Our experience with NIH/SMARTT resources to bring PepducinsTM from the bench-into-the-clinic Athan Kuliopulos, MD PhD, CEO, Oasis Pharmaceuticals 19th Annual HHS SBIR/STTR Conference Milwaukee, WI ! November 7, 2017 Overview # $%&'()*(+,-./%0)*(12,34.5'/.06)7,859:,34.,/5.;)<*(*)'<,73'+. *(39,)<*(*)'<,35*'<7,=*34,>?@,'(%,A2$B11,70//953 # C(35./5.(.05*'<,D')E+590(% # CF/.5*.().,=*34,-G;!"HI,?>JK,-4'7.,!,'(%,-4'7.,",35*'<7 # LM$ " The Company 1. Overview and background of Oasis Pharmaceuticals N Oasis Pharmaceuticals !"##"$% &&&&&'()(*$+"%,&+(+-./"%012#(-&34(52+(.6/#&7$5&34(&35(238(%3&$7 #()(5(&915$6/:"%;28823$5<&2%-&=>&-"#(2#(# # ?-,895,-$B",<*/9/./6%.7,P<.%,=*34,/5*95*3Q,%'3.,98,"R!S # 145..,)<*(*)'<,)'(%*%'3.7,4'&.,T..(,3.73.%,*(,'(*:'<7,895,.U)')Q,'(%,7'8.3Q *()<0%*(+,?>J;.('T<*(+,VW-,730%*.7 # -4'7.,!,)<*(*)'<,35*'<,*(,>@XY>$A@,9(,7)4.%0<.,895,"R!H # A.(*95,<.'%.574*/,3.':,=*34,%../,.F/.567.,*(,/5.;)<*(*)'<,'(%,)<*(*)'<,%50+ %.&.<9/:.(3 # A/*(;9Z,859:,10[7,2.%*)'<,\.(3.5,=*34,)9(6(0*(+,)9<<'T95'69(,=*34 ')'%.:*),*(&.76+'3957 O Pepducin Pipeline H@IF -5.)<*(*)'< ?>J -4,! -4," -4,N !"#$%&'()"*+,*+( J$%2*/$4$*"/&K3(23$4(+266#&LJ@KMN&?@0FGB" O-"$+234"/&H.*8$%25<&E"15$#"#&LOHEN&?@0FGB/ D"-%(<&E"15$#"#&?@0FGB" 2;%6"'()+$: -."/(01234(5%6"',78 H@IV 59$%:#%*"* ?@0ABC H@IA&05<=*(>+?"',7(@+/;+$8 59$%:#%*"* &&&&&&&&&&&&&&&&&&&&&&&&&&&=*"%"/2*R5"2*#S,$)&&&&J=RCFBTACCCU&&J=RCFBTACCC S HP0AFQ&@/.3(&/$5$%25<&"%3(5)(%6$%# Oasis Team Athan Kuliopulos, MD PhD, CEO • Inventor of Pepducin™ technology • Founder, CEO of Oasis Pharmaceuticals, LLC, 2013-present • Founder, CSO of Ascent Therapeutics, 2007-2010 • Raised $21M (A) from Novartis Option fund, HCV, TVM, plus additional funding ($10M) and partnerships with Novartis, J&J, and other Pharma • PI of NIH/NHLBI P50 to develop a PAR1 pepducin PZ-128 (currently enrolling PCI patients in a multi-center Phase 2 study) Lidija Covic, PhD, CSO • Co-Inventor of Pepducin™ technology • Founder, CSO of Oasis Pharmaceuticals, LLC, 2013-present • Founded Ascent/Anchor: SAB Member John Amedio, PhD, VP Chemistry and Manufacturing • CMC for lipopeptide therapeutics including PZ-128 • VP, Manufacturing and Chemistry, Seaside Therapeutics, Ziopharm Richard Looby, Director of Peptide Chemistry • Expert in pepducin design and synthesis Dana Minnick, PhD Regulatory Toxicology, IND-enabling studies, FDA Interactions Clinical Team: NASH CRN-Dr. Manal Abdelmalek, MD, Hepatologist, Duke Medical Center IPF-Dr. Steven Nathans, MD, Chief Pulmonary Medicine, Inova, VA AD-Dr. Alice Gottlieb, MD, Dermatologist-in-Chief, Tufts University School of Medicine 6 Pepducin technology 2.PAR2-a difficult-to drug receptor: Solution: Pepducin technologyTM ] Protease-Activated Receptor-2 (PAR2) J*U)0<3,39,')).77,12,%9:'*(,)95.,^<*+'(%_,7*3.7,'(%, Xa/TrypsinD<9)E,/593.'7.;')6&'3.%,5.)./395 Synthetic SKGR Ligand N 46 LDPR-SFLLSKGR Ligand R N OR LBS-1 LBS-1 Ligand LBS-2 N 37 LBS-2 TM3 TM6 ON TM3 OFF TM6 G!"# + G! + "# GDP GTP PepducinTM Technology Pepducin Lipopeptide structure: GPCR 1. Synthetic Peptide • 7-19 amino acid fragment of GPCR intracellular loop • Nature-engineered specificity 2. Hydrophobic moiety • Cell-penetrating / membrane tethering lipid (e.g., palmitate) 3. Screened PAR2-derived pepducins • Identified PZ-235 Sevigny et al PNAS (2011) 108:8491-6 ` PAR2 Antagonist: Rational Design of PZ-235 • Based on the PAR2 receptor structural model • Pharmacologic data identified key residues (red and blue) important in eliminating PAR2 receptor constitutive (ligand independent) activity -$B",/./%0)*(-$B", -G;"NS -$B" -$B" !R PD-PK Pepducins are stable and have long half-lives in plasma t1/2~4-6h !! W"$-"#35"1.6$%&$7&AV=0*21(**(-&&HP0FGB Into fibrosis-prone Organs, e.g. lung, liver, kidney PAR2 pepducin has long tissue half-life and is widely distributed !" Opportunity: Large Unmet Medical Need in IPF • Two approved oral drugs sold at high cost Nintedanib (Ofev) Boehringer Ingelheim Pirfenidone (Esbriet) Roche • Limited benefit with high potential side effects • IPF market to surpass $1 Billion in 2017 H@IF&"#&4",4*<&.+5(,.*23(-&"%&*.%,&6##.( 75$8&OHE&#.1X(/3#&2%-&"#&/$55(*23(-&Y"34 Y$5#(&/*"%"/2*&$.3/$8( 13 Summary of effort in IPF • Product: OA-235c Lead Clinical Candidate Idiopathic Pulmonary Fibrosis (IPF) • Identified OA-235c as a protease-resistant lipopeptide • SubQ injectable developed for systemic administration; aerosol delivery is a long-term goal • PK conducted in mouse and dog showing high AUC and sustained drug levels in plasma • Milestones completed in partnership with NHLBI SMARTT program • Dose-escalation dog safety study • CV (GLP) dog pharmacology-tox study • Genotox panel (GLP) • AMES • Mouse micronucleus study (up to 200 mg/kg) • Chromosomal abnormality (Clastogenic) • Remaining IND-enabling studies - funding pending !O Summary of efforts in NASH • Product: OA-235i Lead Clinical Candidate • Nonalcoholic steatohepatitis (NASH) • Currently no approved treatments for NASH except for life style change and antioxidants • Major milestones accomplished: • Identified OA-235i with 25-fold higher potency • SubQ injectable developed for daily-to-weekly administration • PK conducted in mouse, rat, dog showing high AUC and sustained drug levels in target tissue-namely liver • 28 day rat and 7 day dog completed showing high therapeutic safety margin • Pre-IND meeting held with FDA and identified regulatory pathway through IND and phase 1 trial • Additional indication is kidney fibrosis • Expected IND in mid-2018 for NASH (funding secured) • First-in-human trial in NHV and NASH subjects in late-2018 (funding secured): single and multi-dose ascending study to be done at Duke Medical Center !S Future earning Projections for entire market !a Competition in NASH $GILD(ACC) $BMS(FGF-21) Majority of experimental Limited number of anti-fibrotic agents agents target steatosis !] Z#321*"#4(-&I$*(&$7&H@IF&"%&[")(5&E"15$#"#&2%-&O%;28826$% Normal NASH Fibrotic/Cirrhotic Liver Coagulation proteases Liver Inflammatory proteases protease Activated cleavage PAR2 PAR2 TF in Cirrhotic liver Stellate Cell Proliferative Myofibroblast LX-2 Proliferation/ERK signaling PAR2-ab Extracellular matrix deposition collagen 2o-ab Production of inflammatory Cytokines !H TNF!, IL-6, MCP-1, IL-8 @%60J@E['&2/6)"3<&"%&#()(5(&G&Y((\&!='&8$-(* !` @%60915$6/&2,(%3&"%&Q&Y((\&==*V&8$-(* '(*2<(-&R5(238(%3&Y"34&HP0FGB&K.++5(##(#&&[")(5&E"15$#"# "R W5$2-&!?@&7$5&H@IF&H(+-./"%&3$&K.++5(##&J@KM >%?+(%A(,'&%/(0>%28B @&H@IF&+(+-./"%&Y"**&1(&/*"%"/2**<&-"](5(%623(-&1<&2/6%,&2#&2%^ CD(,/&3E#$%&'(,F+/;B(4'<3,95,5.&.57.,PT596),*(%*).7 GD(,/&3"/H,::,;%$I(,F+/; 4D(A,JI(7"K+$3*<66$+**"K+(,F+/;B(D<9)E,95,5.&.57.,/59+5.77*9(,98,8'bQ,<*&.5K,4./'39).<<0<'5 *(c05Q,d$W1K,$A1eK,35*+<Q).5*%.7K,<9=.5,@T$!),*(,%*'T.6)7 L:67%I,$%#<*;(M9,$:,'%?I/,:"'(:,$.+$*(34'3,)955.<'3.,=*34,-$B",')6&*3QK,.f+f,@T$!)K $W1K,g$\7;T'7.%,'77'Q,98,:9(9)Q3.7 M9,*+(NNB(M$%%A3%A3@%/'+6;(0M%@8(A30%Q,*(,aR,/'6.(37,d!,:9(34,;,a,:9(34,903)9:.7eK,<*&.5 .<'739+5'/4QK,2B,<*&.5,73.'397*7,d)'(,'))05'3.<Q,:.'705.,hSi,)4'(+.e "! Timeline for Completion of IND/Phase 1 for OA-235i in NASH # J@KM0H5(OJ'&8((6%,&Y"34&E'@&Y2#&4(*-&_G&FCATS&@%&2,5((8(%3&Y2# 5(2/4(-&$%&34(&+5(/*"%"/2*&2%-&/*"%"/2*&-()(*$+8(%3&+*2%#&7$5&34(&()2*.26$% $7&?@0FGB"&2#&2&35(238(%3&$7&J@KM&+26(%3#&"%&4.82%&/*"%"/2*&35"2*# # OJ'&3$&1(&/$8+*(3(-&1<&72**&$7&FCAQ # H42#(&A&K@'&2%-&!@'&"%&GV&JM>#&2%-&J@KM&#.1X(/3# 3$&1(&"%"623(-&"%&*23(&_V&FCAQ Q3 Phase 1 2016 Phase 1 GLP tox/safety IND complete FDA preIND initiation meeting completion FPFV Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 2017 2018 2019 "" Utilizing the NHLBI SMARTT Program 3. Developing a PAR1 pepducin from bench-to-Phase 2 clinical trials and beyond "N @/.3(&8<$/25-"2*&"%725/6$% • Interruption of oxygen supply to the heart • Causes death of the heart muscle • A leading cause of death in both men and women • Patients with ACS treated with PCI/stent and anti-platelet agents QTV CVD deaths vs. cancer deaths by age (United States) NHLBI Increased bleeding risk ?)(52**&`$2*#&$7&34(&H5$X(/3 ! )+K+7%6(,/("/;$,K+/%<*(,/&67,;+7+;(,F+/;(A%$(2@-(6,&+/;*(</?+$F%"/F(M@N ! )<,7(:%?+(%A(,'&%/(0>%28B CD(!,*;(%/*+;B(I2+"-&+5$3(/6$%&23&34(&#3253&$7&H=O&+5$/(-.5( GD(O+K+$*"#7+(:+'9,/"*:(%A(,'&%/^&H5$3(/6$%&-.5"%,&H=O&+5$/(-.5(&Y"34&3(58"%2* 42*70*"7(&aFV&4S ! @%/?<';(NP)3+/,#7"/F(+Q','IR(*,A+;I(,/?(;%S"'%7%FI(*;<?"+*("/(G(*6+'"+* ! M9,*+(NB(-,A+;IR(;%7+$,#"7";IR(?%*+($,/F"/F("/(4G(*<#T+';*(U";9(@2)V$"*.(A,';%$* MW('%$$+7,;+*(U";9(,/&367,;+7+;(+X+';* ! M9,*+(NNB(CYY(M,&+/;*(</?+$F%"/F(M@N (><7&'+/;+$R(M7,'+#%3'%/;$%77+?()%<#7+(Z7"/?+?R()%*+3+*',7,&%/ (-,A+;IR(LQ','I ! M9,*+(NNNB([4\(M,&+/;*(U";9(P-5L>NV2@-(%$(*;,#7+(@2)(06+/?"/F(A</?"/F8 ]<+*&%/B(@,/(;9"*(#+(,''%:67"*9+?(;9$%<F9(PN^(!</?"/F(>+'9,/"*:*_ Center of Hemostasis and Thrombosis Research at Tufts and NHLBI / RTI / SRI SMARTT 36 Opened IND "a Protease-Activated Receptor-1 (PAR1) Thrombin TR16 Synthetic Ligand N 26 LDPR Ligand 26 LDPRLDPR Ligand OR LBS-1 LBS-1 H Ligand i LBS-2 r N 42 LBS-2 TM3 TM6 ON TM3 OFF TM6 G!"# + G! + "# GDP GTP =$**2,(%&5(*(2#(# #.572/(&1$.%-&!!H0A& 75$8&+*23(*(3# !!HA&@/6)23(#&H@IA MMP1 cleaves PAR1 extracellular domain at a novel site R Trivedi et al.