MEDI7219 / AstraZeneca - LARVOL DELTA

In-vitro metabolite identification for MEDI7219, an oral GLP-1 analog, using LC-MS/MS with CID and EAD approaches. (PubMed, Bioanalysis) - "Oral peptide therapeutics typically have short half-lives due to rapid degradation by digestive enzymes. However, α-methyl-L-phenylalanine appeared to be well protected from chymotrypsin and pepsin digestion since no cleavage peptides ending with α-methyl-L-phenylalanine were observed. These study results provide further structural details explaining previously published stability data and provide new insights into potential GLP1 proteolytic liabilities for future engineering."

Journal • Preclinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • ELANE

Impact of chemical structure, lipidation and formulation on luminal stability and intestinal absorption of GLP-1 analogues. (PubMed, J Control Release) - "We compared four peptides: J211 (non-lipidated; modified), J229 (mono-lipidated; modified), MEDI7219 (bis-lipidated; modified), and semaglutide (mono-lipidated control; least modified)...These results demonstrate that C10 enhances peptide absorption primarily by increasing intestinal permeability but also likely by improving enzymatic stability of a labile peptide like semaglutide. Furthermore, when comparing the three modified peptides, the degree of lipidation positively correlated with increased intestinal absorption in both the presence and absence of C10."

Journal

Investigations of Enteric-Coated Tablet Propyl Gallate-Induced Nephrotoxicity in Beagles as well as Human and Dog Renal Proximal Tubule Epithelial Cells. (PubMed, ACS Pharmacol Transl Sci) - P1 | "During nonclinical development of an oral formulation for a glucagon-like peptide-1 (GLP-1) receptor agonist, MEDI7219, toxicology studies revealed that propyl gallate (PG), when administered in enteric-coated (EC) tablets, led to nephrotoxicity in beagles...Furthermore, to characterize the pharmacokinetics and metabolism of PG we developed a 10-plex, highly sensitive and robust LC-MS/MS-based quantification method for PG and its phase-I and phase-II metabolites. The methods were employed to support preclinical dog studies and clinical study (NCT03362593)."

Journal

Pharmaceutical Analysis of Protein-Peptide Coformulations and the Influence of Polysorbates. (PubMed, Mol Pharm) - "Their effects were assessed through their interactions with human serum albumin (HSA) and a glucagon-like peptide-1 (GLP-1) receptor agonist (MEDI7219)...Combining peptide and polysorbate did not further increase the thermal stability of HSA; however, it did reduce the unfolding of HSA molecules in the absence of heat. Overall, the unique findings in this study have demonstrated that the order of addition in a ternary coformulation affects the final composition which is an important consideration for pharmaceutical development."

Journal

A microfluidic in vitro method predicting the fate of peptide drugs after subcutaneous administration. (PubMed, Int J Pharm) - "The results from MIS studies of the peptide drugs exenatide, pramlintide, vancomycin, polymyxin B, lanreotide, MEDI7219 and AZD2820 are compared with results from measurements with the commercially available SCISSOR system and in vivo absorption and bioavailability data from the literature. A correlation is found between the 1st order release rate constant determined with SCISSOR and ka for lanreotide (Autogel), exenatide and AZD2820. A mechanism relating the magnitude of ka to the peptides' charge is proposed."

Journal • Preclinical

Experiences and Translatability of In Vitro and In Vivo Models to Evaluate Caprate as a Permeation Enhancer. (PubMed, Mol Pharm) - "All studies use solution formulation of sodium caprate, which has been widely used as a PE, and two macromolecules, being FITC-dextran 4000 Da and MEDI7219, a GLP-1 receptor agonist peptide. The paper shares our experiences of using these models and the challenges with the in vitro models in mimicking the processes occurring in vivo. The paper highlights the need to consider these differences when translating data generated using these in vitro models for evaluating macromolecules, PE, and combinations thereof for enabling oral delivery."

Journal • Preclinical

Systems Biology and Peptide Engineering to Overcome Absorption Barriers for Oral Peptide Delivery: Dosage Form Optimization Case Study Preceding Clinical Translation. (PubMed, Pharmaceutics) - "In addition to immediate- and enteric-coated formulations, we also tested a proprietary delayed release erodible barrier layer tablet (OralogiK) to deliver the payload to the target site in the gastrointestinal tract. The design of tablet dosage forms based on the optimization of formulations resulted in up to 10.1% absolute oral bioavailability in dogs with variability as low as 26% for MEDI7219, paving the way for its clinical development."

Journal • Gastrointestinal Disorder

Evaluation in pig of an intestinal administration device for oral peptide delivery. (PubMed, J Control Release) - "The variability in plasma concentrations of MEDI7219 were however lower when delivered using the IAD as compared to the solution and enteric coated capsule formulations. This suggests that dosage forms that can limit intestinal dilution and control the position of drug release can be a way to reduce the absorptive variability of peptides delivered with permeation enhancers but do not offer significant benefits in terms of increasing bioavailability."

Journal

Intestinal Absorption of FITC-Dextrans and Macromolecular Model Drugs in the Rat Intestinal Instillation Model. (PubMed, Mol Pharm) - "In this work, we studied the intestinal absorption of a peptide with a molecular weight of 4353 Da (MEDI7219) and a protein having a molecular weight of 11 740 Da (PEP12210) in the rat intestinal instillation model and compared their absorption to fluorescein isothiocyanate (FITC)-labeled dextrans of similar molecular weights (4 and 10 kDa)...Furthermore, to maximize the absorption of a macromolecule delivered together with C10, prolonging the duration of absorption appears to be important. In addition, the macromolecule needs to be stable enough in the intestinal lumen to take advantage of the prolonged absorption time window enabled by the permeation enhancer."

Journal • Preclinical

Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease. (PubMed, Sci Rep) - "In a dog model of obesity and insulin resistance, MEDI7219 oral tablets significantly decreased food intake, body weight and glucose excursions, validating the approach. This novel approach to the development of MEDI7219 provides a template for the development of other oral peptide therapeutics."

Journal • Diabetes • Gastrointestinal Disorder • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

A 6-Part Study In Healthy Volunteers To Evaluate Safety, Tolerability and Uptake Of MEDI7219 in the Body When Given as Single and Multiple Doses (clinicaltrials.gov) - P1; N=186; Terminated; Sponsor: MedImmune LLC; Trial completion date: Oct 2020 ➔ May 2020; Recruiting ➔ Terminated; Trial primary completion date: Oct 2020 ➔ May 2020; The program is canceled due to company strategic reasons.

Clinical • Trial completion date • Trial primary completion date • Trial termination

A 6-Part Study In Healthy Volunteers To Evaluate Safety, Tolerability and Uptake Of MEDI7219 in the Body When Given as Single and Multiple Doses (clinicaltrials.gov) - P1; N=162; Recruiting; Sponsor: MedImmune LLC; Active, not recruiting ➔ Recruiting

Clinical • Enrollment open

A 6-Part Study In Healthy Volunteers To Evaluate Safety, Tolerability and Uptake Of MEDI7219 in the Body When Given as Single and Multiple Doses (clinicaltrials.gov) - P1; N=162; Active, not recruiting; Sponsor: MedImmune LLC; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

A 5-Part Study In Healthy Volunteers To Evaluate Safety, Tolerability and Uptake Of MEDI7219 in the Body When Given as Single and Multiple Doses (clinicaltrials.gov) - P1; N=118; Recruiting; Sponsor: MedImmune LLC; Trial completion date: Sep 2019 ➔ Apr 2020; Trial primary completion date: Sep 2019 ➔ Apr 2020

Clinical • Trial completion date • Trial primary completion date

A 4-Part Study In Healthy Volunteers To Evaluate Safety And Tolerability Of The Test Medicine MEDI7219 and to See How it is Taken up by the Body When Given as Single and Multiple Doses (clinicaltrials.gov) - P1; N=104; Recruiting; Sponsor: MedImmune LLC; Trial completion date: Mar 2019 ➔ Sep 2019; Trial primary completion date: Mar 2019 ➔ Sep 2019

Clinical • Trial completion date • Trial primary completion date