Drug Discovery

Question 1

Drug development entails 3 main components

Answer 1

➢Drug discovery
➢Preclinical development (small pharma companies)
➢Clinical development

❖ For most part it takes at least 12 years for a
drug to make it to market

Question 2

Target Selection

what are me too drugs

Answer 2

➢Exenatide first GLP-1R agonist for type 2 diabetes
➢Liraglutide
➢Albiglutide
➢Lixisenatide
➢Dulaglutide

• Usually many similar drugs are made as exenatide is in development
• Aggressive marketing to get me too drugs approved
• Lixisenatide - no increase in HR - musch shorter half life
• Liraglutide - weight loss
• Not always better than first in class

Question 3

Target Selection
first in class drug ex

Answer 3

Canagliflozin as the 1st SGLT2 inhibitor approved for the treatment of T2D

Question 4

Drug Discovery Phase

what is target selection based on (3)
what happens after?

Answer 4

If not designing a ‘me-too’ drug, one needs to
identify the new molecular target

based on current knowledge of disease pathology/mechanisms
➢Altered signaling pathways
➢Genomic data
➢Proteomic data

Once target identified, need to develop an assay to measure whether a drug candidate modifies the target

Question 5

Examples of target selection using current

biological knowledge

Answer 5

ACE inhibitors improve hypertension by preventing
formation of angiotensin II
➢ Rationale to identify and develop antagonists for the angiotensin II receptor (“sartan” class of drugs)

Effectiveness of GLP-1 to enhance insulin secretion is
limited due to immediate cleavage via dipeptidyl
peptidase 4 (DPP-4)
➢ Rationale to developing degradation-resistant GLP-1 receptor agonists (e.g. exenatide)
➢ Rationale to develop DPP-4 inhibitors (e.g. “gliptin” class of drugs)

Question 6

Preclinical Development

4 components

Answer 6

• Pharmacological testing (safety pharmacology)
• Preliminary toxicology testing
• Pharmacokinetic/Pharmacodynamic testing
• Chemical/Pharmaceutical development

Much of the preclinical development stage is
performed under a standard operating code referred
to as “Good Laboratory Practice (GLP)”

Question 7

Clinical Development Phase I Studies

Answer 7

small group of healthy volunteers (20-80

people) to assess safety and pharmacokinetics of the drug

Question 8

Clinical Development Phase II Studies

Answer 8

performed in small groups of patients (100-
300 people) to determine whether the lead compound has clinically beneficial pharmacodynamic effects for the intended patient population

Question 9

Clinical Development Phase III Studies

Answer 9

double-blind randomized placebo controlled trials on 1000s of patients to assess efficacy of the drug versus placebo or standard of care

Question 10

Clinical Development Phase IV Studies

Answer 10

post-marketing surveillance studies with the purpose of detecting long-term or rare adverse effects from using the drug in the real clinical setting

Question 11

GLP-1 Increases Insulin Secretion

Answer 11

Initial discovery of GLP-1’s biological action
- In 1987 it is observed that GLP-1 increases gene expression of insulin and intracellular cAMP levels in a rat islet cell line
- Treatment of the isolated perfused pancreas with
truncated GLP-1 (7-37) results in increased insulin
secretion. Follow up studies demonstrated that GLP-1 was released from the intestine following meal ingestion and became the 2nd identified incretin hormone

Question 12

Use of Genetically Modified Mice to Illustrate a Key Role for GLP-1 as a Critical Regulator of Glycemia

Answer 12

If GLP-1 promotes glucose uptake following nutrient
ingestion, then mice with reduced GLP-1 action (via deletion of the GLP-1 receptor) should have elevated blood glucose levels following glucose ingestion

Question 13

Limitations of Native GLP-1

Answer 13

• Dipeptidyl-peptidase 4 (DPP-4) is the primary enzyme responsible for the inactivation of GLP-1
  • Degradation-resistant GLP-1R agonists and DPP-4
  inhibitors were thus developed for the treatment of type 2 diabetes

Question 14

what does the gila monster produce?

Answer 14

GLP-1 Homologue Exendin-4 (from venom) that Activates the GLP-1 Receptor
- Actions above are prevented via treatment with a GLP-1R antagonist?

Question 15

Exendin-4 Overexpression in Mice Increases ________ and ___________

Answer 15

Insulin Secretion & Improves Glycemia

• Exendin-4 is the lizard homologue of GLP-1 and mice were made to overexpress this protein
• These mice exhibit improved glucose tolerance and increased plasma insulin levels

Question 16

What was shown in a phase II study with exenatide?

Answer 16

a Phase II study, exenatide (recombinant exendin-4,
AC2993), improved glucose tolerance in people with type 2 diabetes not achieving optimal control with metformin and/or sulfonylurea therapy
• A total of 109 patients studied over 4-weeks

Question 17

What was shown in a phase III study with exenatide?

Exenatide is Approved for the Treatment
of Type 2 Diabetes on April 28, 2005

Answer 17

• In a Phase III study, exenatide improved glucose tolerance in people with type 2 diabetes also receiving metformin
• A total of 336 patients were studied over 30-weeks in 82 clinical sites in the USA

Question 18

“Me-Too” GLP-1R Agonists (4)

Answer 18

• Exenatide (2005)
• Liraglutide (2010)
• Albiglutide (2014)
• Dulaglutide (2014)
• Lixisenatide (2016)

Question 19

A Changing Landscape for Drug
Development in Type 2 Diabetes

why have many drug manufacturers have exited the business of drug development in the area of type 2 diabetes

Answer 19

■ Historical pathway for drug development involved 6-12 month studies in phase 3 trials of 1000 – 3000 patients, with a primary endpoint of significant reductions in glycated hemoglobin (HbA1C levels)
■ Because heart disease represents the number one cause of death for people with type 2 diabetes, in order to get a drug for type 2 diabetes approved by a regulatory agency, large-scale cardiovascular outcomes trials in thousands of patients over an additional 2 – 5 years are required