SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of report (Date of earliest event reported): October 3, 2018
WAVE LIFE SCIENCES LTD.
(Exact name of registrant as specified in its charter)
(State or other jurisdiction
7 Straits View #12-00 Marina One East Tower
|(Address of principal executive offices)||(Zip Code)|
Registrants telephone number, including area code: +65 6236 3388
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):
Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☒
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☒
|Item 7.01|| |
Regulation FD Disclosure.
On October 3, 2018, Wave Life Sciences Ltd. (the Company) held a presentation entitled Stereochemical Control of Antisense Oligonucleotides Enhances Target Efficacy at the 14th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS) in Seattle, Washington. The presentation contains data highlighting advances in the Companys novel chemistry platform and its ability to precisely design, optimize and manufacture stereopure oligonucleotides. A copy of the presentation is furnished as Exhibit 99.1 to this Current Report on Form 8-K.
The information in this report furnished pursuant to Item 7.01 shall not be deemed filed for the purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the Exchange Act), or otherwise subject to the liabilities of that section. It may only be incorporated by reference in another filing under the Exchange Act or the Securities Act of 1933, as amended, if such subsequent filing specifically references the information furnished pursuant to Item 7.01 of this report.
|Item 9.01|| |
Financial Statements and Exhibits.
The following exhibit relating to Item 7.01 shall be deemed to be furnished, and not filed:
|99.1||Wave Life Sciences Ltd. Presentation at OTS on October 3, 2018|
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
|WAVE LIFE SCIENCES LTD.|
Date: October 3, 2018
Keith C. Regnante
Chief Financial Officer
Stereochemical Control of Antisense Oligonucleotides Enhances Target Efficacy Chandra Vargeese, PhD SVP, Drug Discovery Wave Life Sciences October 3, 2018 Exhibit 99.1
Acknowledgements & Disclosures All Wave Life Sciences employees Prof. Gregory Verdine, co-founder & Director Wave Life Sciences Prof. Takeshi Wada, co-founder Wave Life Sciences Prof. Matthew Wood, Department of Physiology, Anatomy and Genetics, University of Oxford Chandra Vargeese is an employee of Wave Life Sciences
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, preclinical and clinical studies, business strategies, research and development plans, collaborations and partnerships, regulatory activities and timing thereof, 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.
Architects of transformation Wave Life Sciences is a clinical-stage, genetic medicines company unlocking the potential of a proprietary chemistry platform that enables the precise design, optimization and production of stereopure nucleic acid therapies. Wave has reinvented the design, synthesis and manufacture of nucleic acid therapies to potentially optimize potency, durability and safety PRECISION Ability to design nucleic acid compounds that have one defined and consistent profile SCALE Platform potential across multiple modalities and tissues Internal expertise and capacity for large-scale GMP manufacturing Wave’s chemistry platform is built on a foundation of two core capabilities
History of oligonucleotide therapeutics Backbone modifications • Introduce chiral centers • Generate mixtures Sugar modifications Drug approvals (FDA) Chiral Phosphorothioate Chiral Phosphorodiamidite Morpholino (PMO) Mixtures of 2n molecules (n=No. of chiral centers) SEQUENCE STEREOCHEMISTRY CHEMISTRY Fomiversen Pegaptanib Mipomerse Eteplirsen Nusinersen Patisiran Stereopure ASOs enter clinic Wave Stereopure ASOs Oka N, Wada T, Saigo K. JACS. 2002 Stec WJ, et al. J Am Chem Soc. 1989 ~500,000 different molecules per dose
Advances in stereopure oligonucleotide synthesis and manufacturing Versatility in Chemistry Versatility in Scale High Crude Purity • Improved synthetic capabilities • Custom building blocks – Tunable ‘R’ groups – Various 2’-modifications Candidate Optimization and Selection GMP Quality High-throughput scale Manufacturing scale
Wave’s chemistry platform INDICATION, TARGET TRANSCRIPT, PRODUCT PROFILE SPLICING RNAi ANTISENSE DEFINE MODALITY DESIGN & OPTIMIZE VALIDATE SEQUENCE STEREOCHEMISTRY CHEMISTRY Free uptake in cellular models Animal models POTENCY STABILITY SPECIFICITY IMMUNE POTENCY DURABILITY TOXICOLOGY Candidates
INDICATION, TARGET TRANSCRIPT, PRODUCT PROFILE SPLICING RNAi ANTISENSE DEFINE MODALITY DESIGN & OPTIMIZE VALIDATE SEQUENCE STEREOCHEMISTRY Free uptake in cellular models Animal models POTENCY STABILITY SPECIFICITY IMMUNE POTENCY DURABILITY TOXICOLOGY Candidates CHEMISTRY Wave’s chemistry platform: Antisense
Precision RNase H-mediated RNA degradation Antisense In RNase H1 assay, ASOs were pre-annealed to surrogate MALAT1 mRNA (1:1, Cf=5 mM). RNase H (250:1, E:S) was added and quenched with EDTA at the indicated times. Products were quantified, and V0 was calculated from the best-fit line (n=3 per time point). RNA-Stereorandom ASO RNA-Stereopure ASO Rp Sp Rp or Sp Linker Nucleotide Initial Velocity (V0) Cleavage Activity
Potency of stereopure oligonucleotides under in vitro free-uptake conditions translates in vivo In vitro: In iCell neurons, 10, 30, 100, 300, 1,000 or 3,000 nM ASO was added to iCell neurons under free-uptake conditions. 4-days post-treatment, RNA was harvested and processed. MALAT1 mRNA expression was determined by qPCR (n=2 per concentration). In vivo: Mice received a single IVT injection. 1 week post-injection, tissues were frozen and processed for RNA. MALAT1 mRNA expression was determined by qPCR (n=7). Antisense MALAT1 Knockdown in Posterior Mouse Eye at 1 Week MALAT1 Knockown in iCell Neurons In Vitro In Vivo
Stereopure oligonucleotides enhance potency across tissues in vivo Muscle Single SC injection in Mice (25 mg/kg) Eye Single IVT injection in Mice (50 µg) CNS Single ICV injection in Mice (50 µg) Antisense Tissues were harvested 1 week post-dose and processed for RNA. mRNAs were quantified by qPCR. Plots show relative fold change or percentage mRNA remaining with respect to control mRNA. Each symbol represents one animal. SR = Stereorandom
Stereopure oligonucleotides induce potent and durable activity in the eye Tissues were harvested at the indicated time points, post-dose and processed for RNA. mRNAs were quantified by qPCR. Plots show percentage mRNA remaining with respect to control mRNA. Each symbol represents one animal. 9-fold greater eye volume Antisense (OTS poster #030)
Stereopurity improves potency and durability of GalNAc-conjugated oligonucleotides Antisense Stereopure ASO yields potency comparable to state-of-the-art GalNAc-dsRNAi Stereopure ASO yields durable effect in transgenic mice
INDICATION, TARGET TRANSCRIPT, PRODUCT PROFILE SPLICING RNAi ANTISENSE DEFINE MODALITY DESIGN & OPTIMIZE VALIDATE Free uptake in cellular models Animal models POTENCY STABILITY SPECIFICITY IMMUNE POTENCY DURABILITY TOXICOLOGY SEQUENCE STEREOCHEMISTRY CHEMISTRY Candidates Wave’s chemistry platform: Splicing
Stereopure oligonucleotides induce exon 23 skipped transcript (OTS poster #119) Splicing Stereorandom (SR) Stereopure
Stereopure oligonucleotide induces dystrophin protein restoration and reduces elevated serum enzymes Splicing Multiple Doses (in vivo mdx23 mice) 70-90% of natural dystrophin restoration 87% reduction in creatine kinase levels ALT=alanine aminotransferase; AST=aspartate aminotransferase; CK=creatine kinase; GLDH=glutamate dehydrogenase. Serum and plasma clinical chemistry were measured with an Olympus AU640 (Olympus America) and the manufacturer’s reagents and procedures. Dystrophin Protein Restoration Serum Enzyme Levels
Stereopure surrogate restores dystrophin in muscle fibers after single dose Neuro DMD PBS DMD-1742 Immunohistochemistry of dystrophin in gastrocnemius in mdx23 mice at 4 weeks 10X Experimental conditions: mdx23 mice received a single IV injection of PBS or DMD-1742 (150 mg/kg). Immunohistochemistry: Blue: Nuclei, Hoechest; Yellow: Rabbit anti-Dystrophin(#ab15277) 1:400 diluent, 555/Cy3, Yellow is a fake color for Cy3. 10X magnification.
Stereopure surrogate restores dystrophin in muscle fibers after multiple doses Experimental conditions: mdx23 mice received 4 weekly IV injections of PBS or DMD-1742 (150 mg/kg). Immunohistochemistry: Blue: Nuclei, Hoechest; Yellow: Rabbit anti-Dystrophin(#ab15277) 1:400 diluent, 555/Cy3, Yellow is a fake color for Cy3. 10X magnification. Neuro DMD PBS DMD-1742 Immunohistochemistry of dystrophin in gastrocnemius in mdx23 mice at 4 weeks 10X 0X
Stereopure oligonucleotide traffics to nuclei in myoblasts Cultured myoblasts were treated with 10 mM of the indicated ASO under free-uptake conditions. ASO was detected with ViewRNA; nuclei are stained with DAPI. Exon skipping efficiency was quantified by Taqman assay. Nuclear ASO was quantified with ImageJ software (https://imagej.nih.gov/ij/). Stereorandom (SR) Stereopure Stereopure (opposite) Splicing Stereopure ASO enters the nuclei of cultured myoblasts and promotes efficient exon 51 skipping WV-3 SR WV-5
Mdx23 mice were treated with a single 30 mg/kg dose of optimized, stereopure ASO (IV). Tissues were collected 24-hours post-dose. ASO was detected using ViewRNA, and nuclei were stained with Hoechst33342 or hematoxylin. Nucleus: Hematoxylin (blue) ASO: ViewRNA (red) Nucleus: Hoechst33342 (blue) ASO: Fast Red (pink) Stereopure oligonucleotides access myofiber nuclei in mice Splicing Stereopure ASO targeting exon 53 rapidly enters myofibers in mdx23 mice 30 mg/kg, 24 hours Bright-field view Fluorescence-field view (z stack)
We have developed a scalable process for generating stereopure ASOs Compared with stereorandom, stereopure ASOs are: Taken up more readily by cells under gymnotic conditions in multiple cell lines More potent in multiple tissues More durable in vivo Optimized, stereopure ASOs exhibit improvements in multiple properties: Precision and activity of RNase H Potency correlation between in vitro and in vivo Exon skipping efficiency Rapid and broad tissue distribution Nuclear uptake Summary
Future: Improving nucleic acid therapeutics through greater understanding of protein-nucleic acid interactions Understanding innate immune receptor and broader DNA/RNA-protein interactions TLR9 bound to stereopure, CpG-containing oligonucleotide Stereochemistry of CpG-containing oligonucleotides impacts TLR9 activity Fold-increase TLR9 signaling Concentration ASO (mM)
Future: More potent and durable CNS targeting with new chemistries PBS = phosphate buffered saline; Ctx = cortex; Str = striatum; Cb = cerebellum; Hp = hippocampus; SC = spinal cord. PBS Stereopure Cortex Spinal cord 15.9 nM 150 nM 2,900 nM Stereopure Stereopure Stereorandom IC50 MALAT1 Knockdown in Mice 10 weeks after single 100 µg injection MALAT1 Knockdown in Mice 1 week after single ICV injection MALAT1 Knockdown in Human iCell Neurons Under Free-Uptake Conditions Antisense In vitro potency In vivo potency In vivo durability