Exon Skipping. Wendy Erler Patient Advocacy Wave Life Sciences

Transcription

1 Exon Skipping Wendy Erler Patient Advocacy Wave Life Sciences

2 Forward Looking Statements This document contains forward-looking statements. All statements other than statements of historical facts contained in this document, including statements regarding possible or assumed future results of operations, business strategies, development plans, regulatory activities, competitive position, potential growth opportunities, use of proceeds and the effects of competition are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause the actual results, performance or achievements of WAVE Life Sciences Ltd. (the Company ) to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. In some cases, you can identify forward-looking statements by terms such as may, will, should, expect, plan, aim, anticipate, could, intend, target, project, contemplate, believe, estimate, predict, potential or continue or the negative of these terms or other similar expressions. The forward-looking statements in this presentation are only predictions. The Company has based these forward-looking statements largely on its current expectations and projections about future events and financial trends that it believes may affect the Company s business, financial condition and results of operations. These forward-looking statements speak only as of the date of this presentation and are subject to a number of risks, uncertainties and assumptions, including those listed under Risk Factors in the Company s Form 10-K and other filings with the SEC, some of which cannot be predicted or quantified and some of which are beyond the Company s control. The events and circumstances reflected in the Company s forward-looking statements may not be achieved or occur, and actual results could differ materially from those projected in the forward-looking statements. Moreover, the Company operates in a dynamic industry and economy. New risk factors and uncertainties may emerge from time to time, and it is not possible for management to predict all risk factors and uncertainties that the Company may face. Except as required by applicable law, the Company does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. 2

3 Wave Life Sciences Overview Genetic medicines company developing targeted nucleic acid therapies for patients impacted by rare diseases Rationally designed nucleic acid therapeutics optimized by stereochemistry Three lead neurology candidates initiating clinical trials in 2017 Six development programs by end of 2018 Core focus and expertise in neurological rare genetic diseases Building manufacturing facility in Lexington, MA 3 3

4 Wave Life Sciences Overview Founded Chiralgen (Japan) Takeshi Wada Ontorii (USA) Greg Verdine Wave Life Sciences Formed Paul Bolno joins as CEO License Tuschl ssrnai Pfizer Collaboration 5 Hepatic Targets GMP Manufacturing Facility Secured Initiate Clinical Development for HD Programs Initiate Clinical Development for DMD Program Data readouts expected for 3 Lead Candidates in HD, DMD Entering Clinic in 2017 Foundation of Intellectual Property Manufacturing Capabilities Expanded Platform Expansion & Pipeline Development 4

5 Wave Life Sciences R&D Exploratory Platform Mid 2017 Neurology Portfolio Mid H 2017 Non-Core Portfolio 5

6 Natural Oligonucleotides Make Poor Drugs Natural oligonucleotides are unstable and are easily degraded in the body Chemistry must be applied to make them more stable 1 Freier SM, Altmann K-H. Nucleic Acids Res. 1997;25:

7 PROBLEM OF MIXTURES Stereoisomers are molecules with identical chemical composition but different three-dimensional arrangement of the atoms Stereoisomers often possess different pharmacologic properties Complex pharmacology of stereoisomer drug mixtures have a greater potential to diminish a drug s efficacy and safety Consequently full characterization of drug mixtures has been recommended by the FDA since 1992* * 7

8 NUCLEIC ACID BASED THERAPIES Phosphorothioate (PS) chemical modifications introduced into nucleic acid based therapies adopt random three-dimensional arrangements during synthesis This results in exponentially diverse drug mixtures with 2 N stereoisomers (N = number of PS) 19 phosphorothioate (PS) linkers Each PS linker = OR = 2 19 Mipomersen (2 19 = 524,288) Stereo-random Rp-stereoisomer Sp-stereoisomer Drug mixture 8

9 Importance of Chirality in Oligonucleotide Therapies Phosphorothioate (PS) backbone modification Provides good stability and bio-availability Introduces chirality to each linkage Uncontrolled chirality results in exponentially diverse drug mixtures Wave can control the orientation of the chiral linkages Precisely designing and controlling chirality improves stability, potency, specificity, and immunogenicity 9

10 Wave s Approach to Nucleic Acid Therapeutics Traditional Method Mixture of various drugs within dose Each nucleic acid therapeutic is made of strings of nucleotides held together by chemical linkages Wave Method Same drug throughout dose The orientation of atoms at each linkage occurs randomly using conventional synthesis, adopting either an up or down orientation These random orientations have implications for drug stability, efficacy, and safety Uncontrolled 19 phosphorothioate (PS) linkers Controlled (2 19 = 524,288) 10

11 Duchenne Muscular Dystrophy (DMD) Muscles are made up of bundles of fibers (cells), with a group of interdependent proteins on the membrane surrounding each fiber maintaining proper muscle cell function 1 One of these proteins, dystrophin, is critical for normal muscle function 2,3 DMD is caused by a defective gene for dystrophin 1 Muscular Dystrophy Association. Accessed at: June 7, 2017; 2 Kole R, Krieg AM. Adv Drug Deliv Rev. 2015;87: ; 3 Wallace GQ, McNally EM. Annu Rev Physiol. 2009;71:

12 Exon 51 Skipping Therapeutic Approach Exon skipping approaches enable production of functional dystrophin protein Partial restoration of dystrophin is expected to result in therapeutic benefit Dysfunctional splicing (Disease) Exon skipping (Potential Remedy) Pre-mRNA Pre-mRNA Wave oligonucleotide mrna mrna skip Protein Disrupted reading frame Protein Restored reading frame 12

13 Development of DMD Exon 51 Candidate Select Target Sequence Control Chirality Optimize Chemistry Test Lead Oligomer DMD Investigational Compound WVE Selected sequence Created panel of oligomers with same sequence but different placements of Rp and Sp linkages (control of chirality) Tested skipping efficiency of panels Oligomers with highest skipping efficiencies were chemically optimized Selected lead compound Tested lead for in vitro efficacy and in vivo tolerability Selected investigational compound 13

14 WVE : Exon 51 Skipping Efficiency WVE demonstrated a dose-dependent increase in skipping efficiency Dose Response on Skipping Efficiency (mrna, in vitro) m R N A S k i p p i n g E f f i c i e n c y ( % E x o n S k i p p i n g ) (4 Days) T r e a t m e n t C o n c e n t r a t i o n ( mm ) W V E P M O A S O P S A S O PMO ASO = Morpholino Antisense Oligonucleotide; PS ASO = Phosphorothioate Antisense Oligonucleotide; RNA skipping determined by quantitative RT-PCR. 14

15 WVE : Dystrophin Protein Restoration WVE demonstrated a dose-dependent increase in dystrophin protein expression in vitro Dystrophin ( kda) Vinculin (120 kda) Note: ASOs were delivered to DMD Δ48-50 cells under free-uptake conditions; ie, no transfection agents were used. 15

16 WVE : Dystrophin Protein Restoration Results on dystrophin protein expression were shown in two cell lines with different mutations Δ48-50 Myoblasts Δ52 Myoblasts Dystrophin ( kda) Vinculin (120 kda) PMO ASO = Morpholino Antisense Oligonucleotide; PS ASO = Phosphorothioate Antisense Oligonucleotide. Note: ASOs (10 µm) were delivered to DMD Δ48-50 cells under free-uptake conditions; ie, no transfection agents were used. 16

17 Wave s Investigational Compound DMD Exon 51, WVE Global clinical trials on track to initiate 2H 2017 Protocol development in collaboration with DMD community Study can include patients previously treated with other exon skipping therapies after washout period GMP manufacturing has been initiated 17

18 To all of our families who participate in clinical trials, THANK YOU we could not do this without you!