January 1, 1970 (Vol. , No. )

Bobby W. Sandage, Jr., Ph.D. Coronado Biosciences

Autoimmune diseases such as Crohn’s disease might be curbed by reintroducing parasitic worms into our bodies.

Rates of autoimmune disorders—including Crohn’s disease, ulcerative colitis, multiple sclerosis, and type 1 diabetes—are relatively high across the developed world. According to the idea known as the “hygiene hypothesis,” there is a direct link between these high rates and Western society’s obsession with sterile, germ-free environments. Is it possible that improved hygiene, by ridding our bodies of parasitic worms (also known as helminths) and beneficial bacteria, made way for the newer problems of immune-mediated diseases?

In an idea originated by Joel V. Weinstock, M.D., of Tufts University and recently summarized by him in Nature (“The worm returns,” 8 November 2012), a significant reduction in exposure to helminths has eliminated a natural mechanism in our bodies that prevents the onset of certain autoimmune disorders. Furthermore, the reintroduction of helminths into our bodies might help reduce the rates of these conditions across the Western world.

Several ongoing clinical trials have produced early evidence that such treatment may be safe and effective. One promising approach comes in the form of a treatment involving Trichuris suis ova (TSO)—pig whipworm eggs. Studies, conducted initially by Weinstock and subsequently by others, have shown that once the treatment (purified eggs mixed with saline) has been swallowed by a patient, the eggs take up residence in the gut and regulate the immune system in a way that can reduce a range of symptoms without any harmful side effects.

The use of TSO appears promising since it does not multiply in humans outside of the gastrointestinal tract and does not enter the bloodstream. Previous studies have indicated a positive response to the treatment in Crohn’s, ulcerative colitis and multiple sclerosis patients. Based on those studies, researchers are taking on the task of developing TSO as a drug, specifically a biologic. Both the U.S. Food and Drug Administration and the European Medicines Agency have allowed further testing. There are trials under way in Crohn’s disease, multiple sclerosis, and autism, and others set to begin in ulcerative colitis, psoriasis, type 1 diabetes, and other immune-mediated diseases.

The worms appear to have three major effects on the immune system: They seem to cause changes that activate regulatory T cells, which dampen immune responses and curb autoimmunity; they seem to act on other cells to prevent the “switching on” of dangerous effector T cells, which normally leads to inflammation and disease; and they alter the composition of intestinal flora—they promote the growth of gut microorganisms typically considered “probiotic,” which help maintain intestinal health.

Bobby W. Sandage, Jr., Ph.D.

Clinical Trials

The initial safety and efficacy of TSO in Crohn’s disease has been evaluated in two open-label investigator-sponsored clinical trials. The first, a small pilot clinical trial conducted by Summers et al., and reported in the American Journal of Gastroenterology in 2003, administered a single dose of 2,500 embryonated TSO orally to four patients with refractory Crohn’s. Patients were followed every two weeks for at least 12 weeks, with the efficacy of therapy determined by the Crohn’s Disease Activity Index (CDAI) and the Inflammatory Bowel Disease Quality of Life questionnaire (IBDQ). Using an IBDQ score >170 to indicate remission, three of four patients achieved remission by week eight. Similarly, three of four patients achieved remission during the observation period as assessed by a CDAI <150. Following this single dose study two of the three patients who achieved remission relapsed at the end of the 12-week observation period.

In a subsequent open-label clinical trial reported in Gut in 2004, Summers et al., examined the safety and efficacy of TSO in 29 patients with active Crohn’s, defined by a CDAI >220. Patients received TSO in individual aliquots of 2,500 ova suspended in a solution every three weeks for 24 weeks. Patients maintained diaries of clinical symptoms, and disease activity was measured by CDAI. Therapy with TSO was associated with substantial and sustained improvement, with 79.3% of patients experiencing a response (decrease in CDAI >100 points or CDAI <150) and 72.4% achieving remission (CDAI <150) at week 24. TSO was well tolerated. Currently, two Phase II clinical trials evaluating the safety and efficacy of TSO in Crohn’s patients (TRUST-I and TRUST-II) are being conducted in the U.S. and Europe.

Two investigator-sponsored studies of TSO have been conducted in patients with ulcerative colitis. The first of these was the 2003 study (described above) by Summers et al., in which three patients with refractory ulcerative colitis were treated with a single dose of 2,500 embryonated TSO orally and observed every two weeks for 12 weeks. The IBDQ and Simple Clinical Colitis Activity Index (SCCAI) were used to determine the efficacy of therapy. Using an IBDQ score >170 to define remission, all three patients had achieved remission by week eight. Using an SCCAI <4 to indicate remission, each of the ulcerative colitis patients achieved remission during the treatment and observation period, and one patient experienced a relapse.

As reported in Gastroenterology in 2005, Summers et al., subsequently conducted a randomized, double-blind, placebo-controlled clinical trial to determine the safety and efficacy of TSO in 54 patients with active ulcerative colitis (defined by an Ulcerative Colitis Disease Activity Index (UCDAI) >4) who were treated with placebo or 2,500 TSO every two weeks for 12 weeks. After the first 12 weeks of treatment, placebo-treated patients were switched to TSO for a second 12-week interval, and TSO patients were switched to placebo. The blind was maintained during the crossover phase. In order to calculate UCDAI and SCCAI scores, patients kept diaries detailing their clinical symptoms. The primary measure of efficacy was clinical improvement at 12 weeks, defined as a decrease in UCDAI >4. Clinical remission, defined as UCDAI <2, was a secondary endpoint. Of the 54 patients enrolled in the study, 24 received placebo and 30 received TSO during the first 12 weeks of the study.

The proportion of patients achieving a favorable response was significantly higher with TSO compared with placebo in both the intention-to-treat (“ITT”) (43.3% vs. 16.7%, p=0.04) and per protocol (PP) (44.8% vs. 17.4%, p=0.04) populations. Only patients with active disease (UCDAI >4) were included in the analysis of the crossover phase of the study. Among 31 patients (n=15 for placebo, n=16 for TSO) analyzed, the percentage of TSO-treated patients achieving response was higher than that for placebo-treated patients (56.3% vs. 13.3%, p=0.02). When the two study periods were combined, TSO administration was associated with significantly higher responses in both the ITT and PP populations.

In a study reported in the Multiple Sclerosis Journal in 2011, Fleming et al., at the University of Wisconsin studied five subjects with newly diagnosed, treatment-naïve, relapsing–remitting multiple sclerosis (RRMS). They were given 2,500 TSO orally every two weeks for three months in a baseline-versus-treatment controlled trial. They showed that the mean number of new gadolinium-enhancing magnetic resonance imaging (MRI) lesions (n-Gdþ) fell from 6.6 at baseline to 2.0 at the end of TSO administration, and two months after TSO was discontinued, the mean number of n-Gdþ rose to 5.8 new lesions. No significant adverse effects were observed. In preliminary immunological investigations, increases in the serum level of the cytokines IL-4 and IL-10 were noted in four of the five subjects. These first five patients represented the first part of a two-part study (known as HINT-1 and HINT-2). Additional patients are currently being studied for up to 10 months. Results from this second cohort are expected in the second half of 2013.

As suggested by the results summarized above and others, the ova of parasitic worms such as Trichuris suis might hold a substantial promise in the treatment of a wide range of autoimmune diseases. Ongoing and future studies will sharpen our understanding of the efficacy of this approach and the viability of FDA-approved treatments based on it.

Researchers are taking on the task of developing Trichuris suis ova (TSO), or pig whipworm eggs, as a biologic.

Bobby W. Sandage, Jr., Ph.D., ([email protected]) is CEO of Coronado Biosciences.

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