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Inflammatory Bowel Diseases

News Post: 26 August 2016

Helminth Regulation of Immunity: A Three-pronged Approach to Treat Colitis.
Fernando Lopes, Chelsea Matisz, José L Reyes, Humberto Jijon, Ahmed Al-Darmaki, Gilaad G Kaplan, Derek M McKay
Read full Publication as PDF here.

Sweet secrets of a therapeutic worm:
mass-spectrometric N-glycomic analysis of Trichuris

News Post: 17. Dezember 2015

By Iain B. H.

Abstract

Trichuris suis, a nematode parasite of pigs, has attracted attention as its eggs have been administered to human patients as a potential therapy for inflammatory diseases. The immunomodulatory factors remain molecularly uncharacterised, but in vitro studies suggest that glycans on the parasite’s excretory/secretory proteins may play a role. Using an off-line LC-MS approach in combination with chemical and enzymatic treatments, we have examined the N-linked oligosaccharides of T. suis. In addition to the paucimannosidic and oligomannosidic N-glycans typical of many invertebrates, a number of glycans carry N,N′-diacetyllactosamine (LacdiNAc) modified by fucose and/or phosphorylcholine. Such antennal epitopes are similar to ones previously associated with immunomodulation by helminths; here we propose phosphorylcholine modifications predominantly of terminal N-acetylgalactosamine but also of subterminal α1,3-fucosylated N-acetylglucosamine. Exact knowledge of the glycome of T. suis will facilitate more targeted studies on glycan receptors in the host as well as the engineering of cell lines to produce correctly glycosylated recombinant forms of candidate proteins for future studies on immunomodulation.

We are mourning the passing of our dear friend and collleague

News Post: 19. October 2015

Prof. Dr. Robert (Bob) Wendell Summers, MD

Bob will be remembered as an especially giving person of great character, highly respected partner and outstanding gastroenterologist. He was one of the most important members of the pioneering team that discovered and developed the helminth therapy . Bob died in the morning of October 14, 2015 in the age of 77 suffering from a bladder cancer. He was an inspiration to all who knew him and the memory of him will always be with us.

Comments on TSO for Autism from a European Biomedical Center for Autism Resarch and treatment on the CNDO study:

News Post: 11. May 2015

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ASD (Autism Spectrum Disorder) is nowadays a only behaviourally defined syndrome but that origines from a complex interactions among multiple genetic and environmental factors which contribute to the onset and progress of ASD, as seen in other polygenic diseases. Starting from this background we should consider that under the label of ASD we have several different clinical subtypes of ASD with different signs and symptoms and conseguently we should think about specific therapy for each subtype of ASD.

Therefore there is an urgent need for identifying objective biomarkers that may guide to distinguish different clinical subtypes of Autim. Otherwise clinical trials that try to identify an effective treatment for ASD will fail because recruiting ASD patients only on behavioral criteria and not on clinical criteria. That's what could have happened in the clinical trial that has used Trichuris suis Ova (TSO) in ASD patient. We belive they didn't consider a specific clinical subtype as target of treatment.

In our clinical experience a first simple distinction in the field of ASD should be between Inflammatory ASD (I-ASD) and not Inflammatory-ASD (NI-ASD). The I-ASD should be the subtype that exhibit chronic and/or recurrent sino-pulmonary infection, asthma, persistent GI symptoms with high frequency non-IgE mediated food allergy. In these I-ASD patients the severity of behavioural and cognitive symptoms could vary in base of exposure to specific diets (gluten, casein, sugars, histaminergic foods), environmental allergenes or pathogenic microorganisms.

This subtype of Autism is more likely to have a better outcome to antinflammatory therapies such as TSO instead of NI-ASD. Ashwood and collegues in 2004 have found in duodenum and colonic biopsy of I-ASD an elevated level of pro-inflammatory cytokines (TNFalfa, IL4, INFgamma) and a reduced counter regulatory IL-10 cytokine. It is likely that in this specific subset of ASD those cytokines produced in the gut pass in blood stream and then throu the Blood-Brain-Barrier activating the microglia in the brain and conseguently generating “neuro-inflammation”. While the IL-10 is protective for the microglia.

Considering this specific abnormal inflammatory pattern is reasonable that the I-ASD (and not NI-ASD) patients could have a beneficial clinical effect by treatment with Trichuris suis Ova (TSO), In fact the immunomodulatory mechanism of TSO could involve the induction of the potent anti-inflammatory interleukin IL-10. With an increase of antinflammatory IL-10, TSO could improve intestinal barrier function by inducing a rapid turnover of intestinal epithelial cells and goblet cell differentiation , maturation and hyperplasia. And consequently reduce the inflammatory responses to luminal bacteria and intestinal inflammation.

We've treated more then 60 I-ASD patients using TSO (pH2.7) in the last 4-5 year observing significant results in more the 70% of them.

Considering the clinical features we've found that best candidate for treatment with TSO is a patient with allergic symptoms such us chronical nasal congestion, or season rhinitis/conjunctivitis, or asthma and chronic or recurrent episode of diarrhea. The improvements observed in those patients are not only in the quality of stool and control of allergic symptoms but also in improvement of behavioural problem (reduction of stimming and stereotipies, hyperactivity, aggressive behaviours, mood swings and improvement in sleeping disturbances and obsessive compulsive behaviours) and cognitive skills (attention and focus).

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Impressive results on autoimmune diseases - TSO

News Post: 7. July 2014

Trichuris suis ova have been studied in numerous clinical trials for the treatment of inflammatory bowel diseases and other autoimmune diseases with quite impressive results. Recently the interim analysis of the TRUST-1 and TRUST-2 Crohn studies revealed no significant difference between the verum group and the placebo group. However, the way this announcement was made was extremely brief and lacks a lot of very important background information that is totally misleading on the helminth therapy concept, which is one of the most effective and definitely the safest treatments available if it is used right.

Of course it is indispensable to evaluate the final study reports with all data first for an objective analysis on the TRUST studies and the efficacy of this particular formulation of the TSO suspension used for these studies. However, certain things need to be discussed:

While in the TRUST studies the ova were placed in an isotonic phosphate buffered saline solution (containing natriumdihydrogenphosphatdihydrat, NaOH and 0,05% potassium sorbate as a preservative at pH5), all previous studies used a phosphate buffer of potassium chloride, sodium chloride, phosphoric acid and sodium phosphate monobasic dihydrate at a pH level between 2.7-3.

In the natural environment of Trichuris suis (pig’s gut, where they attach to the mucosa and hatch) they find a pH level of around 8. The adult worms shed their unembryonated eggs inside the pig’s gut, which are then leaving the gut with the feces into the soil. Depending on the kind of soil present, the pH value can vary from acid to neutral, where the eggs will find a nice environment to embryonate into the larval stage 1 and stay at rest with an extremely low metabolism until the next pig will serve them as a new host and pick them up. Although it has not yet been fully discovered how the eggs detect when they arrive in the area of their final destination, but certainly the sudden increase of the pH value is definitely a very important trigger, as in vitro tests were able to demonstrate.

During the pharmaceutical manufacturing process the ova are transferred into a solution of a very low pH value for decontamination and embryonation, after which they go into the final formulation. All prior and very successful studies, this final formulation was of a pH value between 2.7 – 3 and had no preservative, while for the TRUST and some other newly pilot studies on other indications a formulation of a pH value of 5 plus potassium sorbate as a preservative was used. In comparison of the two different formulation the jump into pH 2.7-3 of the original formulation was pretty mild and did not trigger any increased development process on the larvae inside the eggs, while the sudden jump into pH5 of the TRUST formulation obviously was enough to start the larval development process beginning with an increased metabolism. Due to the fact that the eggs are floating in a neutral solution, where they have nothing to metabolize other than the preservative (which cannot do them any good at all), they are getting weak, but not weak enough to die.

Nevertheless, the decision of changing the formulation for the drug approval studies is understandable if one takes into account what the common practice is in normal drug development according to the pharmacopeia, but a living organism does not necessarily fit into these regulations designed for single molecules and chemical compounds. Of course, the drug product was tested prior to release on its viability, but none of the possible tests can reliably duplicate the human gut environment. Re-infecting pigs can show that the eggs attach to the mucosa, larvae hatch, mature and reproduce again, but only because in their natural host the worms can access the pig’s bloodstream through the crypts, from which they can feed and fully revitalize. This does not work in a human gut, which is actually one of the safety features which the species of Trichuris suis was chosen to prevent any transfer from one host to another and not any human helminth. So the eggs in the original formulation with a lower pH and without potassium sorbate were able to survive longer in the human gut, thus being more effective, because they began their increased metabolism when already inside the human gut and not, like the eggs in the new formulation, already in the suspension of the vials. The weak eggs would also pass other possible viability tests, such as measuring actively growing microorganisms through detection of adenosine triphosphate or by a simple microscopic evaluation of their motility inside the eggs, but still this does not prove that they can at least survive for 2 weeks inside a human gut. Anyway, there is no doubt that even in the formulation used in the studies, the ova may have arrived still viable in the patient’s gut, but they definitely do not survive there for the time needed, wherefore they lose the efficiency they otherwise would still have.

Another critical issue in the TRUST studies was that the endpoint was set after just 12 weeks of treatment, which is known to be the time frame where the agent just begins to unfold its mode of action effectively. Especially IBD studies are known for their extremely high placebo rate and therefore it is not surprising that at this point of time there is no significant difference between verum and placebo. For the TRUST-2 study the 12 weeks endpoint is understandable, because there the participants were treatment naïve, and it always would be a risk not to offer them any treatment for a prolonged time. However, in TRUST-1 the participants were allowed on anti-suppressants, just excluding TNF inhibitors. At least this study could have been for a longer time of treatment.

Still, even taking the above out of consideration, several questions remain and can be found on a forum as follows:

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The CDAI 290 to 450 group represented half the group tested. It just so happens that 290 was the median. The results for the 290 to 450 group was efficacious but technically not statistically significant, but WOULD BE statistically significant if you doubled the 290-450 CDAI group. In other words, with just about 62 (half of the 125 getting TSO) having a CDAI of 290-450 you didn’t have enough power to the subset group to reach statistical significance for that subgroup. If you did it again with double the CDAI 290-450 participants and had the exact same results, it would be a statistically significant result.

The TRUST-2 participants have lower CDAI’s (max 350) but unlike TRUST-1 are treatment naive (no prednisone etc. or anti-inflammatory drugs allowed as part of the inclusion criteria). The TSO could easily help a treatment naive patient with CDAI of say 250, while the patient with CDAI of 250 on prednisone can’t be helped further by the TSO. But, of course, given the choice if both would work independently TSO is much safer.

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At the end of the day, TSO has undoubtfully shown its efficacy, at minimum identical to currently available other medication, but with a way higher safety profile, so that patients and physicians won’t need to worry anymore about the possible and severe side effects that all other medications but TSO have in common. Needless to say what impact this would have for the pediatric gastroenterology. The number one thing that the health authorities want to see and the main purpose why clinical studies must be conducted is to demonstrate the safety of a drug before it can be officially approved in humans, which TSO has once again impressively demonstrated although the TRUST studies had their weaknesses. If the responsible people would stop the drug approval process just because they don’t want to learn from the TRUST studies and not willing to do better in phase 3, they would deprive millions of patients from an efficient and extremely well tolerated therapy. It may very well be, that simply returning to a lower pH value in the formulation could make all the difference. It also is a matter of definition when TSO is best to apply. It can serve very well as a prophylaxis, as a therapy of first choice right after diagnosis or as a highly effective add-on to either avoid high risk medications or help in combination if even high risk medications fail.

New technology in production reduce costs

News Post: 7. November 2014

Tanawisa proudly presents a new Technology in the production of TSO that has just been implemented and which reduces the costs of production considerably. So far the first seperation step of the micro-organisms from the pigs natural excretions was a time consuming and manual sieving process involving the manpower of 20 people for at least 2 full days. After several monthes of designing and testing a new automated sieving process in a 3 -dimensional vibrating unit now allows this process to be even more accurate and within a fraction of the previous time and manpower.

Since it has always been our aim to make the helminth therapy more affordable we are glad to pass this benefit directly to our customers as shown in the new pricelist in our shop section.