Saturday, 23 June 2012 15:50

The Mystery Application- Fistula after Crohn´s Disease

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On July 27 2010, Cytori surprised its investors by announcing that approval was received (together with breast augmentation and re-construction) for: The delivery of the Celution(R) System cellular output to facilitate healing of rectal and vaginal fistulas (wounds) resulting from Crohn's disease, the first stem cell-based approval in Europe for this condition.
Up to that day, a coincidental statement by Chris Calhoun, CEO on the treatment of some patients with this disorder, was subsequently corrected by the legal department "as a slip of the tongue". This article will try to shed some light on this "mystery" approval and will explain the aspects of the condition.

First what is Crohn´s disease-

Crohn's disease is an auto immune disease and often a chronic, life-long condition with relapsing inflammation of the bowels and gastrointestinal tract. Its fundamental cause is unknown, but it is suspected to come from a genetic predisposition of the body’s overreaction to the environment, items in the diet, or an infection. Severe Crohn's disease can cause pain, undesirable changes in lifestyle, hospitalizations, and side-effects from medications used for treatment. While Crohn's disease often first occurs in people between the ages of 20 and 30, it can occur in children or at any other age. In the majority of sufferers, it requires surgery at least once. Over 500,000 people in the U.S. are afflicted with Crohn's disease, and approximately 20,000 new cases areperianal abscess 1 diagnosed each year.

Approx. 25% of Crohn´s sufferers develop fistulae- abscesses between the skin and the intestinal tract-which can occur all over the tract, but are prevalent in the rectum or vagina- one speaks of perianal fistulae- see picture.

And- how can ADRCs help close and cure the fistulae?

In case of chronic inflammation caused by an auto immune disorder, the body is not able to upregulate the necessary growth factors to facilitate the healing process, Basically, the bioavailability of the cells that are naturally occurring at the injury site are not sufficient to effectively conduct the body through the closure process. Supplementation with ADRCs is believed to initiate the necessary growth factor expression and cell signaling pathways that facilitate the proliferation of new blood vessels and modulate the immune response within the wound. However, the most important mechanism of these cells is thought to be their ability to change in response to their environment and accurately mimic the overlapping phases of the wound healing process. This dynamic response distinguishes ADRC treatment from competing treatments that can only target a specific phase of the healing process.

The Mystery Fistulae EMA Approval unraveled

At the very early beginning of the Cytori/Olympus business relationship-that is soon after Cytori closed its manufacturing agreement with Olympus in November 2005- it became clear to me, after studyinolympus-hdtv endo picg the details of that particular agreement, that the agreement didnt make economic sense for Olympus and that an alterior motive HAD to exist in order for them to close that deal. That motive "revealed" itself shortly thereafter, when in February 2006 Cytori provided Olympus the option for first rights of partner deal negotiations on an "undisclosed therapeutic application" in return for a payment of 1,5Mio$. Obviously Olympus intended to enter the field of THERAPEUTIC regenerative medicine synergistic to their main competency- the field of gastroenterology- where they are global market leader in endoscopy with a 75% market share.

The deal was not just "a right to negotiate" but a little bit more....that is  Olympus received SIX Celutions at locations of their choice to conduct a feasibility clinic, which you can read in the two page excerpt from an appendix to the 10Q of the 2006 first quarter. pdfolympus-first-right-2006.pdf48.91 KB22/06/2012, 16:32

Obviously Olympus wanted to take the "safe route" and not leave the engineering of the core business device to a small group of "talented" molecular biologists, but take it in their ownpipeline early 2007 competent engineering hands. Anyway- the following slide was presented by Calhoun at the Stem Cell Summit in San Diego in February 2007- under the heading "gastro-intestinal. Fistulae was in clinical investigation and the immune disorder Crohn´s itself in pre-clinical investigation. This was confirmed a few times by "editing mishaps" in several 10Qs, when fistulae was mentioned instead of "undisclosed" application, when describing Olympus´rights from this deal. Of course- a deal was never made (at least as of today June 24 2012). On the other side Cytori never picked up the 50% of the development cost for Celution One from the JV (estimated north of 50 Mio$). One can assume some compensation being done here. Some more confirmation of the ongoing trial was noted again late 2008, but silence untill approval was received as indicated in the introduction to this article. Approval was announced on July 27, 2010 and considering that never clinical data were presented on the app and the foregoing write-up, there can hardly be any doubt in respect of the identity of the third party owning this data- Olympus of course.

More clinical development of the Fistulae application with ADRCs- Cellerix.

Fistulae after Crohn´s are by far the indication most studied in clinical efforts with ADRCs- there are 17 known (completed or in process) and since registration is voluntary- an unknown amount NEVER registered, amongst them the Olympus clinic. Four registered ones are in the name of Cellerix, a spanish company now merged with Tigenix (Belgium), which is listed. Tigenix has the first approved stem cell drug in Europe- ChondroCelect- a knee cartilage product. As Cytori they are struggling with revenues, which only will come after reimbursement of the procedure.

tigenix-pipeCellerix started already in 2002 first with CULTURED autologous cells to treat fistulae. The phase 3 concluded in 2009 was NOT succesful and recently reported upon. Link here

A second autologous clinic was abandoned because of "clinical reality", after which they switched to allogeneic CULTURED cells. Here the approach is more SYSTEMIC and also aiming at curing Crohn´s, by inputting 120 Mio cells by intralesional injection (under the skin).

Personally I think they know what they are doing and learned the hard way and I must say- I like their pipeline (picture) a lot. From a feasibility study with allogeneic cells, a scientific paper was written on the treatment of a female patient. It describes this horrible disorder in a concise manner and only makes you wish that patients get access to the treatment from whatever source. Sometimes top managers not achieving deals at the same time extend the plight of patients in a dire a-social fashion.

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Case Report

Adipose-Derived Stem Cells in Crohn's Rectovaginal Fistula -D. Garcia-Olmo et al

Department of Surgery, La Paz University Hospital-IdiPAZ, 28046 Madrid, Spain
Cell Therapy Laboratory, Foundation to Biomedical Research of La Paz University Hospital-IdiAZ, 28046 Madrid, Spain
School of Medicine, Autonomous University of Madrid, 28029 Madrid, Spain

Received 14 October 2009; Accepted 26 January 2010 - Academic Editor: Hugh J. Freeman

Copyright © 2010 D. García-Olmo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Therapeutic options for recto-vaginal fistula in the setting of Crohn's disease are limited and many data are available in the literature. The manuscript describes the history of a patient who has been the pioneer of our Clinical Trials in treating this disease in fistulizing Crohn's disease environment. We believe it is the first time that a patient with this disease has been treated by adipose-derived stem cells in allogeneic form. The conclusion of our study with Mary is that the use of mesenchymal stem cells derived from adipose tissue is secure, either in autologous or allogeneic form. Furthermore, we have proved that if we use multi-dose and multiple applications on a patient, it does not produce any adverse effect, which confirms us the safety of using these cells in patients at least in the fistulizing Crohn's disease environment.

Continue reading this two page case-story by downloading it- pdfcellerix-vaginal-fistula.pdf957.9 KB24/06/2012, 14:58

Read 413 times Last modified on Sunday, 29 December 2019 10:33

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