Pharmacokinetics, adverse effects and tolerability of a novel analogue of human pancreatic polypeptide, PP 1420

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Human pancreatic polypeptide (hPP) is a natural pancreatic hormone that suppresses appetite after meals.• When exogenous hPP is given to healthy human volunteers, it causes a reduction in food intake.• PP 1420 is a longer acting analogue of hPP that has been developed as a novel treatment for obesity.WHAT THIS STUDY ADDS• PP 1420 has been shown to be well tolerated in healthy human volunteers.• PP 1420 has been shown to have an extended terminal elimination half‐life compared with hPP.AIMS The objectives of this phase 1 study were to confirm the tolerability of single ascending subcutaneous doses of PP 1420 in healthy subjects, to assess its adverse effects and to investigate the drug's pharmacokinetics and dose proportionality.METHODS This was a double‐blind, placebo‐controlled, randomized study. There were three dosing periods. Each subject (n= 12) was randomized to receive one dose of placebo and two ascending doses of PP 1420, given as a subcutaneous injection. Blood samples were taken over 24 h to assess pharmacokinetics. Standard safety and laboratory data were collected. The primary endpoint was the tolerability of PP 1420. The secondary endpoint was exposure to PP 1420 as assessed by Cmax and AUC(0,∞).RESULTS PP 1420 was well tolerated by all subjects with no serious adverse effects. Following single subcutaneous doses of PP 1420 at 2, 4 and 8 mg to male subjects, Cmax was reached at a median tmax of approximately 1 h post dose (range 0.32–2.00 h). Thereafter, plasma concentrations of PP 1420 declined with geometric mean apparent terminal elimination t1/2 ranging from 2.42–2.61 h (range 1.64–3.95 h) across all dose levels.CONCLUSIONS Subcutaneous PP 1420 was well tolerated in healthy human subjects at single doses between 2–8 mg, with no tolerability issues arising. Where observed, adverse events were not serious, and there was no evidence of a dose‐relationship to frequency of adverse events. The results therefore support the conduct of clinical trials to investigate efficacy, tolerability and pharmacokinetics during repeated dosing.

Obesity: Lifestyle management, bariatric surgery, drugs, and the therapeutic exploitation of gut hormones

“…Intravenous infusion of PP has been shown to achieve food intake reduction of 25% over 24 hours in lean healthy volunteers [117]. Furthermore, a Phase Ia clinical trial of PP1420, a long-acting potent PP analog, showed promise in terms of safety and tolerability profile when given as a subcutaneous injection [118]. Phase Ib and Ic studies, which will focus on further safety and efficacy parameters such as food intake, at various ascending doses, are currently in progress (ClinicalTrials.gov identifier: NCT01052493).…”

New Perspectives on the Development of Antiobesity Drugs

“…Evidence: low MW FTO inhibitors; in vitro assays [177] hPP: this is a peptide secreted by the PP cells of the islets of Langerhans, that binds to the Y4R in the CNS. Evidence: PP1420, a peptide analog of hPP, reduces food intake (Phase I studies) [178] FGFR4: this protein is expressed mainly in hepatocytes and is involved in energy homeostasis and hepatic bile acid metabolism. Evidence: effect of ASO in DIO mice [179] TGR5 receptor: its activation leads to secretion of GLP-1 and other related incretins in gut enteroendocrine cells and to a decrease in LPS Th1 cytokines like TNF-α and IL-12 in monocytes/macrophages and dendritic cells.…”

The future role of gut hormones in the treatment of obesity

“…Thus, long-acting analogues of PP have been developed in order to overcome the short t 1/2 and the need to deliver peptide as an infusion. Bloom and colleagues published their phase I study of a PP analogue, PP1420, last year [Tan et al 2012]. They altered the amino acid sequence of PP adding a glycine residue at position 0, and substituting various other amino acids to make the analogue peptidase resistant.…”