GLP-1 New Drug R&D Service

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  In the formulation of GLP-1 integrated research plan, Medicilon has in-depth communication with customers. The backbone of scientific research has combined the characteristics of each case with years of practical experience and technical accumulation, and carefully submitted high-quality experimental plans and results to customers. Medicilon provides GLP-1 drug discovery, CMC research (API + formulation), pharmacodynamics research, PK study, GLP-1 safety evaluation and other services. As of the end of June 2023, Medicilon has successfully assisted in the clinical approval of 8 GLP-1 drugs (3 approved by FDA and NMPA，1 approved by FDA, NMPA, and TGA) and has multiple GLP-1 projects under development.

GLP-1 drug

• Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have multiple physiological effects such as hypoglycemia, hypotension, weight loss and vascular protection. The development of hypoglycemic drugs targeting GLP-1R is becoming a hot spot in the field of diabetes drug research and development in recent years.
  Glucagon like peptide-1 (GLP-1) is the second incretin identified in 1983. GLP-1 is a polypeptide that is mainly produced by intestinal L cells and is encoded by the proglucagon gene. GLP-1 exists in the human body in two active forms, GLP-1 (7-36 amide) and GLP-1 (7-37), with the proportion of GLP-1 (7-36 amide) being higher.

  GLP-1 mainly targets pancreatic islet cells and exerts its effects through specific receptors. GLP-1 also increases pancreatic β-cell proliferation by stimulating genes involved in cell proliferation and decreases the apoptosis of these cells by inhibiting caspase-3 expression. Furthermore, GLP-1 delays gastric emptying, suppresses glucagon secretion, and decreases gastrointestinal motility and nutrient ingestion. GLP-1 shows numerous actions in different tissues and a broad therapeutic potential. Therefore, GLP-1 plays a very active role both in the treatment and pathogenesis of diabetes.

  

  Multiple physiological effects of GLP-1^[1]
• Medications for diabetes comprise either GLP-1 receptor agonists, with short (one or two daily injections: Exenatide, Liraglutide, Lixisenatide) or long duration (one injection once weekly: extended-released Exenatide, Albiglutide, Dulaglutide, Taspoglutide); or oral compounds inhibiting dipeptidyl peptidase-4 (DPP-4), the enzyme that inactives GLP-1, also called gliptins (Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Alogliptin).

  GLP-1 drugs can be devided into:

  ❖ Short duration: one or two daily injections

  Exenatide, Liraglutide, Lixisenatide

  ❖ Long duration: one injection once weekly

  Extended-released Exenatide, Albiglutide, Dulaglutide, Taspoglutide

  ❖ Oral compounds inhibiting dipeptidyl peptidase-4 (DPP-4)

  The enzyme that inactives GLP-1, also called gliptins (Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Alogliptin).

  Differences between GLP-1R agonists and DPP-4 inhibitors：

  ❖ The mode of administration: subcutaneous injection versus oral ingestion

  ❖ The efficacy: better with GLP-1 agonists

  ❖ The effects on body weight and systolic blood pressure: diminution with agonists versus neutrality with gliptins

  ❖ The tolerance profile: nausea and possibly vomiting with agonists

  ❖ Cost: higher with GLP-1 receptor agonists

  Both agents may exert favourable cardiovascular effects. Gliptins may represent a valuable alternative to a sulfonylurea or a glitazone after failure of monotherapy with metformin while GLP-1 receptor agonists may be considered as a good alternative to insulin (especially in obese patients) after failure of a dual oral therapy. Intravenously administered GLP-1 has a biological half-time of approximately only 1–2 min. GLP-1 is degraded rapidly by the ubiquitous enzyme dipeptidyl-peptidase IV (DPP-4).
  
  Differences between GLP-1 receptor agonists and DPP-4 inhibitors^[1]

Service:

• CMC Research of GLP-1

  Medicilon can provide API process development and preparation R&D services for GLP-1 drugs. Medicilon has established a platform for the development of cGMP APIs and has developed GMP APIs for clinical trials for innovative drug companies. Medicilon team continues to assist the development of GLP-1 drugs through rigorous design of experiments (DOE), professional R&D technology, standardized project management, efficient communication, etc.

• Pharmacology Evaluation of GLP-1

  Medcilon provides mature models for for evaluating the efficacy of GLP-1 in vivo. Our animal models are all established and maintained under the regulation of AAALAC. Pharmacology studies are conducted according to GLP-like standards. At present, more than 300 tumor evaluation models in six categories have been established by Medicilon.
  Various laboratory animal species
  Rodents: Mouse/Rat, RabbitNon-Rodents: Beagle Dog, Mini Pig, Non-human Primate
  Medicilon Case:

  Active GLP-1 assay

  This study was conducted in a small, selected population of healthy subjects with normoglycaemia. The results suggest that Cetagliptin, at doses ≥50 mg once daily (QD), exhibited minimal accumulation, inhibited plasma DPP-4 activity by >80% over a 24-hour dosing interval, and increased active glucagon-like-1 peptide (GLP-1) levels without producing hypoglycaemia. The active GLP-1 assays were performed by Medicilon Preclinical Research LLC. Generally, Cetagliptin has favourable clinical tolerability and safety.

  

  Active GLP-1 Assay^[2]
  Recommend: Medicilon Assists CGeneTech's Oral Hypoglycemic DPP-4 Inhibitor, New Drug Application (NDA) Accepted

• Pharmacokinetic (PK) Studies of GLP-1

  Medcilon provides high quality quantitative assays for key pharmacokinetic parameters in a GLP-1 PK study, presenting accurate results.

  Medicilon Case: Pharmacokinetic (PK) studies

  
  Pharmacokinetic properties of Compound A
  The experimental results showed that Cmax and AUC(0-t) increase approximately in proportion to the dose increase. After a single subcutaneous administration of 0.04 mg/kg Compound A and 0.04 mg/kg Reference compound, the relative bioavailability was 83.17%.

Medicilon Assist Projects

• Semaglutide Injection (ZT001 Injection)

  On September 30, 2022, Beijing Peptide Biomedical Technology Co., Ltd. (Bejing Peptide) Semaglutide (ZT001) injection was officially accepted by CDE. Semaglutide is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management.
  As a partner of Bejing Peptide, Medicilon provides a full set of preclinical research services for Bejing Peptide semaglutide Injection.

• ZT002

  On August 29, 2022, Beijing Peptide Biomedical Technology Co., Ltd. (Bejing Peptide) ZT002 injection was approved by the Australian Human Research Ethics Committee for Phase I clinical trials. On October 5, Bejing Peptide's ZT002 completed the administration of the first participants in Phase I clinical trials in Australia. Under the guidance of the innovation strategy, the R&D pipeline of Bejing Peptide has been advanced efficiently and the results have been continuous, which reflects the outstanding ability of Bejing Peptide in the field of innovative research and development in the field of metabolic diseases.
  As a partner of Bejing Peptide, Medicilon provides pharmacodynamics services to ZT002 that comply with the application in China, US and Australia.
  Recommend:Medicilon assists Beijing Peptide's clinical application of semaglutide injection of semaglutide was accepted by CDE; ZT002 was promoted in China, US and Australia Filing

• MDR-001

  On December 26, 2022, MindRank announced US FDA clearance of IND application for MDR-001. MDR-001 is a novel, orally bioavailable small-molecule GLP-1R agonist discovered using MindRank's proprietary AI platform, Molecule Pro™. In the comprehensive preclinical studies, MDR-001 has demonstrated excellent functional potency and selectivity, with favorable ADME properties and oral bioavailability, as well as desirable pharmacokinetics and tolerability. MDR-001's superior preclinical efficacy and safety profiles indicate its best-in-class potential for obesity and type 2 diabetes mellitus indications with large unmet medical needs.
  As a partner of MindRank, Medicilon provides API process development and preparation R&D services for MDR-001.
  Recommend:Medicilon congratulates MindRank's GLP-1RA small molecule oral drug for successfully administering the first subject in clinical phase I

References:

• [1] Baptist Gallwitz. The evolving place of incretin-based therapies in type 2 diabetes. Pediatr Nephrol. 2010 Jul;25(7):1207-17. doi: 10.1007/s00467-009-1435-z.

  [2] Jinmiao Lu, et al. A double-blind, randomized, placebo and positive-controlled study in healthy volunteers to evaluate pharmacokinetic and pharmacodynamic properties of multiple oral doses of Cetagliptin. Br J Clin Pharmacol. 2022 Jun;88(6):2946-2958. doi: 10.1111/bcp.15209.

Service Cases

Learn more about "GLP-1 New Drug R&D Service"

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  [Video]Physiological Actions of GLP-1s

  

  [video]Introduction of GLP-1s

  

  [video]Evolution of GLP-1 Receptor Agonists

FAQs

• What are the Preclinical PK Data Analysis Methods?

  (1) Noncompartmental Analysis non-atrial model fully meets IND filing requirements but cannot be used for prediction and simulation.

  (2) Traditional Compartmental PK Model can be used for prediction and simulation.

  (3) Population PK Model is a population pharmacogenetic model, which is less used in preclinical settings and more suitable for sparse data and covariate analysis.

  
  

• Can Medicilon Complete Preclinical DMPK Services?

  (1) 19⁺ years of accumulated experience.

  (2) Completing preclinical DMPK filing studies for about 20 new drugs per year.

  (3) In vivo PK screening of >2000 compounds per year.

  (4) One-stop service for PK/PD.

  (5) Antibody/ADC preclinical DMPK services.

  (6)Technical service solution for isotope drug metabolism research.

• 所有研究均在同一园区内实验室有序完成，切实保证实验进度和项目沟通的高效性，占据数据获取和评估的行业优越性。