1. "Value-added" medicines: therapeutic improvement … … or just "life-cycle management"?
Henning H. Blume, PhD DSc
SocraTec C&S, Oberursel
Concepts and Strategies in Clinical Drug Development
3rd symposium on bioequivalence requirements
Amman/Jordan, May 2/3, 2018

2. "Real" innovations vs. "me-too's"??
Blockbusters
new molecular entities (NME)
breakthroughs/first in class … (new therapies/indications)
… and their step-wise further improvements
Innovations
Value-added medicines (VAM)
known compounds
optimization of current treatments (e.g. first MR forms or ODTs)
alternative route of administration
other indications
improvement of patient compliance

3. VAMs: goals & expectations
Development options
improvement of existing products in the same indication(s)
optimised administration scheme … … prolonged release preparations, e.g. QD instead of BID/TID
easier administration conditions, e.g. for elderly patients or children … … effervescent tablets, ODT, buccal films, etc.
step-wise, innovative evolution related to known compounds
novel routes of application, e.g. transdermal vs. oral … … or also completely new indications
optimisation of current treatments … … e.g. equivalent therapy/improved safety with significantly lower dose
, e.g. diclofenac in actinic keratosis

4. Examples Statins – necessity for optimisation?
standard therapy not without problems
therapeutic benefit proven in numerous outcome studies …
… GI intolerability, myopathies, critical risk factor: rhabdomyolysis
improvement desirable
development goal: optimized risk-benefit relationship …
… to be achieved via better tolerability/safety (efficacy sufficient)
DPP-4 inhibitors – further optimisation possible?
standard therapy does not generate relevant problems
therapeutic benefit proven in clinical studies with different derivatives
signals for safety concerns (pancreatitis) not confirmed
preference for NCEs: once weekly candidate omarigliptin …
… improvement of existing IR tablets not considered

5. Development case: simvastatin
Drug substance properties
poor solubility (5mg/250mL), thus …
… pharmaceutical form should impact absorption/exposure
pharmacokinetic properties
pro-drug with active metabolite (first-pass effect: 95%)
rapid elimination from plasma (t1/2: 2h), excretion primarily via bile
Straight-forward drug product development
pharmaceutical form: conventional immediate release tablet
specific excipients needed to increase solubility (e.g. Tween 80)
… proof-of-concept study confirmed clinical efficacy
entire clinical programme realised with conventional tablet
clinical efficacy & safety assessed in Phase-III studies in patients

6. Cerivastatin "case" initiated discussion
Lipobay® introduced as "optimum" statin
highest bioavailability of all statins, very good efficacy
low interaction potential, except gemfibrozil (contraindication)
market withdrawal (8/2001) due to cases of rhabdomyolysis
What did we learn from the discussion?
determinant for efficacy: dose/extent of exposure  optimum efficacy requires sufficiently high concentrations at the site of action (hepatocytes)
safety: primarily determined by plasma peak concentrations  goal: reduction of maximum exposure (in plasma)

7. Rationale for product improvement
Essential finding …
selective, transporter-mediated uptake into hepatocytes …
… thus, access to site of action should be saturable
… and consequence(s) for product improvement
goal: reduction of statin concentration in portal blood stream
expected effect: reduced saturation of OATP1B1  higher statin exposure in hepatocytes; lower systemic BA

8. OATP1B1: uptake into hepatocytes
[ng/ml]
[h]
OATP1B1
OATP1B1
statins in plasma
bile
bile
bile
Development rationale
product with retarded drug release/delivery
HMG-CoA
reductase
HMG-CoA
reductase

9. Proof of concept Pilot ER simvastatin vs. IR market form
bioavailability [n=36]
[ng/ml]
[h]
SocraTec R&D, 2000 (data on file)
clinical (LDL-cholesterol)
[mg/dl]
[weeks]
diet -4
[weeks] -4
40 mg
60 mg
active treatment
Problem
development prematurely terminated …
… reimbursement policy does not allow return of investment
Conclusions, consequences
same/better efficacy despite lower systemic exposure …
… rationale for improved safety margin

10. Development option: DPP-4 inhibitors
Sitagliptin: drug substance properties
very high solubility (5'000mg/250mL) …
… thus, unproblematic systemic exposure expected
pharmacokinetic properties
rapid absorption, high systemic exposure/bioavailability (>85%)
slow elimination/dissociation from enzyme DPP-4 (t1/ h)
Consequences for straight-forward drug development
uncomplicated compound  no formulation problems …
… intended pharmaceutical form: IR tablet
entire clinical programme realised with conventional tablet
once daily administration sufficient for 24h glycaemic control
100mg confirmed as sufficient/optimum for QD treatment
clinical efficacy & safety assessed in Phase-III studies in patients

11. Communication between gut & ß-cells
The "entero-insular axis"
Intestine
Pancreas
Insula
Glucagon-like Peptide 1 (GLP-1) … … supporting insulin secretion
Intake of a meal
carbohydrates
amino acids
fatty acids
endocrine transmission
insulin secretion
neurotransmission
e.g. vagus nerve
substrate stimulation
W. Creutzfeldt 1979, Diabetologia 16: 75-85

12. only 10-15 % in general circulation
GLP-1: physiologic pathway
Secretion and metabolism
only % in general circulation
enzymatic inactivation
GLP-1
proteolysis
Very rapid cleavage
exopeptidase DPP-4
ubiquitously available in organism (cell surface: CD26)
membrane-bound (endothelium)
dissolved (e.g. in plasma)
25 % in portal vein
neuronaler Weg wohl mindestens ebenso wichtig!
metabolism by DPP-4
very short t1/2: 1-2 min
 only very low plasma levels
100 % secreted

13. GLP-1: physiologic functions
Concept of GLP-1 mediated signal transduction
GLP-1 stimulates vagus nerves
receptors on nerve endings
afferent signal transduction …
… switching in Medulla oblongata …
… descending impulses, e.g. ß-cells
Holst und Deacon: Diabetologia, 2005
liver
stomach
Pankreas
Medulla
oblongata
Hypothalamus + _
GLP-1 mediated effects
gastric emptying 
insulin availability 
activation of biosynthesis and …
… secretion into blood stream
DPP-4 inhibitors
neuronaler Weg wohl mindestens ebenso wichtig!
Therapeutic intervention
amplification of GLP-1 effect

14. Physiology & incretin-based therapy
Distribution of L-cells in the GI tract
increasing density from proximal to distal intestine …
only relatively few L-cells in upper duodenum/jejunum
highest density in the ileum (responsible for "ileal break")
… thus, stronger GLP-1 mediated effect from distal part
Antidiabetic therapy with DPP-4 inhibitors (IR tablets)
drugs absorbed rapidly from upper GI tract …
distributed throughout organism  ubiquitous inhibition of DPP-4 …
… approach to membrane-bound DPP-4 in gut mucosa from blood side
… only small part of inhibitor reaches its major site of action
neuronaler Weg wohl mindestens ebenso wichtig!
Concept for product/treatment improvement
targeted drug delivery to more distal parts of intestine …
… in order to avoid "early absorption" in upper GI tract

15. Findings supporting the concept
Systematic studies in mice [Waget et al., 2011]
oral administration of (very) low doses of sitagliptin …
… 30 min prior to oral 30% glucose solution (2g/Kg)
4-400 µg/mice (comparable with  mg/70 kg in patients)
intention: selective inhibition of DPP-4 (in intestine only)
in intestine
in plasma
Effect on DPP-4 activity
neuronaler Weg wohl mindestens ebenso wichtig!

16. Findings supporting the concept
Systematic studies in mice [Waget et al., 2011]
oral administration of (very) low doses of sitagliptin …
… 30 min prior to oral 30% glucose solution (2g/Kg)
4-400 µg/mice (comparable with  mg/70 kg in patients)
intention: selective inhibition of DPP-4 (in intestine only)
Glycaemic control (blood glucose after OGTT)
oral administration of sitagliptin
neuronaler Weg wohl mindestens ebenso wichtig!

17. GLP-1 stimulated vagus nerve activity
Glucose-induced activation of vagus nerve transduction
neuronaler Weg wohl mindestens ebenso wichtig!

18. VAMs: perspectives and conclusion
DPP-4 inhibitors: optimisation via intestinal targeting
selective DPP-4 inhibition in endothelium of portal vein …
… necessitates only significantly lower doses
patients may welcome reduction in drug exposure …
… and perspective for even better tolerability/safety margin
In what kind of innovation(s) is the society interested?
also mid-size pharmaceutical industry is willing to invest …
… but needs appropriate return of investment
as long as VAMs are considered generic alternatives only …
… industry might not be able to finance the development

19. "Value-added" medicines: therapeutic improvement … … or just "life-cycle management"?
Henning H. Blume, PhD DSc
SocraTec C&S, Oberursel
Concepts and Strategies in Clinical Drug Development
3rd symposium on bioequivalence requirements
Amman/Jordan, May 2/3, 2018