SARC021

1. SARC021 A Randomized Phase 3, Multicenter, Open-Label Study Comparing TH-302 in Combination with Doxorubicin vs. Doxorubicin Alone in Subjects with Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma PI: William Tap, MD Memorial Sloan-Kettering Cancer Center

2. TH-302 Combination Therapy in Soft Tissue Sarcoma Phase 3 Study Design • Collaborative Trial by Threshold Pharmaceuticals and Sarcoma Alliance for Research through Collaboration (SARC) • Trial managed (including data management) by PAREXEL • An Independent Data Monitoring Committee (IDMC) will monitor the safety and efficacy. (Ron Blum) • An Independent Review Facility will be used to collect radiographs and may be used to independently evaluate tumor response and PFS

3. 3 Hypoxia Activated Prodrugs (HAPs) Hypoxia-activated prodrugs (HAPs) selectively target hypoxic tumor cells Hypoxia is a feature of solid tumors Associated with a worse prognosis Associated with an aggressive phenotype, invasiveness, metastasis, and relapse Often underlies treatment failure HAPs should complement conventional cancer therapies

4. Chemotherapy Targets Oxygenated Tumor Compartment Vessels: Red Doxorubicin: Blue Hypoxia: Green Minchinton, A. and Tannock, I. Nat. Rev. Cancer. 6: 583-92, 2006 Mouse mammary tumor

5. 5 Chemistry Strategy for Targeting HypoxiaHypoxia-Activated Prodrugs (HAPs) TH-302 TH-302 e.g. NADPH-cytochrome P450 reductase O e.g. NADPH-cytochrome P450 reductase O O 2 superoxide 2 2 •- •- •- Radical anion Further reduction Radical anion Fragmentation - Non-toxic prodrug reduced to radical anion (by 1e- reductase) - Back-oxidation to the original compound in presence of O2 and production of superoxide Hydroxyl amine Br-IPM

6. 6 Chemistry Strategy for Targeting HypoxiaHypoxia-Activated Prodrugs (HAPs) 0% O2 0.5% O2 Chemotherapy TH-302 5% O2 10% O2 Blood vessel Normoxic zone Hypoxic zone

7. TH-302 + Doxorubicin in Soft Tissue Sarcoma The 403 Phase 1/2 Trial: 84% of Patients Experienced SD or Better (10/27/11) Waterfall Plot: Change in Target Lesion Diameters

8. Phase 2 Response by Sarcoma Subtype Response rate (CR + PR): 36%

9. TH-302 MAINTENANCE FOLLOWING TH-302 PLUS DOXORUBICIN INDUCTION: THE RESULTS OF A PHASE 2 STUDY OF TH-302 IN COMBINATION WITH DOXORUBICIN IN SOFT TISSUE SARCOMA Ganjoo KN1, Cranmer LD2, Van Tine B3, Reed DR4, Okuno SH5, Butrynski JE6, Adkins D3, Hendifar A7, Chu ED8, Kroll SM8, Chawla SP7 1. Stanford University Medical Center, Stanford, CA, USA; 2. Arizona Cancer Center, Tucson, AZ, USA; 3. Washington University, St. Louis, MO, USA; 4. H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 5. Mayo Clinic, Rochester, MN, USA; 6. Dana-Farber Cancer Institute, Boston, MA, USA; 7. Sarcoma Oncology Center, Santa Monica, CA, USA; 8. Threshold Pharmaceuticals, South San Francisco, CA, USA. Update on Overall Survival of 91 pts and Maintenance of 48 pts

10. TH-302 Maintenance in Soft Tissue Sarcoma- Response Rates Response Rates: • Overall response rate for 48 subjects receiving maintenance was 44% prior to receiving maintenance and 54% including both induction and maintenance. • During the maintenance portion of the study 6 subjects had an upgrade in response category: • 5 SDs converting to PR • 1 PR converting to CR Table 5: Best Response (Unconfirmed) to Overall Treatment * Two patients discontinued with reason subject decision (1) and PI decision (1) prior to initial tumor response assessment.

11. TH-302 Maintenance in Soft Tissue Sarcoma- Progression-free Survival Progression-free Survival: • The median PFS on study was 6.7 months (95% CI: 6.2 to 7.8 months). Figure 1A. • The median PFS after TH-302 maintenance was 3.7 months (95% CI: 2.5 to 5.5 months). Figure1B. Figure 1A: Progression-free Survival on Study (N=91) Figure 1B: Progression-free Survival after Initiating Maintenance (N=48)

12. SARC021 Schema Eligible Patients (N=450) ≥ 15 Years of Age Locally Advanced Unresectableor Metastatic Soft Tissue Sarcoma Stratification/Randomization TH-302 + Doxorubicin 21 Day Cycle Day 1 = TH-302 (300 mg/m2) and Doxorubicin (75 mg/m2) Day 8 = Th-302 (300 mg/m2) andDay 8 or Day 9 = G-CSF Doxorubicin 21 Day Cycle Day 1 = Doxorubicin (75 mg/m2) Response evaluations end of cycles 2, 4 and 6 until progression or discontinuation Note: Patient continues monotherapy TH-302 maintenance after cycle 6 without doxorubicin and G-CSF until discontinuation Response evaluations end of cycles 2, 4 and 6 until progression or discontinuation Note: Patient is discontinued after cycle 6 Survival Follow-up

13. TH-302 Combination Therapy in Soft Tissue Sarcoma Phase 3 Study Status • Approximately 25% of 450 subjects enrolled • Approximately 50% of planned sites now active • Sites open in Belgium, Canada, Germany, Israel, Italy, Hungary, Poland, Spain and United States • Sites soon to open in Austria, Denmark, France and Russia • Initial PFS futility analysis (113 events) projected to occur in 2nd quarter of 2013 • Enrollment on schedule to be completed by end of 2013 • Initial OS interim for early efficacy stoppage (175 deaths) projected for end of 2013 • Primary analysis (323 deaths) projected for end of 2014/beginning of 2015

14. Thank You • William Tap, MD Memorial Sloan-Kettering Cancer Ctr/SARC P: 646-888-4163 tapw@mskcc.org • Denise Reinke, MS, NP SARC P: 734-930-7600 dreinke@sarctrials.org • Clarence Eng Threshold P: 650-474-8222 ceng@thresholdpharm.com • Katherine RandolphPAREXEL InternationalP:858-487-8259 Katherine.Randolph@parexel.com Who to contact if interested or with questions: