Challenges with Conducting Clinical Trials with Drugs Affecting the CNS

1. Challenges with Conducting Clinical Trialswith Drugs Affecting the CNS Dr. Jonathan Stewart Disease Area Head, Neuroscience & Pain BMS

2. Learning objectives Various types of clinical studies in key therapeutic areas and the challenges in choosing the appropriate design and in conducting trials. Evaluation of the outcome of drug development: final therapeutic profile / usage of a medicine. Clinical trial design (including legal, regulatory, ethical and practical aspects): international differences. Choice of trial design and conduct of clinical trials Choice of placebo and of other comparators, of patient populations, of sample size and of locations Postgraduate Course on Pharm Med – Feb 2013

3. Outline • Current situation • Challenges • Targets • Animal models • Clinical studies • Conclusion

4. NEUROSCIENCE CLINICAL TRIALS:THE CHALLENGES Why are we still conducting CNS research? • medical need • commercial value • Zyprexa sales in 2005 were $4.0 billion • Cymbalta sales in 2010 were close $3.0 billion

5. Approved NME’s by therapeutic class over three decades

6. Timelines CNS : 12.6 years CV: 6.3 years GI: 7.5years

7. Probability of Success (POS) CNS : 7% Industry average (across TA’s) : 15% 1994 -2001Tufts Center for study of drug development

8. Why is attrition high in CNS Research? • Lack of understanding of aspects of underlying pathophysiology (complexity of brain) thus flawed hypothesis • Unprecedented targets being pursued • Presence of BBB • Target engagement not confirmed • Preclinical animal models poor clinical face and predictive validity • Lack of validated biomarkers • Clinical trial design flaws • Propensity CNS drugs to cause CNS side effects

9. There are reasons to believe we can ↑POS • Different therapeutic areas have different rates of success • Biologics have higher rate of success from first-in -man to launch • Licensing in compounds has consistently higher probability of success (approx 24% )1 1 Benjamin et al; Industry success rates 2003

10. NEUROSCIENCE CLINICAL TRIALS:THE CHALLENGES The diseases • Pain • Dementia ( AD & mild cognitive impairment) • Cerebrovascular disease • Parkinson’s disease • Epilepsy • Multiple Sclerosis • Depression • Anxiety/phobia/obsessive-compulsive disorder • Schizophrenia • Bipolar disorder

11. Targets

12. Two approaches to target selection • Target based approach • Apply molecular and chemical knowledge to investigate specific molecular hypothesis • However the solution to the above may not be relevant to the disease pathogenesis • Phenotypic approach • Does not require prior understanding of the molecular MOA (MMOA) • Challenge is to optimize the molecular properties of the drug without the design parameters provided by prior knowledge of MMOA

13. Between 1999 and 2008 the majority of first in class drugs discovered utilised phenotypic strategy Swinney, How were new medicines discovered? Nature Reviews 2010

14. 7 out of 9 CNS first in class NME’s discovered utilising phenotypic approach (1999 -2008) Swinney, How were new medicines discovered? Nature Reviews 2010

15. 7 out of 9 CNS first in class NME’s discovered utilising phenotypic approach (1999 -2008) Swinney, How were new medicines discovered? Nature Reviews 2010

16. Neuropathic pain – an integrated view Pathways Specific Targets Glutamate Voltage-Gated Sodium Channels Neuronal: Dysfunction/ Miswiring Glial: Activation Interleukins Calcium Channels Immunune: Cytokine Activation Brain stem Microglia Nerve Growth Factor Trophic Factors: Diseases / Clinical Syndromes Symptom Clusters • Allodynia • Hyperalgesia • Dysthesia • Burning • Pins and Needles • Sharp • Shooting • Itching Positive Symptoms Negative Symptoms CENTRAL • Numbness • Tremor • Gait Abnormality Post Spinal Cord Injury Post Stroke Multiple Sclerosis Parkinson’s Disease PERIPHERAL Inherited Neuropathies DPN PHN Radiculopathy

17. Utilizing genetic models to validate targets • Geneticforms of pain conditions are rare, with small affected numbers • Genetic forms of neuropathic pain (e.g.- Nav 1.7, TRPA1 mutations) allow opportunity to efficiently test for POC with MOA validation • Nav1.7 is implicated in 3 different human pain disorders: (IEM, PEPD, and congenital insensitivity to pain (CIP)) • TRPA1 mutation implicated in familial episodic pain syndrome TRPA1 SCN9A Patient with IEM during an attack

18. Targets • Increase quality of targets - More validated, druggable • ?Increasing selectivity leads to decreased • activity • ? Combine several selective but additive actions in one molecule or a combination of molecules e.g. duloxetine • Ensure brain penetration and target engagement • Multiple MMOA target approach for first in class • Utilisation of genetics – genome wide association studies or stem cell biology • Feasibility of pre-competitive consortium to assess targets pre-POC

19. Preclinical

20. Preclinical models of pain are suboptimal • Screening for novel molecules using animal models validated with opioids and NSAIDs • Doses in animals may exceed those which are possible in humans • Outcomes measure • Stimulus-evoked reflexes (measuring hypersensitivity) instead of assessing spontaneous pain • ?Cognition / affect • Length of dosing – too acute….more chronic models required • Pharmacokinetics and BBB penetration of compounds (ensure adequate exposure of drugs to CNS target) may differ to humans

21. Address issues around predictability of animal models • Replace • Reflexive with non-reflexive measures • Broader range of QOL measures • More data across spectrum of different species • Endogenous pathophysiology: OA dogs; T2DM Goto-Kakizaki rat • Independent replication to increase confidence • Model pain mechanisms (peripheral sensitisation or ectopic excitability in nociceptors) rather than disease states

22. Clinical

23. NEUROSCIENCE CLINICAL TRIALS:THE CHALLENGES Clinical challenges (1) • Proof of concept studies: early information about possible clinical efficacy • Small studies in selected patient population – stratify patients / enrich • Highly specific surrogate marker for the disease DRUG ACTIVITY NATURAL HISTORY TREATMENT INTERMEDIATE CLINICAL BIOMARKER DISEASE ENDPOINT OUTCOME SURROGATE MARKER

24. Alzheimer’s Disease:Evolution of Theories of Causality Plaques Tangles Neurodegeneration Abeta Theory Preventing the production of soluble beta-amyloid peptide oligomers (Abeta), could halt the progression of AD Tau Theory Preventing the production of abnormal Tau could halt the progression of AD

25. Alzheimer’s disease: how can we track and predict efficacy? • Magnetic Resonance Imaging & Spectroscopy: • Easy access • Improved technology • Measures biochemical changes in vivo (i.e. neuronal cytosolic choline compounds, increased in AD, GABA levels). • Disease Biomarkers: • Aβ measurements in Plasma and CSF • easy access • good correlation with disease process.

26. Functional MRI – Analysis of BBB penetrance LY 334XXX Vehicle Image courtesy of Dr. Gómez Ansón Addenbrookes Hospital

27. Neuroimaging: A new window into the brain

28. Minimal Cognitive Impairment (MCI) – Value of MRI volumetric assessment Courtesy of Dr. Gómez Anson Addenbrookes Hospital - Cambridge

29. Alzheimer’s disease: how can we track and predict efficacy? • Magnetic Resonance Imaging & Spectroscopy: • Easy access • Improved technology • Measures biochemical changes in vivo (i.e. neuronal cytosolic choline compounds, increased in AD, GABA levels). • Disease Biomarkers: • Measurements in Plasma and CSF • easy access • good correlation with disease process.

30. Aβ peptide as a marker for disease progression • Aβ is derived from a larger protein (APP) • Various chemical pathways to breakdown APP, releasing more soluble Aβ forms • Aβ has been isolated from plaques • In AD, Aβ levels in plasma and CSF are correlated to disease progression • Aβ is measurable and may correlate to disease progression

31. NEUROSCIENCE CLINICAL TRIALS:THE CHALLENGES Clinical challenges (2) • studies in patients regulatory challenges: • acceptable diagnostic procedures (UK/US, DSM/ICD) • acceptable disease severity/efficacy measures • use of placebo (placebo response, Declaration of Helsinki, “placebo paradox”) • acceptable comparator (EU, US, global) • acceptable duration of treatment • powering (superiority, non-inferiority) • pharmacogenetic differences (CYP2D, Japan)

32. NEUROSCIENCE CLINICAL TRIALS:THE CHALLENGES Clinical challenges (3) • studies in patients patient challenges: • acceptable protocol procedures (washout period, use of placebo) • representative patient population (inclusion and exclusion criteria, ethnicity/genetics) • placebo response (measures to minimise this) • retention in clinical trial (duration of trial, number of visits, demands at visits)

33. NEUROSCIENCE CLINICAL TRIALS:THE CHALLENGES Meeting clinical challenges(1) • you definitely can write simple protocols (less is more - one/few hypotheses, few measures, few visits) ensure adequate duration of trials (2 week saving on trial may mean 2 year delay in approval) default to include test drug + comparator + placebo be aware of current Declaration of Helsinki and EU Clinical Trials Directive train and retrain investigators (and record inter-rater reliability scores) monitor early, monitor often and monitor hard

34. NEUROSCIENCE CLINICAL TRIALS:THE CHALLENGES Meeting clinical challenges(2) • you possibly can reduce placebo response (placebo lead-in, enriched sample) minimise number of sites, investigators, countries, continents (data validity, ethnic/genetic/cultural effects) be honestand realistic at least, with higher management (that’s why they pay you so much and they may not be medics - its impossible to apply a measure that takes 45 minutes every 15 minutes, even if the CEO thinks it’s a great idea and even if you simultaneously use 3 investigators)

35. NEUROSCIENCE CLINICAL TRIALS:THE CHALLENGES Meeting clinical challenges(3) • you definitely should not seek to answer every question with one clinical trial (“enough and no more”) reduce patient numbers to reduce costs (believe statisticians) reduce patient numbers to reduce time (1Q v 2Q, 4Q’02 v 1Q’03) Include a “little bit of everything on top” “a little bit of population PK sampling”, “a few QoL measures - only takes a few minutes” or “random brain biposies”

36. Precompetitive pain partnershipscan be used to validate/qualify translational strategies in pain • European precompetitive partnership to qualify translational research models and develop novel pain biomarkers Innovative Medicines Initiative • The NIH Pain Consortium was established to enhance pain research and promote collaboration among researchers that have programs and activities addressing pain. • (ICD) is a collaborative research effort between academia and pharmaceutical companies who are developing novel drugs to treat central nervous system (CNS) disorders, initially focusing on pain and analgesia

37. Summary of recommendations for CNS drug discovery and development (1) Use disease pathophysiology and genetics to drive target and pathway selection. Target multiple disease pathways and multiple targets for each CNS disorder. Take multiple structurally diverse compounds forward for each target. Use multiple drug discovery platforms such as small molecules, biopharmaceuticals and vaccines. Develop pathophysiology-based animal models that examine the most relevant aspects of the CNS disorder with end points relevant to the clinical setting. Demonstrate efficacy in at least two disease-relevant animal models with multiple efficacy end points that are relevant to the clinical setting. Pay careful attention to the pharmacokinetics and blood–brain barrier penetration properties of compounds, and ensure adequate exposure of drugs to the CNS target.

38. Summary of recommendations for CNS drug discovery and development (2) Drug development for CNS disorders: strategies for balancing risk and reducing attrition, Nature Reviews Drug Discovery 6, 521-532 (July 2007) Collaborate with preclinical discovery teams before drug candidate selection to identify biomarkers for determining adequate drug exposure to the target (for example, receptor occupancy using positron emission tomography). Develop sensitive efficacy biomarkers to predict efficacy for registration-stage trials. Use multiple modalities to develop efficacy biomarkers (for example, biochemistry, imaging, behavioural outcome). Use pharmacogenetics to stratify patient populations into those who are most likely to respond to a given drug or treatment. Understand the metabolism of the drug and the potential for drug–drug interactions. Form strong multidisciplinary teams between private and public preclinical and clinical scientists to guide preclinical and clinical translational research.

39. NEUROSCIENCE CLINICAL TRIALS:THE CHALLENGES Further help • Experienced colleagues • EMEA : Clinical efficacy and safety guidelines: Nervous system • http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000085.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac0580027549

40. General books on clinical trials in CNS • Critical Pathways to Success in CNS Drug Development. N.R. Cutler, J. J. Sramek, M. F. Murphy, H. Riordan, P.Bieck, A. Carta. Blackwell 2010 • Clinical Trials in Neurology. Roberto J. Guiloff (Ed.). Springer-Verlag London (2001). New reprint 2010 • Clinical Trials in Neurological Practice. J. Biller & J Bogousslavsky (Eds.) Butterworth&Heinemann Boston (2001) • Clinical trial in Psychiatry. Brian Everitt, Simon Wesley. 2nd edition Oxford University Press Oxford (2008)

41. Questions?