Direct Anatomic Delivery of Brain Therapeutics OTCQB: ACXA Company - - PowerPoint PPT Presentation

Direct Anatomic Delivery of Brain Therapeutics OTCQB: ACXA Company Presentation January 2015 – San Francisco, CA

Statements made in this presentation that are not historical facts are forward-looking statements that involve risks and uncertainties. The inclusion of forward-looking statements, including those related to the ability of the Company to perform per its license agreement with UCSF and meet its

• bligations; the ability of the Company to successfully develop and commercialize the BranchPoint

device and execute its business plan; the business strategy, plans, and objectives of the Company; and any other statements of non-historical information should not be regarded as a representation that any of our plans will be achieved. Actual results may differ materially from those described in this presentation due to the risks and uncertainties inherent in our business, including, without limitation, risks and uncertainties related to: our research and development efforts, including pre- clinical and clinical testing; regulation by the FDA and other government agencies; the timing of regulatory applications and product launches; our ability to successfully commercialize our products; and other risks detailed in our filings with the Securities and Exchange Commission filings, including our most recent Annual Report on Form 10-K and our most recent Quarterly Report on Form 10-Q. You are cautioned not to place undue reliance on these forward-looking statements, which speak

• nly as of the date hereof. We undertake no obligation to revise or update this presentation to

reflect events or circumstances that occur after the date of this presentation.

Note on Forward-Looking Statements

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Our Mission is to develop and commercialize novel neurological therapies based on our proprietary BranchPoint technology delivering therapeutics directly into specific regions of the brain, to the benefit

• f our patients and shareholders.

Mission

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• Licensed global exclusive rights to the BranchPoint technology from

UCSF with a working commercial prototype

• 510(k) FDA application for BranchPoint expected to be filed in the first

half of 2015

• Complete Product Development Team: Bioengineering, Manufacturing,

Quality Control, Regulatory

• Strong Scientific Advisory Group from UCSF, incl. neurosurgery KOLs
• Revenue opportunity: Product sales of BranchPoint to clinical stem cell

trials upon FDA approval

• Brain Cancer program: Direct anatomic delivery of chemotherapeutics to

brain tumor site

• Stem Cell program: Delivery of dopamine producing, stem cell-derived

neurons for the treatment of Parkinson’s

UCSF: University of California, San Francisco KOLs: Key Opinion Leaders

Investment Thesis Summary

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Management

• George Yu, President & CEO – over 15 years of experience in technology start-ups,

investment banking and management consulting. Previously CEO of Sinobiomed, a biopharmaceutical company focused on developing genetically engineered recombinant protein drugs and vaccines. Co-founded Bay2Peak, a financial advisory and investment management firm that executed strategic partnerships between RxD Pharmaceuticals and Pfizer, and Sinobiopharma and Lupin Pharmaceuticals. Bain, Lehman Brothers. MBA Columbia Business School, Medical Doctor University of Tuebingen, Germany. Board of Directors

• Anchie Kuo – Physician, venture capitalist and entrepreneur with over 25 years of

experience in healthcare. CEO of Arc Medical, first FDA registered suture manufacturer in China, Genaissaince Capital, BankAmerica Ventures, Pfizer. BA Dartmouth, MD Dartmouth Medical School.

• William Callahan – more than 25 years in emerging growth companies in diagnostics,

medical devices and drug delivery, establishing GMP manufacturing operations, support

• f regulatory FDA submissions, new product launches. Avocet Medical, Optiscan

BioMedical, Cygnus Therapeutics, Powderject Technologies, Applied Biosystems, J&J Lifescan, Depomed. BS in Chemistry San Francisco State University.

Management and Board

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Scientific and Clinical Advisors

• Dr. Daniel Lim, Assistant Professor of Neurological Surgery, UCSF – Lead inventor
• f BranchPoint with over 18 years of basic and clinical research experience in neural

stem cell therapies, brain tumors and stereotactic neurosurgery. Co-surgeon in Stem Cells Inc.’s Phase 1 clinical trial of neural cell transplantation to PMD patients.

• Prof. Krys Bankiewicz, Vice-Chair of Neurological Surgery, UCSF – over 20 years

experience with convection enhanced delivery (CED) of therapeutics to brain tumor and Parkinson’s disease patients

• Dr. Alastair Martin, Adjunct Professor Radiology and Biomedical Imaging, UCSF -
• ver 20 years experience in MR imaging, pioneered MRI implantation system for the

delivery of deep brain stimulator electrodes and administration of therapeutics Product Development and Regulatory Advisors

• Prof. Tejal Desai, Chair Bioengineering and Therapeutic Sciences, UCSF – Co-

Inventor of BranchPoint, developed implantable drug delivery devices, implantable biohybrid devices for cell encapsulation, templates for cell and tissue regeneration

• Greg Mathison, Regulatory, Clinical and Quality Assurance – 35 years experience in

regulatory, clinical and quality compliance management positions at Medtronic, American Medical Systems, Cardiac Pacemakers, Clarus Medical and Bacchus Vascular

Advisory Group

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Gupta, et al, Sci Transl Med, 2012

Device used for cell delivery today The Problem: Therapeutic Delivery to the Brain

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Multiple straight penetrations with limited anatomic targeting risk increased trauma and reduce efficacy

9 penetrations for the putamen (each hemisphere) Each penetration risks hemorrhagic stroke

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BranchPoint enables delivery to large, complex targets through a single penetration

Silvestrini, et al, Mol Therapy, 2014

• Platform technology that enables

radially branched deployment (RBD) of cells to multiple target locations at variable radial distances and depths along the initial brain penetration tract

• RBD overcomes some of the

technical limitations inherent to the use of straight cannulas

• This platform technology could

have a major impact on the clinical translation of a wide range of cell therapeutics

iMRI-guided RBD. Targeting is performed with intraoperative MRI scans, which enables corrections for brain “shift,” and delivery can be monitored in “real time” with rapid MRI scans. By controlling guide cannula radial angle and depth and delivery catheter radial distance, cells (schematized as green and purple circles) can be delivered to larger brain target volumes that vary in shape and size due to individual patient anatomy and different disease states. Accurexa Inc. 9

• Integrated RBD with FDA-approved iMRI skull-

mounted aiming device and targeting software.

• “Real-time” MRI monitoring that is easy to

implement in most hospitals worldwide addresses shortcomings inherent to standard stereotaxy

• Enables delivery “tailored” to individual patient

anatomical variation and different disease states

• “Piggybacking” can reduce patient risk and the cost
• f procedures for a wide variety of therapeutics for

brain therapy

iMRI-guided BranchPoint: Leveraging advances in material sciences, modern imaging and neurosurgery

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BranchPoint technology with intuitive, simple controls

(a) Guide cannula with distal side port (white arrow, left) and proximal controls (right). (b) Delivery catheter with dual side infusion ports (not seen at this magnification) at the curved distal end (left) and the proximal locking hub (right). A plunger wire is fitted into the catheter lumen. (c) Positioning collet. Orange arrows indicate the rotational (radial angle) control provided by the white hub (top) and depth control provided by the yellow wheel (right). Horizontal markings (black and red lines, mm spacing) indicate changes in collet depth. Scale bars = 5 mm. (d) RBD use illustrated with a human skull model. View is from the posterior right. The RBD platform was mounted over a right frontal burr hole. (1) Attachment of positioning collet to the MRI- compatible, skull mounted aiming device; (2) insertion of guide cannula through the positioning collet; (3) insertion of delivery catheter with the proximal hub locking into the guide cannula proximal controls (white arrowhead); (4) deployment of the catheter through the opened guide cannula side port; (5) delivery of cells with plunger wire; (6) removal of delivery catheter and closure of the guide cannula side port; (7) repositioning of guide cannula side port to new depth and radial angle; (8) delivery to new location via repetition of (3–7).

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(A) Before SPIO delivery. Arrow indicates the region of the putamen, which is shown enlarged and outlined in the inset at the lower right. (B,C) After six deliveries of SPIO (numbered in red) via a single guide cannula insertion. The two panels show different axial planes to illustrate the different radial and depth locations of the SPIO deposits. (D) Enlarged view of the putamen (red outline) with the regions of the SPIO deposits (blue outline). White scale bars = 1 cm. iMRI, interventional magnetic resonance image; RBD, radially branched deployment; SPIO, super paramagnetic iron oxide.

BranchPoint works at the scale of the human brain

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Immunohistochemistry analysis of dopaminergic neural stem cells grafted to the pig striatum: (d) 4'-6-diamidino-2-phenylindole nuclear stain (e) STEM 121-positive cells at the graft site (f) Green Fluorescent Protein-positive cells at the graft site (g) Merged images showing the border between graft-derived cells and pig striatum

Human graft- derived cells

BranchPoint successfully delivered human stem cell- derived dopamine neurons to pig striatum

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Addressable Market Opportunities

BranchPoint Platform Technology Third Party Stem Cell Trials BranchPoint Chemo Product BranchPoint Parkinson Stem Cell Therapy 40 programs representing a $5mm market value Brain Cancer drugs despite low efficacy generate >$1B Sales / y. Parkinson Treatment market value $3.6B in 2012i

• i. According to Research and consulting firm, GlobalData’s latest report PharmaPoint: Parkinson’s Disease - Global Drug Forecast and Market Analysis to 2022

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• Upon FDA approval, BranchPoint is expected to be

sold as a disposable device per procedure

• BranchPoint can deliver stem cells in large animal and

human clinical trials

• Approx. a dozen research institutions have expressed

interest, e.g. Sanford-Burnham and Texas Biomedical Research Institutes

• Approx. 20 companies are currently developing 40

neural stem cell trial programs (Preclinical to Phase 2) representing a $5mm addressable market potential

Revenue Opportunity: Product Sales to Stem Cell Trials

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BranchPoint enables piggy-backing “triple therapy”

• BranchPoint is designed to

piggy-back on existing, reimbursed procedures, e.g. deep brain stimulation, thereby lowering procedure costs

• Single platform for:
• Stem Cell therapy
• Neuromodulation
• Gene/drug therapy

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• Glioblastoma Multiforme (GBM) is one of the most aggressive forms of

cancer affecting the brain

• Approx. 16,000 new patients diagnosed with GBM each year in the US
• Median survival without treatment 4.5 months, median survival under

current standard of care 14.6 months (primarily surgery and radiation)

• First-line treatment: Merck’s Temodar generated US sales of $420 million

and global sales of $910 million – FDA approved based on improvement

• f survival by 2.5 months
• Second-line treatment: Roche’s Avastin generated US sales of $170

million – FDA approved based on an improvement in progression free survival but did not improve overall survival in later studies.

• Pricing: Gliadel (implantable chemotherapy wafers) priced at $30,000 per

treatment cycle but no control over drug release after implantation

Brain Cancer Program Target Market

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• MJ Ali et al., Northwestern University, Neuro-Oncology, April 2006, 109-118:

“Drug delivery remains a major issue in brain tumor treatment…treatment failures can be expected on the basis of inadequate drug delivery alone, regardless of the effectiveness of the drug.”

• The first Phase 3 trial for direct delivery of a cytotoxin to recurrent GBM

conducted in 52 clinical centers demonstrated clinical efficacy [PRECISE]

• Overall survival was 46.8 weeks in the active vs. 41.6 weeks in the control

arm with Gliadel wafer as standard of care (p=0.288)

• Progression-free survival was 17.7 weeks in the active vs. 11.4 weeks in

the control arm (p=0.008)

• Tocagen is developing a gene therapy to locally produce 5-FU within a brain

tumor Blood-Brain Barrier and lack of anatomic targeting of tumor site limit current chemotherapeutics. Direct targeted delivery by BranchPoint can potentially improve efficacy and safety.

Brain Cancer Program Direct Delivery Key to Efficacy and Safety

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• Development of a modified BranchPoint Convection Enhanced Delivery

(CED) device for the delivery of chemotherapeutics

• Direct anatomically targeted delivery of an approved, generic

chemotherapeutic, e.g 5-FU or Ara-C

• BranchPoint Chemo Product could pursue FDA approval under 505b2

path which would require single human brain tumor trial (Gliadel was approved with one single Phase 3 trial and increased median survival by 2.3 months against placebo which was not statistically significant)

• Potential Orphan Drug Designation with 7-year market exclusivity based
• n a patient population of <200,000 (Gliadel orphan drug)

Brain Cancer Program BranchPoint Chemo Product

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• Approx. 1 million patients have Parkinson’s Disease in the US – 7-10

million patients worldwide

• 60,000 new patients are diagnosed each year and expected to increase

with the ageing of the population – Parkinson’s usually develops after the age 50

• No lasting effective therapy and severe disability occurs within several

years – Mortality rate is 3 times that of the general population

• Parkinson’s drugs generate global sales of approx. $2.5 billion per

year, despite a high degree of motor complications (dyskinesia)

• Direct and indirect costs estimated at $25 billion per year in the US
• Medication costs average $2,500 a year and therapeutic surgery can

cost up to $100,000 per patient

Parkinson’s Stem Cell Program Target Market

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• Parkinson is well suited for cell replacement:
• Loss of one specific type of dopaminergic neuron
• Loss in one brain area (substantia nigra)
• Letter of Intent signed with a stem cell manufacturer to develop

stem cell treatment for Parkinson’s

• Stem cell manufacturer provided human stem cell-derived

dopaminergic neurons for the successful preclinical testing of BranchPoint in pigs

Parkinson’s Stem Cell Program BranchPoint Stem Cell Therapy Product

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Brain Cancer Therapeutic Companies Stem Cell Technology Companies Company Ticker Market Cap (mm) Phase Company Ticker Market Cap (mm) Agenus AGEN $185 2 Athersys ATHX $121 Celldex Therapeutics CLDX $1,740 2 Biotime BTX $229 CTI BioPharma CTIC $340 2 Brainstorm Cell BCLI $55 CytRx Corporation CYTR $135 2 Cesca KOOL $44 DelMar Pharmaceuticals DMPI $40 1 Neuralstem CUR $241 Immunocellular IMUC $43 1/2 Osiris Therapeutics OSIR $478 Northwest Biotherapeutics NWBO $320 3 Pluristem PSTI $189 Peregrine PPHM $257 2 Stemcells STEM $82 Average $383 Average $180 Median $221 Median $155

Comparable Companies

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APPENDIX

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iMRI-guided RBD function in a clinically relevant neurosurgical workflow

Accurexa Inc. 24 (a) Burr hole in the right frontal swine skull. A small opening in the dura and pia mater was made before mounting the aiming device. (b) iMRI-compatible aiming device mounted over the burr hole. (c) Swine head with iMRI-compatible platform in the bore of a clinical 1.5T diagnostic MR scanner. (d) Example of neurosurgical planning with MRI data acquired very shortly before intracerebral delivery. (e) Adjustments to pitch and roll controls (white arrowheads) on the skull-mounted aiming platform to align the fluid-filled guide stem (red arrow) with the planned guide cannula trajectory. (f) Insertion of the guide cannula and conduct of the RBD procedure.

Source: H.C. Wainwright

Stem Cell Therapeutic Companies Numbers in Millions except for Share Price Company Ticker Share Price Shares Out Market Cap Cash Debt Enterprise Value Advanced Cell Technology ACTCD $9.20 33 $305 $4 $0 $301 Aastrom Biosciences ASTM $3.32 8 $27 $7 $3 $22 Asterias Biotherapeutics ASTY $6.17 31 $191 $33 $0 $158 Athersys ATHX $1.40 77 $108 $39 $0 $70 Brainstorm Cell Therapeutics BCLI $0.29 227 $66 $11 $0 $55 Capricor Therapeutics CAPR $4.25 12 $50 $12 $9 $47 Cytomedix CMXI $0.39 122 $48 $25 $0 $23 Cytori Therapeutics CYTX $1.26 80 $100 $13 $27 $114 Fate Therapeutics FATE $5.28 21 $109 $52 $1 $57 Fibrocell Science FCSC $3.01 41 $123 $50 $0 $73 Cesca Therapeutics KOOL $1.34 38 $51 $15 $0 $36 Macrocure MCUR $9.18 16 $150 $16 $0 $134 Mesoblast ASX:MSB $5.28 317 $1,675 $196 $0 $1,478 Neostem NBS $5.58 35 $195 $34 $5 $166 Neuralstem CUR $3.78 87 $330 $30 $6 $306 Osiris Therapeutics OSIR $13.00 34 $446 $64 $0 $383 Pluristem Therapeutics PSTI $2.92 68 $198 $64 $0 $135 StemCells Inc. STEM $1.48 67 $99 $38 $16 $77 Mean $237 $39 $4 $202 Median $116 $31 $0 $95

Comparable Stem Cell Companies

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Selected Financings in Regenerative Medicine 2013-14 Company Raise (mm) Mesoblast 175 bluebird bio 116 Fate Therapeutics 46 Neostem 40 MiMedix Group 34 StemCells Inc. 30 Cardio3 Biosciences 30 Athersys 21 Fate Therapeutics 20 StemCells Inc. 19 Tengion 19 TiGenix 16 Total 566

Source: ARM Regenerative Medicine Annual Industry Report

Financings

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Company Ticker Treatment Name Indication Clinical Phase Medipost KS:078160 Neurostem Alzheimer's Disease 1/2 Neuralstem CUR NSI-566 Alzheimer's Disease Preclinical StemCells Inc. STEM HuCNS-SC Alzheimer's Disease Preclinical BrainStorm Cell Therapeutics BCLI NurOwn Amyotrophic Lateral Sclerosis (ALS) 2 Neuralstem CUR NSI-566 Amyotrophic Lateral Sclerosis (ALS) 2 Kadimastem TLV:KDST hESC-derived astrocyte precursor cell Amyotrophic Lateral Sclerosis (ALS) Preclinical Q Therapeutics Private Q-cells Amyotrophic Lateral Sclerosis (ALS) Preclinical Neuralstem CUR NSI-566 Cerebral Palsy Preclinical Shenzhen Beike Biotech Private hUCMSCs Hereditary Ataxias 1/2 Neuralstem CUR NSI-566 Huntington's Disease Preclinical Pharmicell KS:005690 Autologous bone marrow-derived MSCs Ischemic Stroke 3 Athersys ATHX MultiStem Ischemic Stroke 2 ReNeuron Group LON:RENE ReN001 Ischemic Stroke 2 Cellonis Biotechnology Private BMSCs and EPCs Ischemic Stroke 1/2 Neuralstem CUR NSI-566 Ischemic Stroke 1/2 SanBio Private SB623 Ischemic Stroke 1/2 Stemedica Cell Technologies Private Stemedyne-MSC Ischemic Stroke 1/2 Asterias Biotherapeutics Private AST-OPC1 Ischemic Stroke Preclinical Mesoblast ASX:MSB MPCs Ischemic Stroke Preclinical Opexa Therapeutics (Merck KGaA) OPXA Tcelna Multiple Sclerosis (MS) 2 Shenzhen Beike Biotech Private hUCMSCs Multiple Sclerosis (MS) 1/2 Asterias Biotherapeutics ASTY AST-OPC1 Multiple Sclerosis (MS) Preclinical Athersys ATHX MultiStem Multiple Sclerosis (MS) Preclinical BrainStorm Cell Therapeutics BCLI NurOwn Multiple Sclerosis (MS) Preclinical Neuralstem CUR NSI-566 Multiple Sclerosis (MS) Preclinical Living Cell (Otsuka Pharma) AXC:LCT NTCELL Parkinson's Disease 1/2 BrainStorm Cell Therapeutics BCLI NurOwn Parkinson's Disease Preclinical International Stem Cell Corporation ISCO h-Parthanogenetic Stem Cell Parkinson's Disease Preclinical Neuralstem CUR NSI-566 Parkinson's Disease Preclinical NsGene A/S Private NsG0301 Parkinson's Disease Preclinical Rhinocyte Private Olfactory-derived Stem Cells Parkinson's Disease Preclinical Pharmicell KS:005690 Autologous bone marrow-derived MSCs Spinal Cord Injury 2 Asterias Biotherapeutics Private AST-OPC1 Spinal Cord Injury 1 Neuralstem CUR NSI-566 Spinal Cord Injury 1 Celvive Private Autologous Bone Marro Stem Cells Spinal Cord Injury 1/2 Rhinocyte Private Olfactory-derived Stem Cells Spinal Cord Injury 1/2 StemCells Inc. STEM HuCNS-SC Spinal Cord Injury 1/2 Athersys ATHX MultiStem Spinal Cord Injury Preclinical SanBio Private SB618 Spinal Cord Injury Preclinical SanBio Private SB623 Traumatic Brain Injury 1/2 Athersys ATHX MultiStem Traumatic Brain Injury Preclinical Neuralstem CUR NSI-566 Traumatic Brain Injury Preclinical

Source: H.C. Wainwright

42 Neural Stem Cell Development Programs by 21 Companies

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