CBLB502 Defense Program Overview Investor Day June 8, 2011

Transcription

1 Defense Program Overview Investor Day June 8, 2011

2 Safe-Harbor This presentation includes forward-looking statements and predictions, including statements about potential revenue-bearing transactions, the market potential of CBLI s technologies and product candidates, and the potential value of pipeline products. These statements represent the Company s judgment as of the date of this presentation and are subject to risks and uncertainties that could cause actual results of events to differ materially from those expressed in such forward-looking statements. In particular, CBLI faces risks and uncertainties that it may not be able to sustain its business model, that revenues may be lower or expenses higher than projected, that product sales may not increase, that development of product candidates in the Company s pipeline may not succeed or that commercial transactions may not go forward as planned. 2

3 Mission CBLI develops drugs against major unmet biodefense and medical needs Countermeasures against lethal radiation exposure Supportive care drugs against side effects of radiotherapy and chemotherapy of cancer Novel anticancer therapies 3 3

4 Strategic Advantages Unique drug lead & technology portfolio Paradigm-shifting innovative drug development and treatment concepts Advanced leads of Protectan and Curaxin classes Accelerated drug development path Radiation biodefense countermeasures FDA animal efficacy rule Advanced stage of development Oncology market Alliance with leading partners 4 4

5 Leading Biodefense Drug Landscape Increasingly high risk of nuclear disaster Terrorist attack 10KT nuclear device estimated to cause up to 400,000 casualties if exploded in Manhattan Nuclear stations Fukushima: nuclear industry forced to recognize a need for drugs dealing with consequences of nuclear accidents Lack of approved countermeasures Growing pressure on governments Need for today is higher than yesterday uniquely positioned to become a critical element in defense against such accidents 5

6 Leading Biodefense Drug Competitive Advantages remains strongest radiation countermeasure Lack of reports on comparably powerful drugs Growing information on outstanding efficacy in primates Furthest advancement along the Animal Rule path Established large-scale production line Outstanding stability Streamlined accelerated FDA process Recognition of advantages by government agencies Rapid development process facilitated by top quality regulatory team Clear shortlist of remaining steps 6

7 From June 2010 to June 2011 Critical steps forward Accelerated regulatory approval process FDA s Fast Track drug status for FDA s Orphan Drug status for Reduced number of remaining tasks in preclinical program Completion of reproductive toxicity studies Completion of second human trial for in radioprotection 100 subjects / zoom on projected efficacious dose Material for strengthening choice of biomarkers Strong foundation for dose conversion Strengthened regulatory and clinical development team EVP Regulatory Affairs and Quality Assurance (Dr. Ann Hards) with outstanding credentials Strategic Regulatory Consultant (Dr. Ray Lipicky) with 21 year history at FDA Strategic Regulatory Consultant (Dr. Thomas Fleming) FDA and NIH advisor on aspects of animal rule and clinical trial design 7 7

8 From June 2010 to June 2011 Strengthening IP Protection New US patents granted Composition of matter for and CBLB612 /612 patents granted in major markets European Patent Organization (EPO), Eurasian Patent Organization (EAPO), China, Japan, New Zealand, Australia, and others New applications covering fresh discoveries 8 8

9 From June 2010 to June 2011 Funding Critical Path $45 million development and conditional purchase contract from Dept. of Defense for recognition of leading position $1.6 million grant from DTRA for Extension of Grand Opportunities grant from NIH: second tranche of $5.3M total 9 9

10 Continuous Successful Pursuit of Non-dilutive Funding GRANT/CONTRACT TITLE AMOUNT DATES DoD /DTRA, Med. Chem. & Biol. Defense Res. Program DoD/CBMS-JPEO Chemical Biological Medical Systems Joint Project Mgt. Radioprotective Mechanisms of BAA Advanced Development of a Medical Radiation Countermeasure $1,300,000 3/07-3/10 $10,340,000 3/08-10/09 NIAID (NIH) BioShield Program BARDA (HHS) BioShield Program mitigation of radiation induced thrombocytopenia BAA Development of of mitigation of HP syndrome $1,230,000 9/08-3/10 $15,800,000 9/08-10/10 NIH/NIAID Grand Opportunities (GO) Grant Protectan $5,300,000 9/09-9/11 DoD/CBMS-JPEO Chemical Biological Medical Systems Joint Project Mgt. RFP W9113M-09-R-0010 Advanced Development of a Medical Radiation Countermeasure $45,000,000 (15,000, ,000,000) 9/10-9/13 DoD /DTRA, Med. Chem. & Biol. Defense Res. Program Radioprotective Mechanisms of Several pending proposals >$50,000,000 $1,589,106 1/11-4/12 Expected

11 Major Funding Opportunity for -Defense BARDA History of partnership: September 2008: BARDA awarded CBLI a contract "Therapies for Hematopoietic Syndrome, Bone Marrow Stromal Cell Loss, and Vascular Injury Resulting from Acute Exposure to Ionizing Radiation" covering: Performing selected preclinical experiments with non-human primates Performing stability studies of the GMP-grade Conducting 50-subject healthy volunteer trial Planning, initiating and overseeing 100-subjects dose validation trial on healthy volunteers and drafting and finalizing the clinical report and submitting such reports to the BARDA and the FDA Starting total contract value was $13.3M September 2009: BARDA increased the total contract value adding $2.3 million, the maximum allowed for non-competitive increase CBLI successfully completed all tasks related to this contract by February 15, 2011, 6 months ahead of schedule Since 2010, CBLI and BARDA have been negotiating a new contract to fund the remaining steps of the developmental program May 2011: BARDA requested coordination of development program with FDA as a condition for further contract negotiations 11 11

12 Major Funding Opportunity for -Defense BARDA Path to Contract: Meet with FDA to receive input on development path Update BARDA proposal and resubmit BARDA review and award determination 12 12

13 -Biodefense on Path to Approval Remaining Tasks Completed GMP process developed and tested, drug suitable for clinical trials released Data from ~1,000 primates demonstrates dramatic survival benefits and accelerated recovery CMC Efficacy Remaining steps Additional consistency runs Pivotal animal studies Human safety Two trials: 50-subject dose-escalation and 100- subject study completed Open IND, Fast Track Status, Orphan Drug Status FDA process Definitive safety study Coordinating study protocols, BLA submission 13

14 Scientific and Clinical Program Goals Support Animal Rule-driven development of for biodefense applications Mechanism of action studies: rational choice of biomarkers Defining efficacy range Determination and validation of human dose Moving to oncology clinic Radiotherapy adjuvant (local irradiation models) Chemotherapy adjuvant Effect on tumors 14

15 Biodefense 15 15

16 as Medical Radiation Countermeasure Origin & Mechanism of Action Derivative of a protein of bacterial origin (flagellin) modified to reduce immunogenicity and toxicity and improve production Acts through mobilization of multiple mechanisms all mediated by activation of pro-survival NF-kB signaling pathway selectively protects normal tissues (but not malignant tumors) from radiation Increases survival of stem cells and early progenitors of hematopoietic system and stimulated regeneration of different HP lineages Reduces radiation damage to and stimulate regeneration of crypts, villi and lamina propria of GI tract 16

17 Development of towards Approval as Countermeasure via FDA s Animal Rule Drug candidates, efficacy of which cannot be directly tested in humans due to ethical reasons, are developed according to Animal Rule: Efficacy in animal models that mimic human disease Human safety Well understood mechanism of action to justify selection of objective indicators (biomarkers) in humans 17

18 Survival (%), n=40 is efficacious in mice and monkeys in protecting and mitigating regimens NHPs Mice animal survival, % % of survivors NIH Swiss Survival mice, of rhesus 13 Gy monkeys of total after body 6.5 irradiation Gy -TBI (n=50) protection amifostin (n=13*) AED (n=5) saline (n=25) 20 Vehicle (N=8) at -45' 0, 0.04 mg/kg (N=11) at -45' time after irradiation, days Days after irradiation 27 studies with non-human primates; >180 studies (with multiple strains of mice, types of irradiation, survival, HP, GI and other endpoints) NHPs protection 120 protection Survival of rhesus monkeys after 6.5 Gy -TBI mitigation % of survivors mitigation =37% Gy, + 16h, PBS/Tween Gy, + 16h, PBS/Tween Gy, + 16h, vehicle (PBS), 40 µg/kg n= Gy, + 16h, µg/kg +16h, n=12 =25% +25h, n= h, n= Days 20 after TBI Days after 6.5 Gy gamma-tbi 100 mitigation % of survivors Vehicle (N=8) at -45', 0.04 mg/kg (N=11) at -45' Days after irradiation % of survivors vehicle (PBS), +16h, +25h, +48h, n= Days after 6.5 Gy gamma-tbi 18

19 Methodological Foundation for Radiation Studies final setup door closing anesthesia shielding adjustment monitoring 19

20 Methodological Foundation for Radiation Studies anesthesia shielding irradiator preparation Establishment of mouse model of TBI(S): four mice irradiated (x-ray) simultaneously under isoflurane anesthesia; ~5% BM shielded 20

21 Summary of Efficacy Features in NHPs 27 studies with total of 905 non-human primates Species: rhesus monkey, Macaca mulatta (best-studied primate model in ARS); both sexes, young adults Doses of radiation tested: from LD 10/40 to LD 75/40 TBI in survival studies and LD TBI in GI morphology studies Efficacious times of treatment: at least from -45 to >48 hours (treatment at 120 hours is not efficacious) Efficacious doses of : >=10 ug/kg is efficacious at all time points and radiation doses tested, 3 ug/kg was determined as EC50 treatment increases survival (by up to 40-45%); reduces severity and duration of thrombocytopenia; reduces severity of neutropenia; reduces morphological damage in BM, GI tract, spleen, thymus and lymph nodes 21

22 Summary of Efficacy Features in Mice >180 studies (with multiple strains of mice, different ages, types of irradiation, survival, HP, GI and other endpoints) Species: house mouse, Mus musculus (best-studied mammalian model in radiation-related studies); both sexes, young adults, multiple strains (ICR, NIH- Swiss, Balb/c, CD2F1, etc.) Doses of radiation tested: from LD 20/30 to >LD /30 TBI Efficacious times of treatment: efficacy from -24 to +25 hrs relative to TBI Efficacious doses of : >~20 ug/kg is efficacious at all time points and radiation doses tested, ~10 ug/kg was determined as EC50 treatment increases survival and reduces morphological damage in BM and GI tract 22

23 Strategy for Approaching FDA licensure and Satisfying Stakeholders Requirements Label Indication: For treatment as a single agent to reduce the risk of death following total body irradiation during or after a radiation disaster (quote from FDA Fast Track approval note) Sufficient understanding of the mechanism of action for well-justified selection of efficacy biomarkers applicable to humans Safety, PK and PD assessment trial in human healthy volunteers to determine projected human efficacious dose, characterization of side effects and limitations in drug application to humans. HP-specific requirements: Efficacy in relevant animal models (mice and NHP justified as best models) with supporting care (antibiotics and nutrients) and radiation lethality dose range 30-70% GI-specific requirements: Efficacy in relevant animal models (mice and NHP) with high TBI dose sufficient to induce pure GI damage Histopathological evidence of GI damage and improving GI morphology following total body irradiation 23

24 Mitigating efficacy of against GI manifestation of acute radiation syndrome in primates (Rhesus macaques) that received extremely high radiation doses Small intestine, day 7 after 11 Gy TBI vehicle 24

25 Functional indication (DNA replication) of improved crypt regeneration in jejunum of -treated animals NHP, 11 Gy TBI 25

26 Morphological indications of crypt regeneration in colon of -treated animals NHP, 11 Gy TBI, day 7 vehicle 26

27 Blind assessment of pathological changes in different divisions of GI tract using cumulative scores Cumulative damage 20 bad 18 Severity of damage vehicle Duod Duod E Jejun Jejun E Ileum Ileum E Cecum Cecum E AscCol AscCol E TrCol TrCol E DesCol DesCol E Rec Rec E Divisions of GI tract good 27

28 Blind assessment of pathological changes in different components of duodenum Duodenum 3.6 bad Severity score SRFE=surface epithelium 2.2 VILLI=villi 2.0 LP=lamina propria 1.8 CRYPTS=crypts vehicle SRFE-c SRFE-e VILLI C VILLI E LP C LP E CRYPTS C GI tissue components CRYPTS E MALT C MALT E good MALT=mucosa-associated lymphoid tissue 28

29 Why Bother About Mechanism? To optimize treatment To define biomarkers for determination of human efficacious dose To predict, explain and overcome limitations and adverse effects To reveal new applications To identify new products (endogenous mediators) Understanding mechanisms is essential for approval via Animal Rule. It reduces scientific and business risks and broadens scope and efficiency of applications. 29

30 : Mechanism of Action TLR5 NF-kB IAPs, Bcl-2 SOD2, ferritin Cytokines Suppress apoptosis Inactivate ROS Promote regeneration Preserved tissue integrity, reduced hematopoietic and GI morbidities, increased anti-infective immunity Survival Burdelya et al., 2008 Science. 236: Mechanism is manifold, well understood and exerted through activation of a pro-survival NF-kB pathway 30

31 TLR5 NF-kB IAPs, Bcl-2 SOD2, ferritin Cytokines Suppress apoptosis Inactivate ROS Promote regeneration Reduced HP and GI morbidities Survival is structurally optimized flagellin, a TLR5 agonist 50 times less immunogenic than flagellin Retains TLR5 activating capacity and outstanding stability of flagellin Optimized for large-scale cgmp production 31

32 TLR5 NF-kB IAPs, Bcl-2 SOD2, ferritin Cytokines Suppress apoptosis Inactivate ROS Promote regeneration Reduced HP and GI morbidities Survival No protection without TLR5 in mice No response to of PBMC from TLR5-deficient humans No cytokine response in TLR5-deficient healthy volunteer 32

33 Live mice, % TLR5 NFkB NF-kB IAPs, Bcl-2 SOD2, ferritin Cytokines Suppress apoptosis Inactivate ROS Promote regeneration Reduced HP and GI morbidities Survival NF- kb activation in 293 -TLR5-lacZ reporter cells 1.8 b- galactosidase units AA 1-170A 1-129A ~ 1-170B B B ng/ml , mg B, A, A, 1 Survival after 13 Gy TBI Days Correlation between NF-kB activation and radioprotective efficacy of flagellin variants 33

34 Pg/ml Pg/ml TLR5 NF-kB IAP, IAPs, BCL2 Bcl-2 SOD2, ferritin Cytokines Suppress apoptosis Inactivate ROS Promote regeneration Reduced HP and GI morbidities Survival G-CSF IL ug/kg 3 ug/kg 10 ug/kg 40 ug/kg 100 ug/kg 200 ug/kg Hours after TBI ug/kg 3 ug/kg 10 ug/kg 40 ug/kg 100 ug/kg 200 ug/kg Hours after TBI Dose-dependent induction of cytokines stimulating granulopoiesis (G-CSF) or thrombopoiesis (IL-6) in -treated NHPs 34

35 TLR5 NF-kB IAP, IAPs, BCL2 Bcl-2 SOD2, ferritin Cytokines Suppress apoptosis Inactivate ROS Promote regeneration Reduced HP and GI morbidities Survival SOD2-positive cells (Bright green) in lamina propria (white arrows) and epithelium (white arrowheads) counterstained with DAPI (Blue). Red - smooth muscle actin (stromal myofibroblasts) treatment induces expression of a strong natural antioxidant SOD2 in epithelium & lamina propria of small intestine in irradiated NHPs and mice 35

36 TLR5 NF-kB IAP, IAPs, BCL2 Bcl-2 SOD2, ferritin Cytokines Suppress apoptosis Inactivate ROS Promote regeneration Reduced HP and GI morbidities Survival Genes induced by at transcription level in liver GENE -30min -2hs Antiapoptotic Antimicrobial IRF IER BCL2A1B BCL2A1D SERPINA3G SERPINA3H HAMP S100A S100A S100A SAA SAA Bcl2A1B Bcl2A1D GAPDH u/t min hr Global gene expression profiling reveals activation of numerous genes involved in controlling survival 36

37 TLR5 NF-kB IAPs, Bcl-2 SOD2, ferritin Cytokines Suppress apoptosis Inactivate ROS Promote regeneration Reduced HP and GI morbidities Survival Green apoptotic cells Reduced apoptosis in the GI tract of irradiated NHPs treated with 1 hr after TBI leads to preservation of cells critical for regeneration 11 Gy TBI + vehicle 11 Gy TBI + Massive regeneration of crypts (day 7 post-tbi) in the small intestine of NHP treated with 4 hr after TBI 37

38 TLR5 NF-kB IAPs, Bcl-2 SOD2, ferritin Cytokines Suppress apoptosis Inactivate ROS Promote regeneration Reduced HP and GI morbidities Survival Accelerated BM regeneration in lethally-irradiated mice treated with at 25 hrs after irradiation day 3 day 7 day 14 day 28 day 56 after TBI vehicle Increased number of thrombopoietic colony-forming cells (CFU-MK) in the bone marrow of rhesus monkeys treated with at 25 hrs after 6.75 Gy total body irradiation (d40 after TBI) vehicle 10mg/kg 40mg/kg 38

39 TLR5 NF-kB IAPs, Bcl-2 SOD2, ferritin Cytokines Suppress apoptosis Inactivate ROS Promote regeneration Reduced HP and GI morbidities Survival treatment reduces severity and duration of cytopenias (within mortality period, D6-D29) (dotted line: clinical, dashed: severe cytopenia) PLT<20: days shorter; % of cytopenic days on D6-D29: 22-30% lower NEU<0.5: 0-2 days shorter; % of cytopenic days: 23-28% lower 1000 Platelets (10 9 /L) of monkeys after 6.5 Gy TBI Neutrophils (10 9 /L) of monkeys after 6.5 Gy TBI hr Days relative to irradiation 48hr Days relative to irradiation 39

40 TLR5 NF-kB IAPs, Bcl-2 SOD2, ferritin Cytokines Suppress apoptosis Inactivate ROS Promote regeneration Reduced HP and GI morbidities Survival provides survival benefit to irradiated mice and monkeys in protecting and mitigating regimens Survival (%), n=40 Mice NHPs animal survival, % NIH Swiss mice, 13 Gy of total body irradiation protection 100 (n=50) 5-AED (n=5) 120 saline (n=25) time after irradiation, days amifostin (n=13*) protection 100 Survival of rhesus monkeys after 6.5 Gy -TBI mitigation Days after TBI 100 mitigation =37% 7.5 Gy, + 16h, PBS/Tween80 8 Gy, + 16h, PBS/Tween Gy, + 16h, 40 µg/kg 8 Gy, + 16h, 40 µg/kg =25% % of survivors Vehicle (N=8) at -45', 0.04 mg/kg (N=11) at -45' Days after irradiation % of survivors vehicle (PBS), +16h, +25h, +48h, n= Days after 6.5 Gy gamma-tbi 40

41 Mechanism of Action TLR5 NF-kB IAPs, Bcl-2 SOD2, ferritin Cytokines Suppress apoptosis Inactivate ROS Promote regeneration Preserved tissue integrity, reduced hematopoietic and GI morbidities, increased anti-infective immunity IL8/KC ROS SOD2 Neutrophils Thrombocytes Human Safety G-CSF HSCs NF-kappaB GI-SCs IL6 Survival Human PK Animal PK Human Efficacious Dose Human Biomarkers Animal Biomarkers Apoptosis survival mediators pathology mediators projected biomarkers Animal Efficacy 41

42 Completed Human Safety Studies Escalating dose Phase Ia: Cohorts of 6 healthy volunteers Safety Pharmacokinetics Biomarkers Immunogenicity TLR5 genotyping Dose Validation Phase Ib: Safety of mg doses in 100 healthy volunteers Incorporate limited repeat-dose arm Confirm Safety/PK/Biomarkers Dose selection for Phase II safety trial CNS Comprehensive Phase One (Miramar, Florida, USA) Experience: 14 years Number of beds: 120 State-of-the-art 46,000 sq. ft. No 483 s Completed. 50 subjects received from 2 to 50 mg of i.m. Completed. Study report in review Both clinical studies supported by BARDA 42

43 Biomarkers in Humans Neutrophils IL8/KC ROS SOD2 Thrombocytes IL-8 G-CSF NF-kappaB IL6 HSCs GI-SCs Apoptosis survival mediators pathology mediators projected biomarkers IL-6 G-CSF All markers respond to in a dose dependent manner 43

44 Estimation of Human Dose Based on G-CSF Response human Rhesus macaque Projected human dose Projected full efficacious dose in NHP 44

45 Human Trial Program Summary Total of 150 human volunteers received a range of doses of Dose limiting toxicity defined (severity of flu-like syndrome) Adverse event profile is predictable and directly related to the mechanism of action of Methodology established to determine projected human efficacious dose (based on biomarkers) All biomarkers project similar human dose Collected information enables to start of definitive safety/dose validation trial in healthy volunteers for defense 45

46 CMC Update Studies completed in Q

47 Bulk Drug Substance and Frozen Liquid Drug Product Re-engineered variant of FliC flagellin 329 amino acids (MW=35KDa) His6 tag at the N terminus end Has no cysteine residues; estimated pi is 5.26 Produced in an E. coli as an intracellular soluble protein using expression plasmid High-yield cgmp manuf. process (SynCo Bio Partners, Amsterdam, Netherlands) - Several hundred thousand doses (25-30g of BDS) per single cgmp manufacturing run - Three cgmp batches *Lot #s 07COF02 (July 07), 09COR01 (Feb 09), and 10COF02 (Apr 10)+ and four non-gmp batches run at large scale (1,100 L) - More than 50g of BDS is still available - SynCo was inspected by BARDA RQA Division in July 09 and all of their recommendations have been implemented as of Dec 10 The cgmp drug product (frozen liquid formulation in PBS) was used in Phase 1a & 1b clinical trials and all preclinical studies - 7,000 vials released in Aug 07 (4,500 vials are still available) 47

48 : Lyophilized Drug Product (Lyo DP) Lyophilized Drug Product Formulation: Optimized Lyo DP formulation; single dose vial mM Histidine, 2% Glycine, 1% Trehalose, 0.01% Polysorbate 80 (Tween 80) - Stable for at least 9 months up to 40 o C (as of Nov 2010) - Manufactured by Integrity Bio (Camarillo, CA) - ~4,000 vials per batch capacity Development and cgmp Batches Non-GMP: 100 mg and 2 mg per vial in Nov 08 and 30 mg/ml in June 09 cgmp: 100 mg/ml in Feb 10 and 40 mg/ml in Apr 10 (1,800 vials is available from each batch) Remaining tasks: Demonstrate extended stability of cgmp Lyo DP Complete of remaining assay validation Demonstrate bioequivalence of Lyo DP formulation Scale-up and large scale Lyo DP manufacturing, including process validation Address potential comments from FDA related to Lyo FDP 48

49 as Medical Countermeasure (MRC) against ARS Highly efficacious as a single dose Increases survival of irradiated primates from 20 to >70% Significantly reduces incapacitation of survivors Protects/treats both GI and HP components of acute radiation syndrome Broad application time window From prior (24 hr) to & post (>48 hr) exposure to IR Ease of use Single intramuscular injection suitable for self- or hospital administration Stable Established high-yield cgmp manufacturing process Safety profile defined Completed two Phase I safety trials in total of 150 healthy volunteers Defining human dose Mechanism of action is well understood Biomarkers selected and justified 49