Accelerating Drug

Development using

Biomarkers

Presented by Nabiilah, Naailah & Svenia

Date: 27th Jan 2015

• Introduction on:

– Biomarkers

– Diabetes Type 2

• Application of Biomarkers in drug development

– Sitagliptin

• Preclinical trials

• Clinical trials

• Conclusion

• References

BIOMARKERS

What is a biomarker? A biomarker is a substance in the body that can be measured and used

to tell doctors and scientists something about the state or health of a

person.

Imagine two individuals; each will have a slightly different

composition of substances in their blood; these substances include

protein or small molecules that circulate around the body.

The aim is to measure the substances and build up a fingerprint of the

composition of someone’s blood.

These biomarkers fingerprints are then investigated for specific

substances that may show clear differences between two people or

which mark a difference between groups of people; if one of these

people is a healthy volunteer and the other with a chronic disease

such as diabetes, then we will have to see whether a specific

substance is higher or lower in people with the disease.

BIOMARKERS

If this is the case, this substance can be used as a biomarker

to help doctor with diagnosis and predicting disease stage

or severity or whether it will respond to treatment.

Furthermore, we can look to see whether by bringing the

level of this substance back to the healthy patient’s level,

we can help treat their disease.

If this proves successful, we can use this substance as a

basis for new medicines.

Biomarkers increase probability of success

Biomarkers

• In this review, focus is on

– Proximal and

– Distal markers

• In general, distal biomarkers are closer to disease

symptoms magnification for efficacy and off-target

indirect effects while;

• Target and proximal biomarkers are closer to the direct

exposure effect.

• Thus establishment of PD to PK is usually simpler for

proximal markers.

DIABETES TYPE 2

• Type 2 diabetes mellitus (T2DM)

– global epidemic characterized by high blood sugar (hyperglycemia)

– insulin deficiency and

– tissue resistance to insulin-stimulated glucose uptake and utilization.

• It is estimated that at least 170 million people worldwide have

diabetes, and this number is expected to double by 2030.

• In type 2 diabetes, the body becomes resistant to its insulin and

attempts to compensate by producing a higher quantity of insulin.

• Research has shown that chronically elevated blood glucose levels

(chronic hyperglycemia) over a long period of time can lead to

beta cells wearing out, referred to as beta cell turnover or beta

burnout.

• The mechanisms underlying loss of pancreatic B-cell

function in T2D is poorly understood.

• Defects in incretin hormone contribute to diminished B-cell

function.

• Incretin response due to

– Glucagon-Like Peptide-1 (GLP-1)

– Glucose-Dependent Insulinotropic Peptide (GIP)

DIABETES TYPE 2

DIABETES TYPE 2• DPP-4 is a Key Regulator of Incretin Activity; it inactivates the

hormone Incretin.

• Thus DPP-4 inhibitors (Gliptins) are used to block the action on

DPP-4.

• Sitagliptin is an orally active, potent and selective DPP-4 inhibitor.

• Advantages:

– oral administration;

– low incidence of hypoglycemia, similar to that of a placebo

– low incidence of adverse events, consisting of stomach

discomfort, diarrhea, upper respiratory infection, stuffy or runny

nose, sore throat and headache

– does not cause weight gain.

Application of Biomarkers

in Sitagliptin Clinical

Development Strategy

Sitagliptin - Januvia®

Mechanism of Action

• Used in diabetic patients

• Exert action by slowing the inactivation of incretin hormones.

• GIP and GLP-1 released by intestine in response to meal.

• These hormones are rapidly inactivated by the enzyme, DPP-4.

• Sitagliptin increases concentrations of GLP-1 and GIP thereby

increasing and prolonging the action of these hormones.

• Increased insulin release and decreased glucagon levels in the

circulation.

• Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit

DPP-8 or DPP-9 activity in vitro at concentrations approximating

those from therapeutic doses.

Sitagliptin Activity

Sitagliptin - Januvia®

Preclinical studies• Studies in mice examined the decrease of blood level upon

administration of Sitagliptin.

• Maximun efficacy was obtained at a dose of 1mg/kg which

approximated to 46% inhibition.

• DPP-4 inhibition resulted in

– a 2- to 3-fold increase in circulating levels of active GLP-1 and

GIP,

– decreased glucagon concentrations, and

– increased responsiveness of insulin release to glucose

• From this, end points were obtained in clinical studies with

healthy subjects and patients with T2D.

• The objective in this part of study was to investigate the

DDP4 inhibition of sitagliptin and GLP-1 stabilization.

• Sitagliptin was administered to normoglycemic healthy

subjects.

• Different single doses of sitagliptin were administered with

placebo acting as control (open circles).

• The extent of inhibition of plasma DPP4 activity was

analysed with respect to time in hours.

• A dose of at least 100mg has to be administered to obtain

80% or more inhibition over 24 hours A dose of at least.

Sitagliptin - Januvia®

Single dose clinical studies

• Sitagliptin increases levels of ACTIVE GLP-1 without increasing the

total levels of GLP-1; the ratio of active GLP-1 to total GLP-1 levels

increases.

• It stabilizes the active form of GLP-1 rather than increasing its secretion.

• Sitagliptin did not exert any effect on glucose, insulin, glucagon and C-

peptide.

• In healthy subjects, the decrease in blood glucose level was

insignificantly very small.

• It was reviewed that in diabetic patients, sitagliptin increases the level of

active GLP-1 leading to insulin secretion and thus reducing the blood

glucose level until normal.

Sitagliptin - Januvia®

Single dose clinical studies

• Sitagliptin improves glucose concentrations by causing

inhibition of DPP4 by more than 80% and in turn activating

more incretins.

• Sitagliptin increases post OGTT (oral glucose tolerance test)

levels of active GLP-1 and GIP and the ratio of active to total

GLP-1 levels and active to total GIP levels.

• Sitagliptin increased post glucose challenge insulin and C-

peptide levels and decreased post-glucose challenge glucagon

levels.

• NB: 100 nm or more of sitagliptin must be present in the plasma

to achieve a 75% of the maximal efficacy

Sitagliptin - Januvia®

Single dose clinical studies

Plasma glucose (a), serum insulin (b), serum C-peptide (c), and plasma glucagon (d) concentrations after administration

of single oral doses of sitagliptin 25 (white circles) or 200 mg (black triangles) or placebo (black circles) and an OGTT

at 2 h postdose. Plasma glucose concentrations are also displayed for the 2 h after a standardized meal at 6 h postdose

and an OGTT at 24 h postdose. Data are expressed as geometric mean ± SE. (The Journal of Clinical Endocrinology &

Metabolism Vol. 91, No. 11 4612–4619)

• During the multiple dose study in normal cases, both proximal and distal

biomarkers of DPP4 pathway were used.

– Proximal biomarkers indicate the immediate effect of the drug in its

target while

– Distal biomarkers demonstrate the effect of the drug downstream the

molecular target.

• It was found that the presence of Sitagliptin causes dose and concentration

dependence on the inhibition of plasma DPP4 activity but the inhibitory

level remains constant in both pre-clinical and clinical trials.

• Moreover, the relationship between Sitagliptin plasma concentrations and

inhibition of plasma DPP4 activity was not modified after multiple doses

as the EC50 values did not change.

Sitagliptin - Januvia®Multi dose clinical studies

Sitagliptin - Januvia®Multi dose clinical studies

• The pharmacodynamics effects of Sitagliptin with multiple doses

were also estimated in obese patients.

• The latter were treated twice daily with 200 mg Sitagliptin and this

led to a maximum inhibition of plasma DPP4 activity (90%).

• This means that the inhibition of DPP4 was maintained over a long

dosing period.

• Results show that the activation and rise in the level of GLP-1

increases OGTT by 2-3 times when compared to the placebo.

• Besides, the ratio of Sitagliptin: GLP-1 also increases by the same

amount.

• Concerning the patients, no weight gain was observed after a

treatment of 28 days.

Sitagliptin - Januvia®Special population

• DPP-4 proved to be a successful proximal and distal biomarkerto treat T2D.

• This biomarker helped in early clinical drug development fromwhich Sitagliptin was discovered.

• 100mg dose daily 80% inhibition reduction in HBA1c

• 50mg twice daily have benefits of achieving higher plasmaconcentration of Sitagliptin.

• The use of biomarker allowed Sitagliptin to reach Phase III in2.1 years instead of 3.5 years.

• Use of biomarker :- Simple exposure and increase efficiency ofdrug development.

Sitagliptin - Januvia®Acceterating Early Development

Conclusion

• The use of biomarker is advantageous for drug

development towards novel therapies.

• Sitagliptin can selectively act on DPP-4 to stimulate

insulin production.

• Sitagliptin is used along with diet and exercise and

sometimes with other medications to lower blood

sugar levels in patients with type 2 diabetes.

References• http://www.diabetes.co.uk/body/beta-cells.html

• Biomarkers in Drug Development: A Handbook of Practice,

Application, and ...by Michael R. Bleavins, Claudio Carini, Mallé

Jurima-Romet, Ramin Rahbari

• http://www.currentseparations.com/issues/21-1/cs21-1e.pdf

• http://www.globalrph.com/DPP-4-inhibitors.htm

• FASOLO, A. and SESSA, C., 2001. European Society for Medical

Oncology. The use of biomarkers for treatment decisions in oncology

[online]. Available from:

http://oncologypro.esmo.org/content/download/22272/368716/file/The-

use-of-Biomarkers-for-Treatment-Sessa-Fasolo.pdf [Accessed on 24

January 2015].