The Discovery and Clinical Evaluation of the Cyclophilin Inhibitor SCY-635 in HCV Infected Subjects Michael Peel1, Richard Harris1, Zhuhui Huang2, Sam Hopkins1, Keqiang Li1, Thomas E. Richardson1, Bernard Scorneaux1, Andrew Scribner1, Steve Wring1.1SCYNEXIS INC. and 2Southern Research Institute. HCV2009. SCYNEXIS Proprietary and Confidential Information

Non-immunosuppressive Cyclosporins Hepatitis-C Cyclosporin A (IC50) CypA 10 ng/mL CypB 12 ng/mL HCV EC50 ~ 0.3 uM IL-2 inh. 0.006 ug/mL NIM-811 (IC50) CypA 10 ng/mL CypB 25 ng/mL HCV EC50 0.06 uM IL-2 inh. >10 ug/mL Debio-025 (IC50) CypA 14 ng/mL CypB 10 ng/mL HCV EC50 0.04 uM IL-2 inh. 2.5 ug/mL Watanabe (2004); Bartenschlager (2006); Tang (2008) SCYNEXIS Proprietary and Confidential Information

Designing non-immunosuppressive Cyclosporins Cyclosporin:Cyclophilin A complex SCYNEXIS Proprietary and Confidential Information

4-(g-OH-Leu) Analogs have HCV Activity and Decreased Immunosuppressive Potential CypA 14 ng/mL CypB 20 ng/mL HCV EC50 ~ 0.35 uM IL-2 inh. 0.15 ug/mL CypA/B 11/30 ng/mL HCV EC50 ~ 0.1 uM IL-2 inh. 0.63 ug/mL CypA/B 8/5 ng/mL HCV EC50 ~ 0.07 uM IL-2 inh. 0.1 ug/mL SCYNEXIS Proprietary and Confidential Information

Non-immunosuppressive 4-(g-OH-Leu)-3-Sar-Thioethers with Potent HCV Activity SCY-635 SCYNEXIS Proprietary and Confidential Information

SCY-635 Inhibits Cyclophilin A PPIase Catalytic Activity Cyclosporin A Ki = 1.84 ± 0.33 nM Ki = 2.64 ± 0.56 nM Cyclophilin:Protease coupled assay using N-Suc-Ala-Ala-Pro-Phe-p-nitroanilide. G. Fischer, Max-Planck SCYNEXIS Proprietary and Confidential Information

SCY-635 Binds to the Cyclophilin Active Site Key residues required for PPiase activity are blocked by ligand SCYNEXIS Proprietary and Confidential Information

Effect of Serum on Anti-Viral Activity in the Replicon Assay SCY-635 is ca. 77% protein bound (cf. >99% for CsA) Human serum added to subgenomic replicon system. EC50s determined at 0% 10%, 20%, 40% are 0.08 uM, 0.09 uM, 0.11 uM and 0.12 uM respectively. SCYNEXIS Proprietary and Confidential Information

Synthesis of Cyclosporin Derivatives Biotransformation of Cyclosporin Chemical modification of Cyclosporins X = H or OH SCYNEXIS Proprietary and Confidential Information

SCY-635 Profile SCY-635 Potent inhibitor of HCV RNA replication in con 1b derived replicons; EC50 = 0.1 uM (subgenomic); EC50 = 0.17 uM (full length) Additive or synergistic activity with IFNa, ribavirin, protease, polymerase. (Data to be presented at AASLD 2009, S. Hopkins) No inhibition (IC50 >10 uM) of Cyp450 3A4, 2D6, 2C9, 2C19. No induction of Cyps in primary human hepatocytes. Weak interaction with Pgp transporter (cf. CsA) Low intrinsic clearance rates in microsomal preparations. SCYNEXIS Proprietary and Confidential Information

SCY-635 Profile Orally bioavailable in multiple animal species. Rat: Cl = 110 mL/h/kg; t0.5 = 24 h; F = 22%. Monkey: Cl = 45 mL/h/kg; t0.5 = 32 h; F = 13%. Improved oral exposure compared to CsA, Debio-025 from simple vehicle. Mouse blood concentrations: Oral delivery (8 mpk) of CsA, Debio-025 and SCY-635 SCYNEXIS Proprietary and Confidential Information

Clinical Studies SCYNEXIS Proprietary and Confidential Information

Clinical Proof of Principle Study Design 15-day randomized, double blind assessment of safety, pharmacokinetics, and effect of treatment on plasma viremia. Entry criteria Proof of Principle Study was conducted in two parts: Subjects remained in the CRU on Study Days 1, 2, 3, 4, and 14 for intensive PK and viral load sampling. Adults aged 18 to 65 No co-infections Genotype 1 infection Plasma viral > 100,000 IU/mL Enrollment in Cohort 6 restricted to treatment naïve subjects Cohorts 1-3 (9 active: 3 placebo) Cohorts 4-6 (6 active: 1 placebo) Cohort 1: 30 mg q.d. Cohort 4: 100 mg t.i.d. Cohort 2:100 mg q.d. Cohort 5: 200 mg t.i.d. Cohort 3: 300 mg q.d. Cohort 6: 300 mg t.i.d. SCYNEXIS Proprietary and Confidential Information

Safety Summary No deaths or serious adverse events occurred. No subjects discontinued treatment. One Grade 4 laboratory event (elevated triglycerides following consumption of a high fat meal); resolved without interrupting treatment. One subject missed one dose of study medication due to transient nausea on Day 3. All other treatment-related adverse events resolved without interruption of study medication. SCYNEXIS Proprietary and Confidential Information 14

SCY-635-104: Mean and Median HCV RNA Profiles for Cohort 6 vs SCY-635-104: Mean and Median HCV RNA Profiles for Cohort 6 vs. Pooled Placebo Change in HCV RNA for subjects treated with SCY-635 was significant (p<0.05) from Study Days 2 through 15 (Student’s t-test; one-tailed, unequal variance) SCYNEXIS Proprietary and Confidential Information

Summary Thioether derivatives of [4-hydroxy-Leu]4-cyclosporin A have potent activity in the HCV replicon assay and have low immunosuppressive potential. SCY-635 is a potent inhibitor of the enzymatic activity of Cyclophilin A. The potency of SCY-635 in the replicon system is unaffected by the addition of added serum. SCY-635 achieved a mean 2.3 Log(10) reduction of plasma viral RNA when delivered to treatment naïve HCV patients at a dose of 300 mg t.i.d. No clinical or laboratory evidence of dose limiting toxicities was observed. SCY-635 is a new cyclophilin inhibitor that has robust anti-HCV activity as a single agent and further, dose escalating, clinical studies are planned. SCYNEXIS Proprietary and Confidential Information

Contributors Chemistry Clinical Biochemistry SCYNEXIS DMPK Keqiang Li Andrew Scribner Biochemistry Richard Harris Bernard Scorneaux Mari Vogel Sarah Moser DMPK Steve Wring Ryan Randolph Craig Smittley Clinical Sam Hopkins (CSO) Pam Rusnak Betty DeMassimo SCYNEXIS Yves Ribeill (CEO) Collaborators Zhuhui Huang (SRI) Gunther Fischer (Max-Planck) Hengming Ke (UNC) Doug Heuman, M.D. (Maguire MC) Edith Gavis, R.N. (Maguire MC) Jay Lalezari (Quest) Eileen Glutzer, R.N. (Quest) SCYNEXIS Proprietary and Confidential Information