Voldsgaard et. al. Biotherapy Journal Review Summer 2016

Journal Citation

Voldsgaard A, Bager P, Garde E, Åkeson P, Leffers AM, Madsen CG, Kapel C, Roepstorff A, Thamsborg SM, Melbye M, Siebner H, Søndergaard HB, Sellebjerg F, Sørensen PS.  Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect. Mult Scler. 2015 Nov;21(13):1723-9.

Published Abstract

BACKGROUND: An observational study has suggested that relapsing-remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients.  OBJECTIVE: To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS.  METHODS: The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24-55) years, disease duration 9 (4-34) years, Expanded Disability Status Scale score 2.5 (1-5.0), and number of relapses within the last two years 3 (2-5). Four patients received no disease modifying therapy, while six patients received IFN-β. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests and expression of immunological biomarker genes.  RESULTS: Treatment with Trichuris suis orally was well-tolerated apart from some gastrointestinal symptoms. Magnetic resonance imaging revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did not change.  CONCLUSIONS: In a small group of relapsing multiple sclerosis patients,   oral therapy was well tolerated but without beneficial effect.

Context

Multiple sclerosis (MS) is a debilitating neurological disease which progressively leads to the disappearance of myelin around motor nerve cells, thereby slowing the conduction along those pathways. The result is a progressive weakness or paralysis which may wax and wane over time, but ultimately progresses in severity. MS is much more prevalent in regions of the world with well-developed sanitation, but rare in countries with high rates of helminth carriage. This has led many to believe that helminth exposure may protect against the development of MS, and may even be able to slow the progression of this disease. 

T. suis, the porcine whipworm, is a helminth naturally infecting pigs. It can transiently colonize humans, but generally cannot survive long in the human gut, and has not been observed to cause human disease. In small, unblinded trials, treatment with T. suis ova (TSO) was found to be safe and effective in active in treating inflammatory bowel disease.

While there are some anecdotal reports of MS patients whose symptoms improved with the administration of helminths (helminthic therapy), there has been little in the way of published studies. Correale and colleagues followed 12 patients with MS and various helminth infections for an average of 4.5 years and noted fewer exacerbations, less disease progression and less disease activity on magnetic resonance imaging (MRI) than 12 matched uninfected controls (1). Helminth-infected individuals also had less pro-inflammatory cytokines than non-infected subjects (2).

In 2021, Fleming and colleagues (3) published a Phase 1 trial of 5 treatment-naive relapsing-remitting multiple sclerosis subjects who were given 2500 TSO orally every 2 weeks for 3 months in a baseline versus treatment control exploratory trial. The treatments were well tolerated, MRI lesions decreased, and favorable changes is cytokine levels (increases in IL-4 and IL-10) were measured. The same year, Benzel and colleagues (4) published their studies of 4 MS patients treated with TSO for 6 months. These researchers demonstrated a slight decrease in interleukin (IL)-2, a temporary increase of IL-4, and a mild eosinophily, all suggesting that TSO therapy had a moderate beneficial immunomodulatory impact in MS.

Given these encouraging results, the authors of the present study “conducted a 20-week phase IIa baseline-to-treatment trial to evaluate the safety and efficacy of treatment with TSO in relapsing MS.” Their study design was a prospective randomized pilot study of safety and efficacy, with baseline-to-treatment comparisons of clinical findings and blindly assessed MRIs. The 6-week baseline or run-in period was followed by an early (6-week) and late (6 week) treatment periods, with assessments at the beginning and end of each 6-week interval. The intervention (treatment) consisted of an aqueous suspension 2500 TSO per treatment (15 ml) administered in the outpatient clinic every two weeks (total of 6 doses over the 12 weeks of treatment).

Subjects were recruited from among those with relapsing forms of MS for more than a year, at the outpatient clinic at the Danish Multiple Sclerosis Center in Copenhagen. Subjects needed to be between 19 and 55 years old, with an Expanded Disability Status Scale score ⩽ 5.5, no or unchanged IFN-β therapy for the previous three months, at least two documented relapses during the prior 2 years (at least one of which was within the prior 1 year), and MRI results meeting the Barkhof criteria for MS. Subjects were excluded if they received steroids in the previous month, received previous treatment with cyclophosphamide, mitoxantrone or other intensive immunosuppression, received total body irradiation or any experimental therapy, received treatment with azathioprine or any immunomodulatory drug apart from IFN-β within 6 months prior to enrolment, stayed in tropical areas during the preceding 3 months or had a history of current pregnancy or breastfeeding, cardiac diseases, malignant hypertension, diabetes mellitus, renal insufficiency, concurrent systemic infections with hepatitis B or C virus or HIV, or any medical or psychiatric condition that could interfere with the subject’s participation in the study protocol.

Primary endpoints of efficacy were the number of new or enlarging lesions on T2-weighted MRI scans performed at baseline and every 6 weeks. Secondary endpoints were the number

of gadolinium enhancing lesions in T1-weighted MRI scans and the number of documented relapses. Standard safety parameters were monitored to assess overall safety. Blood samples were obtained at baseline and after 6 and 12 weeks of therapy for the analysis of cytokine gene expression. MRI and immunological results were analyzed using the non-parametrical chi-square contingency table and Friedman tests with post hoc Kruskal–Wallis tests corrected for multiple comparisons yielding a level of statistical significance at p = 0.025. Safety data was assessed using descriptive statistics.

Findings

Ten subjects were enrolled in the study. Six were treated with IFN-β during the study; four patients did not receive any immunomodulating drugs. Four patients missed one MRI scan (no. 2) and one patient missed two scans (no. 2 and 4) due to renovation of the MRI scanner. Due to technical problems with a too-short interval between injection of gadolinium contrast and the T1-weighted MRI scan, the count of the number of contrast-enhancing lesions was unreliable and had to be omitted.

The total number of new and/or enlarged T2 lesions was 6 lesions in the pre-treatment scans, 7 lesions in the early treatment period, and 21 lesions in the later treatment period (p = 0.034). The number of patients with new and/or enlarged T2 lesions was three in the pre-treatment period, two in the early, and eight in the later treatment period. Two patients experienced a relapse during the baseline period; two patients experienced relapses in the late treatment period.

No serious adverse events were reported during the study. Four subjects complained of abdominal discomfort or pain, mostly mild, lasting from days to several weeks. Two patients reported flatulence and one of these patients also had diarrhea. Except for eosinophilia, all other

blood parameters showed no significant changes.

For the whole patient group, the blood eosinophil count was significantly higher at 6 weeks (p = 0.02) and twelve weeks (p = 0.01) than at baseline. No significant difference was found in the level of gene expression for any of the cytokines tested:  Th1 cytokines and transcription factors IFNG, TBX21, HLX1 or EOMES; the Th2 transcription factor GATA3; the Th17 transcription factor RORC; regulatory cytokines and the transcription factor FOXP3, IL10 and TGFB1; the antigen-presenting cell cytokines IL1B, IL12A, IL12B, IL23A, IL27 and EBI3; the tumor necrosis factor superfamily molecules TNF, LTA, LTB and TRAIL; or the matrix metalloproteinase MMP9, TIMP1 or SPP1 molecule.

Discussion

This study is not new (it was published in 2015), but it is the latest helminthic therapy clinical trial to be published, and it is an important contribution on several levels.

The authors successfully demonstrated with this small but rigorous study that TSO is a relatively safe modality, having found no serious adverse events after 12 weeks of use. This is consistent with earlier studies of TSO – in MS patients and non-MS patients – where mild GI complaints are the only side effects attributable to TSO.

However, the authors also demonstrated no clinical benefit for the 10 MS subjects from TSO, in the dosage used. The authors concluded that “treatment with TSO is safe and well tolerated, but was without any trend towards a positive effect on disease activity when administered to patients with relapsing MS. Hence, we found it unjustified to embark on the planned double-blind, placebo-controlled phase II study.”

The authors should be congratulated for having published their work, and the publisher congratulated for printing it, since often studies that fail to prove the desired hypothesis do not see the light of day. The reason? As a result of these findings, some have described this study as a “failure,” or worse yet, they have described helminthic therapy as a failure, at least as a possible treatment for MS. I prefer the interpretation of Thomas Edison, who is reported to have said: “I have not failed. I've just found 10,000 ways that won't work.” Voldsgaard and colleagues may have proved that this treatment did not work, but what treatment will work? What comes next? A different dose or frequency of administration? A different helminth? A different subset of MS patients, or a different target illness altogether?

The authors go through this very process of examination when reviewing their findings. They clearly gave it the same careful thought when designing the project. Prior research with TSO for MS and other disorders used the same dose. Perhaps there was a difference in the method of preparation of the reagents. Perhaps some of the TSO was less viable than normal, or prepared in a different way (which would explain not only why there was no clinical benefit, but also why there was no significant change in immunological cytokines). While MS is probably a heterogeneous disease, and as such, patients should not all be expected to respond to any treatment in the same way, reviewing the subject profiles did not allow me to identify any characteristic that might select a subset of potential responders for the next clinical trial.

What? Another clinical trial? Didn’t the authors state that they found it “unjustified to embark on the planned double-blind, placebo-controlled phase II study.” Yes, they did, but that was a large, expensive trial. But I hope they or someone else will be willing to try another small clinical trial of helminthic therapy for MS, again. After all, if these researchers identified a significant improvement, we would not accept that as the final verdict, but rather would want to repeat the study, likely with additional twists, to make sure that the results were really valid and reproducible. So why not follow this study with another small, relatively inexpensive study – but with a different helminthic product, or a different treatment regimen – to test whether or not helminthic therapy really does not benefit MS. After all, the more we learn what does not work, the closer we get to finding out what does work.

ADDITIONAL  REFERENCES

1) Correale J and Farez M. Association between parasite infections and immune responses in multiple sclerosis. Ann Neurol 2007; 61: 97–108.

2) Correale J and Farez M. Helminth-infections associated with multiple sclerosis induce regulatory B cells. Ann Neurol 2008; 64: 187–199.

3) Fleming JO, Isaak A, Fabry Z, et al. Probiotic helminth administration in relapsing–remitting

multiple sclerosis: A phase 1 study. Multiple Sclerosis 2011; 17(6): 743–754.

4) Benzel F, Erdur H, Rosche B, et al. Immune monitoring of Trichuris suis egg therapy in multiple

sclerosis patients. J Helminthology 2012; 86(3): 339–347.