Neuroimmunology of Mood Disorders and Alzheimer’s Disease an academic/industrial consortium

1. Neuroimmunology of Mood Disorders and Alzheimer’s Diseasean academic/industrial consortium Ed Bullmore Wellcome Trust Investigators Meeting Edinburgh, 22 March 2016

2. What’s the problem? • Mood disorders and Alzheimer’s disease are both areas of major unmet clinical need… • …but industrial investment in R&D for CNS indications is declining… • …indicating major development risks: • lack of mechanistically specific human biomarkers • paucity of novel, tractable targets • poorly predictive animal models Depression is the major cause of disability in working age adults worldwide (WHO, 2001) There is a real danger of a “lost generation” of therapeutic progress in brain and mental health disorders despite their massive personal, social and economic costs.

3. Is there a therapeutic opportunity for MDD and AD by focusing on immune rather than neuronal targets? • Strategic advantages of immuno-psychiatry for drug development • Repurposing of existing drugs and expertise • Access to peripheral, mechanistically specific biomarkers • Innovative approach based on rapidly growing science base Raison et al (2006) Trends Immunol

4. Inflammatory depression is hiding in plain sight Wium-Andersen et al (2013) JAMA Psychiatry Bull et al (2012) Molecular Psychiatry • Epidemiological data show that higher levels of C-reactive protein (CRP) peripherally are associated with increased risk of depressive symptoms in general population top panel • Comorbid depressive symptoms are frequent in non-psychiatric inflammatory disorders, e.g. rheumatoid arthritis • LPS and other pro-inflammatory challenges cause illness behaviour, anhedonia in animals • Interferon-induced inflammation causes depression, replicably conditioned by a functional SNP in the IL6 promoter region, in patients treated for hepatitis C bottom panel

5. Neuroimmunology Consortium Strategic Award activated January 2015 GSK and Pfizer joined October 2015 Industry partners contribute cash, in-kind resources and access to new molecules Mid-point review by Wellcome Trust, 2H 2017 • Part 1 (years 1-3) • Validate new targets and molecules for immunological treatment of major depression and Alzheimer’s disease • Part 2 (years 3-5) • Conduct experimental medicine or therapeutic PoC phase 2a studies of new immune drugs in stratified groups of patients with treatment resistant depression or AD

6. High level timeline and workpackages Complementary expertise and assets - academic strengths in translational research and industrial strengths in drug development – combined in a multidisciplinary consortium Part 2 - Mood Disorders Therapeutic PoC trial of an anti-inflammatory in immuno-stratified TRD patients. Part 1 - Mood Disorders MD WP1 – Inflammatory preclinical models MD WP2 – Immunological biomarkers and treatment resistant depression (TRD) Milestone Review Part 2 - Alzheimer’s Disease Experimental Medicine study of an anti-inflammatory in early AD. Part 1 - Alzheimer’s Disease AD WP1 – Clinical Informatics AD WP2 – Animal models AD WP3 – Hypothesis-driven immune system biomarkers Technical Platforms: TP1 - Peripheral cytometry, cell sorting, transcriptomics TP2 – Proteomics in blood and CSF TP3 – PET imaging of brain inflammation TP4 – MRI of brain structure and function 0 1 2 3 4 5 Years

7. MDWP2: Peripheral and central inflammation in major depressive disorder Harrison et al (2015) Biological Psychiatry • Hypotheses: i) treatment resistance is associated with peripheral inflammation; and ii) peripheral inflammation is linked to CNS inflammation in depression • Multisite UK study • FSFV June 2015 • Primary cohort enrolled April 2016 • Secondary cohort to be completed Dec 2016 • Two-tier sampling strategy with secondary cohort consenting for MRI , PK11195 PET and CSF left panel • MRI markers are sensitive to inflammation induced by typhoid vaccination and correlated with PET FDG markers of brain metabolism and behavioural measures of fatigue bottom panel

8. MDWP2: Primary cohort data Data collection, sample management and patient recruitment is coordinated across 5 sites by an integrated management system Patient recruitment rates have exceeded target hsCRP data approximately replicated prior findings: about 1/3 of TRD patients have CRP > 3 mg/L

9. ADWP1: Target identification of JAK-STAT pathway from genomics and real world data • Generate KEGG pathways from complete GWAS datasets and perform clustering analysis for shared pathways – inflammation, diabetes and neurodegeneration • Correlate pathway load per disease (x-axis) with frequency of coincidence between Alzheimer’s and other diseases from large EHR datasets (y-axis) right panel: JAK-STAT pathway loading had strongest positive correlation with AD co-incidence • Target pathway to be validated in human samples and tested in pre-clinical models using Pfizer’s JAK inhibitor

10. ADWP1: Validation of JAK/STAT target from human cohort studies of AD Altered JAK-STAT gene expression replicates in two studies Batch 1 = AddNeuroMed Batch 2 = KCL Dementia Register JAK-STAT target identification from expression studies JAK-STAT gene expression is altered in AD blood

11. MDWP1 and ADWP2: Coordinated pre-clinical evaluation of new molecules in rodent models of neuroinflammation and AD Vehicle LPS 0.5mg/kg

12. Getting to independent review and decision point in 2017 MRC ImmunoPsychiatry Consortium (end Oct 2016)

13. Immunopsychiatrya consortium to test the opportunity for immunotherapeutics in psychiatry • £500,000 over 2 years • Peer-reviewed MRC Industry Collaboration Award • Activated Oct 2014 • Mental health endpoints in clinical trials of anti-inflammatory drugs for rheumatoid arthritis (GSK, J&J) • Blood microarray analysis in case-control studies of depression (Cambridge, GSK, J&J) • Blood microarray analysis in hepatitis patients treated with interferon and in a prior study of monoaminergic anti-depressant resistance in MDD (KCL) • Analysis of general population epidemiological data (UCL) and large NHS clinical database (KCL) • Gene expression profiling of anti-inflammatory and anti-depressant drug effects on macrophage response to LPS, IFN in vitro (Edinburgh) Immuno-Psychiatry RAB, July 2015

14. Questions?