GTX: AN OPPORTUNITY NOT TO BE MISSED? Carlos Stahlhut ● Elana Fishman ● Dorothy Kwok Juliana Tolles ● Vipender Singh Lucky 13

3. Activated T cells escalate inflammation via cytokine signals to other cells. TH2TH2 TH1TH1 1. Breach of intestinal wall causes abnormal interaction between local immune cells and intestinal bacteria. 2. Inflammatory cytokines attract leukocytes from bloodstream. Crohn’s Disease and Ulcerative Colitis THTH 4. Neutrophils, macrophages, and antibodies attack the intestinal mucosa. UC CD TNF α, IL-2, IL-3 IL-3, IL-4, IL-5 B cells Neutrophil ROS VLA- 1

Epidemiology

Treatment Options Mild Moderate Severe Symptom Severity  Efficacy  High cost  Long term safety  Low cost  Side effects  Low cost  Limited efficacy The current drug options fail to meet the need for an effective and safe treatment

Treatment Limitations Mild Moderate Severe Symptom Severity Moderate-high unmet need  Resistance to treatment  Limited remission sustenance Moderate unmet need  Side effects  Limited efficacy Very low unmet need  Effective and safe Moderate unmet need  Resistance to treatment  Safety risks Moderate unmet need  Side effects  Limited efficacy Low unmet need  Low efficacy Crohn’s Disease Ulcerative Colitis

GTX-001: Monoclonal Antibody Against VLA-1 Antigen  Different mechanism; Most Biologics Target TNF-   Not T-cell specific; Broad Immune Response  Competition: biologics and immunomodulators  Target Groups: Moderate to severe forms of Crohn’s Disease and Ulcerative Colitis VLA-1 GTX-001 Targets Immunomodulators $ 57 MM Cost $ Administered Oral Tysabri $15 MM Cost $20,000-30,000 Administered SC Humira $ 420 MM Cost $15,000-20,000 Administered SC Cimizia $80 MM Cost $12,000-17,000 Administered SC Remicade $ 940 MM Cost $10,000-15,000 Administered IV Remicade $ 660 MM Cost $10,000-15,000 Administered IV Immunomodulators $ 44 MM Cost $ Administered Oral US & EU Market (2008) = $ 1,512 MM US &EU Market (2008) = $ 704 MM

GTX-002: Small Molecule Inhibitor  Kinase inhibitor that targets NF-kB pathway in T-cells  Kills stimulated T-cells  Potential be effective against all forms of disease  Combination therapy: For mild and moderate forms  Potential to replace biologics TH2TH2 TH1TH1 THTH UCCD TNFα, IL-2, IL-3 Cytotoxic T cells IL-3, IL-4, IL-5 B cells US & EU Market (2008) = $2,060 MM US & EU Market (2008) = $1,516 MM Biologics Sales $ 865 MM 5-ASA Sales $ 807 MM Immunomodulators Sales $ 27 MM Steroids < $ 1.1 MM Biologics Sales $ 1,455 MM 5-ASA Sales $ 516 MM Immunomodulators Sales $ 57 MM Steroids Sales $ 33 MM

Achieving Desired Target Profile Preclinical studies  Demonstrate lower inflammation scores with  Alternative delivery method  Lower frequency of administration (compared with IV every other day)  Demonstrate sustained remission Clinical studies  Efficacy in humans  Acceptable levels of toxicity and safety given non-humanized Ab  Equivalence/superiority to standard of care Preclinical studies  Demonstrate lower inflammation scores  Alone  In combination with existing treatment options  Acceptable induction time  Demonstrate sustained remission  Comparable or superior performance to biologics Clinical studies  Efficacy in humans  Acceptable levels of toxicity and safety  Equivalence/superiority to standard of care  GTX-001 GTX-002

GTX001: Financials  Licensing Agreement  Licensing Fee: $10mm  Total Development: $300mm  Milestone Payments: $100 Phase I, $100 Phase II, $200 Phase III  Royalty to Gastrex: 10% of sales  Sales Assumptions  Price per year: $17,000  Peak penetration (both CD and UC)  Operating Assumptions  Sales and marketing: $100mm in 2019 and 2020, 20% of sales through 2032  Cost of goods sold: 40% of sales  Tax rate: 35% Upside Case Base Case Downside Case

GTX002: Financials  Same Licensing Agreement  Sales Assumptions  Price per year: $5,000  Peak penetration (Crohn’s Disease)  Peak penetration (Ulcerative Colitis)  Operating Assumptions  Sales and marketing: $100mm in 2019 and 2020, 20% of sales through 2032  Cost of goods sold: 20% of sales  Tax rate: 35% Upside Case Base Case Downside Case

Recommendations  License GTX-002 under proposed structure  Captures broader segment of market (all levels of disease severity)  Small molecule offers more convenient delivery option at lower cost  High level of return with low downside risk  Offer $2mm per year for 2 years to maintain licensing option for GTX-001 contingent on preclinical performance  Safety concern regarding immune response  Demonstrate effectiveness with lower frequency of administration  Investigate other delivery routes GTX-001 and GTX-002 represent novel and exciting treatments for IBD

Thank You & Questions

Appendix

Summary of Clinical Trials PreclinicalClinical AnimalPhase 1Phase IIPhase III FeasibilityInitial doseIdentify dose- response Confirm dose- response Safety profileDose escalationSafety profile PharmacokineticsMaximum tolerated dose Drug efficacyConfirm drug efficacy PharmacodynamicsToxicityPatient populationRisk/benefit relationship Source: Makuch, R (2009 October) Phase of Clinical Trials Clinical Trials. Lecture conducted from Yale University, New Haven, CT

Top Products by Sales in 2014 ProductCompanyTechnologyWW Sales ($mm) AvastinRocheMonoclonal antibody9,232 HumiraAbott + EisaiMonoclonal antibody9,134 RituxanRocheMonoclonal antibody7,815 EnbrelWyeth + Amgen + Takeda Recombinant product6,583 LantusSanofi-AventisRecombinant product6,386 HerceptinRocheMonoclonal antibody5,796 CrestorAstraZenecaSmall molecule chemistry5,739 SpirivaBoehringer IngelheimSmall molecule chemistry5,552 RemicadeSGP + J&J + MTMonoclonal antibody5,220 Gleevev / GlivecNovartisSmall molecule chemistry5,136 Source: FierceBiotech 18 Jun 2009, courtesy of Pfizer.

DrugDosing Recommendations 70 kg adultTotal drug GTX-12 mg/kg every other day for 6 weeks 140 mg x 22 doses =3080 mg Remicade3 doses 5 mg/kg350 mg x 3 doses =1050 mg Humira4 doses of 160 mg; 1 dose 80 mg; 1 dose 40 mg (at left)=760 mg Calculations to support drug pricing assumptions for GTX-001

Non-case sources  Pfizer Annual Report 2008  Roche Annual Report 2008  Novartis Annual Report 2008  (evidence-based, peer reviewed website)  