| BioWorld

After Coronado Biosciences Inc. reported two trial failures this year in Crohn’s disease with its oral Trichuris suis ova (TSO, or pig whipworm eggs), investors’ faith had fallen low in the unusual immune system-based approach, but Wall Street sang a different song when the company unveiled positive data from a pilot study in the seemingly unlikely indication of autism.

Shares of the Burlington, Mass.-based firm (NASDAQ:CNDO) closed Friday at $2.15, up 37 cents, or 21 percent. The company could not be reached for comment.

It’s known that when helminths invade mammals, a wide-ranging immune response is triggered, with the host making the cytokines interleukin-4 (IL-4), IL-5, IL-10 and IL-13, plus immunoglobulin E. Effector cells such as mast cells, eosinophils and basophils, expand to fight the threat. Together, those resemble the T-helper 2 (Th2) immune response, which may serve the host by limiting the degree of helminthic organization. Under experimental conditions, Coronado said, a number of helminths have been shown to induce Th2-type cytokine release and to down-regulate the Th1 immune responses to unrelated bacterial and viral infections.

The idea, with Coronado’s approach in Crohn’s, was that affecting the immune system that way would improve patients’ conditions safely, since TSO is a pig parasite, and is eliminated harmlessly by human bodies.

In Phase II trials known as TRUST-1 and TRUST-2, the strategy didn’t work. The first experiment enrolled patients with Crohn’s Disease Activity Index (CDAI) baselines of 220 to 450, whereas TRUST-2 capped CDAI severity at baseline at 350. Patients in TRUST-1 were allowed to continue oral immunosuppressive therapy such as steroids, while those enrolled in TRUST-2 were not. But the differences did not alter the outcomes. (See BioWorld Today, Oct. 15, 2013.)

At the time of the TRUST-1 blowup, Roth Capital Partners analyst Joseph Pantginis all but predicted the second, writing in a research report that his “speculative call was wrong regarding TSO in Crohn’s disease, based on all the positive anecdotal clinical data presented to date.” The pair of fizzles put Coronado “in a state of limbo, as investors await what the next steps will be with this significant blow to confidence in the TSO program,” Pantginis wrote.

The wait is over. Coronado’s latest double-blind, randomized, placebo-controlled, crossover study with TSO in autism enrolled 10 high-functioning adult patients who were able to give informed consent to participate in the study and who also had a history of allergies and/or a family history of immune-inflammatory illness.

Subjects were treated with 2,500 ova or placebo, once every two weeks, followed by a four-week washout phase and then 12 weeks of placebo or TSO. In the first five patients who completed the study, there was a statistically significant separation from placebo in favor of TSO on three accepted measures of disease, the company said: the Montefiore-Einstein Rigidity Scale, the Repetitive Behavior Scale-Revised Sameness Scale and the Social Responsiveness Scale-Repetitive Behaviors Scale.

Final results are expected in the middle of 2014.

IT WORKED IN IOWA

A hygiene hypothesis underlies the use of TSO. The immune systems of populations living in the relatively sterile environments, such as those in developed countries, may develop in abnormal ways because they are seldom, if ever, exposed to parasites, the thinking goes. Epidemiologists have noted an inverse relationship between autoimmune diseases (such as inflammatory bowel disease, rare in less developed countries) and colonies of helminths (high in warm climates with overcrowded, poorly sanitized populations).

Another company aiming to capitalize on the hygiene theory is the Australian start-up Helmedix Pty Ltd., which in March raised A$1.25 million (then US$1.29 million) in seed funding for research into molecules based on immune-modulating peptides used by helminth parasites to suppress the immune response of their hosts. (See BioWorld International, March 20, 2013.)

The impact of helminths on the immune system has been of scientific interest for quite a few years. Other work has been done by the University of Edinburgh in Scotland, which launched its research with the certainty that M2 macrophages (also known as TH2 macrophages) were important in the immune response to the worms, and went on to discover more about their activity that drug developers could find useful. (See BioWorld International, May 18, 2011.)

TSO, specifically, began at the University of Iowa, and published data from the university’s randomized, double-blind, placebo-controlled trial of 54 patients with ulcerative colitis (UC) demonstrated that 43.3 percent of patients on TSO improved, compared to 16.7 percent of placebo patients (p = 0.04). There were no adverse events. A separate, open-label study published by the university showed a 79.3 percent response and 72.4 percent remission in 29 patients with Crohn’s disease, again without adverse events. (See BioWorld Today, Jan. 23, 2009.)

The University of Iowa licensed its technology to Ovamed GmbH, of Barsbüttel, Germany, which developed a GMP-compliant manufacturing process. From Ovamed, Asphelia gained worldwide rights to the TSO technology, and from there it fell into the hands of Coronado, which has TSO programs in UC, multiple sclerosis, psoriasis, Type I diabetes, psoriatic arthritis and rheumatoid arthritis.

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