Safety, Tolerability, and Activity of ALV003: Results from Two Phase 1 Single, Escalating-Dose Clinical Trials

Siegel, Matthew; Garber, Mitchell E.; Spencer, Andrew; Botwick, Wendy; Kumar, Pawan; Williams, R.; Kozuka, Kenji; Shreeniwas, Revati; Pratha, Vijaya S.; Adelman, Daniel C.

doi:10.1007/s10620-011-1906-5

Cited by 94 publications

(66 citation statements)

References 33 publications

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“…The glutenase ALV003 has been shown to be safe, well tolerated, and during the clinical studies no serious adverse events or allergic reactions have been observed [33]. Moreover, it has been found to be highly effective in degrading gluten primarily in the stomach before it reached the duodenal compartment.…”

Section: Clinical Studies With Glutenasesmentioning

confidence: 99%

Novel Treatments for Celiac Disease: Glutenases and Beyond

Kaukinen

Lindfors

2015

Dig Dis

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Currently, the only effective treatment for celiac disease is a strict lifelong gluten-free diet. However, gluten-free dieting is restrictive, difficult to maintain and nutritionally less than optimal. The improved knowledge on celiac disease pathogenesis has enabled researchers to suggest alternative strategies to treat the disorder. The drug development poses a challenge as any novel drug for celiac disease should be simultaneously effective and as safe as the gluten-free diet. The rationale behind enzyme supplementation therapy as a future treatment option for celiac patients lies in the fact that gluten is only poorly digested by gastrointestinal proteases. Due to incomplete degradation in the gastrointestinal tract, fairly long gluten peptides enter the small-intestinal lumen and come into contact with the mucosal epithelium, and in celiac disease patients this encounter launches deleterious downstream effects. Enzyme supplement therapy using either bacterial or fungal endopeptidases or proteases from germinating cereals has been proposed to promote complete digestion of prolamins and destroy disease-inducing gluten peptides. A major advantage of these glutenases is that they work in the lumen of the small intestine and do not themselves take part in the immunological cascade of events in the lamina propria, thus being unlikely to cause harmful side effects to the host. Studies to test this rationale, e.g. with Aspergillus niger prolyl endoprotease and a combination enzyme product ALV003, are already ongoing. The development of a novel medication for celiac disease is still in its early days, and thus the conventional dietary treatment will hold its place for the time being.

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Section: Clinical Studies With Glutenasesmentioning

confidence: 99%

Novel Treatments for Celiac Disease: Glutenases and Beyond

Kaukinen

Lindfors

2015

Dig Dis

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“…SC PEP and EP-B2. The latter is the selfactivating isoform 2 of cysteine endoprotease B from germinated barley seeds, a glutamine-specific endoprotease particularly resistant to low pH and pepsin (44). In a phase I clinical trial (NCT00669825), ALV003 was applied as a powder dissolved in water via a nasogastric tube subsequent to a gluten-containing meal (1 g of gluten).…”

Section: Oral Enzyme Supplementationmentioning

confidence: 99%

“…In a phase I clinical trial (NCT00669825), ALV003 was applied as a powder dissolved in water via a nasogastric tube subsequent to a gluten-containing meal (1 g of gluten). Apart from being well tolerated, three hundred mg of ALV003 degraded 80% of administered gluten, which was significantly different from placebo (44). A phase IIa study showed the capacity of nine hundred mg of ALV003 to protect against smallintestinal mucosal injury and to reduce IEL density compared to placebo after a 6 weeks daily gluten challenge (2 g gluten/day) (45).…”

Section: Oral Enzyme Supplementationmentioning

confidence: 99%

Celiac Disease: A Challenging Disease for Pharmaceutical Scientists

2012

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Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten-containing grains that affects~1% of the white ethnic population. In the last decades, a rise in prevalence of CD has been observed that cannot be fully explained by improved diagnostics. Genetic predisposition greatly influences the susceptibility of individuals towards CD, though environmental factors also play a role. With no pharmacological treatments available, the only option to keep CD in remission is a strict and permanent exclusion of dietary gluten. Such a gluten-free diet is difficult to maintain because of gluten's omnipresence in food (e.g., additive in processed food). The development of adjuvant therapies which would permit the intake of small amounts of gluten would be desirable to improve the quality of life of patients on a glutenfree diet. Such therapies include gluten-degrading enzymes, polymeric binders, desensitizing vaccines, anti-inflammatory drugs, transglutaminase 2 inhibitors, and HLA-DQ2 blockers. However, many of these approaches pose pharmaceutical challenges with respect to drug formulation and stability, or application route and dosing interval. This perspective article discusses how pharmaceutical scientists may deal with these challenges and contribute to the implementation of novel therapeutic options for patients with CD.

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“…The potential targets identified for the development of a medical treatment for CD include the improvement of gluten degradation in order to reduce its immunotoxicity. This effect could be achieved by means of oral administration of proteases able to improve gluten degradation in the stomach, before its entry in the duodenum [8][9][10] . Alternatives could be the development of non-immunogenic varieties of gluten [11] or of probiotics able to detoxify gluten [12] .…”

Section: Introductionmentioning

confidence: 99%

Celiac Disease and Drug-Based Therapies: Inquiry into Patients Demands

et al. 2016

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Background/Aim: Medical research is looking for alternative drug-based options to the gluten-free diet (GFD) for celiac disease. We aimed at evaluating the need for alternative therapies perceived by celiac patients. Methods: During the 2013 meeting of the Lombardy section of the Italian Celiac Patients Association, adult subjects were invited to fill in a questionnaire investigating their clinical profile in relation to compliance to the diet, quality of life (QOL) as well as their opinion on alternative therapies. Results: Three hundred and seventy two patients (76 m, mean age 41.7 ± 13.9 years) completed the questionnaire. Patients reported a significant improvement in health status (HS) and QOL after the diet was started (p < 0.001). The GFD was accepted by 88% patients, but the need for alternative therapies was reported by 65%. Subjects expressing the need for a drug-based therapy showed a lower increase in QOL (p = 0.003) and HS (p = 0.005) on GFD. The preferred option for an alternative therapy was the use of enzymes (145 subjects), followed by a vaccine (111 subjects). Conclusion: The GFD is favorably accepted by most celiac patients. Nevertheless, a proportion of patients pronounce themselves in favor of the development of alternative drugs.

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Safety, Tolerability, and Activity of ALV003: Results from Two Phase 1 Single, Escalating-Dose Clinical Trials

Abstract: ALV003 is an orally active protease that appears to be stable in the fed stomach and degrades dietary gluten in this compartment. Single doses of oral ALV003 were not associated with serious adverse reactions.

Cited by 94 publications

References 33 publications

Novel Treatments for Celiac Disease: Glutenases and Beyond

Novel Treatments for Celiac Disease: Glutenases and Beyond

Celiac Disease: A Challenging Disease for Pharmaceutical Scientists

Celiac Disease and Drug-Based Therapies: Inquiry into Patients Demands

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