PAPILOCARE HCP BOOKLET 2025

Now stand up to HPV

DON'T WAIT. TAKE ACTION Proven ecacy in randomised, controlled clinical trials in women with cervical lesions ◊ caused by high-risk HPV 1,2

CLINICAL SUPERIORITY vs spontaneous clearance 1,2

Available in 55 countries

More than 750,000 women treated with Papilocare®

◊ Low-grade lesions / 1. Serrano L. et al. Ecacy of a Coriolus versicolor-based vaginal gel in women withhuman Papillomavirus-dependent cervical lesions: The PALOMA Study. J Low Genit Tract Dis 2021;25:130-136. doi:10.1097/LGT.0000000000000596. 2. Centeno C, Coll M, Fiol G, López B, Riera M, Valenzuela O, Sanmartín P. Ecacy of a multi-ingredient Coriolus versicolor-based vaginal gel on High-risk HPV clearance: preliminary results from the PALOMA 2 clinical trial. [Oral Communication].10th Congress of the European Federation for Colposcopy Riga, September 18-21, 2024.

CHANGE IN THE APPROACH TO HPV MANAGEMENT

New global change in cervical cancer screening established by WHO and recommended in the main cervical cancer guidelines for cervical cancer prevention. 1,2

HPV Test

Cytology

What does this mean?

Normalisation of cervical lesions

HPV clearance

How many patients clear HR-HPV at 6 months spontaneously?

29 % 9 %

of patients with HR-HPV clear the infection spontaneously at 6 months 3

of patients with HPV 16+ clear the infection spontaneously at 6 months 3

1. Cervical cancer screening for individualsat average risk: 2020 guideline update from theAmerican CancerSociety- Fontham- 2020 - CA: A CancerJournal for Clinicians- Wiley Online Library 2.9789240014107-eng.pdf (who.int) 3.Bulkmans, N W J et al. “High-risk HPV type-specic clearance rates in cervical screening.” British journal of cancer vol. 96,9 1419-24 (2007).

NEW RESULTS IN VIRAL CLEARANCE 1

CLINICAL TRIAL

NCT 04199078

RANDOMISED, MULTICENTRE, PROSPECTIVE, OPENLABEL, CONTROLLED CLINICAL TRIAL WITH ROUTINE CLINICAL PRACTICE AT 6 MONTHS

HR-HPV (16-18-31)

HR-HPV

Papilocare® group

N=1 2 4

DON'T WAIT 24 MONTHS. TAKE ACTION NOW.

Clearance at 6 months in HPV 16,18 and 31 population

Clearance at 6 months in HR-HPV population

100 90 80 70 60 50 40 30 20 10 0

93.3%

88.5%

46.4%

30.8%

Control

Papilocare® Intensive regimen

p=0.0011

Control

Papilocare® Intensive regimen

Control

Papilocare® Intensive Regimen: 3 months 1 cannula per day + 3 months 1 cannula every other day

1. Riera M; Fiol G; Valenzuela O ; Centeno C; Lopez B; Coll M.Ecacy of a multi-ingredient Coriolus versicolor-based vaginal gel on High-risk HPV Clearance: Preliminary results from the Paloma 2 Clinical Trial [Poster Viewing #1919] International Papillomavirus Conference (IPVC). Edinburgh 2024

NEW RESULTS IN VIRAL CLEARANCE 1 : INTENSIVE REGIMEN

CLINICAL TRIAL

NCT 04002154

NCT 04199078

265 randomised patients

HR-HPV clearance at 6 months Pool Paloma 1 and Paloma 2

HPV clearance 16-18-31 at 6 months Pool Paloma 1 and Paloma 2

Control

Papilocare® Intensive regimen

Control

Papilocare® Intensive regimen

p=0.0024

p=0.0328

Papilocare® Intensive Regimen: 3 months 1 cannula per day + 3 months 1 cannula every other day

Control

1. Serrano L, Palacios S, Dexeus D, Coronado P, López Fernández JA, Cortés J, Riera M; Fiol G; Valenzuela O; Centeno C; Lopez B; Coll m. Ecacy of intensive regimen of a multi-ingredient Coriolus versicolor-based vaginal gel in HR-HPV clearance: preliminary pooled results from the Paloma 1 and Paloma 2 CTs.

EFFICACY OF PAPILOCARE® VAGINAL GEL IN CLEARING HRHPV IN 6 MONTHS IN OVER 1,000 PATIENTS 17

PAPILOCARE® INTENSIVE REGIMEN** 3+3

PAPILOCARE® STANDARD REGIMEN* 1+5

NEW RESULTS

88%

***

72%

42%

*** 58%

67%

63%

57%

46%

n= 97 p<0.0001 vs control

n=124 p=0.0011 vs control

n=183 p<0.0001 vs baseline

n=86 p<0.0001 vs baseline

n=91 p=0.0767 vs control

n=192

Papilocare ®

Control

A CORUÑA HOSPITALET DE LLOBREGAT

ROMA

OBSERVATIONAL STUDY

CLINICAL TRIAL

NCT 04002154

NCT 04199260

NCT 04199078

*Standard regimen: 1 MONTH + 5 MONTHS 1 cannula per day for 1 MONTH + 1 cannula every other day for 5 MONTHS

**Intensive regimen: 3 MONTHS + 3 MONTHS 1 cannula per day for 3 MONTHS + 1 cannula every other day for 3 MONTHS

1. Serrano, Luis et al. “Ecacy of a Coriolus versicolor-Based Vaginal Gel in Women With Human Papillomavirus-Dependent Cervical Lesions: The PALOMA Study.” Journal of lower genital tract disease vol. 25,2 (2021): 130-136. 2. Cortés Bordoy, Javier et al. “Eect of a Multi-Ingredient Coriolus-versicolor-Based Vaginal Gel in Women with HPV-Dependent Cervical Lesions: The Papilobs Real-Life Prospective Study.” Cancers vol. 15,15 3863. 29 Jul. 2023. 3. Criscuolo, Anna Angela et al. “Therapeutic Ecacy of a Coriolus versicolor-Based Vaginal Gel in Women with Cervical Uterine High-Risk HPV Infection: A Retrospective Observational Study.” Advances in therapy vol. 38,2 (2021): 1202-1211. 4. Riera Blasco MR, Rupérez Pérez B, Lázaro Vicario I, Felgueroso A, Fontanet Pérez E, Aguayo Alba A. Coriolus versicolor and treatment of high-risk HPV. [Abstract-Oral Presentation]. J Low Genit Tract Dis. 2018 April; 22(2S):S9. 5. Gajino C. Use and results of a Coriolus versicolor-based vaginal gel in women HPV+ and/or abnormal pap smear attended in a regional spanish hospital. Preliminary analysis. [Abstract- 00097]. European Research Organization on Genital Infection and Neoplasia (EUROGIN). Lisbon, December 2-5, 2018. 6. Valasoulis G1, Michail G2, Chatzistamatiou K3, Pappa K4, Tsabazis N5, Athanasiou A6, et al. CLINICAL EVALUATION OF MULTI-INGREDIENT CORIOLUS-VERSICOLOR-BASED VAGINAL GEL APPLICATION IN GREEK WOMEN WITH HPV-INDUCED CERVICAL LESIONS– REAL WORLD DATA FROM PAPILOBS GR STUDY. [Poster Presentation] International Papillomavirus Conference (IPVC). Edinburgh 2024 7.Centeno C, Coll M, Fiol G, López B, Riera M, Valenzuela O, Sanmartín P. Ecacy of a multi-ingredient Coriolus versicolor-based vaginal gel on High-risk HPV clearance: preliminary results from the PALOMA 2 clinical trial. [Oral Communication].10th Congress of the European Federation for Colposcopy Riga, September 18-21, 2024.

REPAIR OF CERVICAL LESIONS ◊ + VIRAL CLEARANCE AT 6 MONTHS WITH INTENSIVE REGIMEN 1

CLINICAL TRIAL

NCT 04199078

HR-HPV+ patients with low-grade lesions

HR-HPV+ patients 16,18 and 31 with low-grade lesions

100 90 80 70 60 50 40 30 20 10 0

93.9%

84.6%

46.4%

30.8%

Control

Papilocare®

Control

Papilocare®

n=109 p=0.0033

n=56 p= 0.0011

Papilocare® Intensive Regimen: 3 months 1 cannula per day + 3 months 1 cannula every other day

Control

◊ Low grade cervical lesions ASCUS/LSIL

1. Centeno C, Coll M, Fiol G, López B, Riera M, Valenzuela O, Sanmartín P. Ecacy of a multi-ingredient Coriolus versicolor-based vaginal gel on High-risk HPV clearance: preliminary results from the PALOMA 2 clinical trial. [Oral Communication].10th Congress of the European Federation for Colposcopy Riga, September 18-21, 2024.

HRHPV PERSISTENCE IS A NECESSARY CONDITION TO DEVELOP HIGH GRADE LESIONS 1

Viral persistence 2,3

1020% 21%

LSIL

HPV+

HSIL

48% 35%

Modiable factors associated with clearance and regression of HPV-dependent lesions

Balance of the vaginal microbiota 6

Local immune response 7

Lifestyle 8

Reepithelialisation of the cervical transformation zone 4,5

1. Koshiol, Jill et al. “Persistent human papillomavirus infection and cervical neoplasia: a systematic review and meta-analysis.” American journal of epidemiology vol. 168,2 (2008): 123-37. doi:10.1093/aje/kwn036 2. Stanley, Margaret.“Pathology and epidemiology of HPV infection in females.”Gynecologic oncology vol. 117,2 Suppl (2010): S5-10. doi:10.1016/j.ygyno.2010.01.024 3.Melnikow, J et al. “Natural history of cervical squamous intraepithelial lesions: a meta-analysis.” Obstetrics and gynecology vol. 92,4 Pt 2 (1998): 727-35. doi:10.1016/s0029-7844(98)00245-2 4. Chow, Louise T et al. “The natural history of human papillomavirus infections of the mucosal epithelia.” APMIS: acta pathologica, microbiologica, et immunologica Scandinavica vol. 118,6-7 (2010): 422-49. doi:10.1111/j.1600-0463.2010.02625.x 5. Mirkovic, Jelena et al. “Carcinogenic HPV infection in the cervical squamo-columnar junction.” The Journal of pathology vol. 236,3 (2015): 265-71. doi:10.1002/path.4533 6. Mitra, A et al. “Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity.” Scientic reports vol. 5 16865. 17 Nov. 2015, doi:10.1038/srep16865 7. Stensen, Signe et al. “Factors associated with type-specic persistence of high-risk human papillomavirus infection: A population-based study.”International journal of cancer vol. 138,2 (2016): 361-8. doi:10.1002/ijc.29719 8. Giuliano, Anna R et al. “Clearance of oncogenic human papillomavirus (HPV) infection: eect of smoking (United States).”Cancer causes & control : CCC vol. 13,9 (2002): 839-46. doi:10.1023/a:1020668232219

SPECIFICALLY DESIGNED TO ACTIVATE THE THREE MODIFIABLE HPV CLEARANCE FACTORS

Reepithelialisation of the cervical transformation zone 1

Rebalances the vaginal microbiota 2

62%

Lactobacillus crispatus Gardnerella vaginalis

Reepithelialisation reduces HPV integration

HYALURONIC ACID

ß-GLUCAN

HPV clearance is correlated with a higher amount of Lactobacillus

UNIQUE COMBINATION FOR A SYNERGISTIC ACTION

CENTELLA ASIATICA

BIOECOLIA®

ALOE VERA

NEEM

CORIOLUS VERSICOLOR

HPV creates a non-inflammatory environment that makes detection by the immune system difficult.

Counterbalance the non-inflammatory microenvironment 3

NIOSOMES AND PHYTOSOMES: THE LATEST ENCAPSULATION TECHNOLOGY FOR AN IMPROVED AVAILABILITY & RELEASE INTO TARGET CELLS

HYALURONIC ACID

ß-GLUCAN

CENTELLA ASIATICA

1. Palacios S, et al. Benecial eects of a Coriolus versicolor-based vaginal gel on cervical epithelization, vaginal microbiota and vaginal health: a pilot study in asymptomatic women. BMC Women’s Health. 2017; 17(1):21. doi: 10.1186/s12905-017-0374-2. 2. Gonzalez S, et al. Eect of a Coriolus versicolor based vaginal gel on cervical epithelialization and vaginal microbiota in HPV-positive women: EPICERVIX pilot study. Academic Journal of Health Science. 2022/37 (2):139-145. doi:10.3306/ AJHS.2022.37.02.139. 3. Kenyon J. Mycoloy News 2003 Observational Non-Controlled Study of the Use of Coriolus versicolor. Supplementation in 30 Cancer patients. Mycology News. 7 (1):1-10. 2003. * vs 35% in control group; p= 0.017

VIRAL GENOTYPE IS A NONMODIFIABLE FACTOR THAT IMPACTS THE PROGRESSION OF LESIONS 1

1 in 4 HPV 16+ patients with low grade lesions will progress to CIN 2 immediately 1

1 in 3 HPV 16+ patients with low grade lesions will progress to CIN 2 in 5 years 1

Papilocare® rst treatment with clinical superiority in lesion regression at 6 months in HR-HPV+ patients 2,3

OBSERVATIONAL STUDY

CLINICAL TRIAL

NCT 04002154

Regression of cervical lesions ◊ at 3, 6 and 12 months 2,3

200

100 90 80 70 60 50 40 30 20 10 0

150

88%

179

80%

100

52%

56%

14*

VISIT 1 (BASELINE)

VISIT 2 (6 MONTHS)

GLOBAL (12 MONTHS)

3 months n=69 p=0.0168

n=66 p=0.0034

6 months

1.Demarco M, Egemen D, Raine-Bennett TR, et al. A study of partial human papillomavirus genotyping in support of the 2019 ASCCP risk-based management consensus guidelines. J Low Genit Tract Dis 2020;24:144–7. 2. Serrano, Luis et al. “Ecacy of a Coriolus versicolor-Based Vaginal Gel in Women With Human Papillomavirus-Dependent Cervical Lesions: The PALOMA Study.” Journal of lower genital tract disease vol. 25,2 (2021): 130-136. doi:10.1097/LGT.0000000000000596 3.Cortés Bordoy, Javier et al. “Eect of a Multi-Ingredient Coriolus-versicolor-Based Vaginal Gel in Women with HPV-Dependent Cervical Lesions: The Papilobs Real-Life Prospective Study.” Cancers vol. 15,15 3863. 29 Jul. 2023, doi:10.3390/cancers15153863

Papilocare® rst treatment with clinical superiority vs. spontaneous clearance in HPV+ patients over 40 with cervical lesions ◊2, 3 AGE IS AN INDEPENDENT FACTOR THAT INFLUENCES LESION PROGRESSION

Normalisation of lesions in women HPV+ and over 40 years old 2

CLINICAL TRIAL

100%

p=0.007

p=0.003

NCT 04002154

90%

80%

92% (n=24/26)

90% (n=19/21)

70%

Subanalysis over 40

60%

50%

40%

(n=6/12)

30%

33%

20%

(n=3/9)

10%

Control group

Papilocare® group

Total population

High-risk HPV subpopulation

n=38

n=30

HPV+ clearance

Regression of cervical lesions ◊ in HPV+ patients

OBSERVATIONAL STUDY

NCT 04002154

HPV+ patients over 40 years old 3

VISIT 1 (Baseline)

VISIT 2 6 MONTHS

VISIT 1 (Baseline)

VISIT 2 6 MONTHS

1. Bekos C, Schwameis R, Heinze G, Gärner M, Grimm C, Joura E, Horvat R, Polterauer S, Polterauer M. Inuence of age on histologic outcome of cervical intraepithelial neoplasia during observational management: results from large cohort, systematic review, meta-analysis. Sci Rep. 2018 Apr 23;8(1):6383. doi: 10.1038/s41598-018-24882-2. PMID: 29686397; PMCID: PMC5913272. 2.Gil-Antuñano, S.P.; Serrano Cogollor, L.; López Díaz, A.C.; González Rodríguez, S.P.; Dexeus Carter, D.; Centeno Mediavilla, C.; Coronado Martín, P.; de la Fuente Valero, J.; López Fernández, J.A.; Vanrell Barbat, C.; et al. Ecacy of a Coriolus versicolor-Based Vaginal Gel in Human(Papillomavirus-Positive Women Older Than 40 Years: A Sub-Analysis of PALOMAStudy. J. Pers. Med. 2022, 12, 1559. 3. Cortés Bordoy, Javier et al. “E"ect of a Multi-Ingredient Coriolus-versicolor-Based Vaginal Gel in Women with HPV-Dependent Cervical Lesions: The Papilobs Real-Life Prospective Study.” Cancers vol. 15,15 3863. 29 Jul. 2023, doi:10.3390/cancers15153863. ◊ Low grade cervical lesions ASCUS/LSIL

THE FIRST TREATMENT TO PREVENT AND TREAT CERVICAL LESIONS ◊ CAUSED BY THE HUMAN PAPILLOMAVIRUS

Single-dose cannulas

Patient prole for Papilocare® Vaginal Gel

HPV+ PATIENT WITH CERVICAL LESIONS ESPECIALLY COMPLEX SITUATIONS Papilocare® Vaginal Gel HPV+ PATIENT WITH CERVICAL LESIONS

• Women over 40 • HPV persistency • Very High-Risk HPV genotype • CIN 2 in conservative management • Immunosupression • Smoker

Papilocare® Vaginal Gel + Immunocaps

◊ Low grade cervical lesions ASCUS/LSIL

Food supplement

A SOLUTION FOR EACH PATIENT A complete approach for HPV+ that oers a solution adapted to each patient

HPV+ patient without lesions HPV+ patient's partner

Papilocare® Immunocaps

HPV+ patient with cervical lesions

Papilocare® Vaginal Gel

COMPLEX SITUATIONS HPV+ Patient with cervical lesions

• Women over 40 • HPV persistency • Very High-Risk HPV genotype • CIN 2 in conservative management • Immunosupression • Smoker

Papilocare®Vaginal Gel + Immunocaps

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1. DI Pierro, Francesco et al. “Oral administration of Lactobacillus crispatus M247 to papillomavirus-infected women: results of a preliminary, uncontrolled, open trial.” Minerva obstetrics and gynecology vol. 73,5 (2021): 621-631. doi:10.23736/S2724-606X.21.04752-7 2.Ahmad, Md Faruque et al. “Ganoderma lucidum: A potential source to surmount viral infections through-glucans immunomodulatory and triterpenoids antiviral properties.” International journal of biological macromolecules vol. 187 (2021): 769-779. doi:10.1016/j.ijbiomac.2021.06.122 2. 3. Kunisawa, Jun et al. “A pivotal role of vitamin B9 in the maintenance of regulatory T cells in vitro and in vivo.” PloS one vol. 7,2 (2012): e32094. doi:10.1371/ journal.pone.0032094 3. 4. Donatini, Bruno. “Control of oral human papillomavirus (HPV) by medicinal mushrooms, Trametes versicolor and Ganoderma lucidum: a preliminary clinical trial.” International journal of medicinal mushrooms vol. 16,5 (2014): 497-8. doi:10.1615/intjmedmushrooms.v16.i5.80

VAGINAL MICROBIOTA AND IMMUNE SYSTEM IN HPV INFECTION

INCREASED DIVERSITY OF VAGINAL MICROBIOTA PLAYS A KEY ROLE IN THE IMMUNE SYSTEM AND HPV PERSISTENCE 13

Increased pH and oxidative stress 4

IMMUNE SYSTEM

Bacterial vaginosis decreases the production of pro-inammatory cytokines. 5

Weakened immune system enhances viral persistence. 6

INCREASED HPV PERSISTENCE

INCREASED BACTERIAL VAGINOSIS

Decreased production of defence peptides, which are vital for the survival of lactobacillus 7

• Bacterial vaginosis increases the likelihood of HPV infection by disrupting the protective mucosa, favouring viral attachment. 1 • HPV decreases the inammatory response of the patient's immune system, which hinders viral clearance 5 • HPV itself has a negative impact on the vaginal microbiota, which increases the incidence of bacterial vaginosis. 7

1. Liang, Y., et al. (2019). A meta-analysis of the relationship between vaginal microecology, human papillomavirus infection and cervical intraepithelial neoplasia. Infectious agents and cancer, 14, 29 2. Mitra, Anita et al. “The vaginal microbiota, human papillomavirus infection and cervical intraepithelial neoplasia: what do we know and where are we going next?.” Microbiome vol. 4,1 (2016): 58. doi:10.1186/s40168-016-0203-0 3. Kyrgiou, Maria et al. “Does the vaginal microbiota play a role in the development of cervical cancer?.”Translational research : the journal of laboratory and clinical medicine vol. 179 (2017): 168-182. doi:10.1016/j.trsl.2016.07.0042. 4. Łaniewski, Paweł et al. “The microbiome and gynaecological cancer development, prevention and therapy.” Nature reviews. Urology vol. 17,4 (2020): 232-250. doi:10.1038/s41585-020-0286-z 5. Amador-Molina, Alfredo et al. “Role of innate immunity against human papillomavirus (HPV) infections and eect of adjuvants in promoting specic immune response.” Viruses vol. 5,11 2624-42. 28 Oct. 2013, doi:10.3390/v5112624 6. Song, Dan et al. “Eect of human papillomavirus infection on the immune system and its role in the course of cervical cancer.” Oncology letters vol. 10,2 (2015): 600-606. doi:10.3892/ol.2015.3295 7. Lebeau, Alizee et al. “HPV infection alters vaginal microbiome through down-regulating host mucosal innate peptides used by Lactobacilli as amino acid sources.” Nature communications vol. 13,1 (2022) 1076. doi:10.1038/s41467-022-28724-8

COMPLETE FORMULA BASED ON REISHI EXTRACT

Reishi Extract Antioxidative and immunoregulatory properties 1 50% ß-glucans 50% Biologically active polysaccharides

Quatrefolic® The latest folic acid generation made with innovative technology that allows an increased bioavailability to improve the immune system 2,3

L. crispatus (1x10 10 / Cap) L. rhamnosus (2,5x10 9 / Cap) L. gasseri (2,5x10 9 / Cap)

Synergistic complex of Lactobacillus 4-8 With more than 15 billions per capsule

Vitamins A complete multivitamin complex with more than 100% VRN and 2000 IU of Vitamin D. Vitamins improve the immune response, the skin, mucosa and the nervous system 9

1. Ahmad, Md Faruque et al. “Ganoderma lucidum: A potential source to surmount viral infections through β-glucans immunomodulatory and triterpenoids antiviral properties.” International journal of biological macromolecules vol. 187 (2021): 769-779. doi:10.1016/j.ijbiomac.2021.06.122 2. Kunisawa, Jun et al. “A pivotal role of vitamin B9 in the maintenance of regulatory T cells in vitro and in vivo.” PloS one vol. 7,2 (2012): e32094. doi:10.1371/ journal.pone.0032094 3. Zhao, W et al. “Association between folate status and cervical intraepithelial neoplasia.” European journal of clinical nutrition vol. 70,7 (2016): 837-42. doi:10.1038/ejcn.2016.35 4. DI Pierro, Francesco et al. “Oral administration of Lactobacillus crispatus M247 to papillomavirus-infected women: results of a preliminary, uncontrolled, open trial.” Minerva obstetrics and gynecology vol. 73,5 (2021): 621-631. doi:10.23736/ S2724-606X.21.04752-7 5. Liang, Yuejuan et al. “A meta-analysis of the relationship between vaginal microecology, human papillomavirus infection and cervical intraepithelial neoplasia.” Infectious agents and cancer vol. 14 29. (2019). doi:10.1186/s13027-019-0243-8 6. Brotman, Rebecca M et al. “Interplay between the temporal dynamics of the vaginal microbiota and human papillomavirus detection.”The Journal of infectious diseases vol. 210,11 (2014): 1723-33. doi:10.1093/infdis/jiu330 7. Lebeau, Alizee et al. “HPV infection alters vaginal microbiome through downregulating host mucosal innate peptides used by Lactobacilli as amino acid sources.” Nature communications vol. 13,1 (2022) 1076. doi:10.1038/ s41467-022-28724-8 8. Ou, Yu-Che et al. “The inuence of probiotics on genital high-risk human papilloma virus clearance and quality of cervical smear: a randomized placebo-controlled trial.” BMC women's health vol. 19,1 (2019) 103. doi:10.1186/s12905-019-0798-y 9. Shim, Jinhee et al. “Association Between Serum 25-Hydroxyvitamin D Level and Human Papillomavirus Cervicovaginal Infection in Women in the United States.”The Journal of infectious diseases vol. 213,12 (2016): 1886-92. doi:10.1093/infdis/jiw065.

MEDICAL MUSHROOMS AND THEIR ROLE IN REINFORCING THE IMMUNE SYSTEM

Reishi polysaccharides have demonstrated to enhance the immune system 1,2

Clearance of HPV 16 and 18 after oral supplementation during 2 months with medical mushrooms 3 Medical mushrooms in oral HPV control

***

90 80 70 60 50 40 30 20 10 0

88%

5% Control (n=41)

Reishi + C. versicolor (n=20)

P<0.001

Polysaccharides Activate the humoral and cellular immunity 1,2,4

Polysaccharides

• B cell and T cell proliferation • Monocyte activation • Natural killer cell activation • Increase in interleukin production

• Increase in IFN α production

1. Lin, Zhi-Bin. “Cellular and molecular mechanisms of immuno-modulation by Ganoderma lucidum.” Journal of pharmacological sciences vol. 99,2 (2005): 144-53. doi:10.1254/jphs.crj05008x 2. Xu, Zengtao et al. “Ganoderma lucidum polysaccharides: immunomodulation and potential anti-tumor activities.” The American journal of Chinese medicine vol. 39,1 (2011): 15-27. doi:10.1142/S0192415X11008610 3. Donatini, Bruno. “Control of oral human papillomavirus (HPV) by medicinal mushrooms, Trametes versicolor and Ganoderma lucidum: a preliminary clinical trial.” International journal of medicinal mushrooms vol. 16,5 (2014): 497-8. doi:10.1615/intjmedmushrooms.v16.i5.80 4. Chan, Godfrey Chi-Fung et al. “The eects of beta-glucan on human immune and cancer cells.” Journal of hematology & oncology vol. 2 (2009) 25. doi:10.1186/1756-8722-2-25

VAGINAL MICROBIOTA: FIRST LINE OF DEFENSE AGAINST HPV

Oral Lactobacillus Crispatus M247* administration, enhances HPV clearance 1

HPV clearance 1

Dominance of CST I 1

Baseline

At 90 days of treatment

100

100%

94.3%

68.6%

29%

28.6%

CST I 0%

CST II 0%

2.9% CST II

2.9% 2.9%

CST I

Baseline

90 days

CST III

CST IV

CST III

CST IV

Lactobacilli protect the women's genital tract from pathogens by: 2-4

Adhesion at cervical epithelium avoiding the anchorage of pathogens 2

Decrease of pH through lactic acid production 2-4

Production of antimicrobial compounds 2

*M247 is the probiotic strain of PharmExtracta's Crispact® product

1. DI Pierro, Francesco et al. “Oral administration of Lactobacillus crispatus M247 to papillomavirus-infected women: results of a preliminary, uncontrolled, open trial.” Minerva obstetrics and gynecology vol. 73,5 (2021): 621-631. doi:10.23736/S2724-606X.21.04752-7 2. Łaniewski, Paweł et al. “The microbiome and gynaecological cancer development, prevention and therapy.” Nature reviews. Urology vol. 17,4 (2020): 232-250. doi:10.1038/s41585-020-0286-z 3. Brotman, Rebecca M et al. “Interplay between the temporal dynamics of the vaginal microbiota and human papillomavirus detection.”The Journal of infectious diseases vol. 210,11 (2014): 1723-33. doi:10.1093/infdis/jiu330 4. Kyrgiou, Maria et al. “Does the vaginal microbiota play a role in the development of cervical cancer?.” Translational research : the journal of laboratory and clinical medicine vol. 179 (2017): 168-182.doi:10.1016/j.trsl.2016.07.004

UNIQUE COMBINATION THAT IMPROVES THE MICROBIOTA, BOOSTS IMMUNITY AND ENHANCES HPV CLEARANCE 14

STAND UP TO HPV

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3 MONTHS 1 capsule per day after meals

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Specically designed product to be used in combination with Papilocare® Vaginal Gel for a systemic and local eect.

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HPV+ PATIENT WITH CERVICAL LESIONS

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• Women over 40 • HPV persistency • Very High-Risk HPV genotype • CIN 2 in conservative management • Immunosupression • Smoker

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Papilocare® External Genital Gel Coadjuvant treatment of external genital warts caused by HPV

APPLICATIONS PER DAY UNTIL TOTAL HEALING OR MEDICAL CHECKUP

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1. Lin, Chunqing et al. “Cervical determinants of anal HPV infection and high-grade anal lesions in women: a collaborative pooled analysis.” The Lancet. Infectious diseases vol. 19,8 (2019): 880-891. doi:10.1016/S1473-3099(19)30164-1

Food supplement

A SOLUTION FOR EACH PATIENT

A complete approach for HPV+ that oers a solution adapted to each patient

HPV+ patient without lesions HPV+ patient's partner

Papilocare® Immunocaps

HPV+ patient with cervical lesions

Papilocare® Vaginal Gel

COMPLEX SITUATIONS HPV+ Patient with cervical lesions

• Women over 40 • HPV persistency • Very High-Risk HPV genotype • CIN 2 in conservative management • Immunosupression • Smoker

Papilocare®Vaginal Gel + Immunocaps

PAPINT-0131

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