An opportunity to further develop and commercialise SF68 as pharmaceutical probiotic

This is a unique opportunity to form a partnership with Cerbios-Pharma SA to further develop E. faecium SF68 , a well characterised and well documented probiotic active ingredient, produced with a well standardised process. The partner will gain access to: A well established and effective probiotic An established organisation with cGMP manufacturing capabilities A validated manufacturing process from the fermentation up to the finished product Updated DMF and safety information Clinical data Marketing rights in interesting territories

Opportunity
The available opportunity offers to interested companies the potential to develop SF68 in a number of indications with proven efficacy including: Acute diarrhea in adults Acute diarrhea in children Tourist's diarrhea Dysbiosis due to antibiotic therapy Chronic dysbiosis Irritable bowel syndrome (IBS) Hepatic encephalopathy (HE) Furthermore proof of principle has been given in animal models for: Stimulation of the immune system Vaccine enhancement This document outlines the background of SF68 and gives information for interested parties.

Background of SF68
SF68 is a dry culture of a Lactic Acid Bacteria belonging to the species Enterococcus faecium. The strain was isolated from the faeces of a healthy baby in the sixties and is today considered one of the best characterised probiotic strains for the prevention and treatment of intestinal disorders.

Current treatment
Current treatment with probiotics offers a safe intervention in a number of diseases related to disorders of the intestinal microflora. The Cochrane meta-analysis of 2004 Probiotics for treating infectious diarrhoea reported that, in nearly all trials analysed, probiotics had a beneficial effect in reducing diarrhoea. SF68 stands out among other probiotics as the one with highest statistical significance and confidence of efficacy.

Safety of SF68
The safety profile of SF68 is very good. Thanks to the available data and its long history of safe use, the SF68 strain is now considered as a reference strain for safety among Enterococci. Cerbios owns a complete documentation showing lack of risk regarding all relevant safety aspects, such as determinants of pathogenicity, antibiotic resistance and exchange of genetic information.

Background of Cerbios-Pharma SA
Cerbios-Pharma SA is a Swiss company founded in 1994 by the merger of Bioferment SA (founded in 1976) and Sapec SA (founded in 1979). It specialises in the development and production of high quality active pharmaceutical ingredients (API) in the area of fine chemicals (Chemical Division) and biologicals (Biological Division). After more than 30 years of commercial and manufacturing experience, Cerbios has a deep knowledge on SF68 and of its potential as global probiotic.

Production of SF68
Cerbios manufacturing process for SF68 uses certified materials and a highly standardised procedure based on a master cell bank and working cell bank. Strict quality controls include genetic, physiologic and microbiological purity. This leads to a product with a high quality profile.

SF68 is a registered trademark of Cerbios-Pharma SA SF68 NCI October 2009

The production capabilities cover the fermentation in large scale bioreactors, drying as well as microencapsulation of SF68 . The downstream process is well established, leading to a standardised and highly controlled pure product. Galenic forms available at Cerbios-Pharma SA: spray-dried formulations granulated formulations microencapsulated formulations (ME) Cerbios has a dedicated packaging line to produce finished products based on SF68 hard gelatine capsules in glass bottles.

The graph here below shows the reported persistence of diarrhea in the SF68 group with respect to the placebo.

Persistance of diarrhoea (%)

100 80 60 40 20 0 0 1 2 3 4 5 6 7 Duration of treatment (days) SF68 Placebo

Biological characteristics
Biological characteristics of SF68 are well documented as follows: Quick growth Production of lactic acid (L-Form) High resistance to acidity (passage through stomach) Production of bacteriocine-like substances Inhibition of pathogenic germs Competitive exclusion Stimulation of the resident lactic acid flora Stimulation of the immune system With respect to the stimulation of the immune system a recent trial with young dogs gave proof of principle of vaccine enhancement (Benyacoub et al., 2003). The graph here below shows the increase of specific IgG antibodies after vaccination in the SF68 group compared to the control group.
Specific CDV-IgG (OD 450 nm)

Regulatory compliance
Products based on SF68 have already approval from regulatory authorities and have been marketed starting from 1979 as local product in several countries including Switzerland, Austria and Italy.

Intellectual property
Cerbios is the owner of the strain deposit in the official culture collection NCIMB in Aberdeen. Cerbios is the owner of the know-how related to manufacturing and formulation as well as of the DMF filed for the above mentioned marketing authorisations.

Partnership
Cerbios is looking for partners with the motivation, resources and capabilities to register and introduce pharmaceutical specialities based on its SF68 in new territories, while Cerbios provides its long experience, manufacturing capabilities and DMF to produce the API as well as the finished product.

1 0.8 0.6 0.4 0.2 0 0 10 20

Weeks of trial
* = p < 005

30

40

50

Contact person:
Martin Aeschbacher, Ph. D. Director M&S Biological Division Cerbios-Pharma SA Via Pian Scairolo 6 CH-6917 Barbengo/Lugano Switzerland Telephone: Fax: Internet: e-mail: +41 91 9856311 +41 91 9856325 www.cerbios.ch martin.aeschbacher@cerbios.ch

Control

SF68

Efficacy
A number of clinical trials have been performed, the majority of them during the eighties. The most recent double-blind clinical trial has been published by Buydens and Debeuckelaere in 1996. The results confirm that SF68 shortens the duration and the severity of acute diarrhea in adults.

SF68 NCI October 2009

References
1. Acute Diarrhoea in Adults
Buydens, P., and S. Debeuckelaere. 1996. Efficacy of SF68 in the Treatment of Acute Diarrhea. A Placebo-Controlled Trial. Scand J Gastroenterol. 31:887-891. Bruno, F., and G. Frigerio. 1981. Eine neuartige Mglichkeit zur Behandlung der Enteritis Kontrollierte Doppelblindversuche mit dem Stamm SF68. Schweiz. Rundsch. Med. Prax. 39:1717-1720. Camarri, E., A. Belvisi, G. Guidoni, G. Marini, and G. Frigerio. 1981. A double-blind comparison of two different treatments for acute enteritis in adults. Chemotherapy. 27:466470. Lewenstein, A., G. Frigerio, and M. Moroni. 1979. Biological properties of SF68, a new approach for the treatment of diarrheal diseases. Curr. Ther. Res. 26:967-981.

5. Chronic Dysbiosis
Bruno, F., A. Nastasi, and M. Bruno. 1983. Studio controllato doppio cieco sull'effetto dell'enterococco lattoproduttore ceppo SF68 su manifestazioni associate a forme enterocolitiche varie e a salmonellosi. Clin. Ter. 105:203-207. Schiraldi, O., C. di Bari, and F. Trotta. 1982. Le traitement par Streptococcus faecium des porteurs asymptomatiques de Salmonelles. Md. et Hyg. 40:445-446.

6. Irritable Bowel Syndrom (IBS)

Lami, F. et al. 1982. Breath test evaluation of SF68 in IBS patients. Abstract from the Symposium on Lactic Acid Bacteria - Pescara, Italy. Lami, F., and C. Callegari. 1988. SF68 nella sindrome del colon irritabile: risultati. Simposio Internazionale, Vienna.

2. Acute Diarrhoea in Children

Bellomo, G., C. Finocchiaro, and G. Frigerio. 1979. Une nouvelle approche pour le traitement des entrites en pdiatrie. Md. et Hyg. 37:3781-3784. Bellomo, G., A. Mangiagli, L. Nicastro, and G. Frigerio. 1980. A controlled double-blind study of SF68 strain as a new biological preparation for the treatment of diarrhoea in pediatrics. Curr. Ther. Res. 28:927-936. D'Apuzzo, V., and R. Salzberg. 1982. Die Behandlung der akuten Diarrh in der Pdiatrie mit Streptococcus faecium: Resultate einer Doppelblindstudie. Ther. Umsch. 39:10331035.

Lami, F., C. Callegari, F. Levantesi, M. Tatali, R. Abbiati, and L. Barbara. 1989. Modificazioni indotte dalla somministrazione di Enterococcus faecium in pazienti con sindrome del colon irritabile. Simposio Internazionale su Ecologia intestinale: dalla microbiologia alla clinica, Sardegna. p. 77-82.

7. Hepatic Encephalopathy (HE)

Del Vecchio-Blanco, C., G. Ambrogio, D. Mattera, and M. Coltorti. 1981. Influence du traitement par Streptococcus faecium (SF68) sur la courbe ammonimique de charge protique chez des sujets atteints de cirrhose hpatique. Md. et Hyg. 39:2387-2389. Loguercio, C., C. Del Vecchio-Blanco, and M. Coltorti. 1987. Enterococcus Lactic Acid Bacteria Strain SF68 and Lactulose in Hepatic Encephalopathy: a Controlled Study. J. Int. Med. Res.15:335-343. Loguercio, C., R. Abbiati, M. Rinaldi, A. Romano, C. Del Vecchio Blanco, and M. Coltorti. 1995. Long-term effects of Enterococcus faecium SF68 versus lactulose in in the treatment of patients with cirrhosis and grade 1-2 hepatic encephalopathy. Journal of Hepathology.23:39-46.

3. Tourists Diarrhoea
Sparre-Linde, L., and L. Lindwall. 1986. The effect of Ventrux Acido (lactic acid-forming bacteria) on tourist diarrhoea - a double blind study. Swed. J. Biol. Med. 3/86.

4. Dysbiosis due to Antibiotic Therapy

Alvisi, V. 1989. Antibioticoterapia-diarrea e disvitaminosi. Interviste d'attualit -Opinioni per il mondo medico. Suppl. 3/89. Borgia, M., N. Sepe, V. Brancato, and R. Borgia. 1982. A controlled clinical study on Streptococcus faecium preparation for the prevention of side reactions during long-term antibiotic treatments. Curr. Ther. Res. 31:265-271. Wunderlich, P.F., L. Braun, I. Fumagalli, V. D'Apuzzo, F. Heim, M. Karly, R. Lodi, G. Politta, F. Vonbank, and L. Zeltner. 1989. Double-blind Report on the Efficacy of Lactic Acid-producing Enterococcus SF68 in the Prevention of Antibiotic-associated Diarrhoea and in the Treatment of Acute Diarrhoea. J.Int. Med. Res. 17:333-338.

8. Further literature and reviews

Allen, S.J., B. Okoko, E. Martinez, G. Gregorio, L.F. Dans. 2004. Probiotics for treating infectious diarrhoea. Cochrane Review. The Cochrane Library 2004, Issue 3. Loizeau, D. 1994. Place de lEntrocoque SF68 dans la prvention et le traitement des gastro-entrites infectieuses et lies aux antibiotiques. Revue Mdicale de la Suisse Romande.114:651-654. Salvioli, G., R. Salati, M. Bondi, A. Fratalocchi, B.M. Sala and A. Gibertini. 1982. Bile Acid Transformation by the Intestinal Flora and Cholesterol Saturation in Bile. Digestion. 23: 80-88.

SF68 NCI October 2009