods (oral, injected or im-planted hormonal
 contraceptive methods, intrauterine pessar, sterilisation or real abstinence) in all
 female patients with childbearing potential

 8. Absence of liver disease documented by transaminases and bilirubin below 2-folds of
 the upper normal level.

 Exclusion Criteria:

 1. Hoehn & Yahr stage > III (loss of postural reflexes, no independent walking possible,
 inability to stand unassisted, wheelchair-bound).

 2. Neurodegenerative diseases other than MSA

 3. Severe liver disease with elevation of transaminases and bilirubin above 2-folds of
 the upper normal level or regular intake of hepatotoxic drugs

 4. Known hypersensitivity to EGCG or to drugs with similar chemical structure

 5. Participation in another clinical trial involving administration of an investigational
 medicinal product within 1 month prior to V1

 6. A physical or psychiatric condition, which at the investigator's discretion may put
 the subject at risk, may confound the trial results, or may interfere with the
 subject's participation in this clinical trial

 7. Persistent abuse of medication, drugs or alcohol

 8. Consumption of > 500 ml grapefruit juice per day (leading to inhibition of cytochrome
 P-450 isoenzyme 3A4, which may be involved in degradation of EGCG).

 9. Current or planned pregnancy or breast feeding in females

 10. Females of childbearing potential, who are not using medically reliable methods of
 contraception for the entire study duration (such as oral, inject-able, or implantable
 contraceptives, or intrauterine contraceptive devices).

 11. Intake of COMT-inhibitors (e.g. Entacapone, Tolcapone)

 12. Current or planned therapy with Bortezomib and/ or history of plasmocytoma.

 13. Anemia at Screening (Hb < 10g/dl)

 14. Other severe medical conditions upon discretion of the LKP