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

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Abstract

Background

Celiac disease is the most common hereditary autoimmune disease in humans. The only treatment option for non-refractory celiac disease patients is adherence to a strict life-long gluten-free diet, which often fails to normalize small bowel histology. ALV003 is a mixture of two proteases that degrades gluten and is in clinical development as an oral therapy for patients with celiac disease.

Aims

The safety, tolerability, and activity of ALV003 were assessed in two phase 1 clinical trials.

Methods

In study 1 (N = 28) the study drug was administered in the fasted state; in study 2 (N = 53) the study drug was administered together with a gluten-containing meal. Both studies were single-dose, single-blind, placebo-controlled, cross-over trials. ALV003 was dosed at escalating dose levels by cohort (100, 300, 900, and 1,800 mg) and gastric samples were aspirated using a nasogastric tube. Adverse events, serum drug levels, and anti-drug antibody titers were measured. Gastric samples were assessed for ALV003 enzymatic activity over time (gastric pharmacokinetics) and gluten degradation (gastric pharmacodynamics).

Results

All doses were well tolerated, and no serious adverse events or allergic reactions were observed. Gastric aspirates collected 30 min following a meal showed that 100 and 300 mg ALV003 degraded 75 ± 10% (N = 8) and 88 ± 5% (N = 8), respectively, of one gram of wheat bread gluten.

Conclusions

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.

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Acknowledgments

We acknowledge David A. Wagner from Metabolic Solutions, Inc. for data collection and analysis of 13C-acetate data. We acknowledge Biomedal S. L. for generously providing the A1 antibody. We also acknowledge Kirk Essenmacher for critical examination and helpful comments during manuscript preparation.

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Authors and Affiliations

  1. Alvine Pharmaceuticals, 75 Shoreway Road, Suite B, San Carlos, CA, 94070, USA

    Matthew Siegel, Mitchell E. Garber, Andrew G. Spencer, Wendy Botwick, Pawan Kumar, Robert N. Williams, Kenji Kozuka, Revati Shreeniwas & Daniel C. Adelman

  2. Clinical Applications Laboratories, 3330 Third Ave #303, San Diego, CA, 92103, USA

    Vijaya Pratha

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  1. Matthew Siegel
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  2. Mitchell E. Garber
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Correspondence to Matthew Siegel.

Additional information

Matthew Siegel, Mitchell E. Garber, and Andrew G. Spencer contributed equally to this work.

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Siegel, M., Garber, M.E., Spencer, A.G. et al. Safety, Tolerability, and Activity of ALV003: Results from Two Phase 1 Single, Escalating-Dose Clinical Trials. Dig Dis Sci 57, 440–450 (2012). https://doi.org/10.1007/s10620-011-1906-5

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