Polyclonal Antibody Stimulator (PAS) A Phase III Ready Anti-Gastrin Vaccine Cancer Advances Inc. Vaccicure Limited Non-Confidential Introduction 2019
Executive Summary • Cancer Advances Inc. (Durham, NC) is a privately held biotechnology company focused on impacting human health and the progression of gastrointestinal cancers by enhancing the adaptive immune system • Lead compound Polyclonal Antibody Stimulator (PAS) vaccine is potentially applicability in multiple cancer types including gastric, pancreatic, colorectal and liver • PAS has already been studied in multiple clinical trials in 1,500+ subjects • Excellent safety and tolerability profile • Clinical proof of concept has been achieved in gastric and pancreatic cancers • The company is led by an experienced management team and has a broad intellectual property portfolio
Executive Summary (2) • Cancer Advances Inc. has a UK subsidiary Vaccicure Limited which has received some funding (about £3.2m to date) in the form of redeemable preference shares which pay out up to 7.5 times investment on a liquidity event. • Time to liquidity event is 18 months to 3 years post funding • Cost to a liquidity event about $35.5m net (less if the liquidity event is earlier then 3 years) • Meets a real unmet need so acceptance likely to be rapid. • Market is large >$3.5bn per year • This suggests a valuation of >>$1bn on a liquidity event • The project is de-risked because phase 3 trials have already been done and shown safety and when properly interpreted, as the FDA agrees, efficacy.
Gastrointestinal Cancers Present a Unique Challenge • GI cancers as a group are the most common cancers in the U.S. (2019 prevalence below) • Gastric ~100,000 • Pancreatic ~75,000 • Esophagus ~47,000 • Colorectal ~1.3 M • Often diagnosed at an advanced stage • Extremely poor prognosis • Few effective treatment options for advanced patients Polyclonal Stimulator Vaccine (PAS) targets gastrin, which promotes cellular proliferation and tumorigenesis in GI cancers Source: GI Alliance, seer.cancer.gov
Physiological Function of Gastrointestinal Peptide Gastrin • Gastrin is normally produced in the G-cells of stomach antrum. • Gastrin acts on CCK-B receptors of the stomach cells to produce gastric acid. • In cancer, gastrin is a DRIVER peptide that stimulates growth of GI cancers through the CCK-B receptor. • If gastrin is neutralized with antibodies or down-regulation, GI cancers fail to grow. Stanislaw J. Konturek, Jagiellonian University Medical College, Cracow, Poland
CCK-B Receptors and Cancer • CCK-B receptors are normally located in the stomach, colon, and pancreas. • CCK- B receptors are over-expressed in cancers, especially of the GI tract. • Gastrin stimulates growth of these cancers. • No CCK-B small molecule inhibitor has yet been proven effective in humans. Medullary thyroid cancer Barrett’s Esophagus & Esophageal Cancer Lung cancer Gastric Cancer Pancreatic Cancer Colorectal Cancer Carcinoids Digestive Systems by OpenStaxCollege licensed under Creative Commons Attribution 4.0 International License
Diphtheria toxin backbone Gastrin peptide linker Polyclonal Antibody Stimulator Vaccine (PAS) • PAS immunogen is a peptide-conjugate that includes an N-terminal epitope of human gastrin-17 (G17) linked to carrier diphtheria toxoid. • PAS activates B-cells and elicits specific and high-affinity anti-gastrin Abs, which prevent trophic activity of gastrin at the CCK-B receptor. • PAS is administered in humans as an intramuscular injection over a multi-week regimen. • The Polyclonal Antibody Stimulator (PAS) vaccine was discovered and developed to the Phase 3 stage by Aphton, then acquired by Receptor Biologix, and then by Cancer Advances. Program was halted by Aphton due to lack of funding. • Cancer Advances exclusively owns PAS and is funding and managing all aspects of the PAS gastrin vaccine program.
PAS Clinical Program Overview • 22 clinical studies have been completed in over 1,500 subjects, including 2 placebo-controlled Phase 3 studies • PAS has been actively investigated in three different indications: • 6 pancreatic cancer studies, Phases 1-3 • Total exposure: n = 654 • 5 gastric cancer studies, Phases 1-2 • Total exposure: n = 234 • 5 colorectal cancer studies, Phases 1-2 • Total exposure: n = 368 • Excellent safety and tolerability profile. Injection site irritation only notable AE. No adverse reactions or autoimmune effects were detected effecting the normal functions of gastrin. • Provides survival benefit in pancreatic and metastatic gastric cancer patients that show an immune response (≥65% of all treated patients) • Recent pre-clinical work by Georgetown University validates efficacy as a monotherapy and supports further exploration of PAS in combination with checkpoint inhibitors
PAS Monotherapy - Summary of Survival data in Pancreatic and Gastric Cancer GASTRIC CANCER, 1ST LINE , OPEN LABEL, TO DETERMINE OVERAL SURVIVAL IN SUBJECTS TREATED WITH PAS IN COMBINATION WITH CISPLATIN AND 5-FU (GC4) Pancreatic cancer, 1st line , Randomized, double blind, multinational study (PC6) KPS ≥ 60 Primary endpoint: Overall Survival Secondary endpoints: ORR, Weight, KPS, QoL KPS ≥ 70 Primary endpoint: Overall Survival Secondary endpoints: TTP,ORR, QoL CDDP + 5-FU + PAS PAS -Responder CDDP + 5-FU + PAS PAS Non-responder
Gastric Cancer: Overview • Stomach cancer (gastric adenocarcinoma) has one of the poorest prognoses of all cancers with 5-year survival of ~30%. • U.S. 2019: Incidence 27,510//Mortality 11,140 • Current standard of care includes surgery followed by radiation and/or chemotherapy with DNA synthesis inhibitors (5-fluorouracil), or DNA damaging agents (platinum-based). • Newer agents approved to treat advanced gastric cancer offer only incremental survival benefits: • Keytruda (pembrolizumab) Merck - checkpoint inhibitor - response rate only ~13-14%, • Cyramza (ramucirumab) Lilly - anti-angiogenic • Herceptin (trastuzumab) Genentech/Various - HER2+ • Additional treatment innovations are needed Globally, 952,000 new cases of gastric cancer were diagnosed in 2012. Gastric cancer was the fifth-most common type of cancer in the world. Source: SEER, cancer.gov, Keytruda.com , Cyramza.com, Herceptin.com, World Cancer Research Fund International,
Pancreatic Cancer: Overview • Pancreatic cancer is a complex disease with current 5-year survival rate only 9.3%, the lowest of any cancer. • Multidisciplinary diagnosis followed by surgery, chemotherapy, +/- radiation is the current treatment approach. • Chemotherapy with gemcitabine-Abraxane or FOLFIRINOX do not result in median survivals beyond 1 year. • Poor survival rate due in part to: dense fibrotic microenvironment that inhibits drug penetration into pancreatic tumor tissue; and lack of targeted approach. • Challenges for treating with immunotherapy: acquired immune privilege, poor T cell infiltration, high fibrosis, low mutational burden Sheir, Butler, & Lewis Hole's Human Anatomy 10th edition McGraw Hill, Boston 2004
Pancreatic Cancer is an Important Clinical and Commercial Opportunity • U.S. 2019: Incidence 56,770 / Mortality 45,750 • PDAC has surpassed breast cancer in cancer deaths and is now the #3 leading cause of cancer mortality in US. • U.S. projected pancreatic cancer deaths 50k/yr in 2020 increasing to ~65k/yr in 2030 • Global pancreatic cancer therapeutics market projected to grow from $2.4 B in 2018 to $3.5 B in 2023 Reference: Rahib L. et al., Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913–21. PDAC = Pancreatic ductal adenocarcinoma, 94% of all pancreatic cancers Source: Market Data Forecast, seer.cancer.gov
Experienced Management Team Lynda Sutton, President 25 years experience in the drug development industry, specializing in the development of regulatory strategies for drugs and biologics Alan Cato, MD, PhD Chief Executive Officer and Chief Medical Officer More than 40 years of experience in clinical study design and new drug development. John Wingen Acting CFO 8+ years experience in the drug development industry in finance and operational roles Jill B. Smith, MD Lead KOL Professor, Department of Medicine, Division of Gastroenterology & Hepatology, Georgetown University Katy Kuipers Business Development 19+ years pharma experience, past affiliations include Eisai Inc. & OSI Pharmaceuticals Teresa Phillips Director of Development 20 + years pharmaceutical research experience Additional team members will be added once P3 funding is secured
Cancer Advances and Cato Research Working Relationship • Cancer Advances has contracted with Cato Research to handle all aspects of R&D including clinical trials, drug supply, regulatory affairs and business development. • Cato Research, is a full-service 300 staff CRO, headquartered in RTP with sites worldwide. • Cato is capable of conducting the Phase 2/3 clinical development and manufacturing of PAS • Cancer Advances is also funding supportive immunotherapy research at Georgetown University Medical Center, with a global expert in gastrin biology and GI cancers clinical translation. Latest results presented at ASCO GI conference.
Development Timeline Additional Development: Pancreatic, Colorectal, Liver, IIS’s etc. Manufacture new batch of PAS Phase 3 Gastric cancer controlled study FDA Approval and Launch NDA Filing FDA meeting 2021 2022 2019 2023 2020 2024 Pharmaceutical partnership process Fundraising efforts for Phase 3 gastric cancer study Pharma partnership signed - Potential EXIT Cancer Advances intends to pursue FDA fast track designation
Proposed Phase 3 Gastric Cancer Study • Patients: 400 • Open label bridging phase: in 10-20 patients to establish equivalence of newly manufactured PAS • Controlled phase: Standard of care (SOC) + PAS vs. SOC + placebo • Primary Endpoint: Overall Survival • Secondary Endpoints: Safety,Quality of life (QoL) • Exploratory Endpoints: Responder analysis, Biomarker analysis • Timeline: 24 months (12 months enrollment, 12 months treatment) • Target Indication: PAS as a first line treatment in gastric cancer Cancer Advances will seek FDA input on design and objectives
Funding Request & Use of Proceeds Costs spread over 3 years through NDA filing
PAS Global Development Opportunities • Historically, favorable discussions have been had with regulatory authorities (FDA, Health Canada, EMA)given PAS’s extremely benign safety profile and the urgent unmet need in GI cancers • U.S. – potential for approval in 1st Line Gastric cancer in 3-4 years • Canada – potential approval in pancreatic cancer even earlier by completing BLA requirements and Phase II bridging study • Potential for combination studies with checkpoint inhibitors given very encouraging pre-clinical data • Anticipated additional NDA filings in pancreatic and Zollinger Ellison syndrome • Follow-on indications in esophageal and colorectal cancer • $>4B potential market opportunity
PAS vaccine with PD-1 checkpoint inhibitor results in both B and T cell responses. • Isolated T-cells from PAS-treated mice responded to gastrin by releasing activated cytokines. • PAS vaccine was successful in inducing a target-specific T-cell response to the ligand gastrin. • High dose PAS, and combination therapy of PAS with PD-1 Ab decreases tumor mass. Combination therapy also decreases tumor fibrosis and promotes influx of CD8+ cells and efflux of FoxP3+ cells. • Looking Forward: • PAS combination therapy changes the tumor signature that renders tumors more susceptible to treatment with a checkpoint inhibitor. • Turns immunologically “cold” tumors into “hot” tumors responsive to immunotherapy. What PAS Could Achieve in Combination Therapy with a PD-1/PD-L1 Checkpoint Inhibitor
IP and Market Exclusivities • Cancer Advances holds and is pursuing patent protection for the PAS anti-gastrin vaccine, its manufacture, biomarkers, and method of use in combination with checkpoint inhibitor and other immunotherapies for GI cancers. (100+ patents issued) • Most recent PCT in examination internationally, for claims that issue will have protection to 2040. • PAS also will be awarded exclusive marketing protection that includes: • United States Biologics Price Competition and Innovation Act - Upon approval guarantees 12 years of market exclusivity for a new biological agent before any biosimilar product can be approved • US Orphan Designation (Gastric and Pancreatic Cancers) - 7 years of marketing exclusivity • EU Orphan Designation (Gastric and Pancreatic Cancers) - 10 years of marketing exclusivity • Australia Orphan Designation (Gastric and Pancreatic Cancers) • Japan – 8 years of marketing exclusivity for a New Chemical Entity
Key Highlights • Novel immunological approach to cancer treatment • Provides survival benefit in pancreatic and metastatic gastric cancer patients that show an immune response (≥65% of all treated patients) • No indication of any significant safety concerns – large database • Potential for synergy with checkpoint inhibitors • Large market – GI Cancers - with high unmet need • Lengthy market exclusivities for biologics plus solid IP portfolio • Seasoned leadership team with vast clinical and regulatory experience in oncology • Targeting exit within 3-4 years
Please direct inquiries to: • Lynda Sutton • President • Cancer Advances, Inc. • E-mail: firstname.lastname@example.org • Phone: 919-422-8248 Thank you CancerAdvancesInc.com
Description of Gastric Cancer (GC4) Trial • Subjects were treatment-naïve, with metastatic gastric cancer, unresectable gastric cancer or adenocarcinoma of the GE junction. • Subjects received PAS intramuscularly during Weeks 1, 5, 9, and 25, and cisplatin plus 5-fluorouracil every 28 days. • Primary endpoint was the overall response rate; secondary endpoints included overall survival, safety, and impact on subject outcome. PAS vaccination was combined with cisplatin and 5-FU in a Phase 2 study:
GC4 Trial Efficacy Summary • Results: • A protective anti-gastrin Ab response is needed for efficacy. • Subjects with Ab response (“PARs”) showed improved survival. ITT = intent-to-treat (population); PAR = protective antibody response. • Historical controls: • J ClinOncol. 2003;21:54-59. • J ClinOncol. 2000;18(14):p2648-p2657. • J ClinOncol. 2006;24(31):4991-4997. Protective Antibody Responder: Two definitions of a PAR subject: • Primary definition: subjects immunized (vaccinated) if they had an anti-gastrin antibodies titerELISA unit for two consecutive assays. • Secondary definition: subjects vaccinated if they had anti-gastrin Ab titer 1.2 ELISA units at any time during the study after baseline and after PAS treatment.
GC4: Survival Results In total, 103 subjects were enrolled in five countries. Results were as follows: All Subjects • Results: • The confirmed overall response rate was 30% in 79 subjects who were evaluated for response. • The median time-to-progression was 5.4 months. • Median Survival: • PAR: 10.3 months • Non-PAR: 4.8 months • p < 0.0001 p < 0.0001 PAR Non-PAR
PAS: Pancreatic Cancer (PC6) Trial • This was a placebo-controlled, double-blind, PAS monotherapy in treatment-naïve advanced-stage pancreatic cancer patients not suitable for chemotherapy or who refused chemotherapy (Karnofsky 60 or above) • Stage II, III, or IV disease • Total enrollment 154 subjects; 79 subjects received PAS immunotherapy. • Primary endpoint was overall ITT survival. • Secondary endpoints were as follows: • Objective tumor response • Weight change • Karnofsky Index • Quality of life
PC6: Increased Number of Survivors at 2 Years Subjects alive in Study PC6 (ITT/anyone who received the dose) ITT = Intent-to-treat (population)
PAS used in Combination with PD-1 Checkpoint Inhibitor in Pancreatic Cancer Animal Model
Checkpoint Inhibitors and Targeting of Multiple Components of Immune System • Because tumors limit immune responses through multiple mechanisms, simultaneous targeting of multiple pathways to recognized to be essential for optimal antitumor responses. • Reshaping the tumor microenvironment with combination therapies rapidly evolving areas of research Ref: Evolution of checkpoint inhibitors for the treatment of metastatic gastric cancers: Current status and future perspectives. Taieb, Julien et al., 2018, Cancer Treatment Reviews, Volume 66 , 104 - 113
New Murine Preclinical Study: Study Synergistic Effects of PAS and PD-1 Antibody in Pancreatic Cancer ASCO Gastrointestinal 2019 Symposium Poster Abstract 259
A. Mean tumor volumes and standard error of the mean plotted for each weekly assessment over time. Tumor volumes were equal at baseline in all treatment groups. B. Final tumor weights in the mice compared to tumors weights of PBS or PD-1 treated mice. PAS250 monotherapy decreased growth of pancreatic cancers in mice. PAS100 in combination with PD-1 Ab decreased tumor growth at a dose of PAS that had no effect alone.
Intratumoral fibrosis A. Masson’s trichrome staining demonstrates fibrosis of the pancreatic tumor microenvironment in tumors of mice treated with PBS, PD-1 Ab, or PAS100 monotherapy. Significantly decreased fibrosis was found in tumors of mice treated with the combination of PAS100 and PD-1 Ab. (Objective 20X). B. Computer analysis quantification demonstrated lower fibrosis in mice treated with the combination of PAS100 and PD-1 Ab. *** p<0.005 compared to PBS and p<0.001 compared to PAS100.
Tumor infiltrating lymphocytes (TILs): A. CD8+ cells with each treatmentB. CD8+ TILs significantly increase with combination PAS and PD-1 C. FoxP3+ TILs change with therapyD. FoxP3+ lymphocytes decrease in tumors of mice treated with the combination therapy
Please direct inquiries to: • Lynda Sutton • President • Cancer Advances, Inc. • E-mail: email@example.com • Phone: 919-422-8248 Thank you CancerAdvancesInc.com