CBLB502 Medical and Curaxins Overview Investor Day June 8, 2011

Transcription

1 CBLB502 Medical and Curaxins 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 Scientific and Clinical Program Goals Support Animal Rule-driven development of CBLB502 for biodefense applications Mechanism of action studies: rational choice of biomarkers Defining CBLB502 efficacy range Determination and validation of human dose Moving CBLB502 to oncology clinic Radiotherapy adjuvant (local irradiation models) Chemotherapy adjuvant Effect on tumors 3

4 CBLB502 in Preclinical Model of Local Irradiation Goal: Head and neck irradiation model in mice Justification of use of CBLB502 as a supporting care radioprotection adjuvant Results: CBLB502 is efficacious against radiationinduced mucositis and dermatitis Significance: Strong preclinical support of use of CBLB502 as radiotherapy adjuvant Justification of new application (protection from radiation-induced dermatitis) Toll-like Receptor 5 Agonist Protects Mice from Dermatitis and Oral Mucositis Caused by Local Radiation: Implications for Head and Neck Cancer Radiotherapy. (Int. J. Rad. Onc. Biol. Phys., in press) Approval of CBLB502 as supportive care trial protocol in head and neck cancer patients by Scientific Review Committee of Roswell Park 4

5 Extending Indications of CBLB502 Mitigation of chemotherapy side effects and direct anticancer action Irinotecan and CBLB502 against Wart colon tumors in Fisher rats Antitumor activity and toxicity of Irinotecan ± CBLB502 Indivadual rat bearing advanced Ward colorectal carcinoma Irinotecan rats bearingadvanced daily x3, 200 mg/kg Ward colorectal i.v. +/- CBLB502 carcinoma response to CBLB502, 0.2 x3 mg/kg/day daily, 0.2 by mg/kg i.p. daily x "Antitumor Activity" 5000 placebo 5000 "Antitumor Activity" Mean Tumor Weight (mg) Mean Body Weight (%) Irinitecan alone CBLB mg/kg(3) + Irinotecan 200 mg/kg (all dead from GI Irinotecan toxicity) 200 mg/kg + CBLB mg/kg "Toxicity" 100 interference with its antitumor CBLB502 displays both supportive care and direct antitumor activities in rat model of colon cancer 80 Irinitecan+CBLB502 Control CBLB mg/kg x 5 Irinotecan 200 mg/kg x 3 CBLB mg/kg(5) + Irinotecan 200 mg/kg CBLB502 rescues animals from 105 Irinotecan toxicity with no activity Time (Days) Mean Tumor Weight (mg) Mean Body Weight (%) "Toxicity" Time (Days) Rat # 1 Rat # 2 Rat # 3 Rat # 4 CBLB502 caused complete regression of tumors in part of the animals

6 Radioprotective Effect of CBLB502 is Indirect Granulocyte colony formation in vitro by mouse BM cells irradiated CBLB502 in vivo CBLB502 in vitro 6

7 Luciferase fold induction Histological Atlas of CBLB502 Activity Identification of Target Organs NFkB reporter mice vehicle CBLB502 liver control CBLB502 NF-kB DNA NFkB reporter induction in various tissues CBLB502 LPS Liver is the primary target organ of CBLB502-5 Liver Small intestine Large intestine Kidneys Lungs Brain Spleen 7

8 Luciferase units Assessing Role of Hepatocytes in Radioprotection: surgical exclusion of liver from blood circulation Step 1. Occluding the hepatoduodenal ligament containing hepatic artery and portal vein with a non-traumatic clamp. Step 2. CBLB502/PBS injections. Step 3. The blood supply occluded for 30 minutes then clamp released and blood circulation restored Balb/C-Tg(IkBa-luc)Xen mice NF-kB activation in livers No surgery Liver isolation Step 4. Mice were irradiated immediately after the surgery with 10 Gy TBI. Step 5. Bone marrow cells isolated from femura and total colony formation estimated using MethoCult media and standard protocol for CFU assay Intact CBLB502 PBS PBS CBLB502 CBLB502

9 Colony Colony number/ number 5x10 4 BMCs No liver = No radioprotection of bone marrow Step 1. Occluding the hepatoduodenal ligament containing hepatic artery and portal vein with a non-traumatic clamp. Step 2. CBLB502/PBS injections BMC-CFU BMC-CFU No surgery No surgery Liver isolation Liver isolation Step 3. The blood supply occluded for 30 minutes then clamp released and blood circulation restored Step 4. Mice were irradiated immediately after the surgery with 10 Gy TBI Step 5. Bone marrow cells isolated from femura and total colony formation estimated using MethoCult media and standard protocol for CFU assay. Liver is the source of endogenous HP-protecting factors mobilized by CBLB502

10 TLR5 Activation Protects Liver from Fas 10

11 Serum ALT (U/L) Animal survival (%) Caspase 3,7 activity TLR5 Agonist Protects Mice from Fas Liver condition Mouse survival Caspase activation PBS (n=16) CBLB502, 0.5 h (n=16) CBLB502, 2 hs (n=10) CBLB502, 6 hs (n=10) Days Intact Fas CBLB502 CBLB502 +Fas Liver enzymes Intact Fas CBLB502 CBLB502 +Fas 11

12 Percent survival CBLB502 control CBLB502 against liver metastases of colon cancer in mice Control (no drug) CBLB502, 5hrs post injection Intact metastase liver metastase liver Anti-Fas CBLB502 + anti-fas CT26, TLR5-negative syngeneic colon cancer, was grown as liver metastases in Balb/c mice Tumor growth was monitored using luminometer imager (tumors express luciferase) Tumor suppressive effect of CBLB502 is associated with tumor infiltration with immunocytes CT26 tumor-free mice (liver) 100 Intact, n=15 CBLB502, n=19 80 log rank p= Days 12

13 CBLB502 Direct Anti-tumor Effects of CBLB502 healthy No toxicity TLR5- tumors in liver Tumor suppression TLR5+ tumors in liver Tumor suppression TLR5+ tumors Tumor suppression TLR5- tumors No antitumor effect TLR5-negative tumors TLR5-positive tumors Identification of target tissues enables rational choice of indications and regimens Phase I/II CBLB502 as a single agent trial protocol was approved by Scientific Review Committee of Roswell Park 13

14 CBLB502 as Direct Antitumor Agent Has direct suppressive effect in several animal models of TLR5-positive tumors (lung, colon cancer, melanoma) Effective against liver metastases regardless of TLR5 status of the tumor Acts by mobilizing antitumor immunity Expected to provide anti-tumor vaccination Fits several clinical trial scenarios, including liver metastasis of colon cancer, liver cancer, bladder cancer, H&N cancer, etc. 14

15 Prospective Clinical Trials of CBLB502 in Cancer Patients Reducing severity of mucositis and enhancing efficacy of radiotherapy of H&N cancer Reducing severity of bowel toxicity and enhancing efficacy of radiotherapy of pancreatic cancer Reducing severity of diarrhea in colon cancer patients treated with Irinotecan Treating primary hepatocellular carcinoma (liver cancer) Treating liver metastasis of colon cancer Treating liver metastasis of breast cancer Pre-operational treatment of prostate cancer Many of these trials enable assessment of both supportive care and direct anti-tumor activity of CBLB502 15

16 CBLB502: Major Scientific and Clinical Updates Demonstration of CBLB502 efficacy in preclinical model of local irradiation Approval of Phase I/II CBLB502 as supportive care trial in head and neck cancer patients by Scientific Review Committee of Roswell Park Discovery of direct anticancer action of CBLB502: from supportive care only drug to combined supportive care and anticancer drug Approval of Phase I/II CBLB502 as a single agent trial by Scientific Review Committee of Roswell Park Demonstration of radiomitigating efficacy of CBLB502 against GI manifestation of acute radiation syndrome in primates that received extremely high radiation doses Critical result for justifying extended indications of CBLB502 Building of Histological Atlas of CBLB502 activity, identification of target organs Path to optimal indications and regimens Completion of Phase Ib human dose validation trial 16

17 Curaxins Anticancer drugs 17 17

18 Curaxin s Targets р53, NF-kB, HSF1 in Cancer Normal cell response to stresses infection survival death survival t 0 survival CANCER DNA damage target for activation (doxorubicin, 5FU, cisplatin, etc.) target for inhibition (bortezomib) death or arrest target for inhibition (geladanomycin)

19 Curaxins Target FACT-dependent Transcription NF-kB-dependent transcription requires FACT + Curaxin Trap of FACT on chromatin blocks FACT-dependent transcription and causes CK2-mediated p53 activation Gasparian et al., Science Translational Research, in final revision

20 Antitumor Effects of Curaxins live tumor cell dead tumor cell Curaxin activator inhibitor inhibitor Non-genotoxic anticancer drug candidates with triple mechanism of action suitable for use in combinations with conventional drugs

21 Curaxins: Safe Multi-targeted Drugs Property Genotoxicity Conventional drugs yes Curaxins no NF-kB inhibition no yes p53 activation Heat shock inhibition yes no YES yes

22 tumor-f ree animals (proportion) Curaxins in Cancer Prophylaxis 1.2 Appearance of palpable tumors in mice of different groups Control CBL137, 0.1mg/ml p=10-5 p= % reduction in breast tumor incidence in transgenic MMTV-neu mice that were maintained on drinking water with non-toxic doses of curaxin CBLC137 during 10 months 0 CBL137, 0.2mg/ml Age (weeks) Lack of genotoxicity, combined with p53 activation and NF-kB and HSF1 suppression, opens the opportunity of using Curaxins as cancer preventing agents

23 Curaxins Synthetic small molecules with proprietary structure Unique mechanism of action: simultaneously affect multiple molecular targets in cancer cell Efficacious in a broad spectrum of preclinical tumor models Mechanism of action enables additional clinical indications beyond cancer treatment (anti-inflammatory, anti-infective) First generation Curaxin CBLC102 is in clinical trial in patients with liver metastases New generation Curaxin CBLC137 is at advanced stage of preclinical development 23 23

24 Incuron JV for Curaxin Development 50/50 joint venture with Bioprocess Ventures, Moscow ~$18M to reach Phase II for new generation of Curaxins in US and Russia and conduct human trials in liver cancer in Russia for CBLC102 CBLI oversees mechanistic studies and formal development Phase Ib trial for CBLC102 in liver started October 2010 IND-enabling studies for new generation of Curaxins on track for IND Demonstrates feasibility of model combining advantages of US and Russian development platforms 24 24

25 Milestones Start of pivotal animal efficacy studies for CBLB502 defense Start of definitive safety/dose validation trial in healthy volunteers for CBLB502 defense Start of CBLB502 Phase I/II trial in head and neck cancer patients for supportive care indication Start of CBLB502 Phase I/II trial in advanced liver metastases patients for safety/antitumor effect Completion of CBLC102 trial in liver cancer patients in Russia Filing of IND for studies of new generation curaxins Top level peer reviewed publications 25 25