Number of Companies Investing in Neuroscience Drug Discovery

Home , Imepitoin, Phensuximide, Piriformis syndrome, Thyrotoxic myopathy

10/26/2015

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke

NINDS Office of Translational Research: New Programs to Rajesh Ranganathan, PhD Support Therapy and Director, Office of Translational Research Device Discovery and NINDS Development [email protected]

July 2015

Number of companies investing in Neuroscience drug discovery

1 10/26/2015

Number of companies investing in Neuroscience drug discovery

CNS drug discovery portfolio

2 10/26/2015

3 10/26/2015

Ecosystem is pursuing new models – eliminate silos

Academia Biotech

Pharma

Project 1 Project 2 Project 3 Carsten Skarke and Garret A. FitzGerald, Science Translational Medicine April 2010 7

What should NINDS’s role be in this changing climate?

4 10/26/2015

Appropriations (Dollars in Thousands)

FY 2011 FY 2012 FY 2013 FY2014 FY 2015

NINDS $1,622,003 $1,624,830 $1,533,795 $1,588,904 $1,604,607 NINDS % Base 0.2% -5.6% 3.6% 1.0% Change

NIH $30,687,290 $30,860,387 $29,151,462 $30,150,853 $30,311,349

NIH % Change Base 0.6% -5.5% 3.4% 0.5% Average IC increase was 0.31% NINDS and NIMH each received increase of $12.3 M for BRAIN Initiative Funding up to 14 th percentile

Total NINDS Extramural Grants Budget

1.6 NINDS Extramural 1.4

1.2 adjusted to 1995 1 dollars

0.8 with ARRA Billions) 0.6

0.4 with ARRA-- 0.2 adjusted to 1995 NINDS Extramural Grant Dollars (in (in Dollars Grant Extramural NINDS dollars 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

5 10/26/2015

FY 2013 Taxpayer Investment in Neuroscience Now Exceeds Cancer

6 5.274 5.34 4.887 5

Dollars in Billions (FY 2013) BillionsinDollars(FY 2

0 Cancer Neurosciences Infectious Diseases Research Category

Source: http://report.nih.gov/categorical_spending.aspx 11

NIH Neuroscience Research

Other Includes: NIDDK NIAAA NCI FIC 0.03% OTHER 3% 3% 3% TYPE 1 0.01% NINDS 10% NLM 0.02% 27% NIGMS NCMHD 0.05% 3% NCATS 0.14% NHLBI NHGRI 0.26% 4% NIDCR 0.52% NIMH NINR 0.52% 15% NICHD NIAMS 0.59% NIA NEI 4% NCCAM 0.60% 8% 8% NIDCD NIAID 1.06% 4% NIBIB 1.22% NIEHS 1.50% NIDA RMAP 1.64% 8% OD 2.14%

Source: http://report.nih.gov/categorical_spending.aspx 12

6 10/26/2015

The Problem

Unmet need in hundreds of neurological disorders

Chronic Orthostatic Intolerance Globoid Cell Leukodystrophy Metachromatic Leukodystrophy Pinched Nerve Tabes Dorsalis Absence of the Septum Pellucidum Chronic Pain Glossopharyngeal Neuralgia Microcephaly Piriformis Syndrome Tardive Dyskinesia Acquired Epileptiform Aphasia Cockayne Syndrome Type II Guillain-Barre Syndrome Migraine Pituitary Tumors Tarlov Cysts Acute Disseminated Coffin Lowry Syndrome Hallervorden-Spatz Disease Miller Fisher Syndrome Polymyositis Tay-Sachs Disease Encephalomyelitis COFS Head Injury Mini-Strokes Pompe Disease Temporal Arteritis ADHD Coma and Persistent Vegetative Headache Mitochondrial Myopathies Porencephaly Tethered Spinal Cord Syndrome Adrenoleukodystrophy State Hemicrania Continua Mobius Syndrome Postherpetic Neuralgia Thomsen Disease Agenesis of the Corpus Callosum Complex Regional Pain Syndrome Hemifacial Spasm Monomelic Amyotrophy Postinfectious Encephalomyelitis Thoracic Outlet Syndrome Agnosia Congenital Facial Diplegia Hemiplegia Alterans Motor Neuron Diseases Post-Polio Syndrome Thyrotoxic Myopathy Aicardi Syndrome Congenital Myasthenia Hereditary Neuropathies Moyamoya Disease Postural Hypotension Tic Douloureux AIDS - Neurological Complications Congenital Myopathy Hereditary Spastic Paraplegia Mucolipidoses Postural Orthostatic Tachycardia Todd's Paralysis Alexander Disease Congenital Vascular Cavernous Heredopathia Atactica Mucopolysaccharidoses Syndrome Tourette Syndrome Alpers' Disease Malformations Polyneuritiformis Multifocal Motor Neuropathy Postural achycardia Syndrome Transient Ischemic Attack Alternating Hemiplegia Corticobasal Degeneration Herpes Zoster Multi-Infarct Dementia Primary Dentatum Atrophy Transmissible Spongiform Alzheimer's Disease Cranial Arteritis Herpes Zoster Oticus Multiple Sclerosis Primary Lateral Sclerosis Encephalopathies Amyotrophic Lateral Sclerosis Craniosynostosis Hirayama Syndrome Multiple System Atrophy Prion Diseases Transverse Myelitis Anencephaly Creutzfeldt-Jakob Disease Holoprosencephaly Multiple System Atrophy with Progressive Hemifacial Atrophy Traumatic Brain Injury Aneurysm Cumulative Trauma Disorders HTLV-1 Associated Myelopathy Orthostatic Hypotension Progressive Locomotor Ataxia Tremor Angelman Syndrome Cushing's Syndrome Huntington's Disease Muscular Dystrophy Progressive Multifocal Trigeminal Neuralgia Angiomatosis Cytomegalic Inclusion Body Disease Hydranencephaly Myasthenia - Congenital Leukoencephalopathy Tropical Spastic Paraparesis Anoxia (CIBD) Hydrocephalus Myasthenia Gravis Progressive Sclerosing Tuberous Sclerosis Aphasia Cytomegalovirus Infection Hydrocephalus - Normal Pressure Myelinoclastic Diffuse Sclerosis Poliodystrophy Vascular Erectile Tumor Arteriovenous Malformation Dancing Eyes-Dancing Feet Hydromyelia Myoclonic Encephalopathy of Progressive Supranuclear Palsy Vasculitis including Temporal Asperger Syndrome Syndrome Hypercortisolism Infants Pseudotumor Cerebri Arteritis Ataxia Dandy-Walker Syndrome Hypersomnia Myoclonus Ramsay Hunt Syndrome Von Economo’s Disease Ataxia Telangiectasia Dawson Disease Hypertonia Myopathy Ramsay Hunt Syndrome I (formerly Von Hippel-Lindau Disease (VHL) Ataxias and De Morsier's Syndrome Hypotonia - Infantile Myopathy - Congenital known as) Von Recklinghausen's Disease Cerebellar/Spinocerebellar Deep Brain Stimulation for Hypoxia Myopathy - Thyrotoxic Ramsay Hunt Syndrome II Wallenberg's Syndrome Degeneration Parkinson's Disease Immune-Mediated Myotonia Rasmussen's Encephalitis Werdnig-Hoffman Disease Attention Deficit-Hyperactivity Dejerine-Klumpke Palsy Encephalomyelitis Myotonia Congenita Reflex Sympathetic Dystrophy Wernicke-Korsakoff Syndrome Disorder Dementia - Multi-Infarct Inclusion Body Myositis Narcolepsy Syndrome West Syndrome Autism Dementia - Subcortical Incontinentia Pigmenti Neuroacanthocytosis Refsum Disease Whiplash Autonomic Dysfunction Dementia With Lewy Bodies Infantile Hypotonia Neurodegeneration with Brain Iron Refsum Disease - Infantile Whipple's Disease Back Pain Dentate Cerebellar Ataxia Infantile Phytanic Acid Storage Accumulation Repetitive Motion Disorders Williams Syndrome Barth Syndrome Dentatorubral Atrophy Disease Neurofibromatosis Repetitive Stress Injuries Wilson's Disease Batten Disease Dermatomyositis Infantile Refsum Disease Neuroleptic Malignant Syndrome Restless Legs Syndrome X-Linked Spinal and Bulbar Behcet's Disease Developmental Dyspraxia Infantile Spasms Retrovirus-Associated Myelopathy Muscular Atrophy Bell's Palsy Devic's Syndrome Inflammatory Myopathy Neurological Complications of AIDS Rett Syndrome Zellweger Syndrome Benign Essential Blepharospasm Diabetic Neuropathy Intestinal Lipodystrophy Neurological Complications Of Lyme Reye's Syndrome Benign Focal Amyotrophy Diffuse Sclerosis Intracranial Cysts Disease Riley-Day Syndrome Benign Intracranial Hypertension Dysautonomia Intracranial Hypertension Neurological Manifestations of Sacral Nerve Root Cysts Bernhardt-Roth Syndrome Dysgraphia Isaac's Syndrome Pompe Disease Saint Vitus Dance Binswanger's Disease Dyslexia Joubert Syndrome Neurological Sequelae Of Lupus Salivary Gland Disease Blepharospasm Dysphagia Kearns-Sayre Syndrome Neuromyelitis Optica Sandhoff Disease Bloch-Sulzberger Syndrome Dyspraxia Kennedy's Disease Neuromyotonia Schilder's Disease Brachial Plexus Birth Injuries Dyssynergia Cerebellaris Kinsbourne syndrome Neuronal Ceroid Lipofuscinosis Schizencephaly Brachial Plexus Injuries Myoclonica Kleine-Levin Syndrome Neuronal Migration Disorders Seizure Disorder Bradbury-Eggleston Syndrome Dyssynergia Cerebellaris Klippel-Feil Syndrome Neuropathy - Hereditary Septo-Optic Dysplasia Brain and Spinal Tumors Progressiva Klippel-Trenaunay Syndrome (KTS) Neurosarcoidosis Shaken Baby Syndrome Brain Aneurysm Dystonias Klüver-Bucy Syndrome Neurotoxicity Shingles Brain Injury Early Infantile Epileptic Korsakoff's Amnesic Syndrome Nevus Cavernosus Shy-Drager Syndrome Brown-Sequard Syndrome Encephalopathy Krabbe Disease Niemann-Pick Disease Sjogren's Syndrome Bulbospinal Muscular Atrophy Empty Sella Syndrome Kugelberg-Welander Disease Normal Pressure Hydrocephalus Sleep Apnea Canavan Disease Encephalitis and Meningitis Kuru Occipital Neuralgia Sleeping Sickness Carpal Tunnel Syndrome Encephalitis Lethargica Lambert-Eaton Myasthenic Occult Spinal Dysraphism Sequence Soto's Syndrome WWW.NINDS.NIH.GOV Causalgia Encephaloceles Syndrome Ohtahara Syndrome Spasticity Cavernomas Encephalopathy Landau-Kleffner Syndrome Olivopontocerebellar Atrophy Spina Bifida Cavernous Angioma Encephalotrigeminal Angiomatosis Lateral Femoral Cutaneous Nerve Opsoclonus Myoclonus Spinal Cord Infarction Cavernous Malformation Epilepsy Entrapment Orthostatic Hypotension Spinal Cord Injury Central Cervical Cord Syndrome Erb-Duchenne and Dejerine- Lateral Medullary Syndrome O'Sullivan-McLeod Syndrome Spinal Cord Tumors Central Cord Syndrome Klumpke Palsies Learning Disabilities Overuse Syndrome Spinal Muscular Atrophy Central Pain Syndrome Erb's Palsy Leigh's Disease Pain - Chronic Spinocerebellar Atrophy Cephalic Disorders Fabry's Disease Lennox-Gastaut Syndrome Pantothenate Kinase-Associated Spinocerebellar Degeneration Cerebellar Degeneration Fahr's Syndrome Lesch-Nyhan Syndrome Neurodegeneration Steele-Richardson-Olszewski Cerebellar Hypoplasia Fainting Leukodystrophy Paraneoplastic Syndromes Syndrome Cerebral Aneurysm Familial Dysautonomia Levine-Critchley Syndrome Paresthesia Stiff-Person Syndrome Cerebral Arteriosclerosis Familial Hemangioma Lewy Body Dementia Parkinson's Disease Striatonigral Degeneration Cerebral Atrophy Familial Idiopathic Basal Ganglia Lipid Storage Diseases Parmyotonia Congenita Stroke Cerebral Beriberi Calcification Lissencephaly Paroxysmal Choreoathetosis Sturge-Weber Syndrome Cerebral Gigantism Familial Periodic Paralyses Locked-In Syndrome Paroxysmal Hemicrania Subacute Sclerosing Cerebral Hypoxia Familial Spastic Paralysis Lou Gehrig's Disease Parry-Romberg Panencephalitis Cerebral Palsy Febrile Seizures Lupus - Neurological Sequelae Pelizaeus-Merzbacher Disease Subcortical Arteriosclerotic Cerebro-Oculo-Facio-Skeletal Fisher Syndrome Lyme Disease - Neurological Pena Shokeir II Syndrome Encephalopathy Syndrome Floppy Infant Syndrome Complications Perineural Cysts SUNCT Headache Charcot-Marie-Tooth Disease Friedreich's Ataxia Machado-Joseph Disease Periodic Paralyses Swallowing Disorders Chiari Malformation Gaucher's Disease Macrencephaly Peripheral Neuropathy Sydenham Chorea Chorea Gerstmann's Syndrome Megalencephaly Periventricular Leukomalacia Syncope Choreoacanthocytosis Gerstmann-Straussler-Scheinker Melkersson-Rosenthal Syndrome Persistent Vegetative State Syphilitic Spinal Sclerosis Chronic Inflammatory Demyelinating Disease Meningitis Pervasive Developmental Disorders Syringohydromyelia Polyneuropathy (CIDP) Giant Cell Arteritis Menkes Disease Phytanic Acid Storage Disease Syringomyelia Giant Cell Inclusion Disease Meralgia Paresthetica Pick's Disease Systemic Lupus Erythematosus

13 13

FY 2015 Appropriation Budget Distribution

FY 2015 Budget Authority: 59,239, 3.7% 159,498, 9.9% $1,604,607K

Extramural Intramural RMS

1,385,870, 86.4%

Dollars in Thousands

14 14

7 10/26/2015

NINDS Office of Translational Research (OTR)

Bench Mission: To facilitate the preclinical discovery and development of new Preclinical therapeutic interventions for neurological disorders

Patients

NINDS Translational Guiding Principles

• Need to get therapeutics to humans (not bench to bookshelf) o Develop translatable measures of PK/PD and target engagement o Integrate clinical perspective

• Establish fail-early, fail-fast approach to portfolio management o Milestone assessment critical to project progression o Embrace early termination as success and learning opportunity

• Can’t do it alone – need partnerships and handoffs o De-risk projects for downstream funding o Actively facilitate partnership discussions

8 10/26/2015

NINDS uses a Variety of Translational Approaches

Discovery Preclinical Development Small Clinical Trials

Anticonvulsant Screening Program (ASP) $3.5 M

Translational R21 (all modalities) / IGNITE $10 M

CREATE Bio for Biotechnology Products and Biologics $19 M

CREATE Devices $2 M

Small Business Program: SBIR & STTR $46 M

Blueprint Neurotherapeutics (BPN 2.0) for Small Molecules $14 M

Countermeasures Against Chemical Threats (CounterACT) $47 M

IGNITE: Innovation Grants to Nurture Initial Translational Efforts CREATE: Cooperative Research to Enable and Advance Translational Enterprises

NINDS Anticonvulsant Screening Program (ASP)

Approach: Provide services and expertise to investigators developing anticonvulsants Established in 1975 (Dr. Steve White: PI, Univ. of Utah) Screening performed via a contract mechanism using a battery of seizure models NINDS staff report results to participants, advise on future development Supplier IP protected; confidentiality maintained Role in 10 marketed drugs since 1990

9 10/26/2015

History of Antiepileptic Drugs (AEDs) Imepitoin (dogs) 40 Perampanel Retigabine (ezogabine) Eslicarbazepine acetate Lacosamide Rufinamide 35 Stiripentol Pregabalin ASP Mission: To encourage Third generation Levetiracetam Tiagabine Topiramate 30 and facilitate the discovery of Gabapentin Felbamate new therapeutic agents for Oxcarbazepine Lamotrigine epilepsy Zonisamide 25 Vigabatrin Clobazam Progabide Clonazepam Valproate 20 Carbamazepine Diazepam Second generation Sulthiame Chlordiazepoxide

Number of AEDs of Number Ethosuximide 15 Ethotoin Methsuximide Primidone Phensuximide Phenacemide 10 First generation Corticosteroids/ACTH Paramethadione Mephenytoin Trimethadione Acetazolamide 5 Phenytoin Start of ASP Phenobarbital Mephobarbital Bromide 0 1850 1870 1890 1910 1930 1950 1970 1990 2010 Year of introduction

Adapted from Loscher & Schmidt, 2011, Epilepsia, 52:657 19

History of Antiepileptic Drugs (AEDs)

18 * 16

Number of AEDs Number of 6 * Start 4 of * ASP * 2 * 0 * = ASP Contribution = Major contribution Year of introduction

Adapted from Loscher & Schmidt, 2011, Epilepsia, 52:657 20

10 10/26/2015

NINDS uses a Variety of Translational Approaches

Discovery Preclinical Development Small Clinical Trials

Anticonvulsant Screening Program (ASP) $3.5 M

Translational R21 (all modalities) / IGNITE $10 M

CREATE Bio for Biotechnology Products and Biologics $19 M

CREATE Devices $2 M

Small Business Program: SBIR & STTR $46 M

Blueprint Neurotherapeutics (BPN 2.0) for Small Molecules $14 M

Countermeasures Against Chemical Threats (CounterACT) $47 M

IGNITE: Innovation Grants to Nurture Initial Translational Efforts CREATE: Cooperative Research to Enable and Advance Translational Enterprises

Cooperative Program Purpose and Goals

• Program launched in 2002 and includes drugs, biologics, and devices

• Purpose: To stimulate preclinical development of therapeutics in non-profit and small business sectors

• Features: Special review, milestone-based decisions

11 10/26/2015

Portfolio (n=80) by Indication (2002-2014)

14% 14% 10 Other: 13% Batten disease Down Syndrome 8 Neurodegeneration Neurofibroma 6 Insecticide poisoning 7% 7% 7%

Peripheral nerve Projects # 6% 6% 6% injury 4 Phenylketonuria 4% 4% SMA 3% 3% 3% 3% 2 Spinal and Bulbar Muscular Atrophy 0

Portfolio (n=80) by Interventional Modality (2002-2014)

Other: Vaccine Dog Center Drug Discovery Center

12 10/26/2015

Translational R21 by Indication 2014 (n=54)

13% Muscular Dystrophy Stroke 30% Lysosomal Storage 11% Epilepsy SMA Tumors 9% ALS 4% Alzheimer's 4% Multiple Sclerosis 4% 9% Sleep Disorders 4% Other 5% 7%

Other: Arteriovenous Malformation, CIDP, Guillain-Barre Syndrome, HIV, Huntington's, Neonatal Encephalopathy, Nerve Injury, Neurodegenerative Diseases, Neurofibromatosis, Neuropathy, Parkinson's, PSP, Rett's Syndrome, Spinocerebellar Ataxia, TBI

Achievements of the Legacy Program

• At least 8 projects have graduated to clinical trials – 80+ projects actively managed in 10+ years • Progressive strengthening of peer-review and milestone assessments – 15 discontinuations for not meeting milestones • In 2014, at least 5 INDs were filed: • a small molecule in Alzheimer’s Disease; • a gene therapy in Glioblastoma; • gene therapy and antisense oligos in Muscular Dystrophy

13 10/26/2015

Case Study #1

Mitochondrial inhibitor to treat acute spinal cord injury (SCI)

• Demonstrate recovery • PK to determine treatment • Demonstrate motor and • Submit IND in a severe SCI model regimen sensory recovery in either gender • Improve mitochondrial • pre-IND meeting function in animals

Year 01 Year 02 Year 03 Year 04

4 month NCE to address differences in injury severity $$ awarded And ultimately discontinued

Efficacy criteria not fully met in either gender

Case Study #2

Gene therapy to treat Batten Disease / late infantile neuronal ceroid lipofuscinosis (LINCL)

• Assess anti-vector • Demonstrate efficacy in • pre-IND meeting • biodistribution study • Submit IND immunity LINCL KO mice • Manufacture and IND-enabling • Increase functional enzyme vector toxicity studies in rat levels in NHP and NHP • IRB, RAC submissions

Year 01 Year 02 Year 03 Year 04 Year 05

Modified milestones Modified milestones Delayed funding until $$ awarded $$ awarded $$ awarded $$ awarded IND feedback. Reduced budget

• Met criteria for • Met efficacy criteria in KO mice • Passed vector • No toxicity in NHP enzyme • Pre-IND meeting held Yr 2 lot release • Received IRB approval expression • Advance NHP milestone Yr 3 criteria • IND submitted in Yr 4 • Met functional enzyme criteria in NHP

14 10/26/2015

Translating a CSF delivered AAV9-SMN for treatment of Spinal Muscular Atrophy

Opportunities for Further Enhancement

• Tailored approach: Cater to the various modalities

• Transitions: Reduce delay between funding mechanisms

• Risk management: More points for attrition

• Due Diligence: Implement RIGOR guidelines; increase progress review frequency

• Flexibility: Access to contracts and consultants; project entry at various points; supplements to address unanticipated needs

15 10/26/2015

Cooperative Research to Enable and Advance Translational Enterprises (CREATE)

Funding to advance potential therapeutics (biologics or devices) into clinical development

CREATE Bio Program Modality: Biologics/Biotechnology Products Purpose • Discovery: Optimization of therapeutic leads • Development: IND-enabling studies/Early phase clinical trials

End Goals • Discovery: Characterize and select a lead candidate • Development: Submit an IND application

CREATE Bio Program

Animal Lead IND Enabling Small Clinical Trials Clinical POC POC Optimization Studies

Discovery Track Leads U01

Candidate Development Track IND Preparatory Small Clinical Trials Enabling Early Clinical UH2 UH3 (optional) UH3 Development Asset IND

Discovery Track (U01) Development Track (UH2/UH3)

Budget per year <$0.5 M year < $1- 1.5 M

Duration Up to 4 years Up to 5 years

Next Application Date: August 11, 2015

16 10/26/2015

Cooperative Research to Enable and Advance Translational Enterprises (CREATE)

Funding to advance potential therapeutics (biologics or devices) into clinical development CREATE Devices Program Modality: Therapeutic Devices

• Informing Device Design: Pre-clinical/clinical studies to inform final device design

• 510(k) Market Approval: Pre-clinical/clinical studies leading to a 510(k)/510(k) De Novo submission

• PMA or HDE*: Pre-clinical/early clinical studies leading to a full Feasibility Study/Pivotal Trial in support of a PMA/HDE

*Pre-Market Approval (PMA) or Humanitarian Device Exemption (HDE)

CREATE Devices

Pre-Clinical Clinical Study (UH3/U44-II) Informing Device Design (UH2/U44-I)

Pre-Clinical Clinical Study (UH3/U44-II) 510(k) Market Approval (UH2/U44-I)

Optional Clinical Pre-Clinical Pre-Clinical Study PMA or HDE (UH2/U44-I) (UH3/U44-II) (UH3/U44-II)

FDA Pre-Submission FDA Submission Guidance

UH2/U44-I UH3/U44-II

Budget per year <$1 M <$1.5 M

Duration Up to 3 years Up to 4 years

Budget total <$3 M <$6 M

Next Application Date: August 11, 2015

17 10/26/2015

NINDS uses a Variety of Translational Approaches

Discovery Preclinical Development Small Clinical Trials

Anticonvulsant Screening Program (ASP) $3.5 M

Translational R21 (all modalities) / IGNITE $10 M

CREATE Bio for Biotechnology Products and Biologics $19 M

CREATE Devices $2 M

Small Business Program: SBIR & STTR $46 M

Blueprint Neurotherapeutics (BPN 2.0) for Small Molecules $14 M

Countermeasures Against Chemical Threats (CounterACT) $47 M

IGNITE: Innovation Grants to Nurture Initial Translational Efforts CREATE: Cooperative Research to Enable and Advance Translational Enterprises

Blueprint Neurotherapeutics Network (BPN)

Combining strengths of NIH and industry for small molecule therapeutics

BPN Program Modality: Small Molecule • Discovery: Hit-to-lead and lead optimization • Development: Formulation, scale up and manufacture, IND-enabling studies, and first-in- man clinical trials

End Goals • Discovery: Characterize and select a preclinical candidate • Development: Complete IND-enabling studies, file an IND and complete first-in-man trial • Advance projects for hand-off

18 10/26/2015

Blueprint Neurotherapeutics Network Offering Infrastructure, Expertise, and Funding

Medicinal Data Chemistry Management

PK/Tox

Lead Development Team Bioactivity/ Principal Investigator* Efficacy Industry-seasoned consultants Studies NIH staff

*PI retains intellectual property Formulation/ Phase I Manufacturing Clinical Trials

37 37

BPN Consultants

• Assay development, • DMPK pharmacology – Paul Pearson – Lisa Minor – Jiunn Lin – Bill Martin – Ron White – Jeff Conn – Ron Franklin • Toxicology – Marc Bailie – Steve Duddy • Medicinal chemistry – Gary Wolfe – Graham Johnson – Donna Romero • Development – Neil Moss – Peter Farina – Paul C. Anderson – Mike Detke – Steve Young – Cristina Csimma – John McCall – Gian Luca Araldi – Jon P. Lawson – John M. “Jay” Sisco • Upcoming – Regulatory affairs, Phase I Clinical Pharmacology, Medical Writing, & Business Development

See bios at http://neuroscienceblueprint.nih.gov/bpdrugs/bpn.htm 38 38

19 10/26/2015

Projects are Milestone-Driven External Review Committee Assesses Progress Biannually

Projects Launched

Exploratory Studies Milestones Validated Assays Optimization Chemistry Emerging SAR High attrition rate anticipated Pre-clinical safety testing Human safety testing (Phase I)

New drug candidates licensed External Oversight Committee Peter Farina, PhD (chair) Jeffrey Conn, PhD Michael J. Detke, MD, PhD John McCall, PhD Cristina Csimma, PhD

39 39

Who Applies for BPN?

• Researchers who are new to drug discovery

• Researchers who are experienced in drug discovery but lack necessary research facilities

• Academic labs and small businesses

40 40

20 10/26/2015

15 Projects Initiated 2011- 2013

Principal Investigator Institution Disorder Mark Gurney Tetra Discovery Partners Alzheimer’s Susan Slaugenhaupt Mass. General Hospital Familial Dysautonomia Paul Kenny Eolas Therapeutics Smoking Cessation Steven Wagner UC San Diego Alzheimer’s Konstantin Petrukhin Columbia University/iCura Macular Degeneration Kirill Ostanin Navigen Macular Degeneration Paul Humphries Reset Therapeutics Narcolepsy

George Maynard Axerion Alzheimer’s Discontinued John Bixby University of Miami Optic Neuropathy Raymond Dingledine Emory University Stroke Marcie Glicksman Brigham and Women ’s Hospital ALS Michael Lark Trevena Depression Al Robichaud Sage Therapeutics Fragile X Edwin Rubel University of Washington Hearing Loss D. James Surmeier Northwestern University Parkinson ’s

See abstracts at http://neuroscienceblueprint.nih.gov/bpdrugs/bpn.htm 41 41

Advance Projects for Hand-Off

Entry: •Strong science Phase I •BPN mission IND Enabling Scale up & Manufacturing Lead Optimization Exit: • External funding/ Exploratory/ partnership Hit to Lead • Other grants • Attrition Decreases risk as projects successfully advance development stages

21 10/26/2015

BPN Recent Successes

Facilitated licensing of drug candidates:

• Macular degeneration drug candidate licensed to iCura

• New drug for mild cognitive impairment led to investment by Johnson & Johnson to project’s industry partner, Tetra Discovery Partners

• Orexin-1 receptor antagonist as a tobacco addiction treatment licensed to Eolas, who just signed an agreement with Astra Zeneca

43 43

What’s New in BPN 2016-2020

• Flexibility in mix of contract access and grant support

– Investigators choose what combination best fits their needs

– Offers option for grant-only support

• Flexibility in entry point

– Projects can enter during Discovery or Development

• Phased funding allows for due diligence, filling in data gaps

• SBIR track available

44 44

22 10/26/2015

Projects Can Enter at Any Preclinical Stage

All Projects Begin with Preparatory Phase

• Complete entry criteria for Preparatory SAR or IND-enabling studies Phase • Conduct due diligence

Discovery Development

Lead Hit to Lead IND Enabling Phase I Trial Optimization

General (UH2/UH3) SBIR (U44-I/II) UH2: Up to $300K direct costs x 1 year Phase I: Up to $400K total costs x 1 year UH3: Up to $1.5M/year direct costs x 4 years Phase II: Up to $4M total across 3 years

Next Application Date: August 11, 2015 45

Now Accepting New Applications

• PAR-14-293 for all applicants • PAR-14-292 for small businesses (SBIR) • Next applications due Aug. 11, 2015 • Peer review in Dec. 2015 (special review panel) • Grants awarded Jan. 2016 • For the following indications • Psychiatric disorders • Neurological disorders • Degenerative dementias of aging • Developmental disorders • Chronic pain conditions • Alcohol dependence • Drug addiction

46 46

23 10/26/2015

NINDS uses a Variety of Translational Approaches

Discovery Preclinical Development Small Clinical Trials

Anticonvulsant Screening Program (ASP) $3.5 M

Translational R21 (all modalities) / IGNITE $10 M

CREATE Bio for Biotechnology Products and Biologics $19 M

CREATE Devices $2 M

Small Business Program: SBIR & STTR $46 M

Blueprint Neurotherapeutics (BPN 2.0) for Small Molecules $14 M

Countermeasures Against Chemical Threats (CounterACT) $47 M

IGNITE: Innovation Grants to Nurture Initial Translational Efforts CREATE: Cooperative Research to Enable and Advance Translational Enterprises

Small Business Program Overview

• Congressionally mandated set-aside programs • R&D with potential for commercialization • ~$46M in FY2015 (3.3% of the extramural budget) • Broad scope • Neurotherapeutics, diagnostics, and tools for neuroscience research • Bench research, translational research, and early stage clinical trials

24 10/26/2015

Three Phase Program

• Phase I – Feasibility Study – $225K for up to 2 years – ($700K if a waiver topic) Applicants should propose a • Phase II budget that is reasonable and – Full Research/R&D appropriate for completion of – $1.5M for up to 3 years the research project. – ($3M if a waiver topic) • Phase IIB Please contact us for guidance. – Full Research/R&D – $1M/yr for up to 3 years • Phase III – Commercialization Stage – Use of non-SBIR/STTR funds

Small Businesses by Modality

2014

3% 19% 19% diagnostic biologic small molecule tool 21% 20% therapeutic device other

18%

25 10/26/2015

SBIR Recent Success

Lift Labs funded by SBIR to develop a spoon or fork attachment that cancels out hand tremor. Company acquired by Google in 2014.

http://www.google.com/liftware/

Additional Pipeline Needs to be Addressed

Technology

In Vitro Assays

Basic science Animal CREATE/BPN 2.0 models PD Markers

Tools Rigorous POC

Bioactive Compounds

26 10/26/2015

Innovation Grants to Nurture Initial Translational Efforts (IGNITE)

1. Establish essential assays (in vitro and in vivo) to identify and optimize bioactive leads(s) 2. Characterize bioactive lead(s) 3. Deliver in vivo efficacy data using clinically relevant outcome measures and/or in vivo target engagement

Proposed Feeder Programs for Translational Pipeline

Discovery Preclinical Development Small Clinical Trials

IGNITE (Assay Development) Launch Dec. 2014: Next receipt date Jun. 2015

IGNITE (PD & Efficacy) Launch Dec. 2014: Next receipt date Jun. 2015

IGNITE (Animal Model Dev.) Launch late 2015

CREATE Devices

CREATE Bio for Biotechnology Products and Biologics

Blueprint Neurotherapeutics (BPN 2.0) for Small Molecules

IGNITE (Platform Technology) Launch 2016

IGNITE: Innovation Grants to Nurture Initial Translational Efforts 54

27 10/26/2015

IGNITE Planning/Development Phase PAR-15-070: Assay Development and Validation

R21 PAR-15-071: Further compound characterization including pharmacokinetic studies and planning for in vivo and pharmacodynamic studies Meet Milestones Execution Phase PAR-15-070: Hit identification: screening, physicochemical R33 characterization, in vitro pharmacological characterization

PAR-15-071: Pharmacodynamic, in vivo characterization of compound(s)

R21 R33

Budget per year < $0.25M < $0.5M

Duration No more than 2 years No more than 2 years Budget total <0.75M for Entire 3 Year Period (R21/R33)

IGNITE Key Advantages

• Provides funding to seamlessly advance projects from the early discovery stage into late-stage translational funding programs

• Encourages investigators to clearly focus on stage-specific drug discovery goals and allows the time to do so

• Encourages: 1. Characterization of therapeutic agents 2. Planning, set up, and validation of testing paradigms and models 3. Employment of RIGOR guidance 4. Partnerships between academics and industry

28 10/26/2015

NINDS uses a Variety of Translational Approaches

Discovery Preclinical Development Small Clinical Trials

Anticonvulsant Screening Program (ASP) $3.5 M

Translational R21 (all modalities) / IGNITE $10 M

CREATE Bio for Biotechnology Products and Biologics $19 M

CREATE Devices $2 M

Small Business Program: SBIR & STTR $45 M

Blueprint Neurotherapeutics (BPN 2.0) for Small Molecules $14 M

Countermeasures Against Chemical Threats (CounterACT) $47 M

IGNITE: Innovation Grants to Nurture Initial Translational Efforts CREATE: Cooperative Research to Enable and Advance Translational Enterprises

NIH CounterACT Countermeasures Against Chemical Threats

Mission: To develop FDA-approved therapeutics and diagnostic technologies that will reduce mortality and morbidity during and after chemical emergency events.

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NIH Biodefense Program

NIAID Oversight

NIAID Management NINDS Management

Biological (~$1.7B) Radiation/Nuclear (~$46M) Chemical (~$47M) •Category A, B, C •Bomb detonation •Neurological, e.g., WMDs, sarin, •Bacterial, e.g., anthrax •Radiation Dispersal Device pesticides •Viral, e.g., small pox •Attack on n. reactor •Pulmonary, e.g., chlorine, phosgene •Toxins, e.g., botulinum or on spent fuels •Metabolic, e.g., cyanide, H 2S •Vesicants, e.g., arsenicals

Burden of Illness Chemical Warfare World War I and II: thousands of fatalities Iran-Iraq War (1980-88): thousands of fatalities Current conflicts in the Middle East: thousands of fatalities

Terrorism/Non-military malicious use Tokyo Subway Attacks (1995): thousands affected; 12 dead Jonestown mass suicide (1978): 900 dead Tylenol and Excedrin poisonings (1980’s): few fatalities

Industrial Accidents Occur Daily; thousands of injuries and fatalities annually Dupont Corp. (WV – 2010): 3 Phosgene releases in 1 week Bhopal Union Carbide disaster (1984): 5,000 fatalities from Methyl Isocyanate

General Poisonings 2.2 million calls to Poison Control Centers in 2012 alone Brodifacoum, Pesticides 60

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Mission The mission of the NIH CounterACT Program is to understand fundamental mechanisms of toxicity caused by chemical threat agents and the application of this knowledge to develop promising therapeutics for reducing mortality and morbidity caused by these agents.

Chemical Classes

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Products in the Pipeline

Basic Translational Clinical

Proof Optimization/ Assay Pre-IND/IDE Clinical Target ID Screening of Preclinical Development Principle Efficacy Studies Trials NIH BARDA

Over 30+ Neuregulin Cobinamide (M) Midazolam* “hits” and/or Brovana* targets Rolipram identified Sulfanegen Galantamine* LY293558 AEOL 10150 (M) Drug indication: Doxycycline* Black = Vesicants Red = Nerve Agents Blue = Pulmonary Agents *BARDA: Biomedical Green = Cyanide * Denotes FDA-approved (M) = multiple indications Advanced Research & compound for another indication Development Authority

Advice for Preparing an Application

• Contact NIH staff - Confirm which entry stage is best fit - Discuss activities for Preparatory Phase - Applications $500K+ must be preapproved to submit • Read the FOAs (these are not typical NIH application) • Show the data for assay validation, target validation, etc.

Review FAQs at program websites

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Planning Essentials

Keep the end in mind … Have multidisciplinary team to formulate the Prepare a robustness Target Product Profile (TPP) data package Initial plans for clinical POC plans trial

Rigorous Study Design and Propose rigorous Reporting experiments with clear milestones for success and go/no-go Talk to NINDS Program Know the review Staff environment-NINDS review

Check out FAQs, examples, and resources Address IP Strategy Plan ahead in the NINDS program website

Planning Essentials

Talk to NINDS Program Staff

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Rajesh Ranganathan, Ph.D. Director

Mary Ann Pelleymounter, John Kehne, Ph.D. Ph.D. Program Director Program Director

Shamsi Raeissi, Ph.D Hao Wang, Ph.D. Scientific Project Manager Program Director

Linda McGavern, Ph.D. Charles Cywin, Ph.D. Scientific Project Manager Scientific Project Manager

Stephanie Fertig, MBA Amir Tamiz, Ph.D. Director, Small Business Program Program Director

Chris Boshoff, Ph.D. David A. Jett, Ph.D. Scientific Project Manager Program Director

Dave Yeung, Ph.D. Brian Klein, Ph.D. Scientific Project Manager Scientific Project Manager

Pascal Laeng, Ph.D. Medical Director (1 Vacancy) Scientific Project Manager

Questions?

[email protected]

http://www.ninds.nih.gov/otr

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