A collaborative model for drug development for rare diseases

This month’s issue holds an article by Fiorentino et al. putting forward a model for rare disease drug development and the first realization of this model (J Allergy Clin Immunol 2012;130:613-616). Fiorentino and colleagues at the FDA in CDER’s Division of Gastroenterology and Inborn Error Products chose the rare disease eosinophilic esophagitis (EoE) as the focus of their efforts to establish this new paradigm.

Noting the rise in prevalence and incidence of EoE, the authors discuss the knowledge gaps that create obstacles to effective clinical interventions. They use this information to construct their model of “rational” drug development, which includes defining the disease in clinical, research and sociocultural terms, evaluating the natural history of the disease using the definitions identified, and reliably assessing clinical and patient-reported outcomes.

Fiorentino et al. describe their efforts to date implementing this model. They tapped critical research groups, such as The International Gastrointestinal Eosinophil Researchers (TIGERs), North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) to open discussions on disease definition and urge the inclusion of disease and patient advocacy groups in this early process. Advocacy groups are identified as critical to the success of the model because they bring strong interest in the long-term success of research into the disease.

Early progress is reported for the determination of a functional disease definition and appropriate terminology. The authors note that findings from graduate student research supported by the EoE project demonstrate that inconsistent and vague terminology is impeding research efforts. Additionally, they comment that research is underway to understand the relationship between positive clinical outcomes and the esophageal mucosal eosinophilia that is diagnostic for EoE. They point out that there is a pressing need to define and characterize the EoE patient population in order to develop appropriate patient-reported outcome measures.

An editorial in this issue by Rothenberg et al. presents additional perspectives and considerations (pp#). Dr. Rothenberg notes that an upcoming meeting (Sept. 19) provides an opportunity for more information and exchange of opinion about the subject. For further information: https://www.signup4.net/public/ap.aspx?EID=20123759E&OID=50

A large cohort analysis of allergic outcomes from peanut and tree nut consumption during pregnancy

Current research has challenged the conventional wisdom of dietary avoidance of food allergens during pregnancy. A recent study from the UK found that avoidance of peanuts, specifically, during pregnancy did not confer significant protection from peanut allergy to the infant. Accordingly, the UK removed that recommendation. In the US, avoidance is only recommended for children at risk by heredity.

In this issue, Maslova et al. (J Allergy Clin Immunol 2012;130:724-732) from Center for Fetal Programming, Statens Serum Institut, present important results from an analysis of a very large Danish birth cohort (n=61,908). The authors look at development of asthma, wheeze, and allergic rhinitis – not food allergy – in children whose mothers consumed peanuts and tree nuts during pregnancy as compared to children whose mothers avoided these foods.

At 18 months, children whose mothers ate peanuts more than once a week were less likely to have parent-reported asthma, while children whose mothers ate tree nuts were less likely to report asthma, wheeze and recurrent wheeze. At 7 years, children of mothers who ate peanuts and/or tree nuts were less likely to have a registered diagnosis of asthma. These results all reached statistical significance. The association of tree nut consumption during pregnancy with decreased likelihood of self-reported allergic rhinitis during the first 7 years of life was borderline statistically significant.

Maslova et al conclude by suggesting that their results do not support avoidance or decreased consumption of peanuts and tree nuts during pregnancy. 

Secretory phenotype of mast cells localized in nasal polyps from chronic rhinosinusitis subjects

Takabayashi et al. present novel findings in this issue on the distribution and protease secretion of mast cells (MC) found in nasal polyps from subjects with chronic rhinosinusitis (CRSwNP) (J Allergy Clin Immunol 2012; 130:410-420.e5). The authors compared MC from the epithelium, glands, and submucosa of CRSwNP with uncinate biopsy tissue (UT) from subjects with CRS without nasal polyps (CRSsNP) and control subjects.

They found mast cells numbers were highly increased in NP epithelium and glands, in particular, as compared to UT from CRSsNP and control subjects. Further, the MC populations in NP were distinguishable on the basis of their protease profile. Mast cells from the NP epithelium were tryptase-carboxypeptidase A3 (CPA3)-positive/chymase-negative, while MC from NP glands were tryptase-CPA3-chymase-positive.


The authors note clear expansion in MC numbers that they suggest could be the result of increased migration and accumulation as well as proliferation. Since mast cell tryptase can activate protease-activated receptor (PAR) 2, which facilitates allergic inflammation, and mast cell chymase can activate PAR-1 signaling and is a potent glandular secretagogue, the results of Takabayashi et al suggest that mast cells localized in submucosal glands may be well positioned to drive important features of the inflammatory response associated with chronic rhinosinusitis and nasal polyp formation.

Association between traditional farming and childhood wheeze from the GABRIEL Advanced Study Group

The European GABRIEL Advanced Studies project has provided a large body of data and samples for investigating effects of traditional farm environments on childhood asthma and atopy. Research on the GABRIELA cohort has demonstrated that traditional farming environments like those found in Europe have a protective effect on childhood atopy and, less consistently, childhood asthma. Yet, recent findings show that microbial diversity in farming environments appears to play a stronger role for asthma than for atopy. This month’s issue holds another important report on the impact of farm life on different childhood wheeze phenotypes by Fuchs et al. (J Allergy Clin Immunol 2012;130:382-388.e6).

Fuchs et al note that there are different wheeze phenotypes that correlate to different clinical outcomes, and that comorbid atopy complicates the search for wheeze-specific farm effects. To address this, the authors partition the study population into atopic and non-atopic children. In addition to analyzing the farm effect on atopy, they further investigate the effect on different wheeze phenotypes (transient, current, persistent, late-onset), airway inflammation and lung function for atopic and non-atopic children, separately.

They report that farm environment has a significant beneficial effect on all wheeze phenotypes. This protective effect was independent of atopic sensitization. This was different for lung mechanics as measured by lung function and on airway inflammation, on which farming had no appreciable overall effect. However, farm-exposed atopic children had less severe lung function impairment and lower exhaled nitric oxide (FeNO) than non-exposed atopic children.

Fuchs et al. speculate that farming’s protective effects are mediated through antiviral activities of the innate immune system that minimize respiratory infections. Future steps in their research to better elucidate underlying mechanisms will be analyses in prospective setups and studies further including the analysis of innate and adaptive immune mechanisms related to defense against viral infections and the role of the microbiome in upper and lower airways herein.

Anti-IL17 mAb shows promising results in psoriasis treatment

Exciting – and surprising – results from a clinical trial for psoriasis are presented in this month’s issue by Krueger et al (J Allergy Clin Immunol 2012;130:145-154.e9). The authors report on a randomized trial of a new humanized IgG₄ monoclonal antibody, ixekizumab. It would be fair to say the results from their phase I trial are near astonishing.

Based on published evidence that psoriasis is a T_H17-mediated disease, the authors postulate that IL-17 acts as a “gatekeeping” cytokine in the pathogenesis of psoriasis, noting that much of the evidence from animal studies points to IL-22. They point out that IL-22 in humans is produced from a different T cell subset, T_H22 cells, unlike mice where T_H17 cell produce both.

Their speculation paid off. Krueger et al. report dose-dependent, significant improvement in both pathophysiology and clinical presentation of psoriasis subjects after only 2 weeks of ixekizumab treatment. Skin biopsies from subjects demonstrated rapid improvements in keratinocyte proliferation, hyperplasia, epidermal thickness, T cell and dendritic cell infiltration of the dermis and significantly suppressed expression of innate immunity peptides. After 6 weeks of treatment, the authors report that subjects’ skin appeared normal. Interestingly, 100% of subjects in the 150mg dosing group no longer presented clinically with psoriasis at 6 weeks of therapy. Krueger et al. comment that the effectiveness of ixekizumab at 2 and 6 weeks was surprising since other antibody therapies typically require 12 weeks to demonstrate efficacy. They also note that the adverse effects profile is agreeable and the drug well-tolerated.

Noting that many genes associated with psoriasis are co-regulated by IL-17 and TNF-α, Krueger et al. show that IL-17 blockade with ixekizumab is far more effective in suppressing the co-regulated genes than TNF-α blockade by etanercept. They suggest that their evidence shows that IL-17 is a pivotal cytokine in the pathology of psoriasis, affecting many effector functions of other T cell subsets.  

Immunomodulation of allergic disease by nematode infection

The consistent observation that developing countries have very low frequencies of atopy and allergic diseases has been correlated with environmental exposure to helminth infection. The hygiene hypothesis has been proffered to account for these observations as it has to explain protective effects of living on traditional farms. Small numbers of pilot and proof-of-concept trials have been looking at the nematode-allergy connection as possible therapy for a number of diseases.

This month’s issue presents a review by Jouvin and Kinet (J Allergy Clin Immunol 2012;130:3-10) of this pioneering research and the preliminary results that suggest that certain helminths may be human symbionts rather than parasites.

Jouvin and Kinet begin with an overview of current research into nematode therapy for inflammatory bowel and autoimmune diseases, employing Trichurus suis ova (TSO), or pig whipworm, to treat patients with Crohn’s Disease (CD), ulcerative colitis (UC) and multiple sclerosis (MS). The trials were very small, from 4 subjects to 54 subjects, with safety and tolerability as the endpoints.  There were no AEs reported in the CD and UC trials, and mild GI distress and transient eosinophilia in the MS trial that resolved without subjects dropping out from the studies. Stool specimens collected were all negative for ova and parasites, except an isolated sample in the MS trial. These limited safety results were sufficient for FDA to approve an open-label efficacy study of TSO in MS.

Jouvin and Kinet review the basics of the hygiene hypothesis and discuss the epidemiological and animal evidence for immunomodulatory effects of helminths, as well as limited results of helminth treatment in Western countries. The authors also cover the logic supporting the choice of TSO, in particular because it is not a known human pathogen.

They summarize the safety findings of published research and note their own experience with TSO in the treatment of peanut or tree nut allergy, which was consistent with other reports of transient, mild GI side effects and eosinophilia. Secondary efficacy reports are also included, with some preliminary findings being promising: in a study of CD, 70% of subjects attained remission at the end of the study; in a UC trial, 43% in the treatment group had improved disease compared to 17% in the control group; and in an MS study, a  lower rate of appearance of new lesions imaged by MRI was observed during active treatment. The authors also present an interesting single case report on nematode treatment for autism.

Jouvin and Kinet discuss the potential of other nematodes as therapeutic agents then review the biochemistry of helminth extracts, noting that a phosphorylcholine glycoprotein, ES-62, has been isolated as an effector molecule. They comment that ES-62 prevent mast cell activation and modulate T_H17 responses. Also, ES-62 has been shown to require TLR4 for its activity.

The authors conclude that TSO as seen from very preliminary data is safe and well tolerated, and limited data suggests it ameliorates certain autoimmune diseases. They urge continued research on the mechanisms and optimal dosing to achieve immunomodulation. 

Back to beginnings of farming for answers to protection against allergies and atopy

On behalf of the GABRIEL Advanced Studies Group supported by the European Commission, Illi et al. (J Allergy Clin Immunol 2012;129:1470-1477) provide their results from a survey study designed to address the high variability in reported protective effects associated with farm environments on asthma and allergies (pp#). The study group survey was structured into two phases with questions in phase II targeting exposure to specific elements of the farm environment. Farms were placed in one of three categories depending on farm activities and husbandry: farms with no dairy cows or cattle, but other farm animals, and grain cultivation, farms with dairy cows and/or cattle, but no grain cultivation, and finally, farms with dairy cows and/or cattle, and grain cultivation. Survey queries covered exposure in utero to 3 years.

Illi et al. report that protective effects were highest and most broad for children raised on farms with both cows and cattle and agriculture activities. Exposure to cows, cows’ milk and straw had the greatest protective effect for asthma, exposure to fodder storage and manure were most protective on atopic dermatitis. Interestingly, the data collected could not sufficiently account for the protective effect against hay fever and atopic sensitization. Overall single exposure effect was greatest with cows’ milk, which greatly reduced the risk of asthma, hay fever and atopic sensitization. Exposure to straw had the strongest association with asthma protection, though the authors noted that the effects of individual constituents and contaminants in straw, such as manure, grass pollen, and microbial elements, could not be separated out.

Illi et al. comment that protective associations supported different physiological pathways, noting that cow exposure was associated with respiratory disease protection and cows’ milk association with atopic sensitization pointed to gut-mediated immune development.

The authors conclude that traditional farming environments like those established in humankind’s first non-nomadic lifestyle are the most beneficial from an immunologic natural history perspective. This can account for the variability in farm environment results since farming practices diverge greatly between the US and Central Europe.