March 19, 2013

Fred Hines, Consumer Safety Officer FDA/CFSAN/ONLDS HFS-810 Division of Programs New Dietary Ingredient Review Team Harvey Wiley Building 5100 Paint Branch Parkway College Park, MD 20740

Re: Essence ofYunzhi; 75-day Notice of New Dietary Ingredient (NDJ) Supplemental Materials

Dear Mr. Hines:

In response to the FDA's response letter, dated January 23, 2013, I am providing you additional material to complete the notification which the FDA designated as NDI 785 ( versicolor extract, Trade name: Essence ofYunzhi).

The supplemental materials demonstrate the dosage in this application of l .2g/day is well tolerated and is consistent with the historical use of Yun Zhi. Medicinal are component of many cultures for centuries. Corolious versicolor (a/k/a Trametes versicolor and Yunzhi) is no exception. It has been a component of Traditional Chinese Medicine since the Ming Dynasty. Yun Zhi contains a protein-bound polysaccharide known as PSP, which is extracted by hot water from the 's cultured mycelium

PSP, and its sister complex PSK, have been studied since 1971 and in the US since 1989 at the US National Cancer Institute. Both are the subject of numerous clinical trials and at dosages up to 9g/day in human trials. The NIH concluded in an article published in 2008 that of all of the medicinal mushrooms, Coriolous Versicolor (Yun Zhi) has been studied the "most thoroughly in terms of analysis of active constituents."

The research and historical use demonstrate Yun Zhi is safe for human consumption. l b) (4 ), (b) (6) looks forward to placing the product on the market quickly.

Sincerely, (ll} (4 }, (15) (6)

I Contact In-House Counsel

(o} (4), (o} (6) l l Page HISTORY OF USE YUNZHI (Corio/us versicolor a/k/a Trametes versicolor) Mushroom

Coriolus versicolor was first recorded during the 3 Ming Dynasty of China , and subsequently in a Summary 1965 Japanese report of a patient with stomach cancer who benefited from drinking a tea, Saru­ Mushrooms have been used for at least 5000 no-koshikake, that contained this mushroom. years for nutritional and medicinal purposes.1 Anti-viral and anti-cancer effects have been demonstrated in more than 50 species through Subsequent laboratory and animal research animal and in vitro studies. Six components of identified the source of the tea's anti-tumor 4 these mushrooms have been investigated for effects to be two polysaccharides. their activity in human cancers: the lentinan component of shiitake, schizophyllan, active In 1989, two investigators at the U. S. National hexose correlated compound (AHCC), maitake 5 Cancer Institute (jong and Donovick ) published D-fraction and two components of Coriolus a review of antitumor and antiviral substances versicolor, one of which is the subject of this from fungi including Coriolus versicolor. This NOi submission. review noted seven studies and two U. S. patents issued for polysaccharides extracted According to the review by Kidd, lentinan and from Coriolus versicolor. One extract was a schizophyllan have limited oral bioavailability, polysaccharide-protein (proteoglycan) known as and the AHCC and maitake 0-fractions are still in the early stages of investigation, but the two 3 Cheng, Ket al, General Review of Coriolus versicolor components have been Polysaccharopeptides (PSP) from C. versicolor: extensively investigated and show promise.2 Pharmacological and clinica l studies, Cancer Therapy Vol 6, 117-130 (2008) (citing: Ng TB. A review of research on the protein-bound polysaccharide (polysaccharopeptide, PSP) from the mushroom Coriolus versicolor (Basidiomycetes: ). [Review) (35 refs] . General Pharmacology. 1998 1 Coriolus versicolor Detailed Scientific Review, MD Jan;30(1):1-4). Anderson Cancer Center at the University of Texas, 4 See MD Anderson Cancer Center Id.; See also available at: Kobayashi H, Matsunaga K, Oguchi Y. Antimetastatic http://www.mda nderson .org/ed ucation-and­ effects of PSK (Krestin), a protein-bound research/resources-for-professionals/clinical-tools­ polysaccharide obtained from basidiomycetes: an and-resources/cimer/therapies/herbal-plant­ overview. Cancer Epidemiology, Biomarkers & biologic-therapies/coriolus-versicolor-scientific.html Prevention 1995 Apr-1995 May;4(3):275-81; (citing, Tsukagoshi S, Hashimoto Y, Fujii G, Kobayashi Kobayashi H, Matsun aga K, Fujii M. PSK as a H, Nomoto K, Orita K. Krestin (PSK). Cancer chemopreventive agent. Cancer Epidemiology, Treatment Reviews 1984 Jun;l1(2):131-55); Kidd Biomarkers and Prevention 1993 May-1993 PM. The use of mushroom glucans and Jun;2(3):271-6.; proteoglycans in cancer treatment. [Review] (91 5 see also MD Anderson Cancer Center Id. (citing: refs]. Alternative Medicine Review. 2000 Feb;5(1):4- Jong S-C, Donovick R. Antitumor and antiviral 27. su bstances from fungi. Advances in Applied 2 See Kidd PM Id. ------·-··------·-- -~l~L~~-~9.l~_gy ~~-~~4 : 183 -262) . ··--·-·------··-

Page 1 of 7 polysaccharide Kurcha (PSK or Krestin}, and it development was based off traditional had been found to be effective in the treatment uses of the Chinese herb. of Ehrlich carcinoma and sarcoma 180 tumors in mice. Furthermore, PSK had not exhibited any of the cytotoxicity or other side effects "According to the herbal literature of many commonly seen with conventional anticancer dynasties, YunZhi belongs to a type ofZhi . In 6 treatment • Compendium of Materia Medico (Vol. 28) and Pictures of Collecting Zhi {A.O. 889-896}, there Subsequent laboratory and animal studies have are records of black and green YunZhi. For further defined the antitumor, antimicrobial, thousands of years, Yunlhi has been considered antiviral and immune enhancing properties in to have the effect of supporting health and both PSK and another protein-bound energy and strengthening physique, and polysaccharide known as polysaccharide­ 8 benefiting spirit and vital energy. " protein complex (PSPC or PSP}. Both substances are extracted by hot water from the mushroom's cultured mycelium (thread-like B. The earliest known record of the YunZhi extensions)7. mushroom being used dates to 1368 A.D. during the Ming Dynasty. Ancient References to YunZhi "YunZhi has been Chinese medicine since ancient times. There is a record in the Traditional Chinese medicine safely utilized Compendium of Materia Medico by Li Shi Zhen YunZhi for thousands of years. Reading the of the Ming dynasty: "The black and green historical record one finds references to YunZhi are beneficial to one's spirit and vital prolonged and consistent use of the mushroom energy and strengthen one's tendon and bone. extract in a quantity less than that proposed in If YunZhi is taken for a long time, it will make the NDI as a routine therapy. 9 one vigorous and live long". " The therapy was provided either as a tea or as a dry powder. The references support a history of safe use in human populations. C. The Compendium Medica is interpreted by Traditional Chinese Medicine Practitioners as conveying the benefits A. The YunZhi mushroom was used to described only if taken for an extended produce an essence known as period of time. polysaccharopeptide (PSP}. Its "Old [Traditional Chinese Medicine] practitioners used mushroom color to classify

6 See Id. 7 See Kidd PM Id; See also Ng TB Id.; Sakagami H, 8 Yun Zhi Polysaccharopeptide {PSP) and the General Ta keda M. Diverse biological activity of PSK (Krestin), Aspects of its Research, Yang Q.Y. Dept. of Biol. of a protein-bound polysaccharide from Coriolus Shanghai Teachers University (available at Versicolor (Fr.) Quel.:237-45; see also MD Anderson http://psp-research.com/reviewl.htm#BRM). 9 Cancer Center Id. (citing: Ooi VE, Liu F. A Brief Introduction to Several Chinese Yun Zhi lmmunomodulation and anti-cancer activity of Products, Information Office of the Research polysaccharide-protein complexes. [Review) (179 Institute of Fungi refs]. Current Medicinal Chemistry. 2000 Shanghai Teachers University (available at _JulJ.1?.L?..!:'?.:?.~L. .._ ...... ------·-··· ·· · ··· ·· · ····· ·----· ··· · · · ------~-!!P.:1.1.P..~P.~L~~eax.~!1~.~ !!:!l.P.~.P.~:~.!.~L . ______

Page 2 of 7 zhi, which includes mushrooms with green, red, to treat infection or inflammation of the upper yellow, white, black and purple colors. repository, urinary, and digestive tracts ... " 12 According to TCM's five elements theory, green, F. Other references include a text written red, yellow, white and black zhi mushrooms are on medicinal herbs in the Han Dynasty associated with liver, heart, spleen, lung and around 200 BC and a record in the kidney qi health respectively while purple Compendium of Materia Medica in the mushrooms are related to the health of qi 15th Centrury. essence. Although zhi mushrooms of different colors have different specialized health benefits in the five organs, they all are identified as "Yunlhi (or Yunlhi, which means 'cloud having common general health benefits. If mushroom') was mentioned in the first written taken for an extended period of time, these text on medicinal herbs, Shennong Ben Cao Jing, benefits were described in the Compendium of (around 200 BC - Han Dynasty). There is also a Materia Medico as "keeping our body 'fight' record in the Compendium of Materia Medico (being fit and not too unhealthily heavy or fat), (Ben Cao Gang Mu) by Li Shilhen {15th century preventing (abnormal and unhealthy) aging, - Ming dynasty) ... Teas and decoctions made of and making one live long (healthily and the mushrooms fruiting body were used to 1311 naturally according to life's aging cycle as life is improve general health and vitality. 10 gifted}. " (emphasis added}. G. The use of YunZhi is well documented D. One reference states the traditional and widely used in traditional Chinese administration and dosage of YunZhi medicine. was between 9 and 25 grams. This is H. below the dosage in the Essence of " YunZhi (Trametes versicolor, Fr) and Ling Zhi YunZhi of 1.2grams. were generally called Zhi in ancient times. They "Crude herb for decoction used 9 -27g each were both Chinese traditional medicinal time". 11 materials. Li Shi-zhen in Ming Dynasty classified Zhi into 6 types. Ling Zhi was categorized to red Zhi or violet Zhi and YunZhi to Black Zhi or Blue E. YunZhi is commonly consumed as a tea Zhi..." or dry powder.

For thousands of years, the Chinese mushroom "The therapeutic effectsof Zhi has been verified YunZhi (cloud ) has been considered clinically for thousands of years. In the first beneficial for good health and longevity. Compendium Medic "Shen non Compendium Consumed as a tea or a dried power, it is used

12 PSP - A Powerful Biological Response Modifier from the Mushroom Coriolous Versicolor, Shung­ chang Jong and Xiao-tong Yang, Department of Biology Shanghai Teachers University ((1999} In: 10 Interpretation of the Compendium Materia Yang, Q.Y. International Symposium on Traditional Medico, I'm Yunity* (available at Chinese Medicine and Cancer: Development and http://www.houseofyinyang.com/eng/hoyy/product Clinical Va lidation-Advances research in PSP pp. 16- /product_yun_index.htm). 28, HongKong Association for Health Care Ltd.). 11 Chinese Pharmacopoeia Commission, 13 Brief History of Corio/us Versicolor, Oriveda Pharmacopoeia of the People's Republic of China (available at JY..?J!:l.~.~.!.! !~~-~P. !~:.~-Me.q~~!:~!?.!~~i~~ .!:l.~~~~L 200~:...... - .... !ittf!.:lt.~'!!..:~riveda . c.?..r:i:!LP.~.P.~~-~~.~. !!~:P.!:1.eL.. ____ ......

Page 3 of7 Medico" published at 2000 years ago, Zhi was following an accidental happening. The regarded as a godly medicine. The Compendium neighbor of a pharmaceutical engineer of this Medico concretely described the therapeutic company suffered from late stage gastric cancer effects of Zhi as: invigorating men's vigor and and was rejected by hospital for treatment body fluid and favoring longevity after (sic.). However, after taking the local folk prolonged medication.1411 recipe ... the patient was cured and went to work again ..." (emphasis added). NOTE: Essence of YunZhi does not intended to make the same claims as those made above, but merely Modern References to YunZhi uses the above as evidence of a history of safe consumption.

The YunZhi mushroom extracts modern development and use spans nearly SO years in J. As the National Institute of Health (NIH) Japan, China and across the world. Research notes in its study of YunZhi, it is a indicated there were two closely related common practice among many proteoglycan constituents of YunZhi, naturopathic physicians and integrative polysaccharise-krestin (PSK) and oncologists in the US to "prescribe polysaccharide-peptide (PSP). whole, freeze dried Tv [trametes versicolor] to breast cancer patients." 16 The polypeptides in PSP resemble those of the closely-related proteoglycan PSK, in that they "Three grams per day is the most commonly are enriched w ith aspartic and glutamic acids.15 used dose in natu ropath ic medical practice ... 1117 Although, the claims made by PSK are drug related while the claims by in this application for PSP are only for the "support of a good K. The NIH study used Japan as to model immune system," the development of PSK lead dosage escalation and determine to the extensive study of the safety of ingesting maximum tolerated dose that YunZhi. The overwhelming research on YunZhi demonstrated safety and tolerability. over the past SO years supports the ancient "... the third cohort took 9 grams/day in three known safety of consuming YunZhi. divided doses.. .for six weeks... as high as 9 grams use used in Japan. "18

I. YunZhi extract experiments and consumption began in the 1960s using a L. Clinical studies have administered traditional recipe. various dosages in some studies for up to five (5) and eight (8) years (see Table "[YunZhi] was later developed into an 1 for a summary of some of the clinical anticancer drug by Kureha Company in Japan 16 NIH, "Phase I Clinical Trial ofTrametes versicolor in 14 History, Present Status and Perspectives of the Women with Breast Cancer" ISRN Oncology (2012) Study of Yun Zhi Po/ysaccharopeptide, in "Advanced (citing: L.J. Standish, Ln . Aschuler, A.B. Ready, et al. Research in PSP" (1999). "Botanical Medicine in Integrative Oncology" in 15 Yang Q. Yun Zhi polysaccharopeptide (PSP) Integrated Oncology; D.I. Abrams and A.T. Weil, Eds. and the general aspects of its research. In: . Pp. 104-146, Oxford Unviersity Press, New York, NY Yang Q, ed. Advanced Research in PSP, 1999. USA (2009)). Hong Kong: Hong Kong Association for 17 See NIH Id. _f:!~J~h C~_i:--~-~~9.!..!~2_~ : ?_~_::~~:------~~~-~~--~! -~_!~ ------

Page 4 of 7 studies conducted). The studies have found the dosage well tolerated.

Conclusion

YunZhi is a traditional Chinese herb consumed safety for centuries. In antiquity the Chinese consumed YunZh i medicinally as a tea. The mushroom continues to be used through the East as a traditiona l food, tea, and medicine.

Naturopathic physicians and integrative oncologists also use this traditional Chinese medicine today. The modern development and study of the mushroom and its proteoglycan constituents continues to demonstrate the safe consumption of YunZhi. The product in this submission stands in alignment with traditional Chinese medicine. Providing a safe dosage in capsule form. As can be.seen, the consumption of YunZhi enjoys a long history of safe use.

Page 5 of 7 Reference Dosage Treatment Schedule Number of Patients 19 3g/Day PSP Daily for 3 months so 20 3g/Day PSP Daily for 1 to 2 months 1S1 21 3g/day PSP Daily for 2 months 82 22 3g/Day PSK Daily every other week GS 23 3g/Day PSK Daily for 2 years 3S9 24 Sg PSP Three times a day for 2 months 2S 25 Various PSK 3g/day for 2 months, 2g/day for 24 months, lg/day SS thereafter (up o 8 years) 26 3g/day PSK Daily for 3 years 221 27 3g/day PSK Daily for 2 years 134 28 3g/day PSK Daily for 2 years 20S Animal Trials 29 1-2g/kg/day PSP lS-20 days orally

19 Kidd PM: ''The use of Mushroom Glucans and Proteoglycans in Cancer Treatment" Alternative Med. Rev. 2000;5(1):4-27. 20 See, Chu, K. et al, Coriolus versicolor: A Medicinal Mushroom with Promising lmmunotherapeutic Val ues (citing: Boik J, Cancer and Natural Medicine: A Textbook of Basic Science and Clinical Research. New York: Oregon Medical Press, 1995) Journal of Clinical Pharmacology, 2002;42:976-984 (2002). 21 See, Cheng, Ket al Id. 3 (citing: Torisu M, Hayashi Y, et al (1990) "Significant Prolongation of Disease Free Period Gained by Oral Polysachharide K (PSK) Administration After Curative Surgical Operation of Colorectial Cancer" Cancer lmmunol lmmunother 31, 261-268). 22 See, Chu K. Id. (citing: Suto M, Fukuda S, Moriya N, Watanabe W, Sasaki D, Yoshida Y, "Clinical Study of Biological Response Modifiers as maintenance therapy for Hepatoceullular Carcinoma" Cancer Chemotherpy Pharmacology 1994; 33 (Suppl.) :S145-S 148). 23 Toi M, Hattori T, Akagi M, lnokuchi K, et al, "Randomized Adjuvant Trial to Evaluate the Addition of Tamoxifen and PSK to in Patients with Primary Breast Cancer" Cancer 1992; 70(10):2475-2483. 24 Ebihara K, Minamishima Y (1984), " Positive Effect of Biological Response Modifers on Murine Cytomegalovirus Infection," Journal of Virology 51, 117-122. 25 See, Cheng, Ket al Id. 3 (citing: Mitomi T, et al (1992), "Randomized, Controlled Study on Adjuvant lmmunotherpay with PSK in Curative Resected Colorectal Cancer." The Cooperative Study Group of Surgical Adjuvant lmmunochemotherpahy for Cancer of Colon and Rectum (Kanagawa), Dis. Colon Rectum 35, 123- 30). 26 See, Cheng, Ket al Id. 3 (citing: Ohwada S, Kawate Set al (2003), "Adjuvant Therapy with Protin-Bound Polysaccharide Kand Tegadur/Uracil in Patients with Stage II or Ill Colorectal Cancer: Randomized Control Trial. Dis. Colon Rectum 46, 1060-1068). 27 See, Cheng, Ket al Id. 3( citing: Ohwada S, lkeya T, Yokomori T, et al (2004) "Adjuvant lmmunotherpay with Oral Tegafur/Uracil Plus PSK in Patients with Stage II or Ill Colorectal Cancer: A Randomized Controleed Study. Br J Cancer 90, 1003-1010). 28 See, Cheng, Ket al Id. 3(citing: Ito K, Nakazato H, et al (2004), "Long-term effect of 5-Fluoroacil Enhanced by Intermittent Administration of Polysaccharide K -~_!~_r:_ -~-~-~~!!~-~~~~£!!9_~ _9_f_~~~~~~!.1-~~~'._~- ~~-~9orr:iJ~~~-~.?.~!.?.!!~!!. !~~!.!9!.!.:.'!_~~!. .~~!!.?.~~-~2.:. !!2~:.!.-_~9_{9!..f!.~t_q!_P._[s 1~! ..!~7 :!.~~J:______

Page 6 of7 30 SOmg/kg/day PSP Daily for 3 weeks Intra peritoneal 31 150mg/kg Twice a week

29 See, Cheng, Ket al Id. 3{citing: Zeng SJ et al (1993), ''The Anticancerous Effects of Yun Zhi essence on Human Lung Adenocarinoma Inoculated in Nude Mice" in Proceedings of PSP international Symposium. Shanghai, China: Fudan Unversity Press, 1993; 97-103). 30 See, Cheng, Ket al Id. 3{citing: Wang CA, Ma Al et al (1993), "The Effectof Yun Zhi Essence and Schizophyllan in Activating the Lumphocytes of the Peripheral Blood to Kill Stomach Liver and Lung Cancerous Cells and Leukocytes" in: Preceedings of PSP International Symposium, Fundan University Press, pp. 139-142). 31 See, Cheng, Ket al Id. 3(citing: Fujii T, Sadito K (1995), "Prolonation of the Survival Period w ith the Biological Response Modifier PSK in Rate Bearing N- ~~.!~Y!~~.:~-~~~~~~~~:!~9uc~~-~~-~m~!Y.-~~-~'!:.~'.!1..9rs. In ~!:.? 9~.?.~.:.?.ZL ______

Page 7 of 7 Reasonable Expectation of Safety YUNZHI (Corio/us versicolor a/k/a Trametes versicolor) Mushroom

Summary Toxicological Assessment on Food Safety Acute Toxicity Test (GB 151193.3-94).

Clinical studies involving human subjects consuming various doses of Coriolus versicolor B. Long-Term Toxicity extract extend back forty-years. The studies appear in numerous well-respected, peer­ reviewed, scientific journals. A summary of the Researchers examined sub-chronic and chronic safety results and clinical studies are included toxicity of YunZhi. The researchers below to demonstrate a reasonable expectation continuously administered four (4) oral does (0, of safety. 1.5, 30, and 6.0 mg/kg) to 80 rats for 62 days.2 The results showed no toxic symptoms or It is important to note these studies are used death.3 The rats also showed no obvious signs of only to demonstrate the safety of consuming toxic changes in blood and serum biochemistry.4 doses equal to or greater than the ingredient in this submission. They are not intended, nor will be used, for any claims. The Essence of YunZhi Rats and monkeys were also administered with will limit its claims merely to immunity support PSP by oral dose at higher levels in another claims, not' cancer claims. study. The dose administered was 200 and 100 times the normal human dose.5 It was administered daily for six months. 6 The study Safety Studies observed no abnormal changes in development, hematology, blood chemistry or The toxicological experiments conducted with a electrocardiography. variety of animals have shown negative results for acute, genetic, reproductive and chronic toxicity. Kong Association for Health Care Ltd. Pp. 76-79 (1999) and Ze ZbB, Li CW, Han CT, Huo GB, A. Acute Toxicity Polysaccharopeptide Research Progress: Shandong The LDso value of PSP is 26-300.36mglkg for Yiyao Gongye 23, 30-31 (2003)). 2 mice administered by intraperitoneous injection. See, Cheng, Ket al Id. (citing: Jian XZ, Huang LM, The highest daily tolerant does was over 18- Zhou Y F, Wang MM, Subchornic toxicity test of 20glkg for mice. 1 PSP is considered to be non­ polysaccaropeptide of Yun Zhi (PSP), in Yang, Q.Y. toxic according to the Procedures for International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation -Advances Research in PSP. Hong Kong 1 Cheng, Ket al, General Review of Association for Health Care Ltd. Pp. 272-284 (1999)). Polysaccharopeptides (PSP) from C. versicolor: 3See id. Pharmacological and clinical studies, Cancer Therapy 4 See id. Vol 6, 117-130 (2008) (citing: Jin TY, Toxicological 5 See, Cheng, Ket al Id. (citing: Zou, QG, Zhu L, Wang research on Yun Zhi polyschaccharopeptide (PSP), in W. Xiang BR Research Advance of Yan, Q.T. International Symposium on Traditional Polysaccharopeptides, Chinese Traditional Patent Chinese Medicine and Cancer: Development and Medicine 24, 578-80 (2003)). _Clinical Validat i o~-~dvances __~ -~ea!:.~.h in PSP. -~-~~---· -·----~~~~..!~!:---·-·--·--·------

Page 1 of4 C. Genetic Toxicity in mice. 12 This lead the study to conclude PSP safe during pregnancy. Mutagenicity of PSP was assessed with the Ames test and with the chromosomal aberration test of bone marrow cells in Mice. The test Clinical Studies concluded that PSP showed no evidence of mutagenic or cytogenetic activity. 7 A. Human Trials of PSP and PSK Cytotoxicity tests for PSP with V79 Chinese hamster cells in vitro also showed no toxic effects against the V79 cell line.8 Additionally, PSK has been associated with side effects of 13 Jn vivo micronucleus tests were conducted to gastrointestinal upset and darkening of the assess the cytogenotoxicity on mammalian fingernails, but these effects have been limited somatic cells.9 The results indicated PSP showed and general safety has been demonstrated w ith no evidence of mutagenic potential. daily oral doses for extended periods of time.14 The results of chromosomal aberration tests and It does not seem to interact with hepatic drug­ cytogenetic lesions in mice showed that the metabolizing enzymes involved in the chemical 1 number of chromosomes had not changed in processing of most chemotherapy agents s, and PSP treated groups, even groups receiving the no genetic damage has been detected by the 16 high dose rate of 126 mg/kg. 10 Ames test.

At doses that produced necrotic changes in D. Reproductive Toxicity Tests tumor cells, PSP produced no lesions in the vital organs of tumor-bearing mice after treatment The possible effects on male and female for two months. It has not been associated reproductive physiology and embryonic teratogenic effects in mice or rats.17 development were also examined in clinical studies. Results from these studies suggested that PSP could not cause sperm aberration at a 12 See, Cheng, Ket al Id (citing: Ng TB, Wang HX, Liu dosage I 00 times higher than the usual clinical 11 F, Ho JCK, Liu WK, Polysaccharopeptide (PSP) from dosage. Another study foud no deleterious mycelia of the mushroom Coriolus versicolor possess effects on ovarian follicular development, analgesic activity but does not produce adverse ovulation, pregnancy and embryo development effects on female reproductive or embryonic development in mice, Gen Pharmacol 29, 269-273). 7 Zhong BZ, Zhou VG, Zhou LG, Genetic t oxicity test 13 Kobayash i H, Matsunaga K, Fujii M. PSK as a of Yun Zhi polysaccharopeptide (PSP) in Yang QY chemopreventive agent. Cancer Epidemiology, (ed), International Symposium on Traditional Biomarkers and Prevention 1993 May-1993 Chinese Medicine and Cancer: Development and Jun;2(3):271-6. Clinical validation -Advances Research in PSP. Hong 14 Kidd PM. The use of mushroom glucans and Kong Association for Health Care Ltd. Pp. 285-94. proteoglycans in cancer treatment. [Review] (91 8 See id. Zhong. refs]. Alternative Medicine Review. 2000 Feb;5(1):4- 9 See id. 27. 10 See id. 15 Fisher M, Yang L-X. Anticancer effects and 11 See, Cheng, Ket al Id. (citing: Qian ZB, Zhou LF, mechanisms of polysaccharide-K (PSK): implications Zhang ZD, Xu B, Xin PJ, Zhou LY, Chen RT, Li ZG, The of . Anticancer Research Test of PSP on the Cause of Abnormal Fetus in Two 2002;22:1737-54. 16 Generations of Rates in: Yang QY and C. Kwk (eds), See Kobayashi H, Matsunaga K, Fujii M Id. Proceedings of PSP International Symposium, 17 See, Cheng, Ket al Id (citing: Ng TB. A review of ~~.~nghai , C hin~J~~~-r.:!- ~ nive_:_~i ty _~~~-~.~.. P.P. : }..?.~ ~-?.~_L __ research on the pr~te in-b ou n d polysacch~!~~-~·------

Page 2 of 4 It also concluded oral administration of Trametes versicolor as safe. B. NIH Safety and Tolerability "Findings from this study establish the safety of Study (2012) oral administration ofTrametes vesrcilor (J'v) preparation at 3, 6 and 9 ~am doses with no serious adverse events ... " 1

A Multi-Year study funded by the National Institutes of Health undertook as its "primary objective" evaluating the "safety and tolerability C. Blind Randomized Controlled of Trametes versicolor." 18 Trial The study administered 3, 6 and 9 gram doses over six weeks. All dosages administered are Tsang KW, Lam CL, Yan C, Mak JC, Ooi GC, Ho above the 1.2 gram recommended for the JC, et al. Coriolus versicolor polysaccharide Essence ofYunZhi product. peptide slows progression of advanced non­ "Women between the ages of21 and75 small cell lung cancer. Respir Med 2003 years ... were enrolled in the study. A standard Jun;97(6):618-24. phase 1 design was used with 3 subjects per dose level until the MI'D (maximum tolerated dose) is reached. Dose escalation schedule for Pu rpose: Survival and disease response; each cohort ... was a 3gm (the most commonly immune system outcomes used dose); 6 gm; 9 gm; 12 gm; 18 gm; 24 Type of Study: Randomized controlled trial, gm . .,19 double blinded Methods: (Lung) Sixty-eight patients (out of an The study found all dosages well tolerated. unknown eligible number) with advanced and inoperable non-small cell lung cancer (NSCLC) who had a Karnofsky performance scale 60, life "Findings from this dose escalation study expectancy of 12 weeks or greater and TNM showed that up to 9 grams/day of Tv [Trametes stage Ill or IV with at least one measurable versicolor} preparation was well tolerated.. .for lesion were recruited into the study. Previous six weeks .. .All three doses were well radiotherapy and chemotherapy was permitted tolerated.. . Ofnote is that neither nausea nor GI upset was reported; two side effects were if it was completed at least four weeks prior to reported in previous clinical trials ofo ther Tv the study. Patients were randomly assigned to extracts. "20 receive either polysaccharide peptides (PSP) (n=34) or placebo (n=34) three times daily for four weeks. Clinical and laboratory evaluations were performed on patients at baseline and four weeks to evaluate the effect of PSP on (polysaccharopeptide, PSP) from the mushroom NSCLC-specific morbidity and the safety profile Coriolus versicolor (Basidiomycetes: Polyporaceae). [Review] [35 refs]. General Pharmacology. 1998 of this preparation. Both the patients and Jan;30(1):1-4). evaluators were blinded to the treatment. 18 "Phase 1 Clinical Trial of Trametes Versicolor in Patients were required to have a minimum of Women with Breast Cancer," Carolyn T. Jackson et. two weeks treatment to be evaluable for al, ISRN OncologyVolume 2012 (2012), Article ID response. 251632 19 See Id. 20 See Id. 21 See Id.

Page 3 of 4 Results: The two groups did not differ at colorectal cancer have been published, baseline with respect to previous treatment, including one meta-analysis in 1,094 colorectal performance scale or TNM staging, although cancer patients, all showing a positive impact 23 PSP patients were significantly older than on clinical outcomes. control patients. All patients had 100% compliance with treatment. There was a Time does not permit a full discussion of each significant increase in the level of lgG and lgM study, but the research on Tv lead the NIH to after four-week treatment with PSP (p=.002 and conclude: .01), but not with placebo (p=.57 and .31). Total leukocyte and neutrophil counts increased significantly after PSP (p=.003 and .005), but "Of all of the medicinal decreased significantly after placebo treatment mushrooms, Tv has been studied the most (p=.006 and .01}. Body mass index was not thoroughly in terms of analysis ofactive found to be sign ificantly different between constituents. "2 4 treatment groups. A significant increase in percent body fat content after PSP (p=.02) was Based on the extensive study of YunZhi there is found, but not after placebo (p>.05); however, ample basis to expect it is safe for human the PSP group had a lower percent body fat at consumption. the beginning of treatment. Hemoglobin levels rose after the four-week treatment with PSP, but this was not statistically significant. Tumor response was evaluated on 58 patients who attended reassessment at four weeks and none of the patients in either group were found to have complete or partial clinical response. Significantly less PSP patients were withdrawn from the study, compared with the placebo group, due to disease progression (5.9% and 23.5% respectively; p=.04). Adverse Events: No patients reported any adverse reactions to either placebo or PSP.

D. Conclusion

There have been many peer-reviewed publications on YunZhi (Trametes versicolor). In 2008, the NIH found 37 in vitro articles, 55 animal studies, 43 published human clinical studies, and 11 review articles in gastrointestinal, breast, and lung cancer.22 It further found, five Krestin (PSK) trials in

22Leanna J. Standish, et. al "Trametes versicolor 23 Mushroom Immune Therapy in Breast Cancer", J Soc See Id. 24 J~!~_

Page 4 of 4 December 20, 2012

Division of Dietary Supplement Progr:ims Office of Nutrition, Labeling, and Dietary Supplements (HFS-8 JO) Center for Food Safety and Applied Nutrition Food and Drug Administration 5100 Paint Branch Parkway College Park, MD, 20740-3835 Telephone Number: (240) 402-2375

Re: ;Essene~ of Yun_zhi; 75~ _Noti~ of ~~~Di eta n0_ngredient (NDI)

Dear Sir or Madam:

(b) (4), (b) (6) is the authorizi.:d US (b) (4), (b) (6) Pursuant to 21 CFR § 190.6 the Distributor proxides the attached 75-day no tice of its intent to market and distribute in the US its product "Essence ofYunzhi" which contains the NDI myceJium from the Trametes Versicolor, a/k/a Coriolus versicolor.

~~~--/-~--S~inc er.eJv~-~ (b) (4), (b) (6)

Contract In-House Counsel (b) (4), (b) (6)

(b) (4 ), (b) (6) 75-Day Notification ofNDI

Distributor: (b) (4), (b) (6)

Manufacturer

PNP Pharmaceuticals Inc. 110-3728 North Fraser Way, Burnaby B.C. Canada VSJ SO I 604.435.6200 · 1: ,_ ~-..: ~ u ~ · :.. .2 :<:.l ~

Nome of Ingredient:

Binomial Name: Trametes versicolor (L.) Lloyd (1920)

Synonyms: Coriolus versicolor (L.) Quel. (1886) Boletus versicolor L. ( 1753) Polyporus versicolor (L.) fr. ( 1821)

Common Name: Yun Zhi (Traditional Chinese Medicine) Turkey Tail

Description of Supplement:

Each ingestible cnpsule contains 100-mg polysaccharidc peptide (PSP) extracted from the rnycelum strain of the C. Ve1 sicolor mushroom. The capsule is taken or<1lly three (3) limes a day. It is recommended to improve the immune system of the human body and to elevate the body's se11: healing ability. /\duhs and children ages 12 and over are recommended to take three (3) capsules orally per day (sec attached label).

C. Versicolur is generally considered safe for human consumption, irrespective of age and gender. However, the use ofC. Versicolor may be contraindicated in patients recovering from an organ transplant or receiving a bone marrow transplant

Reasonable Expectation of Safety: Then: is a reasonable basis to expect safety from the consumphon of J 200mg of PSP extracted from the C. Verslcolor mushroom. As discussed below rhcre arc no adverse e(focts from human consumption and no clearly defined drug interactions. The basis of lhis expectatioo arises from 11 multiycar srudy by the NAtuonal lnstituttl of Health (NIH) as well a.s other scholarship.

In a mu!tiyear srudy funded by the NIH and conducted by the University of Minno10111 Medical School nnd Dascyr University Research lnsritute researchers found no adverse elT~ ts from ingi:sti1 1g Trv.meto:s versicolor a/kJa Coriolous versicolor. 111e study titled "Phase I Clinical Trials ofTrametes versicolor in Women with Breast Cancer" found evidence that Trametes venicolr. which is the idL-ntie11l botanical ingredient used in Essence ofYunzhi, was "well tolerated" (see attached Study /\bsl11lct),

The ~tudy utilized a considerably higher dosage and found no bll$is to question T. versicolor's safety. lo it$ Adverse Event reporting the study, which p;oviclcd pnticnts !>-grams T. ver~icolor in capsule fonn to ingMt orally ( 900mg/dny, or 7.Sx. the l.2-grain, 1,200-mg, dose recommended 011 the label of the E~scncc of Yunzhi) found "all three doses were well IQ ler~tcd " and ''neither nausea nor GI upset was rep011td" This study provides a reasonable basis to c.~pect this new dietary iogredi~nt is Slife. Thu srutly's phase I article is auached 10 chi~ Notification.

There is no sut>,.bntive difference between the T. vesicolor insC3ted by patients the NIH study and the proposed iogJedicnt in this Notification. The only difference lies in the clt1Jms mlde by each product. The Esse1Jce of Yunihi mtlles no claims related to cancer, only claims concerning the ingredients immune stimulant propenics generally.

The scientific hrecarure also supports the wety of T. vesicolor. For eumple. in an article ntled KCoriolus venicolor: A Medicinal Mushroom wi!h Promisini: lmmunotherapeutic Values" in the Journal o/Uinica/ PJrormacology, discussed the effect of mice ingesting 18 grams, or JSOOmg, ofC Versicolor over a three month period. The researchers found lhe mice eithibitcd "No death, tox1e symptoms, or obvious h1:metological and pathohistological changes were observed aOcr t 3·month dosing period.. (sec 01111cbed an.icle pg. 982). The researchers also found no clearly defined drug interaction for C. Versicolor (see pg. 9). The article cautioned that as an effective stimulanr of vnrious immune competent cells, C. Vcrsicolor CJIO potentially counteract the effect of any co-aeminisrcred imrnuno-supprcssonl, such as may be the case for a patien1 recieving a bone mWTow or organ 1ranspl3llt

Then: is llll1ple evidence from the scientific community that demonstra.tes ingesting Cnv-1 mycel111n srroin of the C. Versicolor mushroom ("Essence of Yunz.hi") is Sllfe. Therefore, we ask that the FDA approve this new dietary ingredienl.

Slgnnlure: (b) (4), (b) (6) . , .. '.:I;-... 'l'• .. Fr~-V.J: ;.,: so,- • .,. ~ n,t.•_ ,·r. r. ~· ~-.MM PhJm'laceut/ca/s

Def:ember, 2012

To Whom It May Concern:

This Is to confirm thatc(lj) (4) (.b}:(.6) ------·· In accordance with the current good manufacturing practices (GM P's) and standards set forth by Health Canada and the Natural Health Products Directorate.

This product contains the following formulation.

(D) (4)

Dr. Dennis Thneah, ~ffe- Vlce-Presldent PNP Pharmaceuticals Inc•

• GMP !~~ (b) (4) (b) (4) (b) (4) (b) (4) (b) (4) PROPOSED LABELING