Bionomics KOL Luncheon London April 17 th, 2018

Transcription

1 Bionomics KOL Luncheon London April 17 th, 2018

2 Safe Harbor Statement Factors Affecting Future Performance This presentation contains "forward looking" statements within the meaning of the United States Private Securities Litigation Reform Act of Any statements contained in this presentation that relate to prospective events or developments, including, without limitation, statements made regarding Bionomics drug candidates (including BNC210, BNC105 and BNC101), its licensing agreement with Merck & Co. and any milestone or royalty payments thereunder, drug discovery programs, ongoing and future clinical trials, and timing of the receipt of clinical data for our drug candidates are deemed to be forward looking statements. Words such as "believes," "anticipates," "plans," "expects," "projects," "forecasts," "will" and similar expressions are intended to identify forward looking statements. There are a number of important factors that could cause actual results or events to differ materially from those indicated by these forward looking statements, including unexpected safety or efficacy data, unexpected side effects observed in clinical trials, risks related to our available funds or existing funding arrangements, our failure to introduce new drug candidates or platform technologies or obtain regulatory approvals in a timely manner or at all, regulatory changes, inability to protect our intellectual property, risks related to our international operations, our inability to integrate acquired businesses and technologies into our existing business and to our competitive advantage, as well as other factors. Results of studies performed on our drug candidates and competitors drugs and drug candidates may vary from those reported when tested in different settings. Subject to the requirements of any applicable legislation or the listing rules of any stock exchange on which our securities are quoted, we disclaim any intention or obligation to update any forward looking statements as a result of developments occurring after the date of this presentation. 2

3 Speaker and Management Introduction Professor Edgar Jones MA, DPhil, PhD, DipClinPsych. Professor of the History of Medicine and Psychiatry, Programme Leader for MSc in War and Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King s College London Dr Mario F. Juruena, MD, MSc, Dip CBT, MPhil, PhD Clinical Senior Lecturer in Translational Psychiatry, Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, King s College London Consultant Psychiatrist South London and Maudsley NHS Foundation Trust Lambeth North Mood and Anxiety Treatment Team Professor Allan H Young, MB ChB, MPhil, PhD, FRCPsych, FRCPC, FRSB. Director, Centre for Affective Disorders, Department of Psychological Medicine, NIHR Senior Investigator, Academic Director Psychological Medicine and Integrated Care Clinical Academic Group Institute of Psychiatry, Psychology and Neuroscience, King s College London Sue O Connor, PhD Vice President of Neuroscience Research, Bionomics Steve Lydeamore Chief Financial Officer, Bionomics 3

4 Robust CNS Pipeline of Ion Channel Programs Program Mechanism of Action Indication Pre IND Phase 1 / 2a Phase 2b Bionomics Commercial Rights Market Opportunity BNC210 α7 nicotinic acetylcholine receptor NAM PTSD Agitation Ongoing; results expected 2H 2018 Phase 2a expected to initiate Q WW WW US$4.7B 3.4 4% prevalence >18 yrs ~25% of patients diagnosed and treated US$1.6B ~3.1% dementia prevalence >40yrs ~9% agitation patients diagnosed and treated US$2.7B GAD Positive Phase 2a data WW 3.1% GAD prevalence ~25% diagnosed and treated ~50% of SSRI patients treated are partial responders or have relapsed US$4.4B Panic Positive CCK-4 induced panic data WW 2.7% prevalence ~50% diagnosed and treated Assumes 5% premium to Trintellix 2016 AWP for 30 day supply of $380 compliance adjusted MK# α7 nicotinic acetylcholine receptor PAM Alzheimer s, Parkinson s Phase 1 ongoing WW Merck Partnership US$506M total deal value including upfront and milestones payments Tiered royalties Pain, Depression, Memory Enhancement Undisclosed WW 4

5 Global License and Collaboration Agreement with Merck & Co in Cognition Provides Validation Validates ionx and MultiCore drug discovery platforms Partnership with Merck & Co in cognition generated US$20M in upfront payment in 2014, research funding and US$10M first clinical milestone in February 2017 Deal valued up to US$506M in upfront, research and milestone payments plus additional royalties on net sales of licensed drugs Agreement covers research on BNC375 and related compounds PARTNERSHIP BNC375 demonstrated potent memory enhancing properties in animal models both episodic and working memory improved Targeting cognitive impairment in Alzheimer s and Parkinson s and other conditions 5

6 Innovative Discovery Engine: First In Class Ion Channel Modulators α7 nicotinic acetylcholine receptor Targeting amygdala hyperactivity Anxiety, Depression, PTSD, Agitation Wholly owned by Bionomics NAM BNC210 PAM BNC375 and related molecules α7 nicotinic acetylcholine receptor Licensed to Merck Cognitive dysfunction Depression PTSD Panic Cognition Multiple targets within parvalbumin interneurons Wholly owned by Bionomics Anxiety Multiple targets within parvalbumin interneurons Wholly owned by Bionomics 6

7 BNC210 Action Depends on Dampening the Effects of Elevated Acetylcholine Transmission in Brain Circuits Involved in Mood Disorders NORMAL ANXIETY & DEPRESSION ACh Ca ++ BNC210 NORMAL MOOD a7 nachr Ca ++ INFLUX MOOD DISORDER + BNC210 BNC210 RESTORES NORMAL MOOD 7

8 BNC210: Next Generation Drug Candidate with Potential to Treat PTSD, Anxiety & Depression Potential Competitive Advantages of BNC210* Drug No sedation No withdrawal syndrome Dominated by benzodiazepines Associated with sedation, abuse liability, tolerance and cognitive disturbances Not recommended for long-term treatment SSRIs and SNRIs used to treat depression and anxiety Modest efficacy, late onset of action, discontinuation, weight gain, sexual dysfunction and increased thoughts of suicide in adolescents Many have black box warnings No memory impairment Fast acting No drug/drug interactions Once a day dosing BNC210 Valium and other BZD x x x x Prozac and certain other SSRI/SNRI x x x Anxiety Treatments Depression Treatments Post Traumatic Stress Disorder (PTSD) Treatments Sertraline (Zoloft) and paroxetine (Paxil) are only US FDA approved anti-depressants drugs for PTSD. Despite lack of efficacy, addictive potential and other harms associated with chronic use, BZDs are still over-prescribed. An estimated 2.8M scripts are written off-label for management of PTSD symptoms. VA/DoD Practice Guideline for PTSD recommends against the use of benzodiazepines (BZDs) such as Valium for PTSD. 50% increase in overall mortality rates associated with long-term benzodiazepine use in PTSD patients overdosing, sudden unexplained deaths, car crashes, falls. *Based on data from preclinical studies, Phase 1 & 2 clinical trials. 8

9 BNC210 Targets Multi Billion Dollar Markets with Unmet Need: US Market Potential PTSD MDD + Anx BP+Anx Panic SAD Agitation GAD Innovative, first inclass 17M Unmet need in large patient population 8.7 9M 8 8.5M 6.5 7M 7M Advancement in care 5M Limited branded competition 3 3.5M Ability to achieve large market share 1.7M 1.0M 0.5M 1.5M 1.0M 0.5M US$4.7b US$3.2b US$1.5b US$4.4b US$2.5b US$1.6b Eligible Patient US$ Market Potential Assume 5% premium to Trintellix 2016 AWP for 30 day supply of $380 Compliance Adjusted 0.9M US$2.7b US Prevalence Eligible Patient Population % prevalence >18yrs., ~25% of patients diagnosed and treated 2 6.7% prevalence, ~50% co morbid anxiety, ~50% diagnosed and treated 3 ~2.9% prevalence, 50% co morbid anxiety (range in literature 25 to 75%), ~50% diagnosed and treated 4 ~2.7% prevalence, ~50% diagnosed and treated 5 ~6.8% prevalence, 15 20% diagnosed and treated 6 ~3.1% dementia prevalence >40yrs., ~9% agitation patients diagnosed and treated 7 3.1% GAD prevalence, assumes ~25% diagnosed and treated, ~50% of SSRI patients treated are partial responders or relapsers 9

10 Bionomics KOL Post traumatic stress disorder Edgar Jones Institute of Psychiatry Psychology & Neuroscience King s College London

11 Bionomics KOL Post traumatic stress disorder (PTSD) was formally recognised by the American Psychiatric Association in It arose in the context of the Vietnam War and was designed to diagnose post traumatic illness in returning service personnel. Precursor terms included delayed stress syndrome and post Vietnam syndrome. Diagnostic and Statistical Manual of Mental disorders, DSM III (1980), pp

12 Bionomics KOL DSM III (1980) Professor Nancy Andreasen, chairman of the Committee on Reactive Disorders, had researched the psychological effects of severe burns and was sympathetic to the notion of a post traumatic stress disorder, recommending its inclusion in DSM III published in Hence, PTSD was formally acknowledged only after it was recognised as being applicable to all adults exposed to terrifying event. Allan Young, The Harmony of Illusions, Inventing Posttraumatic stress disorder, Princeton UP (1995). 12

13 Bionomics KOL Classification and description From 1980 to the present, PTSD has gone through five iterations. The current American classification is found in DSM 5 (2013). In 1980 PTSD was classified as an anxiety disorder, but from 2013 falls within a new chapter entitled trauma and stressorrelated disorders. The WHO international classification of diseases, ICD 10 (1992) also includes a definition of PTSD, though an updated version is due to be published this year. 13

14 Bionomics KOL DSM V (May 2013) A complex definition, which has evolved since its inception in 1980, involves eight elements in total: Criterion A, Exposure to trauma The person was exposed to: death, threatened death, actual or threatened serious injury, or actual or threatened sexual violence. 14

15 Bionomics KOL DSM V (May 2013) There are four symptom elements: Criterion B, Intrusion symptoms Memories, nightmares, dissociative reactions such as flashbacks, distress after traumatic reminders. Criterion C, Avoidance Trauma related thoughts, feelings, people and situations. Criterion D, Negative alterations in cognition and mood Negative beliefs and emotions, alienation, constricted affect. Criterion E, Alterations in arousal and reactivity Irritable, aggressive, hyper vigilance, startle reaction, poor concentration, sleep disturbance. 15

16 Bionomics KOL DSM V (May 2013) And three further characteristics: Criterion F, Duration Symptoms in B, C, D and E have to be present for over a month (28 days). Until this point symptoms are classified as acute stress disorder. Criterion G, Functional Significance Significant distress or functional impairment as a result of symptoms. Criterion H, Exclusion Not result of medication, drug abuse or illness. 16

17 Bionomics KOL Primacy of the event Criterion A, which assigned responsibility to the event, was very broad when first proposed: Existence of a recognisable stressor that would evoke significant symptoms of distress in almost everyone (DSM III, 1980, 238). The defining criterion was narrowed in 1987: The person has experienced an event that is outside the range of usual human experience and that would be markedly distressing to almost anyone, e.g. serious threat to one s life or physical integrity (DSM IIIR, 1987). 17

18 Bionomics KOL Criteria A exposure to trauma in DSM V (2013) The person was exposed to: death, threatened death, actual or threatened serious injury, or actual or threatened sexual violence, as follows: (1 required) 1.Direct exposure. 2. Witnessing, in person. 3. Indirectly, by learning that a close relative or close friend was exposed to trauma. If the event involved actual or threatened death, it must have been violent or accidental. 4. Repeated or extreme indirect exposure to aversive details of the event(s), usually in the course of professional duties (e.g., first responders, collecting body parts; professionals repeatedly exposed to details of child abuse). This does not include indirect non professional exposure through electronic media, television, movies, or pictures. 18

19 Bionomics KOL Sub types of PTSD By timing of onset and duration: 1. Acute form of PTSD one to three months. 2. Chronic PTSD present for more than three months 3. Delayed form onset of symptoms at least 6 months after the event. 19

20 Bionomics KOL Sub types of PTSD By causal event: Type 1 PTSD exposure to a single terrifying event. Type 2 PTSD repeated exposure to unpleasant events in the course of professional duties. 20

21 Bionomics KOL Complex PTSD in ICD 11 (2018) ICD 11 (2018) will include a new category of complex PTSD that has three additional clusters that reflect disturbances in self organization : (1) affective dysregulation, (2) negative self concept, and (3) disturbances in relationships. These disturbances are proposed to be typically associated with sustained, repeated, or multiple forms of traumatic exposure (such as genocide campaigns, childhood sexual abuse, child soldiering, severe domestic violence, torture, or slavery), reflecting loss of emotional, psychological, and social resources under conditions of prolonged adversity. CPTSD is associated with greater functional impairment than PTSD. Karatzias, T. et al. (2017), PTSD and Complex PTSD: ICD 11 updates on concept and measurement in the UK, USA, Germany and Lithuania, European Journal of Psychotraumatology, 8 (Suppl. 7): Brewin, C.R. et al (2017), A review of current evidence regarding the ICD 11 proposals for diagnosing PTSD and complex PTSD, Clinical Psychology Review, 58:

22 Bionomics KOL Co morbidity and PTSD Posttraumatic stress disorder (PTSD) commonly co occurs with other psychiatric disorders. Data from epidemiologic surveys indicate that the vast majority of individuals with PTSD meet criteria for at least one other psychiatric disorder, and a substantial percentage have three or more other psychiatric diagnoses. These include depression, anxiety state, alcohol and drug abuse. Approximately 50% of people diagnosed with PTSD also suffer from major depression. Brady, K.T. (2000), Comorbidity of psychiatric disorders and post traumatic stress disorder, Journal of Clinical Psychiatry, 61 (Suppl. 7):

23 Bionomics KOL How common is PTSD? Initially most studies of prevalence were conducted in veteran populations. As PTSD has been recognised and incorporated within diagnostic classification systems across the world, evidence has been gathered for civilians exposed to conflict and discrete traumatic events 23

24 Bionomics KOL National Vietnam Veterans Readjustment Study (1990) Mandated by Congress in 1983 and taking four years to complete at a cost of $9 million, the National Vietnam Veterans Readjustment Study found that 15.2% of male veterans and 8.5% of female veterans met the criteria for PTSD. A further 11.1% of males and 7.8% of females had clinically significant stress symptoms ( partial PTSD ) that adversely affected their lives. The NVVRS analysis of the lifetime prevalence of PTSD indicated that 30.6% of male Vietnam veterans (over 960,000 servicemen) and 26.9% of females (1,900) had PTSD at some time during their lives. Kulka, R. A., Schlenger, W. E., Fairbank, J. A., Hough, R. L., Jordan, B. K., Marmar, C. R., et al. (1990). Trauma and the Vietnam War generation: Report of findings from the National Vietnam Veterans Readjustment Study. New York: Brunner/Mazel. 24

25 Bionomics KOL NVVRS (1990) The study also demonstrated that those with PTSD are significantly more likely to have other psychiatric disorders and re adjustment problems. The estimated lifetime prevalence of alcohol abuse or dependence amongst male Vietnam veterans was 39.2%, and that for drug abuse was 5.7%. Male veterans with PTSD were found to be two to six times more likely to abuse alcohol or drugs as those without the disorder. The prevalence of PTSD was correlated with high levels of combat exposure and other warzone stressors. 25

26 Bionomics KOL US population The National Comorbidity Survey Replication (NCS R), conducted between February 2001 and April 2003, comprised interviews of a nationally representative sample of 9,282 Americans aged 18 years and older. PTSD was assessed among 5,692 participants, using DSM IV criteria. The NCS R estimated the lifetime prevalence of PTSD among adult Americans to be 6.8%. The lifetime prevalence of PTSD among men was 3.6% and among women was 9.7%. Kessler, R.C., Berglund, P., Delmer, O., Jin, R., Merikangas, K.R., & Walters, E.E. (2005). Lifetime prevalence and age of onset distributions of DSM IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 62(6): overview/epidemiological facts ptsd.asp 26

27 Bionomics KOL UK population In the 2014 adult psychiatric morbidity survey, one participant in twenty (4.4%) screened positive for PTSD in the past month, with similar rates for men and women. Among women, the likelihood of screening positive for PTSD was particularly high among year olds (12.6%) and then declined sharply with age. In men, the rate remained stable between the ages of 16 and 64, only declining in much later life. For UK armed forces, studies have found a rate of 4% overall with a rate of 7% for those in front line roles. Fear N.T. et al. (2014), Adult Psychiatric Morbidity Survey, Chapter 4; Fear, N.T., et al. (2010), What are the consequences of deployment to Iraq and Afghanistan on the mental health of the UK armed forces, Lancet, 375:

28 Bionomics KOL Australian population The Australian prevalence rates for PTSD are 4.4% (over a 12 month period) and 7.2% (lifetime). Rates are higher after specific traumas; interpersonal trauma such as rape and torture leading to lifetime prevalence rates as high as 50%. McEvoy PM, Grove R, Slade T. Epidemiology of anxiety disorders in the Australian general population: findings of the 2007 Australian National Survey of Mental Health and Wellbeing. Aust N Z J Psychiatry 2011;45: Breslau N, Peterson E, Poisson L, Schultz L, Lucia V. Estimating posttraumatic stress disorder in the community: lifetime perspective and the impact of typical traumatic events. Psychol Med 2004;34:

29 Bionomics KOL PTSD rates in Israeli population Studies of Israelis exposed to suicide bombers and rocket attacks have demonstrated elevated rates of PTSD: Bleich et al (2003) and (2006) 9% Shalev et al (2006) 21% Palmieri et al (2008) 7% Hall et al (2008) 26% Besser and Neria (2009) 27% Bleich et al (2003), Exposure to terrorism, stress related mental health symptoms in Israel, JAMA, 290(5): ; Bleich et al (2006), Mental health and resiliency following 44 months of terrorism, BMC Medicine, 4 (21):

30 Bionomics KOL PTSD and treatment Treatments for PTSD are designed for civilians and discrete episodes: rape, violent assault, road traffic accident. There are few clinical interventions designed for veterans. Outcomes for veterans (particularly those with chronic symptoms or older veterans in longterm treatment) in standard PTSD treatment programmes are less effective. Bisson J, Ehlers A, Matthews R, et al. Psychological treatments for chronic post traumatic stress disorder: systematic review andmeta analysis. Br J Psychiatry 2007;190: Bradley R, Greene J, Russ E, et al. A multi dimensional meta analysis of psychotherapy for PTSD. Am J Psychiatry 2005;162:

31 Bionomics KOL Although the intensive, six week PTSD programme run by Combat Stress reduces the number of symptoms and improve functioning for 87% of participants, most still meet the criteria for PTSD either on discharge or at 6 months follow up. Murphy, D. et al. (2015) Mental health and functional impairment outcomes following a 6 week treatment programme for UK military veterans, BMJ Open 5:e

32 Bionomics KOL Cognitive processing therapy (CPT) and prolonged exposure therapy for PTSD in military and veteran populations both outperformed waitlist and treatment as usual. 49% to 70% of both treatments achieved a meaningful symptom reduction. However, 60% to 72% continued to meet the criteria for PTSD after treatment. Non response rates were high in follow up studies. Steenkamp recommended improvements to existing treatments and research into new interventions for military PTSD. M.M. Steenkamp et al (2015), Psychotherapy for military related PTSD: a review of randomised controlled trials, JAMA, 314(5): M.M. Steenkamp et al (2016), True evidence based care for PTSD in military personnel and veterans, JAMA Psychiatry, 73(5):

33 Bionomics KOL Summary PTSD is a well recognised and validated disorder, having been the subject of a large number of studies in many nations. It is a common illness. PTSD is often co morbid with other disorders. Outcomes are varied and depend on the severity of the traumatic exposure, pre existing vulnerabilities and post event care. A significant proportion of those with PTSD develop a chronic or severe disorder which is currently difficult to treat with psychological therapies such as exposure based CBT and EMDR. 33

34 PTSD subtypes regarding Pharmacotherapy Types, pros and cons; Context to the Clinical Endpoints Dr Mario F. P. Juruena MD, MSc, Dip CBT, MPhil, PhD - Clinical Senior Lecturer in Translational Psychiatry Centre for Affective Disorders, Dept of Psychological Medicine Institute of Psychiatry, Psychology and Neuroscience King s College London Honorary Consultant Psychiatrist South London and Maudsley Trust Mood, Anxiety and Personality Treatment Team Mario.Juruena@slam.nhs.uk mario.juruena@kcl.ac.uk

35 Disclosures I have an interest in relation with one or more organizations that could be perceived as a possible conflict of interest in the context of this presentation. The relationships are summarized below. Interest Grants/clinical trial payments Advisory board/honoraria Paid positions Other Name of organisation Academy of Medical Sciences/Royal Society UK Sao Paulo Research Foundation Lundbeck, Pfizer, GSK, Sanofi, AstraZeneca, Abbott, Bionomics WHO, UNESCO, CNPq, FAPESP and NIHR King s College London and NHS, UK No share holdings in pharmaceutical companies 35

36 Definitions Stress and its conceptualisations Bernard (1859): The importance of the organism s inner environment. Cannon ( ): (Wisdom of the body, 1932): Homeostasis. Fight or flight response. The role of the autonomic nervous system. Selye ( ): General Adaptation Syndrome Model (GAS): Acute stress reaction Resistance Exhaustion. Lazarus ( ): The importance of appraisal in coping with stress. Epidemiological research, Barker: Insufficient nutrition in prenatal period leads to an increased risk of type 2 diabetes and heart disease. Behavioral genetics, Caspi: MAO A polymorphism, early maltreatment & increased stress vulnerability; 5 HT polymorphism, stress & onset of psychiatric diseases. Neuroendocrinological research: HPA axis (hypothalamic pituitary adrenal axis). 36

37 Consequences of uncontrollable stress When stress is uncontrollable, chronic and overwhelming it can be negative to the individual and result in: Burnout General Adaptation Syndrome (GAS) Post Traumatic Stress Disorder (PTSD) Physical disorders (e.g. cardiac disorders) When stress is manageable, it can become positive and lead to both growth and enhanced stress competence 37

38 Disasters and traumatic events Traumatic Events Individuals Exposed Disasters Communities Exposed Intentional War assault robbery rape Unintentional Accident MVA injury Human Made War industrial acc. plane crash toxic exposure Natural hurricane earthquake tornado 38

39 Post traumatic stress disorder Traumatic event Fearful reaction Symptoms Re experiencing avoidance Numbness Hyperarousal Peter Corlett, Man in the mud. I World war These pathological responses of PTSD have been proposed to result from the failure of the stress response system to appropriately react, adapt and recover from the traumatic event 39

40 Who gets PTSD? It depends on: Severity Duration Proximity. PTSD is mitigated or worsened by: Childhood Traumatic Experience Personality characteristics Family history Social support. 40

41 Stress and adaptation McEween, Physiol Rev 87:

42 Prevalence Bipolar Disorder and PTSD Lifetime prevalence of bipolar disorder (BD) types I and II is 2.1% in the world. Subthreshold forms affecting another 2.4% Lifetime prevalence of PTSD in general population is 10 12% in women and 5 6% in men Prevalence of PTSD comorbidity among BD patients = 20.3% Merikangas et al., JAMA 2007 Yehuda et al., NEJM 2002 Assion HJ et al., Soc Psy Epi

43 Does PTSD impact child functioning? Child functioning is predicted by PTSD symptoms and positive parenting behaviors Age, Gender, Race PTSD symptoms Child Problems Positive Parenting Behaviors 43

44 Attachment John Bowlby Allen & Badcock. Progr Neuropsychol Biol Psychiatry, 30: ,

45 Stress Across Lifespan on the Brain, Behaviour and Cognition 45

46 Hypothalamic Pituitary Adrenal axis Activity UK/VOR/1603/0276z Date of preparation: May 2016 Yehuda NEJM

47 Hormonal dysfunctions in PTSD Other hormonal dysfunction in relation to trauma Cortisol levels in PTSD patients: DECREASED basal cortisol levels ENHANCED negative feedback inhibition. 47

48 Lower levels of Cortisol in PTSD Young and Breslau Arch Gen Psychiatry 2004 Oquendo Neuropsychopharmacol

49 Pathways Between Trauma related Disorders and Substance Use PTSD TRAUMA SUD Hien,

50 Substance use disorders in veterans Most common substances abused by veterans Alcohol Marijuana Crack cocaine Heroin Anxiolytics Opiate painkillers The National Vietnam Veterans Readjustment Study (NVVRS), found that 75% of combat veterans with a diagnosis of PTSD met criteria for lifetime alcohol abuse or dependence (Kulka et al., 1990) More recently, co-occurring PTSD and SUD have been reported in US Troops returning from conflicts in Iraq and Afghanistan and estimates of prevalence have been reported to be as high as 50% 50 (Gulliver & Steffen, 2010)

51 Canterbury (NZ) Earthquake Series 7.1 magnitude earthquake around 4am on 4 September February 2011 earthquake greatest shaking forces ever recorded in an urban area 185 deaths, multiple injuries 80% of city centre buildings irreparably damaged plus approximately 20,000 homes Widespread damage to infrastructure Declaration of a national state of emergency 51

52 The Mental Health (DSM IV) Consequences of the Canterbury Earthquakes 52

53 Adjusted rates of mental disorder 53

54 Summary Compared with people not exposed, those with the highest level of EQ exposure had: 68% increase in symptoms of depression Almost 4 times as many PTSD symptoms Rates of regular smoking that were 2.5 times higher EQ exposure accounted for ~ 11% of mental health problems in the cohort Most marked for PTSD and nicotine dependence. 54

55 Treating PTSD Biopsychosocial Model of Health & Disability Lifestyle: Exercise, Smoking, Alcohol and Drugs, Obesity / Diet Work Attachment / Age Chronic Pain & Disability Behavior Depression / Anxiety Personality Disorders Hx of Childhood Abuse Perceived Injustice (retribution owed) Fear Avoidant Behavior (Guarding) Catastrophic Thinking 55

56 NICE Treatment Guidelines PTSD, 2005 Trauma focused psychological treatment Trauma focused CBT should be offered to those with severe PTSD symptoms or with severe PTSD in the 1 st month after the traumatic event. These treatments should normally be provided on an individual outpatient basis All people with PTSD should be offered a course of trauma focused psychological treatment (trauma focused cognitive behavioural therapy [CBT] or eye movement desensitisation and reprocessing [EMDR]). Individual outpatient basis Children and young people Trauma focused CBT should be offered to older children with severe PTSD symptoms or with severe PTSD in the 1 st month after the traumatic event Children and young people with PTSD, including those who have been sexually abused, should be offered a course of trauma focused CBT adapted appropriately to suit their age, circumstances and level of development 56

57 NICE treatment guidelines 2005 Drug treatments for adults Drug treatments for PTSD should not be used as a routine first line treatment for adults in preference to a trauma focused psychological therapy Drug treatments (Paroxetine or Mirtazapine for general use, and Amitriptyline or Phenelzine should be considered for the treatment of PTSD in adults who express a preference not to engage in trauma focused psychological treatment 1 Screening for PTSD For individuals at high risk of developing PTSD following a major disaster, consideration should be given to the routine use of a brief screening instrument for PTSD at 1 st month after the disaster 1 Paroxetine was the only drug listed with a current UK product licence for PTSD at the date of publication (March 2005) 57

58 Response to Paroxetine in PTSD Davidson, J. et al. J Neuropsychiatry and clinical neurosciences 2004; 16(2):

59 Conclusions PTSD is perhaps the most painful mental disorder to have treatment for and it can be a life long process through either therapy or medication to manage and control symptoms The reintegration of these patients into being active and participating members of society is paramount to the overall success of the community They have valuable skills and experience that contribute to the success of a sustainable economy, planning and strategies to address how to best help reintegrate these are fundamental 59

60 60

61 Creating and developing innovative therapies Dr. Sue O Connor Overview of BNC210 61

62 BNC210 is a novel, selective negative allosteric modulator of 7 nachr in Phase II for the treatment of PTSD BNC210 has been evaluated in 7 clinical trials and demonstrated: In HEALTHY VOLUNTEERS Reduced number and intensity of panic symptoms in a CCK challenge model of panic attack Target engagement in an EEG paradigm (inhibition of nicotine induced EEG changes) In GENERALISED ANXIETY DISORDER PATIENTS Effects on anxiety related brain changes while performing the emotional faces task during fmri; Reduction in defensive behavior in a behavioral task (JORT) Safety and tolerability in >392 subjects; no signs of cognitive impairment, sedation or effects on motor coordination Phase II study in patients with PTSD has completed recruitment Read out expected Q

63 How Does BNC210 Work? Dysregulation of acetylcholine, a neurotransmitter in human brain, has been implicated in the stress induced behaviors of depression and anxiety. This involves the hippocampus and amygdala The alpha 7 nicotinic receptor ( 7nAChR) is highly expressed in both regions 63

64 Pre Clinical Experiments* have Demonstrated the Role of the 7nAChR in Stress Induced Behaviour Hippocampus Amygdala 7 receptor 7 receptor Behaviour measured in mice in hippocampus and amygdala * Mineur, et al, PNAS, 2013 Mineur et al, NPP, 2015 Mineur, et al, BJP, 2017 Mineur, et al, NPP, Levels of acetylcholine increased by genetic knock down of ACHE or pharmacological block of ACHE by physostigmine 2. 7 receptor blocked with antagonists 7 specific (MLA) and non specific (MECA) nicotinic receptor blocker 3. Genetic knock down of 7 receptor 64

65 Action of BNC210 Depends on Acetylcholine Neurotransmission and Allosteric Modulation of 7 nachr NORMAL ANXIETY & DEPRESSION ACh Ca ++ BNC210 NORMAL MOOD a7 nachr Ca ++ INFLUX MOOD DISORDER + BNC210 BNC210 RESTORES NORMAL MOOD NAMs have self limiting activity determined by the cooperative interaction between the compounds binding at the allosteric and orthosteric sites e.g. BNC210 and acetylcholine 65

66 BNC20 Clinical Data Demonstrated Anxiolytic Activity in Healthy Volunteers and Patients While Maintaining Unique Safety Profile Protocol Number Phase Description Subjects Location BNC & 2 1 BNC b BNC b BNC b BNC a BNC Safety and Tolerability of Single Ascending Doses SAFETY AND TOLERABILITY Lorazepam & BNC210 Comparison plus EEG SAFETY AND TOLERABILITY LORAZEPAM COMPARISON Panic Attack Model in Healthy Volunteers EFFICACY 24 Australia 22 France 59 France Safety and Tolerability of Multiple Ascending Doses Target Engagement Study with Nicotine and EEG 42 France SAFETY AND TOLERABILITY TARGET ENGAGEMENT Imaging and Behavioural Study In Generalised Anxiety Disorder Patients 24 UK EFFICACY Post Traumatic Stress Disorder 192 EFFICACY read out in Q3, 2018 Australia USA 66

67 Single and Multiple Doses of BNC210 Show No Impairment of Cognition or Mood, No Sedation and No Abuse Potential in Humans Assessments SINGLE DOSES Lorazepam Comparison Study REPEAT DOSING 8 DAYS Multiple Ascending Dose Study Attention Multiple Choice Reaction Time Psychomotor Speed /Sustained Attention /Working memory Digital Substitution Test BNC210 BOTH DOSES LORAZEPAM BNC210 ALL DOSES No effect Slowed No effect No effect Slowed No effect Visual/motor Co ordination; Sleep Saccades No effect Slowed Not Done Emotion evas No effect Lower scores No effect Sleep Karolinska Sleepiness Scale No effect Sedative Not Done Verbal Memory Perceptual Priming Test No effect Impaired No effect Numeric Working Memory Not Done Not Done No effect Spatial working memory Not Done Not Done No effect Addiction Potential ARCI49 No effect Association with LSD and Phenobarbital/ Alcohol Group No effect Lorazepam Comparison Study Single doses of BNC210 (300 and 2000 mg), Lorazepam (2 mg) and placebo. N=24 healthy volunteers. Multiple Ascending Dose Study Assessed Day 1 and Day 8. N=6 for 300, 600 and 1200 mg/day; N=24 for 2000 mg/day, N=2 and 6 for placebo. All healthy volunteers. 67

68 qeeg Study Confirms BNC210 Brain Penetration, Lack of Sedation and Unique EEG Signature Compared with Lorazepam EEG Spectrum BNC210 Lorazepam Increase in power was not seen with BNC210 during the vigilance controlled session Increase in spectral power during vigilance control session is sign of Lorazepam induced sedation Increase in 3 spectralpoweris associated with the anxiolytic activity of Lorazepam Arrows represent statistically significant changes in spectral power compared to placebo qeeg showed: BNC210 affects on the brain BNC210 is not sedating BNC210 and Lorazepam share an EEG response associated with the anxiolytic effects of Lorazepam 68

69 Human Clinical Data Indicates BNC210 May Impact Multiple PTSD Symptom Clusters INTRUSION Phase 1 CCK 4 Induced Panic NEGATIVE ALTERATIONS IN COGNITION & MOOD THE MECHANISM AND PHARMACOLOGY OF BNC210 INDICATE ITS THERAPEUTIC POTENTIAL FOR SEVERAL PTSD SYMPTOM CLUSTERS AVOIDANCE GAD Phase 2 Trial AROUSAL & REACTIVITY GAD Phase 2 Trial Phase 1 CCK 4 Induced Panic 69

70 BNC210 Significantly Reduced CCK 4 Induced Panic Symptoms in Rodents and Humans RODENTS HUMANS Protocol in Healthy Volunteers BNC210 Reversed the Anxiogenic Effect of CCK 4 in the Rat EPM, out performed Diazepam Randomized double blinded, placebo controlled Subjects received single dose of placebo and BNC210 (2,000 mg) Primary Endpoints Changes in the PSS (Panic Symptom Scale) Secondary Endpoints Change in anxiety, following the panic attack, by means of the e VAS (emotional Visual Analog Scale) scales % Reduction in Total Number of Symptoms and Symptom Intensity Score % * 10' after CCK Injection When treated with BNC210, subjects experiencing panic symptoms showed: Reduction in number and intensity of Symptoms More rapid return to baseline emotional stability compared to placebo 70

71 Effect of BNC210 on Fear Extinction in Mouse Assay Translated to evas Results Following a CCK 4 Challenge in HVs Conditioned Fear Extinction Model Emotional Visual Analog Scale (evas) Time Spent Freezing (sec) Placebo BNC ' 10' 20' 30' 60' Time After CCK Injection MICE BNC210 enhanced fear extinction following conditioned stimulus training HUMANS BNC210 improved rate of return to emotional stability following CCK 4 challenge 71

72 BNC210 May Also Inhibit PTSD Associated Panic Attacks Increasing evidence that panic attacks are common in people with PTSD US National Comorbidity Survey found that 35% of people with PTSD had panic attacks Evidence that panic attacks in the context of PTSD are associated with fear of trauma memories 72

73 BNC210 Treatment Reduced Nicotine Induced EEG Responses and Provided Evidence for BNC210 Target Engagement in Humans NICOTINE Responding Nicotinic Receptors EEG Spike in 2 band The EEG response to nicotine is achieved through activation of nicotinic receptors in the brain. The major populations targeted are 4 2 and 7 receptors. Reduction in the response is due to negative allosteric modulation of the 7 receptors by BNC Day 1 No BNC210 Day7 with BNC210 NICOTINE PLUS BNC Responding Nicotinic Receptors EEG Spike in 2 band 0.5 NS p= p= p= p= Nicotine (mg) Oral dosing with 2000 mg BNC210 for 7 days reduced EEG power in the 2 band (N=24 healthy volunteers) 73

74 BNC210 Phase 2 Trial in Generalized Anxiety Disorder (GAD) Demonstrated Acute Anxiolytic Activity Randomized, double blind, placebo and Lorazepam controlled, 4 way crossover design BNC210 King s College London Institute of Psychology, Psychiatry and Neuroscience Primary Endpoints Met: Phase 2 24 GAD subjects Secondary Endpoints Met: Initiated March 2015 Positive results reported Q Changes in cerebral perfusion with BNC210 Changes in brain activation (amygdala) and pathways relevant to anxiety during the performance of an emotional faces task Emotional Faces Task Functional MRI JORT Significant Changes in defensive behavior using the Joystick Operated Runway Task Safe and well tolerated BNC210 is not sedating or addictive and does not impair memory or motor co ordination 74

75 Arterial Spin Labelling Showed BNC210 Caused Significant Local Changes in Cerebral Blood Flow PRIMARY OBJECTIVE: To determine whether BNC210 causes significant changes in cerebral perfusion using (ASL) in the resting state. 75

76 BNC210 Caused Significant Changes in Anxiety Related Brain Activity While Viewing Emotional Faces During fmri Emotional Faces Task There was significant activation to fearful faces in both left (t(20) = 5.32, p <.001) and right (t(20) = 4.51, p <.001) amygdala. This was significantly reduced by BNC210 (300 mg) Thomas et al Arch Gen Psychiatry , Neutral 20% 40% 60% 80% Fearful Left Amygdala 0.33 Right Amygdala 1.75 MALE? FEMALE? Fu et al Am. J. Psychiatry 164, (2007) Decide whether the face is male or female and press left/right button This involves implicit processing of emotional faces and robust amygdala activation Note: N = 21 (19 Female, 2 Male). Three subjects excluded for excessive head movement.* Placebo Lorazepam 1.5 mg * BNC mg BNC mg Placebo 0.4 Lorazepam 1.5 mg * BNC mg BNC mg 76

77 BNC210 Treatment Reduced Connectivity Between Left Amygdala and Anterior Cingulate Cortex in GAD Patients BNC210 (300 mg) reduced connectivity between the left amygdala and anterior cingulate cortex while viewing fearful faces (p = 0.04 corrected) This finding is highly supportive for the anxiolytic activity of BNC210: Interactions between the dmpfc/acc and amygdala constitute an aversive amplification circuit increased positive coupling between these regions is associated with elevated threat processing under stress. In pathological anxiety this circuit becomes permanently switched on (Robinson et al. 2011) Placebo 0.04 BNC210 77

78 Effect of BNC210 on Defensive Behaviour Evaluated in Joystick Operated Runway Task (JORT) Measure of defensive behaviour Flight intensity = Average velocity/ force used to escape in trials with threat Average velocity/ force used to escape in trials with no threat Significant separation from placebo occurred in the case of both the low and high dose of BNC210 (simple contrasts showed p = and = respectively) Lorazepam showed a similar direction of effect but failed to separate significantly from placebo (F = 2.072, p =.165) Note: n = 21 (females only) Mean Intensity of Threat Avoidance Behaviour Mean Intensity of Threat Avoidance Behavior P=0.165 P=0.033 P=0.007 Placebo Lorazepam BNC mg BNC mg Error Bars ± SEM 78

79 PTSD Trial will Provide a Comprehensive Data Package to Guide Path Forward for BNC210 One primary end point Several secondary end points Other rating scales included to capture efficacy of BNC210 for a range of symptoms and disorders 79

80 BIONOMICS PTSD TRIAL Approach, Considerations, and Decisions Professor Allan H Young, MB ChB, MPhil, PhD, FRCPsych, FRCPC, FRSB. Institute of Psychiatry, Psychology and Neuroscience, King s College London 80

81 The Mechanism and Pharmacology of BNC210 Indicate Therapeutic Potential for Several PTSD Symptom Clusters Four main PTSD symptom clusters (DSM 5 criteria) Intrusive thoughts Nightmares Avoidance Negative alterations in cognition and mood. Arousal and reactivity Anxiolytic in rodents and man Acute effects on neural circuitry associated with anxiety and PTSD in man Enhances fear extinction in mice and emotional recovery in man following panic attack Acute doses reduce defensive behavior in man Antidepressant effects in rats, acute efficacy which is enhanced with repeat dosing Promotes neurite outgrowth in primary neurons Reduces amygdala hyperactivity a feature shared by anxious patients and PTSD patients Inhibition of a7 nachr inhibits release of excitatory neurotransmitters associated with hypercholinergic state; including NA, DA, GLUT, ACh potential to reduce NA induced hyperarousal Clinical efficacy in model of panic in HVs, elevated levels of ACh stimulate the HPA axis, BNC210 treatment significantly reduced levels of ACTH in CCK study 7 nachrs modulate GABA and glutamate signaling in the amygdala and hippocampus 81

82 BNC210 PTSD Clinical Trial Overview Overall Design: Study Duration: Primary Objectives: Secondary Objectives: Randomized, double blind, parallel, placebo controlled, multi center study in Australia (6) and U.S.A. (20) 192 subjects, 4 treatment arms: placebo, 150 mg, 300 mg and 600 mg BNC210, twice daily. Randomization 1:1:1:1. Treatment phase: 12 weeks Target enrolment completed Q1, 2018 Read out Q3, 2018 To assess the effects of BNC210 on investigator rated symptoms of PTSD as measured by the CAPS 5 (Clinician Administered PTSD Scale for the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM 5)) To assess the effects of BNC210 on individual symptom clusters (CAPS 5) To assess the effects of BNC210 on other psychiatric outcomes including anxiety and depression To assess the effects of BNC210 on global functioning and Quality of Life To assess the effects of BNC210 on patient reported outcomes To assess the safety and tolerability of BNC210 82

83 Several Rating Scales Included to Capture Efficacy of BNC210 For Range of Symptoms and Disorders PTSD Scales CAPS 5 (Clinician Administered PTSD Scale for DSM 5) Primary endpoint PTSD Checklist for DSM 5 (PCL 5) Self reporting scale Affective Disorders Montgomery Åsberg Depression Rating Scale (MADRS) Hamilton Anxiety Rating Scale (HAM A) Scales to assess symptom severity, treatment response and efficacy Clinical Global Impressions severity and improvement scale (CGI S/CGI I) Patient Global Impression Severity and improvement Scale (PGI S/PGI I) Assessment of Quality of Life (AQoL 8D) Social functioning: Sheehan Disability Scale (SDS) Sleep monitoring: Pittsburgh Sleep Quality Index (PSQI) 83

84 BNC : Key Patient Selection Criteria for Study Entry INCLUSION CRITERIA A current diagnosis of PTSD as defined by CAPS 5 (Clinician Administered PTSD Scale for DSM 5) Males and females between the ages of Concomitant use of current anti depressant medication allowed (1 anti depressant only (SSRI or SNRI)) Rescue use of benzodiazepines allowed (not to exceed 2 days / week) Continuation/maintenance of long term ( 3 months) counseling support and /or behavior therapy allowed EXCLUSION CRITERIA Subjects with MADRS score >23 (MADRS) Increased risk of suicidal behavior or suicidal ideation with intent Moderate to severe substance use disorder in the 2 months prior to study Patients with borderline personality disorder, bipolar disorder, psychotic disorders, and significant traumatic brain injury 84

85 Noteworthy Trial Design Elements Patient Population Active duty military Broadly inclusive Military veterans Exclude Borderline Civilians Personality Disorder Trauma type Trauma duration PTSD focus of treatment - Depression cutoff on MADRS Trauma age at onset Comorbidity Well established therapy Current Treatment and/or antidepressant 85

86 Safety Evaluations Conducted Throughout the Study Adverse event reporting Vital signs Physical examinations Standard 12 Lead ECG Safety Labs: Hematology, Biochemistry, Urinalysis Suicidal behavior (Columbia Suicide Severity Rating Scale, C SSRS) CANTAB Cognitive Assessments: Paired Associates Learning (episodic memory) Spatial Working Memory (working memory) Rapid Visual Information Processing (sustained attention) 86

87 Potential Positive Outcomes from Bionomics PTSD Trial PTSD Anxiety Depression ENDPOINT CAPS 5 Total Score Intrusive Thoughts, Nightmares Avoidance Negative Alterations in Cognition and Mood Arousal and Reactivity CGI I/CGI S PCL 5 HAM A (+/ antidepressants) MADRS (+/ antidepressants) PGI: Patient Global Impression Scale Severity and Improvement AQoL 8D: Assessment of Quality of Life SDS: Sheehan Disability Scale PSQI: Pittsburgh Sleep Quality Index C SSRS: Columbia Suicide Severity Rating Scale Statistically Significant p 0.05 Meaningful Effect Size 87

88 Creating and developing innovative therapies Dr. Deborah Rathjen Closing Remarks 88

89 Well-Positioned For A Catalyst Rich BNC210 Positive Phase 1 MAD Target Engagement Demonstrated 2016 BNC210 Phase 2 trial successfully completed (GAD) BNC210 Phase 2 trial initiated (PTSD) 2017 Milestone payment from Merck & Co. upon initiation of Phase 1 (Alzheimer s disease) BNC210 Phase 2 (PTSD) trial results (2 nd half) 2019 Merck & Co. collaboration Phase 2 trial initiation Merck Cognition Partnership BNC210 Phase 2 trial initiated (GAD) Merck & Co. equity investment in BNO 89