Lessons learned from the clinical development of oral peptides

Abstract

The oral delivery of peptides and proteins has been hampered by an array of obstacles. However, several promising novel oral delivery systems have been developed. This paper reviews the most advanced oral formulation technologies, and highlights key lessons and implications from studies undertaken to date with these oral formulations. Special interest is given to oral salmon calcitonin (CT), glucagon-like peptide-1 (GLP-1), insulin, PYY-(3-36), recombinant human parathyroid hormone (rhPTH(1-31)-NH2) and PTH(1-34), by different technologies. The issues addressed include (i) interaction with water, (ii) interaction with food, (iii) diurnal variation, (iv) inter- and intra-subject variability, (v) correlation between efficacy and exposure and (vi) key deliverables of different technologies. These key lessons may aid research in the development of other oral formulations.

Keywords: bone; calcitonin; cartilage; clinical trial; diabetes; oral formulation.

Figure 1

Linear relationship between plasma sCT concentrations and reduction in CTX-I. Reproduced from with permission

Figure 2

Barriers to oral delivery of peptides

1. Acidic milieu in the stomach induces need for protection of peptide, i.e. protection against acid-mediated degradation is essential through a coating or a chemical modification

2. Removal of acid protective coat needed to ensure exposure and allow uptake

3. Uptake across the tight junctions in the epithelium, made difficult by the presence of tight junctions sealing off the lumen from the surrounding regions to ensure that only ‘the right material’ gets taken up. Requires permeability enhancers

Figure 3

Pharmacokinetic parameters from a phase 2 proof of concept study with oral tablet formulation of PTH(1-31)NH₂. A 6 month phase 2 study was carried out to compare the bone anabolic response of oral PTH(1-31)NH₂ with that of s.c. PTH1-34 (Forsteo®) by measurement of lumbar spine bone mineral density (BMD). Blood samples were collected after the first dose (week 0) and at the end of the study (week 24). Samples were analysed with a sandwich ELISA assay that specifically measures only the intact PTH molecules. Figure reprinted from with permission. , PTH(1-31)NH₂ (week 0); , PTH(1-31)NH₂ (week 24); , Forsteo (week 0); , Forsteo (week 24). *time relative to t_max for oral PTH

Figure 4

One year double-blind placebo controlled phase 3 study conducted by Tarsa Therapeutics comparing orally delivered salmon calcitonin with a nasal spray calcitonin product (Miacalcin®). Change in lumbar spine bone mineral density (BMD) from baseline to week 48. Figure reprinted from with permission. , rsCT tablet; ,nasal spray; , placebo

Figure 5

Continuous blood glucose measurements (full traces) and standard errors (dotted traces) before and after treatment with ORMD-0801. Reproduced from . , pretreatment; , ORMD-0801