B. G. Redman University of Michigan, Ann Arbor, MI. J. A. Thompson University of Washington, Seattle, WA

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1 Identification of a well-tolerated outpatient regimen of intravenous recombinant human interleukin-2 (IL-2) in patients with metastatic melanoma and metastatic renal cell carcinoma J. A. Thompson University of Washington, Seattle, WA B.D. Curti Providence Portland Medical Center, Portland, OR B. G. Redman University of Michigan, Ann Arbor, MI E. L. Sievers ZymoGenetics Inc., Seattle, WA

2 Interleukin 2 Novel class I cytokine Produced by activated CD4+ T cells Signals through dimer of unique IL-2 receptor and common gamma chain Recombinant IL-2 has demonstrated anti-tumor efficacy in preclinical models

3 IL-2 Elicits Pleiotropic Immune Modulation

4 Open Label, Phase Dose Escalation Study Population Patients with measurable metastatic melanoma or renal cell carcinoma Objectives Primary Determine maximum tolerated dose of IL-2 (using CTCAE criteria) Secondary Pharmacokinetics Immunogenicity Clinical or biological parameters that may correlate with efficacy Anti-tumor effect

5 Key inclusion criteria Metastatic melanoma (non ocular) or metastatic renal cell carcinoma (clear cell) ECOG or Standard laboratory parameters No more than one prior treatment Hemoglobin > 2 g/dl

6 Part a Study Demographics (n = 5) Gender Male 3 Female 2 Age, median (range) 6 (39 76) Malignancy Melanoma 9 Renal Cell 6 Mean years since diagnosis 4 Number with prior immunotherapy IL-2 5 Interferon 4

7 IL-2 Treatment Schedule CT CT Dosing cycle (5 days) Rest period (9 days) Dosing cycle (5 days) Follow-up period (28 days) Days Dosing cycle = 5 consecutive daily doses of IL-2 delivered by IV push in the outpatient setting

8 IL-2 Monotherapy Phase Study (U.S.) n = 2 Dose (µg/kg) 5 3 n = 6 n = a 3 n = 3 n = 3 Phase a Dose escalate to MTD (3 + 3 design) Phase b a n = up to 3 subjects (5 of each disease type) including Phase a subjects dosed at 3 µg/kg

9 IL-2 Safety All but 2 adverse events were mild to moderate in severity Most common adverse events Fatigue, Pyrexia, Arthralgia, Chills, Headache, Myalgia, Rash Grade 3 or higher adverse events included Grade 4 acute liver toxicity probably related to IL-2 (occurred in Cycle 4) 3 µg/kg Grade 3 hemoptysis unrelated to IL-2 3 µg/kg /5 patients treated with 2 cycles developed specific antibody response

10 Most Common Adverse Events through 2 Cycles by Dose (µg/kg) 3 (n = 3) (n = 3) 3 (n = 6) 5 (n = ) (n = 2) Total (n = 5) Fatigue Pyrexia 2 6 Arthralgia Chills Headache Myalgia Rash Constipation 4 7 Nausea Edema Peripheral Anorexia Insomnia 3 6

11 Grade 3 Laboratory Toxicities through 2 Cycles by Dose (µg/kg) 7 of 9 patients at doses 3 µg/kg experienced Grade 3 toxicity One patient at µg/kg experienced transient Grade 4 lymphopenia 3 5 Total (n = 6) (n = 6) (n = ) (n = 2) (n = 5) Lymphopenia Hypophosphatemia Increased ALT Hyperbilirubinemia Thrombocytopenia Leukocytosis Neutropenia Hyponatremia

12 Median ALT Over Time for 3 µg/kg ALT (U/L) a Cycle Cycle 2 a median with IQR

13 IL-2 Pharmacokinetics The half-life (t /2 ) of IL-2 was approximately.5 hours Dose (µg/kg) N Cmax (ng/ml) Median (CV%) AUC INF (hr*ng/ml) t ½ (hr) (7.8) 22.9 (37.3).88 (3.4) (8.) 68.2 (4.5).3 (5.5) (5) 26 (4.6).69 (.8) 5 2 (--) 95 (--).4 (--) (48.) 62 (4.3).89 (2.63)

14 Median Lymphocytes and Median Soluble CD25 2 Median Soluble CD25 (ng/ml) Median Lymphocytes (x 9 /ml) Cycle Cycle 2 µg/kg 5µg/kg 3µg/kg µg/kg 3µg/kg

15 Changes in Target Lesion Diameter after Receiving 2 Cycles of IL-2 Treatment PD due to new lesion Percent change from baseline MM MM RCC MM MM MM MM RCC MM MM RCC MM MM = metastatic melanoma RCC = renal cell carcinoma Dose units = µg/kg 3 3 only four doses per subject RCC 5 RCC 3 RCC

16 RECIST Responses through 2 Cycles by Dose (µg/kg) a (n = 3) (n = 3) (n = 6) (n = ) (n = 2) PR (RCC) (RCC) SD 2 (MM) 2 (MM) 2 (RCC) (RCC) (MM) PD 2 (MM) (MM) (RCC) (MM) a Each patient at µg/kg received only 4 of planned doses MM = metastatic melanoma RCC = renal cell carcinoma

17 Conclusions Outpatient MTD selected for further study in Part b: 2 cycles of 3 µg/kg/day x 5 days with 9-day rest interval Reasonably well-tolerated by 6 patients AUC of IL-2 increased in dose-proportional manner Dose-related biological effects as measured by scd25 and lymphocytes Objective evidence of anti-tumor activity

18 Plans Completing enrollment of 3 patients treated at 3 µg/kg/day 5 renal cell carcinoma 5 metastatic melanoma Goals Further characterize safety of this outpatient regimen Estimate overall response rate for each cancer Plan Phase 2 studies

19 Acknowledgements Providence Portland Medical Center, Portland, OR Brendan Curti Lisa Justice Katrina Herz University of Michigan, Ann Arbor, MI Bruce Redman Peg Esper Barbara Rinna University of Pittsburgh Cancer Institute Sanjiv Agarwala Lori Stover USC/Norris Cancer Center Jeff Weber Georgia Jeffery University of Washington, Seattle, WA John Thompson Linda Kirsch Elissa Ross ZymoGenetics (Sponsor) Eric Sievers Patty Pedersen Susanne Frahm Todd DeVries Mary Fleischer Janet Kramer Kimberly Wood Dennis Miller Jennifer Visich Jeremy Freeman Thomas Spiegelberg Lily Chan Novo-Nordisk (Development partner evaluating IL-2 for melanoma in Australia)

20 Maximum ALT by Patient ALT (U/L) Dose (µg/kg)