RGN investor presentation January 2015

“Pioneering Electroceuticals™”

Developing Non-Invasive Therapeutics for the Brain

Investor Presentation / January 2015

Confidential Rio Grande Neurosciences

Might “Electroceuticals™” just be the next “old new” thing?

“Only at the end of the last century did we learn that we can exquisitely fine-tune molecules and a whole new area of medicine opened up. We are at a similar juncture with the use of electrical impulses.“ Keith Famm Vice President GlaxoSmithKline


Rio Grande Neurosciences (RGN) •  Addressing unmet clinical needs through non-invasive treatment of pathologies of

the central nervous system (CNS) •  Developing, acquiring and licensing non-invasive brain stimulation (NIBS)

technologies for treating neurological conditions •  Lead technology is “targeted Pulsed ElectroMagnetic Field” (tPEMF) therapy

•  Current world-wide licensee for all neurological applications; existing FDA clearance for treating pain and swelling

•  RGN is currently elucidating the anti-neuroinflammatory properties of tPEMF •  Distinguished Medical Advisory Board and Military Medical Advisory Council led

respectively by Mitchel Berger, MD, and Major General (ret.) Gale Pollock •  Top academic neurosurgical and neurosciences collaborators •  Accomplished private and public company management leading current PIPE

Financing and Reverse Merger


To acquire, license, and develop non-invasive therapeutic technologies for the treatment of brain pathologies. To become the first-to-market aggregator of established and experimental technologies in the NIBS area and a conduit through which promising but underdeveloped technologies can be investigated, commercialized, and made available to clinical populations that will benefit from their use.

Commercial Mission


Overview of Non-invasive Neurostimulation (NIBS) Technologies

Induced Electrical Fields: •  tPEMF; Transcranial magnetic stimulation (TMS); pulse external

magnetic fields to induce electrical fields (outside the body) Direct Current and Capacitively-Coupled Electrical Fields:

•  Non-invasive stimulators: cranial electrical stimulation, transcranial direct current stimulation, etc. (on the body) •  FDA cleared/approved: Depression, Anxiety, Insomnia (CES) •  No clearance (transcranial direct current simulation)

Other NIBS Modalities: •  Low-Level Laser Therapy (LLLT), Ultrasound (US), Extremely-Low

Frequency Electromagnetic Fields (ELF-EMF)


Cranial electrical stimulation (Anxiety, Depression, Insomnia)

tDCS (Iontophoresis) ~ 50 trials

Trigeminal Nerve Stimulation

Low-intensity rTMS

LLLT

Examples of NIBS technologies


“TheraCap™” study device for sports concussion clinical trials (therapy embedded in cap)

tPEMF: current FDA-cleared disposable clinical treatment unit

RGN’s proprietary tPEMF Technology


RGN’s first target: Traumatic Brain Injury (TBI)

•  1.8+ million cases present in US hospitals annually •  Up to an additional 3 million go

undiagnosed •  Majority are mild TBI: concussions

!  At least 400,000 annually in youth sports

!  Over 250,000 in the past decade in the military

•  Over 5 million Americans are living with permanent disability due to brain injury

•  Treatments currently available: none


mTBI - Primary and Secondary Injury •  Primary injury – initial insult (e.g. hit to the head) causes a

“concussion” (symptoms include dizziness, loss of consciousness, fogginess, etc.)

•  Secondary injury – neuroinflammation and its resulting chronic damage, reduced blood flow, edema and neuronal death •  Inflammatory response produces further symptoms that can lead to long-term

neurodegenerative pathologies


Significant barriers to treating mTBI Drugs: •  Fundamental challenge of pharmaceutical delivery across the blood-

brain barrier (BBB) •  Unattractive side effect profiles, toxicity problems •  Numerous failed clinical trials for stroke, TBI, etc. Devices: •  Various NIBS therapeutics, hyperbaric oxygen, cooling technologies,

near infrared light therapy are all inhibited by various combinations of: •  lack of effectiveness data •  lack of MOA understanding •  lack of resources •  lack of experienced management teams

tPEMF has clinically relevant bioeffects & is unimpeded by these barriers


•  Reduced microglial proliferation and activation •  Reduced inflammatory (e.g., IL-1β) and apoptotic (TNF family)

cytokines and gene expression •  Increased anti-inflammatory (e.g., IL-10 and IL-11) cytokine gene

expression •  Increased cyclic GMP and AMP production •  Improved blood vessel dilation and integrity •  Reduced capillary shunting •  Increased tissue perfusion and tissue oxygenation

Demonstrated Clinically Relevant tPEMF Effects in Neurological Models


•  Improved blood brain barrier function and repair •  Increased synaptic transmission and long-term potentiation (i.e.,

synaptic plasticity) •  Improved neuronal mitochondrial efficiency •  Enhanced neuritogenesis and growth •  Promoted axonal growth and neuronal survival in the presence of

inflammatory insults •  Provided neuroprotection in ischemic/metabolic injury

•  Potential for prophylactic applications (heat shock protein mechanism)

Page 12

Demonstrated Clinically Relevant tPEMF Effects in Neurological Models (con’t)


tPEMF rationale in mTBI

•  tPEMF is focused on treating mTBI Secondary Injury to alleviate neuroinflammation and enhance blood flow, thereby reducing neuropathology; RGN is evaluating these effects in both ongoing and planned clinical trials

control PEMF

Reduced microglial activation with tPEMF in brain injury

Reduced IL-1β (inflammatory biomarker in concussed animals treated with PEMF)


Pathway to Commercialization for RGN’s tPEMF Clinical Study

Timelines

Friday Night Lights Out

• 4Q ’14 – 3Q ‘15

Indication

EU Launch 4Q ’15 (OTC)

Pre-IDE Meeting 1H ’15

510(k) Filing 3Q ’15

FDA Clearance 2H ’16 (Rx)

Reducing Post Concussion Syndrome

• 3Q ’15 –2Q ‘16

tPEMF’s Effect on Long-Term Neurodegeneration and

Possible CTE

• 2Q ‘16 – 2Q ‘17

Regulatory Milestones

Treatment of Acute Concussive Syndrome

Treatment of Chronic Post Concussive Syndrome

Expand EU OTC Indication 2Q ‘16

510(k) Filing 2Q ‘16

FDA Clearance 4Q ’16 (Rx)

Treatment of Neurodegeneration

associated with history of concussions

Expand EU OTC Indication 3Q ‘17

510(k) Filing 3Q ‘17

FDA Clearance Q1 ‘18


•  Extend current studies using validated animal models of concussion and cell culture models of both neuroinflammation and neuroprotection (Harvard, University of New Mexico & Los Alamos National Labs) •  biomarkers (including tau) and functional outcomes •  dosimetry, signal optimization, and mechanisms of action

•  Basic science work in standard blast injury animal models (Boston University) •  biomarkers (including tau) and functional outcomes

•  Evaluate tPEMF’s potential in synaptic development/transmission and plasticity models including learning and memory (Buck Institute & UCSF’s Gazzaley Laboratory)

•  Evaluate tPEMF in EAE model of multiple sclerosis focusing on blood brain barrier permeability and neuroinflammation (UCSF)

Ongoing Basic Science Research Program


•  “Friday Nights Lights Out” (UT Southwestern, double-blind RCT) •  Post Concussion Syndrome Study (Harvard, double-blind RCT) •  Integration of tPEMF therapy into Harvard’s Neuromodulation Lab

pantheon of modalities (case study collection) •  initial trial on healthy controls focusing on qEEG effects

•  Expansion of clinical trial in severely injured trauma and stroke patients to include comprehensive biomarker analysis directly from ventricular cerebrospinal fluid (UNM)

•  Evaluation of tPEMF in post-concussion patients through Defense Center of Excellence invitation

•  Proposed clinical TBI pilot through DVBIC at Brooke Army Medical Center

Ongoing and Planned Clinical Research Program


Principal Investigators

•  Hunt Batjer, MD, Professor & Chairman, Neurological Surgery, UT–Southwestern; Co-Chair, NFL Head, Neck and Spine Medical Committee

•  Mark Goldberg, MD, Professor & Chairman, Neurology, UT-Southwestern; founding Director, Washington University Hope Center for Neurological Disorders

“Friday Night Lights Out” Study

Proposed NINDS (SBIR) Post Concussion Syndrome Study

•  Ross Zafonte, DO, Professor and Chairman, Department of Physical Medicine & Rehabilitation, Harvard Medical School; Chief of Physical Medicine & Rehabilitation, Spaulding Rehabilitation Hospital (MGH)


NIBS Market is Primed for Consolidation •  Significantly increased prevalence of neurodegenerative disease (i.e.

Alzheimer’s, Parkinson’s, dementia) and brain injury worldwide •  Dramatically heightened societal awareness of its devastating economic and

human consequences •  Failure of pharmaceuticals to successfully address the burgeoning unmet

related medical needs •  While many potentially exciting NIBS technologies exist, this market remains

immature, under-funded and highly fragmented •  Most NIBS companies lack sufficient resources to meet critical scientific, clinical

and commercialization goals and stringent regulatory requirements

RGN’s team will utilize its collective expertise, experience,

relationships and public market presence to lead this rationalization/consolidation by developing, acquiring and

licensing “best-of-breed” NIBS technologies and their supporting software applications


Aggregation Opportunity

•  Sufficient evidence exists to support several NIBS technologies to deliver stimulation where and when it is needed

•  Multiple biological and regulatory pathways to successfully treating patients are being evaluated

•  Multiple single-technology companies are all attempting to bring NIBS therapeutics to market but often: •  Are undercapitalized •  Lack sufficient basic science support •  Have speculative or unknown “mechanisms of action” (MOA)

•  RGN is exploring the following NIBS technologies for acquisition:


tDCS

•  Low-level direct current •  FDA-cleared as iontophoresis devices •  Significant body of clinical literature •  Can enhance as well as degrade cognitive abilities, depending on how applied

•  Strong interest from military •  Enhanced real-time cognitive abilities •  Significant variation in effect across subjects •  MOA not well-described


CES •  Low-level alternating current •  FDA-cleared for treating anxiety, depression and insomnia •  Used in conjunction with counselling for treating PTSD

•  US military use •  Significant body of clinical literature •  MOA not well characterized

•  Where does energy go?


TMS •  Direct descendent of ECT •  Designed to trigger excitable membranes •  High-power, low penetration •  FDA-cleared for treating refractory

depression •  MOA not well understood

•  Half-power TMS designed for home use •  FDA-cleared to treat aura-related migraine at

onset •  RCT support weak •  FDA cleared on potential effectiveness and

safety


LLLT •  FDA-cleared for multiple non-neuroscience

applications •  MOA outlined: neuroprotective and anti-

inflammatory effects

•  Early trial failed Phase III clinical trial in stroke

•  Subset appeared to benefit •  Potential applications in cognition and

neurorehabilitation


Trigeminal Nerve Stimulation

•  Buccal spatially separated stimulation for improved neuroplasticity

•  MOA not well-characterized •  Placebo effect > 40%

•  Transdermal TNS cleared by FDA for treating migraine

•  CE-marked for treating epilepsy •  MOA not well characterized


Emerging NIBS

•  ELF-EMF •  Magnetic field effects •  Variable effects •  Dependent on signal characteristics

•  Transcutaneous Vagal Nerve Stimulation •  Auricular stimulation of vagal nerve •  Treating epilepsy, depression

•  Transcranial ultrasound •  Enhanced cognitive performance •  DARPA prototype


•  Steven Gluckstern, EdD, MBA – Chairman & CEO -  Chairman & CEO, Ivivi Health Sciences -  Chairman, Zurich Scudder Investments -  Expertise: Leadership, Entrepreneurship, Finance, Public Company Executive

Management •  Stephen Juelsgaard, JD DVM – Board member

-  Former General Counsel – Genentech Inc. -  Expertise: Leadership, Public Company Executive Management, Intellectual

Property Development, FDA

Board of Directors


•  Steven Gluckstern – Chairman & CEO •  Sean Hagberg, PhD – Chief Strategist

-  Clinical Assistant Professor, Neurosurgery, UNM -  Co-founder and Chief Science Officer, Ivivi Technologies -  Expertise: Clinical Innovation and Adoption, Strategy, tPEMF Research and Development

•  Blake Gurfein, PhD – Chief Science Officer -  Assistant Professor of Medicine, UCSF -  NIH–funded Principal Investigator -  Expertise: Neuroimmunology, CNS Pathology, Scientific Project Management

•  David Muehsam, PhD – Senior Biophysicist -  Visual Institute of Developmental Arts & Sciences, Bologna, Italy -  Expertise: Bioelectromagnetic Therapeutics, Biophysical Transduction Mechanisms, Mathematical

Modeling •  Shamini Jain, PhD – Director of Technology Discovery

-  Founder and Executive Director, Consciousness and Healing Initiative -  Assistant Professor, Psychiatry & Behavioral Medicine, UCSD -  Expertise: Psychoneuroimmunology, Clinical Psychology, Program Management

•  Michael Weisend – Senior Scientist -  Senior research Scientist, Wright State Research Institute -  Associate Professor of Translational Neuroscience, Mind Research Institute -  Expertise: Clinical Neurophysiology, Neurocognition, tDCS and other NIBS modalities

Executive Management Team


•  Mitchel Berger, MD, Medical Advisory Chair -  Neurosurgery Chair, UCSF -  Member of NFL Head, Neck, & Spine Medical Committee -  Fmr. President, American Association of Neurological Surgeons

•  Adam Gazzaley, MD, PhD, -  Professor Neurology, Physiology and Psychiatry, UCSF -  Director, Neuroscience Imaging Center, UCSF -  Director, Gazzaley Lab for Cognitive Neuroscience Research, UCSF

•  David Hovda, PhD -  Director, UCLA Brain Injury Research Center, Professor of Neurosurgery, Biomedical Physics,

Molecular & Medical Pharmacology -  Fmr. President, National Neurotrauma Society

•  Geoff Manley, MD, PhD -  Professor and Vice Chair Neurosurgery, Co-Director Brain and Spinal Injury Center, UCSF -  Chief of Neurosurgery, SF General Hospital -  Principal Investigator: Transforming Research And Clinical Knowledge in TBI (“TRACK-TBI”,

multicenter $18.8 million, five year NINDS Grant) •  Pratik Mukherjee, MD, PhD

-  Director, Center for Imaging of Neurological Diseases -  Professor of Radiology, Biomedical Imaging and Bioengineering, UCSF -  Principal Investigator TRACK-TBI

•  Howard Yonas, MD -  Neurosurgery Chair, UNM -  Director, UNM Cerebrovascular Center -  Founder and Co-Director of the UPMC Stroke Institute

Medical Advisory Board


Military Medical Advisory Council •  Gale Pollock CRNA, FACHE, FAAN, Chair

-  Fmr. Chief, Army Nurses Corp -  Member of NFL Head, Neck, & Spine Medical Committee -  Fmr. Acting Surgeon General, U.S. Army -  Retired Major General, U.S. Army

•  James Ecklund, MD -  Chairman, Department of Neurosciences Inova Fairfax Hospital -  Fmr. Chairman, Neurosurgery Program - National Capital Consortium (includes Walter Reed

Army Medical Center, National Naval Medical Center and the Uniformed Services University) -  Retired Colonel and trauma surgeon, U.S. Army

•  Kenneth Farmer, MD -  Fmr. Chief, North Atlantic Regional Medical Command and Walter Reed Army Medical Center -  Fmr. Deputy Surgeon General, U.S. Army -  Fmr. Chief of Staff, U.S. Army Medical Command -  Retired Major General, U.S. Army

•  John Holcomb, MD -  Director, Center for Translational Injury Research, Vice Chair and Professor Department of

Surgery, University of Texas Houston -  Fmr. Director, U.S. Army Institute of Surgical Research -  Retired Colonel and trauma surgeon, U.S. Army


Special Advisors

Rio Grande Neurosciences

•  Arthur Pilla, PhD -  Senior Scientific Advisor, Professor Emeritus Mt. Sinai Medical School, Columbia University -  Inventor of tPEMF and bone growth stimulator -  Co-founder EBI, Ivivi Technologies

•  Robert Cantu, MD -  Clinical Professor of Neurosurgery, Boston University, Co-Director, Center for the Study of

Traumatic Encephalopathy, BU -  Chairman, Department of Surgery, Chief Neurosurgery Service, Director, Service Sports Medicine

at Emerson Hospital (MGH) •  Joseph C. Maroon, MD, FACS

-  Professor and Vice Chairman, Department of Neurological Surgery and Heindl Scholar in Neuroscience, UPMC

-  Team neurosurgeon, Pittsburgh Steelers (since 1981) •  Milton McColl, MD

-  Former NFL Player, San Francisco 49ers -  Fmr. Venture Partner, New Leaf Ventures -  Fmr. President, Neurovascular Div., Boston Scientific

•  Christopher Nowinski -  Co-Founder and Executive Director, Sports Legacy Institute (SLI) -  Co-Director, Center for the Study of Traumatic Encephalopathy; advisor, NFL Players Association,

Mackey-White Traumatic Brain Injury Committee


•  Accomplished and visionary management team •  Addressing vast and unprecedented unmet medical need •  Distinguished medical advisors and principal investigators •  Significant IP portfolio and ongoing IP development •  Substantial opportunity to acquire and/or license NIBS

technologies •  “First-to-market” public vehicle for driving consolidation,

innovation and adoption of emerging NIBS therapeutics

RGN Summary

Appendix – Supporting science slides for tPemf/Theracap



Our PEMF device •  Safe and well-tolerated in the periphery •  Provides anti-inflammatory effects •  Reduces edema and pain •  Enhances blood flow

Large unmet need for TBI therapies •  Hallmarks of TBI pathology are neuroinflammation, edema, reduced

blood flow, and neuronal death

•  Whereas drugs may not pass the blood brain barrier, PEMF is an inductive therapy that can easily treat the CNS

CNS-PEMF Rationale


PEMF Effect on Post-op IL-1β•  tPEMF technology has been demonstrated in two post-surgical

controlled trials to significantly reduce pain, swelling, pain medication use and key inflammatory biomarker IL-1β

IL-1β levels 50-75% lower in treated patients; pain and pain medication use reduced by 50% (left: n = 24; right: n = 32)

N=24 (12/12)

N=32(16/16)


tPEMF and Traumatic Brain Injury


Rodents with concussion were treated with SHAM or tPEMF for 6 hours Neuroinflammation occurs after brain injury and higher levels of the inflammatory cytokine IL-1β are associated with worsened pathology and poor functional outcomes (i.e., greater disability)

p ≤ 0.02 *

Rasouli et al. 2012

tPEMF treated animals had 5-fold less IL-1β in the CSF 6 hours after concussion compared to SHAM-treated animals


tPEMF and Traumatic Brain Injury


Rodents with a penetrating TBI treated with SHAM or tPEMF tPEMF treated animals had 5-fold less IL-1β in the CSF 18 hours after injury compared to SHAM control animals.

p ≤ 0.001

p ≤ 0.015

Rasouli et al. 2012


tPEMF Reduces Numbers of Activated Microglia

0

50

100

150

200

250

contro l LME PEMF LME+ PEMF

6-OHDA 6-OHDA+ LME

6-OHDA+ PEMF

6-OHDA+ LME

+ PEMF

OX-4

2+ micr

oglia *

0

5 0

100

150

200

250

contro l LME PEMF LME+ PEMF

6-OHDA 6-OHDA+ LME

6-OHDA+ PEMF

6-OHDA+ LME

+ PEMF

OX-4

2+ micr

oglia


Primary co-cultures of neurons and microglia stimulated with LPS (inflammatory agent) for 24h followed by 30 min of tPEMF treatment Microglia are resident immune cells in the brain and activated microglia (OX-42+) are a focal source of local inflammation

p < 0.05

Quantification demonstrated that there were significantly fewer activated microglia in tPEMF treated cultures, evidence of anti-neuroinflammatory effects


tPEMF Reduces Microglial Reactivity After Injury

control PEMF


Neuroinflammation induced in response to damage caused by a penetrating injury in rodent brain. tPEMF applied twice daily for one week. Staining for OX-42+ activated microglial PEMF treated tissue (right) exhibits visibly less microglial activation


tPEMF Effects In High Intracranial Pressure (ICP) Model

Increased Arteriole

Diameter

Increased Tissue

Oxygenation

Rat model of high intracranial pressure •  ICP raised to 30mmHG •  Treated with PEMF for 30 minutes •  Arteriole diameter was measured

using intravital 2-photon microscopy

•  Tissue oxygenation quantitated measuring NADH auto-fluorescence

•  NADH is fluorescent and whereas oxidized NAD+ is not

p < 0.05

p < 0.05


tPEMF Effects In High Intracranial Pressure (ICP) Model

Reduced Microvascular Shunting

*

Reduced BBB Permeability

Rat model of high intracranial pressure •  Ratio of microvascular shunting to

capillary flow (nutritive blood flow) was lower in PEMF treated animals

•  The amount of leakage of a fluorescent agent from the CNS vasculature into the brain parenchyma was lower in PEMF treated animals

•  Suggesting improved blood-brain-barrier function

p < 0.05

p < 0.05


tPEMF Effects in Sub-Acute Stroke Model

Sub-acute stroke study demonstrated substantial effects of tPEMF on gene expression in animals in later stage stroke recovery (7 days)

•  Increased anti-inflammatory gene expression •  Decreased inflammatory & apoptotic gene expressions

PEMF BID for 15 minutes Starting 3 days post-stroke for 7 days


Neuroprotective Effects of tPEMF

Neuronal Insult Model •  Primary cortical neurons exposed to

oxygen and glucose deprivation (OGD) for 1, 2, or 3 hours

•  PEMF treatment for 30 minutes at the onset of OGD

•  Cells stained for TUNEL, a marker of DNA fragmentation and apoptosis

•  50% fewer apoptotic cells found in PEMF-treated compared with untreated cultures


PEMF effects on Long-Term Potentiation

PEMF treatment in a hippocampal slice model significantly increased synaptic transmission, which is associated with long-term potentiation (LTP), a process required for learning and memory.


Effects of tPEMF on EAE

0

1

2

D0 D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12 D13 D14 D15 D16 D17 D18 D19 D20 D21 D22 D23 D24 D25 D26 D27 D28 D29Day

Mea

n EA

E sc

ore

Control

PEMF

Sham

PI: Sergio Baranzini (UCSF) EAE: Inflammatory autoimmune model of multiple sclerosis Scoring: 0 (healthy) – 5 (moribund) PEMF or Sham treatment of mice with EAE (n = 10 per group) Treated 15 minutes twice per day

Repeated Measures ANOVA, p = 0.077 Treatment * Time


Ongoing Research Collaborations

Basic Science Studies Michael Whalen, M.D. Ph.D. – Harvard University

•  Effects of PEMF on rodent concussion and learning. Sergio Baranzini, Ph.D. – University of California San Francisco

•  Effects of PEMF on EAE, an animal model of multiple sclerosis.

Lee Goldstein M.D. Ph.D. – Boston University •  Use of PEMF to prevent CTE pathology and tau deposition.

Pejmun Haghighi, Ph.D. – Buck Institute for Research on Aging •  Effects of PEMF on synaptic function

Kiran Bhaskar Ph.D. – University of New Mexico •  Anti-neuroinflammatory effects on microglia and astrocytes •  Genomics interrogation of PEMF effects on inflammation


Ongoing Research Collaborations Clinical Studies Hunt Batjer, M.D. – UT Southwestern (December 2014)

•  Randomized Controlled Trial – PEMF treatment of sports concussion •  High school and college football players •  Focus: latency of symptom resolution and return to play

Adam Gazzaley, M.D. Ph.D. – UCSF (Ongoing) •  Effects of PEMF on cognitive function and multitasking performance

Leon Morales-Quezada, M.D. – Harvard University •  Effects of PEMF on EEG activity

Howard Yonas, M.D. – University of New Mexico •  PEMF treatment of severe traumatic brain injury


Pending Grant Support

National Institutes of Health National Institute of Neurological Disorders and Stroke

•  STTR Fast Track Phase I/II

•  Effects of PEMF as a treatment for post-concussion syndrome. •  Co-PI – Ross Zafonte PhD (Harvard Medical School) •  Submission: December 5th, 2014

RGN investor presentation January 2015

Health & Medicine

Transcript of RGN investor presentation January 2015