Raymond F Schinazi Chairman Raymond F. Schinazi, Chairman Jeffrey A Meckler Interim CEO Jeffrey A. Meckler, Interim CEO Jefferies Healthcare Conference June 4, 2015 Developing the next generation of antiviral therapies 1
Forward-looking Statements This presentation contains forward-looking statements, including the timing of our drug development programs. Risks include delays in manufacturing created by third parties and the ability of clinical research organizations to recruit patients. Forward looking statements also are prefaced by words such as "expect " "plan " Forward-looking statements also are prefaced by words such as "expect," "plan," "intend," "anticipate," and similar words. Forward-looking statements are based on our current expectations and assumptions regarding our business, the economy and other future conditions. Because forward-looking statements relate to the g future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict. Our actual results may differ materially from those contemplated by the forward-looking statements for a variety of reasons including those contained in our Form 10 K as amended for the year reasons, including those contained in our Form 10-K, as amended, for the year ended December 31, 2014. We caution you, therefore, against relying on any of these forward-looking statements. They are neither statements of historical fact nor guarantees or assurances of future performance. We do not undertake any duty to update these forward-looking statements. 2
Cocrystal Pharma Today A leading antiviral company developing therapies that inhibit the essential replication functions of a virus. World renowned scientific leadership • Dr. Roger Kornberg (2006 Nobel Prize winner in Chemistry) • Dr. Raymond Schinazi (founder of Pharmasset, Idenix, Triangle) • Proprietary technologies • Structure-based drug design platform • Proprietary nucleoside chemistry • Preclinical assets HCV Preclinical assets - HCV • CC-1845 (Nuc) • CC-2068 (NS5A) • CDI-31244 (NNI) • CC 31326 (H li CC-31326 (Helicase) ) • Other Therapeutic targets • Influenza, Norovirus • 3
Opportunity There exists significant unmet medical needs across a large variety of viral infections…. HCV HCV • • 80-170 million chronic infections, >350,000 deaths/year • Growing consensus large market opportunity post-2020 • Influenza • 3-5 million severe cases/year, >250,000 deaths/year • Constantly mutating virus evades current therapeutic and vaccine • approaches approaches Estimated economic impact of seasonal influenza in U.S. varies from • ~$50B to ~$150B (CDC & other research estimates) Norovirus • >250 million acute cases, 3-5 million deaths/year • Large immunocompromised patient population as well as stockpile • markets markets Economic cost in US alone estimated >$5B (University of Michigan) • 4
Technology Platform Structure-Based Drug Discovery Approach – Cocrystal’s integrated suite of drug discovery and design technologies platform with enhanced target selection process - higher probability of yielding successful drug candidates from the start. Example of HCV fragment hits Advantages I hibit Inhibitor C C Inhibitor B � Provides 3D structure of inhibitor complexes at near-atomic resolution with immediate insight to guide SAR ith i di t i i ht t id SAR Inhibitor A � Identifies novel binding sites � Allows rapid turnaround of structural information through highly automated X-ray data processing and refinement X-ray data processing and refinement 5
Cocrystal Pharma Evolution Cocrystal Pharma RFS Pharma Founded in 2008 Founded in 2004 High throughput cocrystal World class nucleoside • • evaluation and structure- discovery/development based drug design team Nobel prize winning expertise N b l i i i ti HCV: Novel nucleosides HCV N l l id • • HCV: NNI & first-in-class (Nuc) and prodrugs • Helicase inhibitor HCV: NS5A Inhibitors • Active discovery programs in y p g Norovirus: Strong & g • • other viruses including: broad Nuc IP influenza and noroviruses Merger in Nov 2014 6
Pipeline Lead Lead Viral Disease Discovery Optimization Preclinical IND Phase I/II Hepatitis C CC-1845 (Nuc) CC 2068 (NS5A) CC-2068 (NS5A) CDI-31244 (NNI) CC-31326 (Helicase) Norovirus CC-1845 (Nuc) Influenza 7
HCV Approach Four different classes of drugs: Expect a pan-genotypic, shorter therapy duration and high SVR CC ‐ 1845 Nuc Cocrystal’s CC ‐ 2068 CC 2068 NNI NNI NS5A NS5A HCV HCV CDI ‐ 31244 CDI 31244 regimens Helicase CC ‐ 31326 8
Nucleoside Prodrug Inhibitors HCV Treatment One of the best classes of anti-HCV direct acting antiviral agents (DAA) • Excellent safety and potency, pan-genotypic and high barrier to resistance Excellent safety and potency, pan genotypic and high barrier to resistance • Must be metabolized to active nucleoside triphosphate form • Prodrugs: bypass non-productive first phosphorylation step and target the liver • Liver cell nucleus prodrug NS5B viral ✖ Chain ‐ termination polymerase HCV No virus replication GGAUAUAA ★ Activation Activation rNTP NTP CC CCUAUAUUACGAAU CG (host kinases) viral RNA genome 9
CC-1845: Pan-Genotypic Nucleoside Compelling potential drug properties Novel pan-genotypic nucleoside Novel pan genotypic nucleoside CC-1845-based combination regimen CC 1845 based combination regimen • • prodrug: delivers three active expects a shorter duration than nucleoside 5’-triphosphates – One Harvoni IND needed Single dose (max. tolerated dose): Single dose (max tolerated dose): • • 2 of the 3 active metabolites of 1,000 mg/kg in both rats and dogs • showed comparable potency to 7-day toxicity: *NOAEL in rats (500 • sofosbuvir mg/kg/day) and in dogs (50 mg/kg/day) and in dogs (50 Equivalent NTP potency compared to mg/kg/day) • sofosbuvir in human hepatocytes Anticipate QD dosing based on t1/2 in • No cytotoxicity observed including No cytotoxicity observed, including primary human hepatocytes (two of primary human hepatocytes (two of • mitochondrial assays the NTPs have T1/2 greater than 20 hr etc.) No resistant virus selected (3 • attempts) tt t ) IND IND-enabling studies (70% complete) bli t di (70% l t ) • * NOAEL = no observable adverse effect level 10
CC-1845: Nucleoside Profile Objective: Develop novel nucleoside analog inhibitors that are: � Cascade of rNTP metabolite � Potent generation g � Non ‐ toxic � Half ‐ lives of rNTP (two NTPs >20 h � High barrier to resistance and one NTP: 5.9 h) will support � No drug ‐ drug interactions once ‐ a ‐ day dosing. Pan ‐ genotypic activity Cytotoxicity 11 11
CC-2068: Pan-Genotypic NS5A Novel highly potent, pan-genotypic, NS5A inhibitor • (GT1b EC 50 , < 10 pM) ( p ) 50 CC-2068 produces an active metabolite (also a pM HCV inhibitor) • Single dose (max tolerated) in rats & dogs: 1,000 mg/kg • 7-day oral toxicology in rats: NOAEL 800 mg/kg/day • Potentially an excellent combination drug candidate with Nuc and/or • NNI IND-enabling studies in progress • * NOAEL = no observable adverse effect level 12
CC-2068: Pan-Genotypic NS5A CC-2068 showed excellent potency against NS5A drug resistant � variants variants CC-2068 showed no cytotoxicity � Large therapeutic index � 13
CDI-31244: Pan-Genotypic NNI • Highly potent (nM) and active against all genotypes (1 – 6) g y p ( ) g g yp ( ) • No cytotoxicity across cell systems • Favorable PK and liver targeting (>2,000 ‐ fold above EC 50 ) • Potential Best ‐ in ‐ Class NNI based on pan ‐ genotypic activity and high barrier to resistance • IND ‐ enabling studies in progress 14
CDI-31244: Pan-Genotypic NNI Cocrystal’s NNIs show a high barrier to drug resistance HCV ‐ 796 (Viropharma) 1800 nge 1600 Drug resistance variants fold cha 1400 S365T (NNI ‐ 4) Cocrystal’s Cocrystal’s 1200 Backup Leads NNI ‐ 4 Leads N316Y (NNI ‐ 4) 1000 IC 50 f 800 800 L419M (NNI 2) L419M (NNI ‐ 2) 600 S282T (Nuc) 400 200 0 1 2 3 4 5 31228 31244 959 985 HCV ‐ 796 15
Hepatitis C Helicase Program Provides unique opportunities for ideal drug combinations Creates a new option for HCV combination therapy Creates a new option for HCV combination therapy • • First-in-class pan-genotypic inhibitors (new mechanism of action) • Highly conserved drug binding mode demonstrated in all • genotype crystals developed (1-6) Potentially an ideal combination candidate with HCV NNI, Nuc • prodrug, NS5A, and/or protease inhibitors Inhibits essential viral RNA unwinding process • No cytotoxicity due to lack of ATPase inhibition • 16
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