Note to Healthcare Professionals and Patients

 

Professor Claudio De Simone, the inventor of the high potency probiotic previously sold under the brand name, “VSL#3*”, recently won a unanimous jury verdict in Federal Court against VSL Pharmaceuticals, Inc., Alfasigma USA, and Leadiant Biosciences, Inc. Elements of the case are relevant to those who work with high potency probiotics.

The litigation was the product of a business dispute between Claudio De Simone and his former business partners. In the early 1990s, De Simone invented the De Simone formulation, a high potency, eight strain probiotic product. The formulation and associated patent were licensed to the VSL Pharmaceuticals, Inc. company (“VSL Inc”). The De Simone Formulation was subsequently sold under the brand name, VSL#3* from 2002 to 2016 (VSL#3 is a registered trademark of VSL Inc). When De Simone terminated his relationship with VSL Inc., the company attempted to produce a copy of the original formulation and pass off the counterfeit as the original product. A legal dispute arose concerning the ownership of the proprietary formulation and claims which were being made about this copy “VSL#3*” product.

The jury’s finding of false advertising relied upon formidable evidence presented to them that the new version of VSL#3, which is manufactured in Italy, is materially different in composition and efficacy from the original De Simone Formulation manufactured in the United States. And, as a result, VSL#3 can no longer be associated with the rich clinical history that applies to the original De Simone formulation.  As of the time of trial, VSL Inc. had not completed a single study on its new formulation showing it performs the same as the original formulation. In this case, the jury unanimously found that the distributors were liable for false advertising, based on overwhelming evidence which showed that they misrepresented new VSL#3® to be the same as the original, which was made with the De Simone Formulation.

Outcomes of the Litigation in Federal Court:

• The seller of VSL#3 in the U.S., Alfasigma USA, was found liable for false advertising under the Lanham Act for making false statements related to the composition and clinical history of new “VSL#3.”
• It was determined that the Know-How required to manufacture the De Simone formulation probiotic is the exclusive property of Professor Claudio De Simone.
• VSL Inc was found to be in breach of contract to De Simone and ordered to pay compensatory damages. VSL Inc. and Leadiant were also found to have been unjustly enriched and were required to pay additional compensation to De Simone.

In the months since the trial, various actions were taken against the VSL#3 product around the world: 

• In the United States (US), major wholesalers of the VSL#3 product in the United States have recently decided to discontinue purchases/sales of the product—Amazon, Cardinal Health, McKesson, CVS/Caremark, Walgreens, and Rite Aid. 
• In Canada, the VSL#3® product was removed from the market, effective November 15, 2018. 
• Six universities in the US and Europe (including Stanford University, Emory University, University of Wisconsin-Madison, and University of Louisville) have halted human clinical trials using VSL#3 in response to the very serious public health concerns that have been raised.
• As of this publication date, six published comparative studies have found stark differences between VSL#3 containing the De Simone Formulation and the new “knock off” product.^1,2,3,4,5,6
• The European Society for Clinical Nutrition and Metabolism (ESPEN) issued a correction to its guidelines for Clinical Nutrition in Inflammatory Bowel Disease⁷, withdrawing the trademark “VSL#3” and replacing this with the generic term “De Simone Formulation”.
• The peer-reviewed journal, Medicine, issued an erratum replacing “VSL#3” with “De Simone Formulation” in the article, “The clinical effects of probiotics for inflammatory bowel disease: A Meta-analysis”.⁸
• In Germany,the District Court of Hamburg, Germany ordered the local distributor of VSL#3 (Ferring) to stop making a series of claims in reference to the effectiveness of the current probiotic formulation commercialized under the brand VSL#3^®

Ongoing False Representations by Alfasigma:

A federal jury has already unanimously found that Alfasigma has made false statements to patients and healthcare professionals. As of the date of this letter their efforts to mislead consumers continues:

Alfasigma Claims:	The Facts
Studies performed on the original probiotic formulation sold under the name “VSL#3”, “…can be relied on to show efficacy and safety of the Italian-made product.”9	-   To date, not one bridging study has been published on the new VSL#3. -   The sole study Alfasigma relies on to establish equivalence only evaluated the genetics of the two products and not the clinical activity.10 -   The authors of that study had to issue a correction because they could not be sure that the tested product actually was commercial VSL#3.11
That genetic similarity alone is sufficient to establish the equivalence of original formulation and the new knock off VSL#3	-   Genetic similarity of live probiotic organisms is not sufficient to establish clinical equivalence.12 -   The Alfasigma position ignores the basic biological concept of “nature vs nurture.”
Regarding the recent litigation “...the verdict contained no specific findings concerning the quality, production, efficacy or safety of VSL#3.”9	-   There was so much evidence presented at trial which questioned the quality, production, efficacy and safety of the new VSL#3 that the Jury could not possibly rule on every specific scientific finding. -   The Jury looked at the totality of the of evidence and ruled unanimously that Alfasigma was falsely advertising.
New VSL#3 contains the same 8 strains as the original.9	-   At trial, significant evidence was presented to show that new VSL#3 actually only contained 7 strains as of the time of the trial.
Alfasigma claims their new product is the same as the original because the strains are genetically similar.	-   Changes in the production and fermentation methods of probiotics can result in performance changes (even when the genetics is the same).13,14,15,16 -   New VSL#3 is not fermented with the necessary dairy ingredients, which are critical to the health and vitality of these yogurt bacteria.
Alfasigma attempts to link the new VSL#3 back to the original by pointing to a few early studies performed on prototypes of the product made prior to 2000.9	-   Alfasigma fails to acknowledge that these early prototypes were created under the direction of the product inventor using his proprietary Know-How and with dairy based fermentation methods.  -   New VSL#3 is made without dairy and without the inventor’s proprietary formula.
Alfasigma endeavors to provide scientific support for its product by citing a genetic characterization study performed by Douillard, et al.9,10	-   The study in question does not establish the clinical or genetic equivalence of the original formulation vs the new VSL#3. - The study was performed only on individual strains given to the investigators by the company and not on commercial VSL#3 product. - The authors of the study had to publish a correction to the original publication conceding that they had not tested commercial VSL#3 product11 - Supplementary Table 3 (Genome sequencing statistics S3 Table) of the analysis indicates that of two of the reported strains genetically correspond to the same strain, suggesting that there were only 7 strains in the VSL#3 formulation at the time of the study (Bifidobacterium_animalis_lactis_Bi_07_uid163693/NC_017867.gbk)

 

The original De Simone formulation, which was previously sold under the name, VSL#3 is currently available in the United States and Canada only under the name, Visbiome.  The Visbiome brands are available online at www.visbiome.com, on Amazon, or by special order from a variety of pharmacies.

We invite you to learn more at www.visbiome.com or by contacting ExeGi Pharma at info@exegipharma.com

*VSL#3^® is a registered trademark and is manufactured exclusively for, VSL Pharmaceuticals, Inc. Visbiome^® is manufactured exclusively for ExeGi Pharma, LLC and is not affiliated with, endorsed by, or distributed by VSL Pharmaceuticals, Inc.

 

References 

1. Biagioli et al. Metabolic Variability of a Multispecies Probiotic Preparation Impacts on the Anti-inflammatory Activity. Frontiers in Pharmacology. 2017.
2. Cinque et al. VSL#3 probiotic differently influence IEC-6 intestinal epithelial cell status and function. Journal of Cellular Physiology.
3. Cinque et al. Production Conditions Affect the In Vitro Anti-Tumoral Effects of a High Concentration Multi-Strain Probiotic Preparation. Journal PLOS ONE. 2016.
4. Trinchieri, et al. Efficacy and Safety of a Multistrain Probiotic Formulation Depends from Manufacturing. Frontiers in Immunology. 2017
5. Palumbo, et al. The Epithelial Barrier Model Shows That the Properties of VSL#3 Depends from Where it is Manufactured. Endocrine, Metabolic, & Immune Disorders. 2019, 19, 1-8
6. Biagioli, et al. Divergent Effectiveness of Multispecies Probiotic Preparation on Intestinal Microbiota Structure Depends on Metabolic Properties. Nutrients 2019 11(2), 325.
7. Forbes, et al. Corrigendum to: ESPEN guideline: Clinical nutrition in inflammatory bowel disease [Clinical Nutrition 36 (2017) 321-347]
8. Erratum: Jia et al. The clinical effects of probiotic for inflammatory bowel disease: A meta-analysis. 97; 51:e13792
9. Alfasigma Jan 31, 2019 Dear Healthcare Provider Letter https://www.vsl3.com/assets/v1/hcp/files/VSL3DoctorLetter_CourtRuling.pdf
10. Douillard et al. Comparative genomic analysis of the multispecies probiotic-marketed product VSL#3. PLoS One 2018; 16;13(2):e0192452
11. Douillard et al. Correction: Comparative genomic analysis of the multispecies probiotic marketed product VSL#3. PLoS One 2018; 13(8): e0203548
12. Sanders ME, Klaenhammer TR, Ouwehand AC, et al. Effects of genetic, processing, or product formulation changes on efficacy and safety of probiotics. Annals of the New York Academy of Sciences 2014; 1309(1): 1±18.
13. Grzesakowiak è, Isolauri E, Salminen S, Gueimonde M. Manufacturing process influences properties of probiotic bacteria. Br J Nutr. 2011 Mar; 105(6):887±94. Epub 2010 Nov 9. PMID: 210592
14. Nivoliez et al. Influence of manufacturing processes on in vitro properties of the probiotic Lactobacillus rhamnosus Lcr35.^Ò Journal of Biotechnology (2012) 236-241.
15. Saarela MH, Alakomi HL, Puhakka A, Matto J. Effect of the fermentation pH on the storage stability of Lactobacillus rhamnosus preparations and suitability of in vitro analyses of cell physiological functions to predict it. J Appl Microbiol 2009; 106(4): 1204±12
16. Deepika G, Green RJ, Frazier RA, et al. (2009) Effect of growth time on the surface and adhesion properties of Lactobacillus rhamnosus J Appl Microbiol 107, 1230–1240.