Hitting HBV everywhere; why RNAi holds so much potential as a platform therapy in CHB

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1 Hitting HBV everywhere; why RNAi holds so much potential as a platform therapy in CHB Bruce D. Given, M.D. COO, Arrowhead Pharmaceuticals Science of HBV Cure 2018 June 8, 2018

2 Safe Harbor Statement This presentation contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of These statements are based upon our current expectations and speak only as of the date hereof. Our actual results may differ materially and adversely from those expressed in any forward-looking statements as a result of various factors and uncertainties, including, without limitation, our developmental stage and limited operating history, our ability to successfully and timely develop products, enter into collaborations and achieve other projected milestones, rapid technological change in our markets, demand for our future products, legislative, regulatory and competitive developments and general economic conditions. Our Annual Report on Form 10-K, recent and forthcoming Quarterly Reports on Form 10-Q, recent Current Reports on Forms 8-K, and other SEC filings discuss some of the important risk factors that may affect our ability to achieve the anticipated results, as well as our business, results of operations and financial condition. Readers are cautioned not to place undue reliance on these forward-looking statements. Additionally, Arrowhead disclaims any intent to update these forward-looking statements to reflect subsequent developments. 2

3 HBV Replication: HBsAg (Episomal [cccdna]) Pathway Spherical & Filamentous HBsAg Mature HBV virion Uncoating GOLGI ER Nuclear Transport RC-DNA viralrna Transcription Translation Surface Core Polymerase Reverse Transcription Immature Nucleocapsid Mature Nucleocapsid Dominant in naïve HBeAg-pos CHB Courtesy of S. Locarnini

4 HBV Replication: HBsAg (Integrated) Pathway HBsAg Pre-S truncation Spherical & Filamentous HBsAg Mature HBV virion Uncoating GOLGI ER Nuclear Transport Viral Integration RC-DNA viralrna Transcription Translation Surface Core Polymerase Reverse Transcription Immature Nucleocapsid Mature Nucleocapsid DSL- DNA Viral Integration Pathway DSL- DNA Dominant in HBeAg-neg CHB Courtesy of S. Locarnini

5 HBV Has Evolved to Defeat Challenges HBeAg has been proposed as important for tolerance development early Later mutations or therapies that lead to elimination of circulating HBeAg are not curative Mutation is a key defense Early Nucs were easily defeated with selection of resistant strains Core antagonist (CPAMs) are predicted to have similar issues cccdna can remain dormant for decades even in the setting of HBsAg seroclearance 5

6 All HBV RNA from cccdna can be targeted with one sirna All HBV transcripts, including pregenomic RNA, terminate with the same polyadenylation signal. A single sirna targeting this common region can reduce all HBV transcripts. Single sirna can reduce all HBV proteins Ghany & Liang (2007), Gastroenterology 132:

7 Patient : Naïve HBeAg Positive Patient H B s A g [IU /m L ] S in g le d o s e M u lti-d o s e C o h o rt 7 C o h o rt W e e k A L T [IU /L ] H B s A g [IU /m L ] A LT F irs t d o s e o f L a s t d o s e o f H B e A g [P E IU /m L ] S in g le d o s e M u lti-d o s e C o h o rt 7 C o h o rt W e e k H B c ra g [k U /m L ] H B c r A g [k U /m L ] H B e A g [P E IU /m L ] F irs t d o s e o f L a s t d o s e o f H B V D N A [IU /m L ] S in g le d o s e M u lti-d o s e C o h o rt 7 C o h o rt 1 0 H B V D N A [IU /m L ] W e e k H B V R N A [L o g U /m L ] L o g H B V R N A [L o g U /m L ] F irs t d o s e o f L a s t d o s e o f HBsAg, RNA, HBeAg, HBcrAg all respond similarly to a single dose of ARC-520 HBV DNA shows synergistic reduction in response to ARC-520 plus entecavir

8 HBV Has Evolved to Defeat Challenges HBeAg has been proposed as important for tolerance development early Later mutations or therapies that lead to elimination of circulating HBeAg are not curative Mutation is a key defense Early Nucs were easily defeated with selection of resistant strains CPAMs are predicted to have similar issues cccdna can remain dormant for decades even in the setting of HBsAg seroclearance Perhaps most ingenious of all is the use of DNA integration to continue HBsAg production in the absence of measurable evidence of ongoing cccdna activity 8

9 Patient : Naive HBeAg Negative Patient S in g le d o s e C o h o rt M u lti-d o s e C o h o rt 1 0 H B s A g [IU /m L ] S in g le d o s e C o h o rt 7 M u lti-d o s e C o h o rt 1 0 A LT H B s A g [IU /m L ] A L T [IU /L ] F irs t d o s e o f H B c r A g [k U /m L ] 1 0 F irs t d o s e o f L a s t d o s e o f W e e k 0 L a s t d o s e o f W e e k H B V D N A [IU /m L ] S in g le d o s e M u lti-d o s e C o h o rt 7 C o h o rt W e e k H B V R N A [L o g U /m L ] H B V D N A [IU /m L ] L o g H B V R N A [L o g U /m L ] F irs t d o s e o f L a s t d o s e o f HBsAg can remain elevated despite undetectable HBV DNA and borderline detectable cccdna driven activity (in this case, HBV RNA and HBcrAg) If cccdna could be totally ablated, would this patient seroclear?

10 Importance of integrated HBV DNA as S mrna source has changed RNAi strategy Single sirna can reduce all mrna from cccdna but can miss integrated HBV-derived mrna Combination of X and S triggers ARO-HBV Greater genome coverage (99.6% full match of 17mer in ~7000 HBV genomes) Reduce chance of resistance HBV Transcript Map New S Trigger Validated X Trigger Ghany & Liang (2007), Gastroenterology 132:

11 Summary Effective RNAi with careful trigger selection should be able to suppress all cccdna transcription products Synergy has been demonstrated with NUCs We expect synergy with other DAAs such as capsid inhibitors RNAi can also address HBsAg produced from integrated DNA Not clear what if any of the other classes will be effective here Functional cure might not be achievable in many/?most patients without addressing this HBsAg source RNAi likely to be a necessary component of finite treatment regimens, at least for the time being 11

12 Thank you! 12