TransMolecular, Inc. A Neuroscience Biotechnology Company Oncology Program Chlorotoxin Technology Platform Corporate Partnering Opportunities Background TransMolecular, Inc. (TMI) is a neuroscience biotechnology company committed to discovering, developing and commercializing novel and proprietary drugs to diagnose and treat diseases of the central nervous system and related tissues having inadequate pharmaceutical alternatives. The Company focuses its drug development on cancer and pain, and has built strong technology platforms to enrich its product discovery and development pipeline. Founded in July 1996, TMI is privately held and venture capital backed, having raised $9.6MM to date through two private placements from internationally recognized investment firms. The Company s peptide-based technology platform for cancer uses a safe, synthetic version of a scorpionderived peptide toxin, known as chlorotoxin. TransMolecular is developing a number of anti-cancer compounds, pharmacologic adjuvants, imaging agents, and diagnostic test kits based on chlorotoxin sequences that are in various stages of research and development. The use of chlorotoxin sequences in the treatment, imaging, and diagnosis of primary (glioma) and metastatic brain cancer and a number of other solid tumors (e.g., melanoma, lung, prostate, colon, and breast cancers, etc.) is not only novel, but is based on strong supporting scientific data. The Company's lead compound ( 131 I-TM-61) is a radiopharmaceutical and its first indication in humans is recurrent glioma. 131 I-TM-61 has shown significant capacity to increase survival in human xenograft brain tumor mouse models and to image brain tumors in vivo. The FDA approved the Company s first IND for a Phase I/II clinical trial for adult high-grade glioma. This Phase I/II clinical trial is currently open for enrollment at multiple sites and will be completed in 23. The FDA has also granted the Company Orphan Drug Designation for use of 131 I-TM-61 in glioma. Additional clinical trials expanding the clinical development of our oncology products are planned for 23 and beyond. The Company believes its oncology product pipeline based on chlorotoxin sequences will revolutionize the way adjuvant therapy is delivered to cancer patients and how the disease is managed.
Chlorotoxin Technology Platform Chlorotoxin peptide sequences form the basis for our cancer technology platform (Figure 1). The biology of chlorotoxin peptide sequences and binding to its receptor have been studied in great detail by the Company. Chlorotoxin is a very small, stable, non-immunogenic and versatile peptide that is able to cross blood brain and tissue barriers. It can be chemically linked to known anti-cancer agents, producing a new class of potent anti-cancer drugs with high selectivity for tumor cells (Table 1). Chlorotoxin specifically seeks out and binds to its target -- a receptor selectively expressed on tumor cells, but not found on normal cells -- very effectively delivering its therapeutic payload only to targeted tumor cells and killing them by a process called molecular surgery. Beyond chlorotoxin s ability to specifically and efficiently deliver therapeutic payloads to the tumor, it also has properties of a pharmacologic adjuvant. In pre-clinical tissue culture and animal tumor model studies, chlorotoxin has also been shown to enhance the sensitivity of tumor cells to the killing effects of many commonly used anti-cancer drugs when they are co-administered with chlorotoxin. TMI APPROACH: Molecular Targeting of the Chlorotoxin Receptor with Peptide Drugs Based on Chlorotoxin Sequences Leiurus quinquestriatus Met-Cys-Met-Pro-Cys-Phe- Thr-Thr-Asp-His-Gln-Met- Ala-Arg-Lys-Cys-Asp-Asp- Cys-Cys-Gly-Gly-Lys-Gly- Arg-Gly-Lys-Cys-Tyr-Gly- Pro-Gln-Cys-Leu-Cys-Arg Chlorotoxin (ClTX ( ClTX) 36 Amino Acid Peptide Obtained from Venom Chemically Synthesized Highly Toxic to Insects Non-Toxic to Mammals Selective Binding to ClTX-R Figure 1. Chlorotoxin Sequences. Chlorotoxin was originally identified in and isolated from the venom of Leiurus quinquestriatus, the giant yellow Israeli scorpion. Its amino acid composition and structure are well understood. Proprietary molecular clones to produce recombinant proteins have also been made by the Company. TABLE 1: Why Use Chlorotoxin Sequences in Oncology Products Small stable peptide (4, MW) Non-toxic in pre-clinical studies Highly diffusible in tissues Cross blood-brain barrier Specifically binds tumor cells Binding is long lasting Can be chemically modified Non-immunogenic Multiple dosing feasible Pharmacological adjuvancy GMP manufacturing scalable Superior cost of goods Highly Specific Drug Discovery and Delivery Technology Platform 2
TMI s Chlorotoxin-Based Oncology Product Development Strategy While TransMolecular is focused on developing brain cancer products, the Company s products for cancer based on its chlorotoxin technology platform are broadly applicable to many solid tumors (Figure 2). Data for specific binding to a variety of solid tumors has come from established tissue cultured tumor cell lines and histochemical staining of human biopsies (Table 2). Drug efficacy studies with human glioma tumors established in in vivo animal models also supports its application to many solid human tumor types. Brain Cancer Primary Brain Cancer Metastatic Brain Cancer Chlorotoxin Scorpion Toxin-Based Peptide Drug Delivery Platform Glioma Rx Neuroectodermal Tumors Melanoma Small Cell Lung Carcinoma Neuroblastoma Medulloblastoma Ewing s Sarcoma Pheochromocytoma Other Tumor Types Figure 2. TMI s Chlorotoxin-based Oncology Product Development Strategy. The Company will focus initially on brain cancer, including primary and metastatic tumors. Chlorotoxin-based products are also applicable to a broader range of solid tumors, including the closely related neuroectodermal tumors, as well as tumors such as breast, non-small cell lung, and prostate cancers, which have much larger markets. TABLE 2: Cell lines and Human Biopsies Positive for Chlorotoxin Binding Biopsies No. Positive/No. Tested Percent Positive Primary Brain Tumors 88/95 92.6 Metastatic Brain Tumors 15/17 88.2 Peripheral Neuroectodermal Tumors 45/48 93.8 Other Non-tumor, Normal Human Tissues /39. Tumor Cell Lines No. Positive/No. Tested Percent Positive Human Glioma 6/6 1. Rat and Mouse Glioma 3/3 1. Human Non-small Cell Lung 2/2 1. Human Small Cell Lung 2/2 1. Human Breast 4/4 1. Human Prostate 3/3 1. Human Melanoma 2/2 1. Human Colon 2/2 1. Normal Human Fibroblast /2. Normal Mouse Fibroblast /2. 3
The Company will focus on brain cancer therapy and imaging with its initial products and clinical trials. The use of chlorotoxin-based products with other human solid tumors are in pre-clinical development. Additional clinical trials to extend the utility of and indications for the Company s chlorotoxin technology platform with other solid tumors are planned for 23. Diagnostic kits, phenotyping services, and integrated manufacturing and delivery are also part of the product and service development plan for 23 and beyond. Oncology Product Pipeline Based on Chlorotoxin Sequences TMI s chlorotoxin-based product pipeline (Figure 3) contains several unique analogs and derivatives, which have been designed specifically for use in therapy, diagnostics, and imaging when coupled with radiological, chemical, or toxin payloads and for use as pharmacologic adjuvants with established anticancer agents, either through coadministration or covalently bonded combinations. Products can be made synthetically or by recombinant DNA methods. All of the synthetic chlorotoxin pipeline products have a superior cost of goods when compared to biologicals. Oncology Products Therapeutics for Brain and Other Cancers In Vivo Imaging Agents Diagnostic Test Kits MD/Patient Support Services TM-61 TM-62 TM-64 TM-71 TM-81 TM-91 TM-92 TM-11 TM-12 Development Status Research Preclinical Clinical PI/II Figure 3. Chlorotoxin Oncololgy Product Pipeline. TransMolecular is using a franchise approach for brain cancer. The Company intends to provide the leading therapeutic, in vivo imaging agents, and diagnostic test kits as well as to provide integrated manufacturing and MD/patient support services. The Company s oncology pipeline is more broadly applicable to other solid tumors. TM-61. TM-61 is the furthest along in the development pipeline. The Company's lead compound, 131 I-TM-61, is a radiopharmaceutical based on TM-61 sequences derivatized with a radioisotope of iodine ( 131 I) of known therapeutic value. 131 I-TM-61 has shown significant capacity to increase survival in human xenograft brain tumor mouse models and to image brain tumors in vivo (see Figures 4 and 5 below). TM-61 has demonstrated a number of properties which significantly support its strong potential as a viable tumor targeting agent as well as an adjuvant to enhance the activity of other anti-cancer therapies. TM-62. TM-62 is a biotinylated derivative of chlorotoxin that is being used to create phenotyping and histologic staining kits. TM-62 is in the research phase of development. TM-64. TM-64 is a recombinant derivative of TM-61 fused to a potent bacterial toxin for use as a targeted therapeutic agent and is in the research phase of development. TM-71. TM-71 is a derivative of chlorotoxin sequences which when used in combination with potent anti-cancer agents can also increase the sensitivity of tumor cells to the cell killing effects of these drugs. The pharmacologic adjuvancy of TM-71 has been studied with a number of anti-cancer agents in in vitro and in vivo models. These anticancer agents are currently being used to treat a broad range of cancers; some of these drugs are important to pharmaceutical company franchises. TM-71 has the potential to impact the use of many of these drugs. TM-71 is in the pre-clinical phase of development. 4
TM-81. Additional new agents that facilitate both in vivo imaging and therapy are also under development. TM-81 is a novel derivative of chlorotoxin that permits a one-step, extremely stable coupling of radioactive elements commonly used in in vivo imaging and therapy of tumors. Proof-of-principle with a number of commonly used isotopes (e.g., 177 Lu, 187 Rh, and 111 In) has already been performed. TM-81 is in pre-clinical phase of development. TM-91 and TM-92. Increasing the potency of the payload in chlorotoxin radiotherapeutics and diagnostics has been achieved by modifying chlorotoxin sequences to permit incremental concentrations of radiation to be attached (2- to 3-fold, respectively). TM-91 and TM-92 are in the research phase of development. TM-11 and 12. Select sequences have been identified and synthesized that segregate the functional binding domains and biology of chlorotoxin sequences in analogs and derivatives. TM-11 and TM-12 are in the research phase of development. Lead Program Brain Cancer TM-61 is the most advanced of TransMolecular s several anti-cancer compounds in R&D. Radioactive iodine ( 131 I) has been coupled to TM-61 creating a potent radiopharmaceutical, 131 I-TM-61, that is the company s lead compound. When 131 I-TM-61 binds its target on the tumor cell, it delivers a potent radioactive payload over several days, specifically killing tumor cells as they enter stages of the cell cycle sensitive to DNA damage. 131 I-TM-61 has shown significant capacity in multiple studies to increase survival (169-27%) in human xenograft brain tumor mouse models (Figure 4). It is also useful in imaging brain tumors in vivo (see Figure 5 below). Kaplan-Meier Survival Chart 1 Percent Survival 75 5 25 Median Survival 21 Days 78 Days TM-61 131 I-TM-61 29 Days Saline 2 4 6 8 Days Post Implantation Figure 4. 131 I-TM-61 exends survival in human xenograft mouse model. Mice were implanted with intracranially xenografted human glioma brain tumors. Animals were treated with either 131 I-TM-61, non-radiolabeled TM-61, or saline. Median survival was measured. 131 I-TM-61 treatment extended survival in this study 169%, and approximately half of the animals were alive at the study end. The Company successfully pursued its pre-clinical drug development program for 131 I-TM-61, carrying the product from manufacturing to an FDA approval of the Company s first IND for a Phase I/II clinical trial for high-grade glioma in less than 12 months. Our Phase I/II clinical trial to treat 18 adults (three dosing panels) with recurrent high-grade glioma with 131 I-TM-61 by the intracavitary route is open for enrollment at multiple sites and will be completed in 23. The FDA has also granted the Company Orphan Drug Designation for 131 I-TM-61 and the Company has requested Fast Track Development. The Company will expand its clinical development of TM-61 products to metastatic brain cancers and other cancers as the next step in the development process. Radio-lmaging Program TMI s lead synthetic chlorotoxin peptide sequence, TM-61, has been studied extensively in vitro. Several lines of study support the use of chlorotoxin derivatives and analogues in radio-imaging. TM-61 binding to its receptor on the tumor cell surface is highly specific (Table 2). The ability of TM-61 and analogues of TM-61 to the cross blood brain barrier (BBB) has been studied in vivo. The biodistribution of TM-61 when radiolabeled with 125 I has been evaluated 5
in human glioma xenograft mouse models after IV tail vein injection. The in vivo distribution of radiolabeled TM-61 was compared to radiolabeled epidermal growth factor (EGF) (Table 3). Human glioma cells have receptors for both chlorotoxin and EGF on their surface. Radiolabeled chlorotoxin localized to the tumors in brains of mice, whereas EGF did not. Morever, there was no signfiicant accumulation of radioactivity in other tissues. The fact that radiolabeled chlorotoxin can cross the blood brain barrier and locate its target at a distal site after IV injection further supports its ability to be delivered systemically. TABLE 3: Biodistribution of TM-61 after IV injection into Tail Vein of Glioma Mouse Model Peptide Human Tumor Xenoplant No. of Mice Tested No. of Animals in Which Peptide Crossed BBB and Bound Tumor 125 I-TM-61 D54 MG 1 8 No Tumor Cells 6 125 I-EGF D54 MG 6 No Tumor Cells 6 Additional gamma camera imaging studies were performed with 131 I-TM-61 which had been administered intracranially to human glioma xenoplanted mice (Figure 5). Gamma camera imaging studies demonstrated that 131 I-TM-61 was not only able to bind specifically to the tumor in the brains of mice, but the binding to tumor cells was long lasting (>96 hours). Imaging with other radioisotopes attached to chlorotoxin have produced similar results. 24 Hours 96 Hours Brain Tumor Stomach Bladder Mouse 6 Mouse 6 Brain Stomach Bladder Mouse 9 Tumor Mouse 9 Figure 5. Gamma camera imaging of 131 I-TM-61. Mouse model implanted intracranially with human glioma cells. 131 I-TM-61 was given intracranially on day 21. Gamma camera imaging performed on Day 22 and 25. 131 I-TM-61 localized to the brain tumor at 24 and 96 hours. Radioactivity was retained in brain for >96 hours. Same study mice were used in Figure 4, supporting the fact that the animals had xenografted glioma tumors. 6
Pharmacologic Adjuvancy and Systemic Delivery in the Treatment of Solid Tumors Chlorotoxin has also been shown to increase the sensitivity of tumor cells to the cytotoxic effects of a number of commonly used anti-cancer agents. The pharmacologic adjuvancy of TM-71 has been studied in vitro with a variety of tumor cell lines derived from metastatic and primary cancers, including glioma, lung cancer, breast, prostate, and melanoma. In vitro data with a human glioma cell line with five different anti-cancer agents is shown in Table 4. TABLE 4: In Vitro Pharmacologic Adjuvancy of TM-71 on Human Glioma Cells Drug Drug IC5 Drug + ClTx IC5 A 2 ug/ml 8 ug/ml B 12 ng/ml 2 ng/ml C 48 nm 25 nm D 2.3 nm.5 nm E 2 um 1.4 um Note: While the IC5 of drugs can be reduced 2-15-fold by the administration of TM-71, the NEC (no effect concentration) is even greater extending the activity of anti-cancer drugs up to 25-fold below their IC5. The pharmacologic adjuvancy of chlorotoxin (TM-71) was also studied in a human glioma xenograft flank tumor mouse model. TM-71 was co-administered with Drug E, a common chemotherapeutic used in the treatment of brain cancer, two to three times a week for eight weeks. This effect has been demonstrated with a number of commonly used anti-cancer agents in animal tumor models. Chlorotoxin enhances the anti-cancer effects of a number of commonly used anti-cancer drugs in animal tumor models when delivered systemically. These data support the systemic administration of chlorotoxin-based oncology products for imaging and therapy. Tumor Volume (mm3) 16 Saline 14 Drug E 12 TM-71 Drug E + TM-71 1 8 6 4 2 25 3 35 4 45 5 55 6 65 7 Days Post-Implantation Figure 6. In vivo pharmacologic adjuvancy of TM-71 co-administered with Drug E. Animals were implanted with human glioma cells in the right flank. Tumors were allowed to grow until palpable (27 days post-implantation). Injections of drugs or saline were administered IP to each group of animals. Drug E was intentionally used at a suboptimal dose to demonstrate the robustness of TM-71 in potentiating the activity of Drug E. Tumor volumes were measured several times a week. 7
Intellectual Property TMI has a broad worldwide portfolio of issued and filed patents protecting products based on chlorotoxin sequences, including composition of matter and usage for both therapeutic and diagnostic applications with brain and other solid tumors. The company maintains an aggressive patenting program regarding all aspects of the chlorotoxin technology and believes that its patent position is early and strong. Partnering Objectives TMI plans to develop its brain cancer franchise using chlorotoxin-based products for its own account in the United States. The Company wishes to secure interested partners for the ongoing development and commercialization of the brain cancer applications of chlorotoxin in other markets, in particular, Europe and Asia. The Company believes that the broader systemic application of the technology in other solid tumor types will require strong regional or multi-national partners and will consider worldwide partnering of these applications with appropriately qualified partners. Contact Information: TransMolecular, Inc. One Perimeter Park South Suite 4 North Birmingham, AL 35243 (25) 972-77 (T) (25) 972-78 (F) Matthew A. Gonda, Ph.D. President & Chief Executive Officer gonda@transmolecular.com The Sage Group, Inc. 3322 Route 22 West Building #2, Suite 21 Bridgewater, NJ 8876 98-231-9644 (T) 98-231-9692 (F) Gordon Ramseier Executive Director gramseier@sagehealthcare.com R. Douglas Hulse Executive Director doughulse@sagehealthcare.com Richard Power Executive Director rgpower123@sagehealthcare.com 8