How predictive is proof of concept for therapeutic success of a new drug?

Joop van Gerven

neurologist-clinical pharmacologist Centre for Human Drug Research Leiden, The Netherlands Costs of Drug Development....

$1000 000 000,- ....3/4 Spent On Failures....

Preclinical 22%

Clinical 6%

Failure 72%

Lehman Brothers. Pharma Values Reducing Attrition in Phase II/II Saves Most

Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, Schacht AL. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat Rev Drug Discov. 2010 Mar;9(3):203-14 ....Attrition Rates Are Increasing....

Pammolli F, Magazzini L, Riccaboni M. The productivity crisis in pharmaceutical R&D. Nat Rev Drug Discov. 2011 Jun;10(6):428-38. …Registrations Are Decreasing: 275 Launches….

275 in 2001-2011 …25 Drugs Withdrawn…

Drug Approved Withdrawn License Reason amineptine (Survector) 1978 2000 22 abuse, acne cisapride (Propulsid) 1993 2000 7 cardiac arrythmia troglitazone (Rezulin) 1999 2000 1 liver failure alosetron (Lotronex) 2000 2000 1 ischemic colitis (Dexatrim) 1970's 2000 30 haemorrhagic stroke cerivastatin (Lipobay, Baycol) 1997 2001 4 rhabdomyolysis rapacuronium (Raplon) 1999 2001 2 bronchospasm trovafloxacin (Trovan) 1998 2001 3 liver failure levomethadyl 1993 2003 10 abuse, cardiac arrythmia rofecoxib (Vioxx) 1999 2004 5 cardiac risk pemoline (Cylert) 1975 2005 30 liver failure valdecoxib (Bextra) 2004 2005 1 cardiac risk natalizumab (Tysabri) 2004 2005 1 leucoencephalopathy Tc fanolesomab 2004 2005 1 allergy (Palladone ER) 2004 2005 1 alcohol interaction pergolide (Permax) 1988 2007 19 valve regurgitation tegaserod (Zelnorm) 2004 2007 3 cardiac risk lumiracoxib (Prexige) 2006 2008 2 liver failure aprotinin (Trasylol) 1993 2008 15 cardiac risk (Acomplia) 2006 2008 2 depression efalizumab (Raptiva) 2003 2009 6 leucoencephalopathy 1988 2010 22 cardiac risk gemtuzumab ozogamicin (Mylotarg) 2000 2010 10 lack of efficacy drotrecogin alfa (Xigris) 2001 2011 10 lack of efficacy pharmacological effect/predictable at time of registration 27% pharmacological effect/predictable after time of registration 9% drug-class specific rare adverse drug reaction 36% rare idiosyncratic/allergic adverse drug reaction 36% Rare Events Kill Blockbusters Constipation drug linked to heart attack risk • odds: 1 in 10 000-100 000 FDA asks Novartis to stop selling pills used for irritable bowel syndrome • risk: ‘dozens of victims’ Washington, 3/30/2007 Carol Ernst, widow of 59-yo

Swiss pharmaceutical maker Novartis AG will stop selling Vioxx-victim Robert Ernst Zelnorm to relieve constipation after it was linked to a higher chance of (before or after she heard she heart attack and stroke. was entitled to $253.4 million compensation) Analyses showed 1313 of of 11,614 11,614 patients given Zelnorm had cardiovascular side effects, while just one of the 7,031 patients given dummy pills…

Diabetes drug Rezulin taken off market Pill linked to 63 liver-poisoning Anticholesterol Drug deaths Pulled After Link With 31 Deaths March 22, 2000 By GINA KOLATA and EDMUND L. Web posted at: 2:05 p.m. EST (1905 GMT) ANDREWS Published: August 09, 2001 From staff and wire reports Bayer A.G., the German pharmaceutical and WASHINGTON (CNN) -- Rezulin, a once- chemical conglomerate, voluntarily withdrew 750,000 Baycol, its highly profitable cholesterol- hailed diabetes drug used by about 750,000 lowering drug, from the world market Americans, has been withdrawn from the yesterday. Thirty-one patients have died while market after it was linked to at least 63 taking it, the company reported, because the drug caused an unusual condition in which deaths from liver poisoning. muscle tissue broke down. Baycol was taken by 700,000700,000 Americans.

1980-2000: Dose Reductions After Launch

 22% of all new FDA-registrations  79% safety-related  three times more often in ’95-’99 than in ’80-’85

Cross J, Lee H, Westelinck A, Nelson J, Grudzinskas C, Peck C. Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980-1999. Pharmacoepidemiol Drug Saf 2002;11:439-46 Failed Clinical Trials in Phase II/III

Phase II Phase III

Arrowsmith J. Trial watch: Phase II failures: 2008-2010. Nat Rev Drug Disc 2011:10:328-9 Arrowsmith J. Trial watch: Phase III and submission failures: Nat Rev Drug Disc 2011:10:82. Stroke Cascades Late Failures: Adverse Drug Reactions

36% 36% Complexity of Metabolites

CYP2C9

immunogenic cysteine diol derivative hepatotoxic

thiol group teratogenic mitochondrial toxic Small Studies Only Detect Frequent Problems

Incidence (%) n 0.1 1 10 10 0.010 0.096 0.651 20 0.020 0.182 0.878 30 0.030 0.260 0.958 40 0.039 0.331 0.985 chance of statistical significance Large Studies Cannot Rule Out Rare Events

frequency in fold increase population (1:n) 2 3 4 5

10 000 305 625 45 510 22 695 13 455 5 000 86 205 20 865 9 885 6 720 2 500 33 645 9 480 4 935 3 363 1 250 15 465 4 740 2 472 1 680

number of person–years needed to detect significant risk increase (one-sided exact test) with significance level α=0.025 and power (1-ß)=0.80

Wu Y, Makuch RW. Sample size for post-marketing safety studies based on historical controls. Pharmacoepidemiol Drug Safety 2010; 19(8):869–875 Variability in Humans

16 Complexity of Drug Development

Miiligan PA. Current position and expectation for use of M&S in drug development and regulatory decision making. EMA-EFPIA Modelling and Simulation Workshop. 30/11/2011 Predicting the Unpredicatable

Cohen AF. Developing drug prototypes: pharmacology replaces safety and tolerability? Nat Rev Drug Discov. 2010;9:856-65 Five main ‘proofs-of-concept’

1. Does the drug/active metabolites get to the site of action? 2. Does the compound cause its intended pharmacological/functional effect(s)? 3. Does the compound have beneficial effects on the disease or its clinical pathophysiology? 4. What is the therapeutic window? 5. How does variability in target population affect the product? Case 1 – Fast Dissociating D2-Antagonist

 JNJ-37822681: D2-antagonist with high specificity and low affinity  novel concept → which level of occupancy needed for optimal therapeutic window?  combined phase I approach:  binding: PET for binding / brain PK  function: CNS-battery for brain PD

D2 5HT2A D1 D2 D3 D3 H1 D4 α1 D2 D2 5-HT2A D3 5-HT2C M α1 α2 quetiapine haloperidol JNJ-37822681 11C Raclopride PET Binding vs Historic Controls: therapeutic range 20-30 mg? dose interval?

haloperidol JNJ-37822681

100 100

80 80

60 60

40 40

o ccup a (%) n cy

o ccup a (%) n cy

2

2

D D

20 20

0 0 0 20 40 60 80 0 10 20 30 40 Plasma JNJ-37822681 (ng/mL) Dose JNJ-37822681 (mg)

Te Beek ET, De Boer P, Moerland M, Schmidt ME, Hoetjes NJ, Windhorst AD, Van Berckel BNM, Cohen AF, Van Gerven JMA Lammertsma AA. In vivo quantification of striatal dopamine D2 receptor occupancy by JNJ-37822681 using [11C]- raclopride and positron emission tomography. J Psychopharmacol 2012 Jan 30. Kapur S, Zipursky R, Roy P, Jones C, Remington G, Reed K, Houle S. The relationship between D2 receptor occupancy and plasma levels on low dose oral haloperidol: a PET study. Psychopharmacology (Berl) 1997;131:148-52 Prolactin Release: Functional D2-Biomarker

De Visser SJ, Van der Post J, Pieters MSM, Cohen AF, Van Gerven JMA. Biomarkers for the effects of antipsychotic drugs in healthy volunteers. Br J Clin Pharmacol 2001; 51:119-132 CNS-PD-Biomarkers vs Historic Controls: functionally optimal dose 5-10 mg BID

40

20 100 35

10 80 300

-1 0 60 25 -2 0

40 -320 0

-4 0 Adaptive Tracking change)(% 15 20 -5 0 0 2 4 6 8 10 Serum prolactin concentration (µU/mL)

-6 0 0 0 120 240 360 480 600 720 0 120 240 360 480 600 720 Ti m e (m in ) Ti m e (m in )

Te Beek ET, Moerland M, De Boer P, Van Nueten L, De Kam ML, Burggraaf J, Cohen AF, Van Gerven JMA. Pharmacokinetics and central nervous system effects of the novel dopamine D2 JNJ-37822681. J Psychopharmacol 2011 Sep 2. Effective Dose in Clinical Trial:

therapeutically effective dose 10 BID

Weight (kg) Weight PANSS

Anghelescu I, Janssens L, Kent J, De Boer P, Van Osselaer N, Tritsmans L, Daly EJ, Van Nueten L, Schmidt ME. Sustained treatment response in schizophrenia to JNJ-37822681 can be predicted within three days. Euro Neuropsychopharmacol 2011;21(suppl3):S490–S491 Case 2 – Partial GABA-A α2,3-Agonist

sedation, memory postural instability anxiolysis disturbance α1 α2 α3 α5

TPA023 0 11 21 5

MK-0343 18 23 45 18

SL65.1498 45 115 83 48

in vitro efficacies relative to full agonist 11C Flumazanil PET: full vs subtype GABA-A-agonist: which dose?

2 mg TPA023 2 mg

Atack JR et al. binding site occupancy by the novel GABAA receptor subtype- selective drug TPA023 in rats, primates, and humans. J Pharmacol Exp Ther. 2010;332:17-25 Saccadic Peak Velocity, Binding Affinity and Anxiolytic Dose

80 16 250

200 Quazepam 70 Temazepam 14 150

100

50 60 12 (deg/sec) SPV Change in 0 0 10 20 30 40 Quazepam Dose Temazepam (mg) 50 10 Temazepam Bromazepam 40 8 Midazolam

30 6

20 4 Bromazepam

Alprazolam Diazepam Kd at benzodiazepine binding site site (nM) binding Kdbenzodiazepine at

10 po/daily) (mg dose maintenance Lowest 2 Midazolam Lorazepam Lorazepam Alprazolam 0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 SPV dose equivalence (10 mg Temazepam) SPV dose equivalence (10 mg Temazepam)

Slope SPV/VAS: Clear α2 Selectivity

10

0

-10

-20

-30

VAS Alertness: change baseline from ● lorazepam 2 mg □ TPA023 1.5 mg -40 -120 -100 -80 -60 -40 -20 0 20 SPV: change from baseline Treatment Lorazepam TPA023 α1/α2-ratio vs SPV/VAS-slope

R2=0.86 p=0.004

TPA023 drug X drug Y drug Z SL65.1498 TPACMP2 Zolpidem Lorazepam Effective TPA023 Dose in Clinical Trials: 1.5-4.5 mg twice daily

Week of study 1 2 3 4 0 PBO/Drug 48/43 45/37 36/33 60/61 -1

-2

-3

-4

Change in HAM-A, in Change TPA023 vs. placebo TPA023 * -5 *** *

Atack JR. Subtype-selective GABAA receptor modulation yields a novel pharmacological profile: the design and development of TPA023. Adv Pharmacol 2009;57:137-85. Case 3 – antagonists

CB1-antagonist has no measurable effects in healthy subjects Phase 0: development of reliable CB1-agonist model (THC) Phase I: measure/model suppression of THC-effects by CB1-antagonist Cannabinoid Challenge: ‘classical’ Dutch mode of administration Cannabinoid Challenge: development of novel mode of administration

 GMP-compliant THC-production  Intrapulmonary administration  Vaporizer  Paced puffing protocol  Dose Finding  2 – 4 – 6 – 8 mg  90 min intervals Cannabinoid Challenge: effects and PK/PD-relationships

2 .9 BodySway VAS alertness 90 2 .8 80

70 2 .7

60

2 .6 Bo d swa(L y y mm) OG

VAS Alertness (mm) 50

2 .5 40

30 2 .4 0 90 180 270 360 450 540 0 90 180 270 360 450 540 Ti m e (m i n ) Ti m e (m i n ) VAS ‘high’ HeartRate 2 .2

2 .0 130

1 .8 120

1 .6 110

1 .4 100

1 .2 90

1 .0 Heart rate (bpm) 80

0 .8 70 VAS Bowdle feeling high (LOG mm)

0 .6 60

0 .4 50 0 90 180 270 360 450 540 0 90 180 270 360 450 540 Ti m e (m i n ) Ti m e (m i n ) Surinabant: no effects of 60 mg alone, but clear suppression100 of THC-effects at 5-20 mg

100 80 Placebo sur inabant + THC

Sur inabant 5 m g + THC

80 60 Sur inabant 20 m g + THC

Sur inabant 60 m g + THC

Placebo sur inabant + placebo THC 60 40

Sur inabant 60 m g + placebo THC VAS Feeling high (mm)

40 20 VAS Feeling high (mm) 0 20 -9 0 -3 0 30 90 150210270330390450510570 Ti m e (m i n )

0 -9 0 -3 0 30 90 150 210 270 330 390 450 510 570 Ti m e (m i n )

Klumpers LE, Roy C, Ferron G, Turpault S, Poitiers S, Pinquier J-L, Van Hasselt JGC, Zuurman L, Erwich FAS, Van Gerven JMA. Surinabant, a selective CB1 antagonist, inhibits THC-induced central nervous system and heart rate effects in humans. Br J Clin Pharmacol 2012 (submitted) Surinabant reduction rate:

60mg

20mg

5mg

2 5 10 20 50 100 200 500 1000 Dose(mg) Effective Surinabant Dose in Clinical Trials: weight change during

1.50

1.00

0.50 weight change during smoking cessation (kg)

0.00 placebo 2. 5 m g 5 m g 10 m g r imonabant 20 m g

surinabant (all treated) (ceased smokers) Tonstad S, Aubin HJ. Efficacy of a dose range of surinabant, a blocker, for smoking cessation: a randomized controlled clinical trial. J Psychopharmacol. 2012 Jan 4. [Epub ahead of print]. Rigotti NA, Gonzales D, Dale LC, Lawrence D, Chang Y; CIRRUS Study Group. A randomized controlled trial of adding the patch to rimonabant for smoking cessation: efficacy, safety and weight gain. Addiction 2009;104:266-76 …Rare Events Can Kill Entire Drug Classes…

9351 four Rimonabant reduction rate: unnecessarily high?

20mg MD

2 5 10 20 50 100 200 500 1000 Dose(mg) Conclusions

 Clinical pharmacology cannot prevent all late phase drug failures:  poorly understood diseases  rare/unpredictable SAEs  benefit/risk considerations  strategic/financial  Good clinical pharmacology can prevent unnecessary late stage failures:  poor action site penetration  suboptimal pharmacological activity  underestimated pharmacological (predictable) SAEs  incorrect dose estimates  drug-disease/-drug interactions  But only if we integrate all available knowledge intelligently and learn from experience The Role of the Clinical Pharmacologist