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

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challenges with conducting clinical trials with drugs affecting the cns
Challenges with Conducting Clinical Trialswith Drugs Affecting the CNS

Dr. Jonathan Stewart

Disease Area Head, Neuroscience & Pain

BMS

learning objectives
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

outline
Outline
  • Current situation
  • Challenges
    • Targets
    • Animal models
    • Clinical studies
  • Conclusion
neuroscience clinical trials the challenges
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
slide6

Timelines

CNS : 12.6 years

CV: 6.3 years

GI: 7.5years

slide7

Probability of Success (POS)

CNS : 7%

Industry average (across TA’s) : 15%

1994 -2001Tufts Center for study of drug development

slide8

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
there are reasons to believe we can pos
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

neuroscience clinical trials the challenges1
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
two approaches to target selection
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
slide13

Between 1999 and 2008 the majority of first in class drugs discovered utilised phenotypic strategy

Swinney, How were new medicines discovered? Nature Reviews 2010

slide14

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

slide15

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

slide16

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

utilizing genetic models to validate targets
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

slide18

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
preclinical models of pain are suboptimal
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
address issues around predictability of animal models
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
neuroscience clinical trials the challenges2
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

alzheimer s disease evolution of theories of causality
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

alzheimer s disease how can we track and predict efficacy
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.
functional mri analysis of bbb penetrance
Functional MRI – Analysis of BBB penetrance

LY 334XXX

Vehicle

Image courtesy of

Dr. Gómez Ansón

Addenbrookes Hospital

slide27

Neuroimaging:

A new window into the brain

slide28

Minimal Cognitive Impairment (MCI) – Value of MRI volumetric assessment

Courtesy of Dr. Gómez Anson

Addenbrookes Hospital - Cambridge

alzheimer s disease how can we track and predict efficacy1
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.
a peptide as a marker for disease progression
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
neuroscience clinical trials the challenges3
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)
neuroscience clinical trials the challenges4
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)
neuroscience clinical trials the challenges5
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

neuroscience clinical trials the challenges6
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)

neuroscience clinical trials the challenges7
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”

precompetitive pain partnerships can be used to validate qualify translational strategies in pain
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
summary of recommendations for cns drug discovery and development 1
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.

summary of recommendations for cns drug discovery and development 2
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.

neuroscience clinical trials the challenges8
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
general books on clinical trials in cns
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)
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