Athersys, Inc.
Forward Looking Statements
The statements and discussions contained in this presentation that are not historical facts constitute forward‐looking statements, which can be identified by the use of forward‐looking words such as “believes,” “expects,” “may,” “intends,” “anticipates,” “plans,” “estimates” and analogous or similar expressions intended to identify forward‐looking statements. These forward‐looking statements and estimates as to future performance, estimates as to future valuations and other statements contained herein regarding matters that are not historical facts, are only predictions, and that actual events or results may differ materially. We cannot assure or guarantee you that any future results described in this presentation will be achieved, and actual results could vary materially from those reflected in such forward‐looking statements. Information contained in this presentation has been compiled from sources believed to be credible and reliable. However, we cannot guarantee such credibility and reliability. The forecasts and projections of events contained herein are based upon subjective valuations, analyses and personal opinions. This presentation shall not constitute an offer to sell or the solicitation of an offer to buy any securities. Such an offer or solicitation, if made, will only be made pursuant to an offering memorandum and definitive subscription documents. 2
Company Highlights Emerging clinical portfolio of “best‐in‐class” product candidates and technologies Multiple clinical stage programs in development , strong preclinical pipeline Focus on biologics (MultiStem ) and pharmaceuticals (for CNS /metabolic related indications including obesity, cognition and others) Multiple clinical trials initiated with MultiStem Highly standardized “Off‐the‐shelf” cell therapy product, produced at scale Administered without tissue matching or immune suppression Multiple disease indications in development ‐ multiple mechanisms of benefit Frost & Sullivan Product Innovation of the Year Award – 10/29/08 Public company with strong cash position NASDAQ: ATHX $65 MM financing completed in June ‘07 3
Business Strategy Develop a portfolio of potential of potential best in class opportunities Maintain lean operational infrastructure / modest core burn Cost effective portfolio diversification + focused core competencies
Using a “Fast Follower” strategy in multiple areas, “Early Mover” in others Reduces risk and development cost Leverage prior knowledge, validation, development efforts of others to produce a better, safer and/or more convenient product Multiple potential advantages to being “best but not first” in certain areas (but also leveraging “early mover” opportunity in areas where it makes sense)
Portfolio based approach enables development & partnering flexibility Advance programs as resources allow Evaluate partnering opportunities as we advance 4
Obesity Program
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Obesity Market Opportunity Clinical Landscape Growing, global health epidemic contributing to heart disease, diabetes, cancer and stroke Estimated 30% of Americans are clinically obese (BMI > 30); an additional ~30% are overweight (BMI > 25) Economic cost in U.S. alone is estimated at $117 billion annually True blockbuster potential for safe and effective therapies
Therapeutic Landscape Increasing recognition of obesity as serious medical condition No highly effective & safe drug therapies currently on market – few in clinical trials, recent additional attrition due to “demise” of CB‐1 antagonist class Several targets are well known but have not been effectively exploited to date Large potential market, patient variability (efficacy and tolerability) creates room for multiple players and MOA’s
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Obesity Program – Overview of 5HT2c Agonists 5HT2c (serotonin) receptor agonists suppress appetite & cause weight loss Mechanism extensively validated in humans (e.g. fenfluramine, dexfenfluramine recognized as highly effective weight loss agents)…but… These non‐selective agents also activate the 5HT2b receptor in the heart and cause cardiovascular toxicity (valvular hypertrophy = valvular regurgitation/heart murmur) Selective 5HT2c agonists (i.e. that do not stimulate 5HT2b) believed to be safe Selectivity relative to 5HT2a important to limiting CNS related side effects
Portfolio of potent and selective compounds established ATHX‐105 has been the lead ‐ Multiple Phase I trials completed in U.K. (good safety & tolerability profile observed) ‐ Excellent regional absorption seen in recent clinical study (important for development of modified release formulation) ‐ Currently on partial clinical hold – have met with FDA, resolved several issues, but significant issue remains – could result in suspension or termination of further development ‐ Intend to provide further update on program this quarter after completion of ongoing work, analysis of results and dialogue with FDA 7
Cognition & Wakefulness ‐ H3 Antagonist Program
Histamine H3 Receptor Extensively Studied – Multiple Potential Applications H3 Receptor Antagonists / Inverse Agonists result in elevated levels of histamine in certain regions of the brain directly affecting cognitive tone Compounds improve wakefulness (e.g. Narcolepsy, EDS) and cognition (e.g. ADHD, Alzheimer’s) May also have relevance in other indications (e.g. obesity, neuropathic pain) High quality portfolio of therapeutic compounds established Multiple compounds currently under evaluation in animal tox, efficacy studies ‐ Potent, highly selective compounds developed by ATHX Intend to select a clinical candidate and one or more back‐up compounds this quarter (pending successful completion of ongoing studies) 8
MultiStem®: Biologic Product Platform
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Historical Limitations to Stem Cell Therapy
Requirement for close Donor – Recipient tissue matching Necessary to avoid transplant rejection Also needed to reduce incidence of Graft vs. Host Disease
Lack of ability to scale production of cells One donor for each recipient – logistically difficult and very costly Biological limitations of most cells prevent large scale production
Mechanistic focus has been primarily cell / tissue replacement Most cell types can produce limited repertoire of more differentiated cells Goal has been to replace lost or damaged cells (e.g. HSC transplantation)
Safety Rejection, GVHD, Ectopic Tissue, Teratoma / Tumor formation 10
2008 – Pharma‐Biotech Arriving to Party …
November 2008 – Pfizer announces launch of ReGenerative Medicine Centers – $100 million program to develop therapies, focused in Cambridge UK (brain / sensory) and Cambridge MA (heart disease / diabetes)
November 2008 – Genzyme and Osiris announce partnership to commercialize Prochymal and Chondrogen (MSC) – $130 million upfront, $1.25 billion in potential milestones – Osiris to commercialize in U.S.; Genzyme in RoW
July 2008 – GSK announces collaboration with Harvard Stem Cell Institute – $25 million research partnership
June 2008 – Pfizer announces investment in EyeCyte – Treatment of eye diseases (e.g., diabetes‐retinopathy) with adult stem cell (EPC) 11
MultiStem®: Best‐in‐Class Cell Therapy Product
“Off the shelf” administration No tissue matching needed Non‐immunogenic ‐ No immunosuppression required
Well defined, FDA‐approved manufacturing process in place (with Lonza) Banked product, highly characterized Large scale production / yield (100k’s to millions of doses possible from a single donor)
Multiple potential mechanisms of therapeutic benefit Dynamically responsive biologic therapy = a drug like therapy Therapeutic effect primarily factor mediated: anti‐inflammatory / immunomodulatory, cytoprotective, trophic & growth factors, angiogenic / vasculogenic Direct cell replacement plays a minor role
Leading IP position for pluripotent, multifunctional non‐embryonic stem cells Multiple IND’s advanced in efficient, cost effective manner 12
Overview of MultiStem® Production Process
Lot Release & Product Characterization Testing Sterility Potency Purity and Viability Stable Cytogenetics Absence of tumorigenic potential in vivo
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MultiStem: Additional Safety Studies ▲
GLP Toxicology and Clinical Pathology (2 week, 4 week) Studies indicate no evidence of acute toxicity or abnormal clinical pathology
▲
Genetic Stability and Tumorigenicity Testing Karyotypic stability Clinical product tested in standard Nude mouse tumor models (both i.v. and s.c.)
▲
Long Term GLP Histopathology Analysis (one year for stroke) Extensive histopathology analysis of animals receiving clinical grade MultiStem indicates no evidence of tumorigenicity or ectopic tissue after one year No other abnormalities or other adverse events noted
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Immune Sensitization Analysis Single or repeat administration (5x) of MultiStem does not cause immune sensitization or abnormal clinical pathology
▲
Gene Expression, Protein Expression and SNP Array Analysis No evidence of variability between working cell banks and production runs after significant expansion of clinical grade cellular product 14
MultiStem: Multiple Potential Mechanisms of Benefit
OPEN Phase I Trial for HSC/BMT Support & GVHD Prophylaxis
OPEN Phase I Trial for AMI
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Focused Product Development Approach o Chronic ischemia / CHF o Peripheral vascular disease
MultiStem®
Treatment Acute/Ischemic Injury
o Acute Myocardial Infarction
o Traumatic brain injury & related o Other Neurological Indications o Other ischemic injury (e.g., kidney)
(Ph 1 initiated)
o Ischemic Stroke o Inflammatory bowel disease Immune System Modulation
o HSC / Bone Marrow Transplant Support / GVHD (Ph 1 initiated)
o Transplantation o Diabetes (type 1) o Multiple Sclerosis o Other autoimmune disorders o Other Neurological Indications
Next generation opportunities Other themes, e.g., protein deficiencies, bone growth 16
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Accelerating MultiStem Proof‐of‐Concept Path Proof‐of‐concept with cell‐therapy products – Standardized and scalable product manufacturing – Basic safety in humans within desired dose ranges and delivery approaches •
Phase I studies (with potential for efficacy signals)
– Efficacy in humans •
Focus in near term on Phase I/II studies in indications with discreet endpoints / readouts over short → showing of desired biological activity and benefit
– Further elucidation of mechanisms of benefit (from animal models, in vitro) support clinical findings
Fastest path likely infused product in immunomodulatory area – Leverage IND BB‐13507 (Evaluation of MTD of Single and Repeated Administration of Allogeneic MultiStem in Patients with AL, CM and Myelodysplasia) – Treatment of (steroid refractory, or acute) GvHD •
Basically, same patient population with well‐defined shorter‐term endpoints; same sites
– Other immunomodulation indication(s): exploit same therapeutic pathways, and conditions with similar treatment approaches 17
MultiStem for Acute Myocardial Infarction
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MultiStem®: Acute Myocardial Infarction
AMI remains a major area of need for improved therapies 865,000 heart attacks annually in the U.S. 156,000 deaths Significant incidence of progression to CHF
Local (catheter) delivery of MultiStem following heart attack Reduces inflammation‐related damage and promotes revascularization Also exploring administration via i.v.
MultiStem demonstrated safe and effective in multiple pre‐clinical models IND approved, clinical trial initiated with co‐development partner (Angiotech)
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Innovative Approach: Standardized Product + Efficient Local Delivery
Administration of bone marrow‐derived, allogeneic MultiStem cells to patients Standardized product (administered without matching or immunosuppressive agents) Reduces inflammation‐related damage and promotes revascularization
Targeted, local delivery in coronary arteries with transarterial catheter Administration of cell product into perivascular region Relative ease of use, comparable to standard angioplasty
Strong partners and leading investigational sites Athersys and partner, Angiotech Pharmaceuticals Cleveland Clinic Foundation, Henry Ford Health System, University of Michigan & others
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Allogeneic MultiStem Delivers Functional Improvement in Pig Models of Cardiovascular Ischemia
Transient ischemia, catheter delivery p-value < .005
P-value < .02
E je c tio n F ra c tio n %
60 55 50 45 40 35 30 25 20 Baseline
• •
1 Wk post-MI
4 Wk post MI
Consistent improvement across multiple functional parameters with single dose administered post‐MI No observed safety issues 21
Transarterial Catheter Delivery Approach Mercator MedSystems, 510(k) approved MicroSyringe Infusion Catheter
• Site‐specific delivery into perivascular space and adventitia – Retain greater number of cells at/near injury site (reduce wash‐away of cells into bloodstream) – Relative ease‐of‐use
• Good cell viability, efficient ease of use 22
Phase I Clinical Protocol Summary ‐ AMI Phase I Study, open label, dose escalation STEMI, LVEF between 30‐45% Administration of MultiStem in coronary artery (via transarterial catheter) delivered on day 2‐5 after Acute MI ‐ Three dose groups (6 patients each) plus 10‐patient registry cohort Multiple sites, largely regional
Objectives Primary endpoints: safety (arrhythmias, acute toxicity, hospitalization, death, mechanical complication) Secondary endpoints: functionality measures (e.g. LVEF)
Strategy Provide safety foundation and information to enable design of meaningful Phase II exploratory study (e.g., dose levels, delivery timing) 23
Delivery of MultiStem in AMI patient
5 sec
30 sec
60 sec
Delivery, retention of cells in area of ischemic damage Vessel patency Rapid, efficient procedure Well tolerated
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MultiStem for Support of Hematological Stem Cell Transplants
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MultiStem®: Transplantation (GvHD)
Frequent, potentially life threatening consequence of HSC / BM transplants Clear need for improved treatments beyond broad immunosuppression Limited treatment options for complications (e.g., GvHD) Other problems associated with conditioning regimen (e.g., GI function)
IV delivery of MultiStem in conjunction with HSC / BM transplant Reduction of GvHD impact and promotion of tissue regeneration and engraftment Potential for GvHD intervention
MultiStem demonstrated safe and effective in pre‐clinical models IND approved, clinical trial initiated
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MultiStem® Immuno‐Privileged In Vitro
Mixed Lymphocyte Reaction Donor 1 Cells (Rare alloreactive Tcells in red)
MultiStem does not elicit In Vitro TCell Response in MLR Studies
Donor 2 Cells
Mixture
Allogeneic Tcell controls
Recognition of allogeneic cells causes T-cell activation and proliferation Proliferation measurable by increase DNA synthesis
Self to self
T-cells don’t react to MultiStem (MAPC)
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MultiStem® Immunosuppress Alloreactive T Cells
MultiStem (like MSC) Exhibits Immunosuppressive Effects On MLR (human)
Dose Dependent Suppression of Allogeneic T Cell Response in MLR (Lewis rat) 180,000
3H-thymidine counts
160,000 140,000
None
0.03x10^5
120,000
0.06x10^5
0.125x10^5
100,000
0.25x10^5
0.5x10^5
1x10^5
2x10^5
80,000 60,000 40,000 20,000 0 R (Lewis )+ S (DA)
MAPC (MultiStem) Suppresses Immune Response
R (Lewis )
No responder or s tim ulator
Dose Dependent Effect
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MultiStem® Does Not Induce Immune Response in vivo
Serial administration of MultiStem does not result in detectable allo‐ antibody or T cell sensitization response ‐ Serial administration is safe ‐ Positive control = splenocytes (which do elicit alloreactivity)
Allogeneic or xenogeneic MultiStem do not require immunosuppression for benefit in acute MI or stroke (e.g. human into rodent) FDA review of pre‐clinical data approved use of single universal donor in multiple indications
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MultiStem Provides Survival Advantage in Rat Acute GvHD Model
Design Survival
•
•
Rats sublethally irradiated and injected with bone marrow cells and T‐cells from different rat strain → creating Graft vs. Host immune response MultiStem administered I.V. at day 1, or at days 1 and 8
100% 90% 80% 70% 60% 50% 40% No treatment
30%
Results • •
Treatment, day 1
20%
Treatment days 1+8
10%
MultiStem provides significant survival benefit versus animals receiving no treatment Benefits observable for other GvHD indicators (body weight, activity, posture, fur texture, skin)
0% 0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34
Days Significant survival advantage in MultiStem treated animals
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Gut Pathology in Rat Acute GVHD Model
Day 15 Pathology, Multi‐treatment Group
GVHD, MultiStem Treated GVHD, PBS Control Treated
Substantially less gastro‐intestinal damage in MultiStem‐treated animals
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Phase I Clinical Protocol Summary – Transplantation / GvHD
Phase I study, open label, dose escalation Patients (leukemia, myelodysplasia) undergoing PBSC / bone marrow transplantation Administration of MultiStem intravenously ‐ Two treatment arms: Single dose co‐administered with transplant, multiple doses administered over first 30 days ‐ Continual reassessment methodology
Objectives Primary endpoints: safety: maximum tolerated dose based on composite of DLTs and AEs through 30 days Secondary endpoints: incidence and severity of GVHD, survival, infection
Strategy Provide safety foundation to allow for (a) prophylactic treatment and intervention for GVHD, and (b) single and multiple dose treatment approaches 32
Opportunities in Other Autoimmune Disease
Treating emergent or chronic autoimmune disease Immunomodulatory activity of MultiStem for GVHD is mechanistically similar to biological conditions for other autoimmune conditions Rapid clinical entry is possible (leveraging off of existing pre‐clinical and clinical data) Manufacturing capability already in place
Multiple indications possible Wide range of autoimmune conditions with unmet medical need as potential therapeutic targets for MultiStem I.V. delivery Other potential benefits to help address tissue damage
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MultiStem for Ischemic Stroke
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MultiStem®: Ischemic Stroke
Substantial unmet need in the treatment of Ischemic Stroke Over 700,000 strokes annually in U.S., and ~80%+ ischemic strokes Substantial functional loss and rehabilitation and follow‐up care costs Limited treatment options, tPA must be administered within 3 – 4.5 hrs of stroke
IV delivery of MultiStem 48 hours (+/‐) following Ischemic Stroke Broad potential treatment window Benefit trophic‐factor mediated: reduce inflammation, stimulate revascularization, override processes of cell / tissue decline & contribute to tissue regeneration
MultiStem demonstrated safe and effective in pre‐clinical models IND filing planned for 2H, 2008
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Animal Models of Cerebral Ischemia MCA Occlusion
MCA Ligation
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Pre‐Clinical Experimental Approach
Key results • Immunosuppression not required for safe improvement to neurological function
Experimental approach 1. Immunosuppression (+/‐) with allo‐/ xenogeneic cells, intracranial delivery 2. Route of administration: viability of IV‐ delivery
• Significant functional improvement (locomoter, neurological) statistically over control • Comparable improvement in locomotor or neurological function observed among animals receiving cells at 1, 2 or 7 days
3. Delivery window: 1‐7 days post‐stroke
• Dose response observed with IV‐infused cells, as measured by neurological improvement
4. Dose escalation
• Engrafted cells display neuronal markers in neonatal model • No abnormal tissues or abnormal pathology observed in animals kept on study for 1 year post cell transplantation
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Single Dose of Human MultiStem Provides Robust, Durable Improvement in Rodent Model of Ischemic Stroke Bederson Composite Score of Neurological Function, IV-delivery of MultiStem day 2 post-stroke
• Dose response – Therapeutic benefit proportional to dose delivered
2.5 2
• Treatment timing – Improvement whether delivery at day 1, 2 or 7
1.5 1 0.5
0.4 units 4 units 10 units 1 units 20 units 2 units 10 units non-viable cells (control)
Day 56
Day 42
Day 28
Day 14
PostStroke
0 Baseline
Mean Neurological Score
3
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MultiStem Program Highlights Broad MultiStem product platform for cell‐based therapy initiating clinical trials Standardized, off‐the‐shelf product (a product, not a procedure) First truly scalable manufacturing platform for cell therapy Strong IP position
2008 Focus: Initiating clinical development activities Ischemic injury: AMI (possibly ischemic stroke) Immunomodulation and tissue damage: Bone Marrow / HSC Transplantation / GvHD
Potential for broad development program Other neurological indications, autoimmune disease, other areas Single “master file” approach = highly efficient development Progress will be based on validation in appropriate models, collaboration with experts 39
Financials & Milestones
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Summary Financial Data $ Thousands
Nine months ended September 30, 2008
Revenues
$2,846
Operating expenses
(17,048)
Interest income and other, net
923
Net loss
(13,279)
Net Cash Use in Operating Activities
(12,536)
Cash and Investments
34,716
Debt
0 41
Athersys – Key Milestones 2007 √ √ √ √ √
Begin ATHX‐105 Phase I study IND approval for MultiStem ‐ HSC transplant support / GvHD IND approval for MultiStem ‐ AMI NASDAQ listing and share registration Evaluate H3 antagonist compounds for multiple indications
2008 √ √ √ √ √ □ □ □
Review/evaluate ATHX‐105 Phase I top line results Submit ATHX‐105 Phase II plan to FDA Complete additional ATHX‐105 clinical studies re: safety, regional drug absorption Launch MultiStem GVHD / Oncology Support Phase I clinical trial Launch MultiStem AMI Phase I clinical trial Resolve Partial Clinical Hold with FDA Complete further pre‐clinical studies for H3 antagonist program/select candidate IND Approval for MultiStem ‐ Stroke (Initiate trial depending on resource availability)
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Athersys, Inc.