Nippon Shinyaku Co., Ltd. · TSE:4516
Nippon Shinyaku — Investor Day (October 2021)
58 slides from Nippon Shinyaku's investor day presentation, Oct 15, 2021
Slide 1: R&D Meeting 2021
R&D Meeting 2021 October 15, 2021 Nippon Shinyaku Co., LTD.
Slide 2: What we aim for
What we aim for Work on R＆D with more speed In-house PLCM development In-licensing 2
Slide 3: Acceleration of global development
Acceleration of global development Head Quarter（Japan） NS Pharma, Inc.（U.S.） Europe China U.S. Japan Beijing Representative Office Led by viltolarsen, we will accelerate our global development. 3
Slide 4: Pharmaceutical R&D strategy
Recalled from FY 2019 6th Five-Year Medium-term Management Plan presentation Pharmaceutical R&D strategy material (partially fixed) Expand the range of drug discovery to create new value by adding new modalities and technologies to our drug discovery platform where we created a small molecule drug U
Slide 5: Progress of products to be launched during the 6th Five-year Mid-term Management Plan
Progress of products to be launched during the 6th Five-year Mid-term Management Plan Progress of products planned for launch during the 6th Five-Year Mid-Term Management Plan (FY2019 to FY2023) In Japan and overseas Launch in Japan on May 2020 NS-065／NCNP-01（DMD） Launch in U.S. on August 2020 In-ho
Slide 6: Progress of products to be launched during the 6th Five-year Mid-term Management Plan
Progress of products to be launched during the 6th Five-year Mid-term Management Plan In Japan NS-304（CTEPH） Launch in Japan on August 2021 In Japan Domestic PⅢ trial in progress Macitentan（CTEPH） by Janssen Pharmaceutical K.K. PLCM In Japan Preparing for next NS-304（Arteriosclerosis obliterans） ver
Slide 7: Products added to pipeline after the start of 6th Five-year Mid-term Plan
Products added to pipeline after the start of 6th Five-year Mid-term Management Plan In Japan NS-304（Pediatric PAH） Domestic PⅡ trial in progress In Japan New NS-229（Inflammatory diseases） Domestic PⅠ trial in progress In Japan NS-401（BPDCN） Preparing for clinical development In addition to these pr
Slide 8: Progress of development: Nucleic acid products
Progress of development Nucleic acid products Pre clinical trial Clinical trial Launch NS-065／NCNP-01 NS-065／NCNP-01 Exon 50 Skipping Exon 53 Skipping Exon 53 Skipping （DMD） （DMD） （DMD） NS-089／NCNP-02 Exon 51 Skipping Exon 44 Skipping （DMD） （DMD） NS-035 Exon 45 Skipping Exon Trapping Inhibitor （DMD）
Slide 9: To establish new technology platforms
～To establish new technology platforms ～ 【Next generation modalities】 【Existing modalities】 9
Slide 10: R&D organization and activities
R&D organization and activities
Slide 11: R&D policy
R&D policy As a slogan for our R＆D division, we aim for “The creation of new drugs to be used worldwide”. We will strive to contribute to the society through creating highly unique and distinctive drugs in the pharmaceutical field of intractable disease where small number of patients are suffering a
Slide 12: R&D approach
R&D approach Approach towards drug discovery modalities In addition to our two pillars of drug discovery modalities in our R＆D; nucleic acid and small molecule, we will continue to work on new modalities such as gene therapy, that are suitable for targeting certain diseases. Promote data-driven dr
Slide 13: R&D organization
R&D organization Discovery Exploratory Research Dept. R＆D research Administration Pharmacokinetics and Safety Dept. Labs. Assessment Dept. Intellectual CMC R&D Dept. Property Dept. Discovery Research Laboratories in Tsukuba R＆D Operation Clinical Global Clinical Development Dept. Dept. Development D
Slide 14: R&D bases and in-house development
R&D bases and in-house development R&D expenditure (FY2020): 16.1 billion yen (13% of net sales) Research and development for drug Discovery Research discovery in pursuit of high added Laboratories (Kyoto) value In addition to small molecule drug discovery which we have cultivated over the years, we
Slide 15: Clinical development: Domestic development
Clinical development Domestic development (As of August 10, 2021) Development Code No. Mechanism Therapeutic Indications Origin Development phase (Generic name) of action field Co-development: Intractable Launch NS-065 / NCNP-01 Exon 53 National Center diseases/ Duchenne muscular dystrophy Nippon Sh
Slide 16: Clinical development: Domestic development
Clinical development Domestic development (As of August 10, 2021) Development Code No. Mechanism Therapeutic Indications Origin Development phase (Generic name) of action field mPGES-1 Nippon P II NS-580 Gynecology Endometriosis Nippon Shinyaku Inhibitor Shinyaku Liposomal Licensed-in from: combinat
Slide 17: Clinical development: Overseas development
Clinical development Overseas Development (As of August 10, 2021) Development Code No. Mechanism Therapeutic Indications Origin Development phase (Generic name) of action field Co-development: Intractable Launch NS-065 / NCNP-01 Exon 53 National Center of Nippon diseases/ Duchenne muscular dystrophy
Slide 18: NS-018 - Treatment for myelofibrosis
NS-018 - Treatment for myelofibrosis - Needs for new JAK inhibitors for patients with myelofibrosis (MF) Survey of 25 U.S. hematologists Q. Is a new JAK inhibitor needed for Q. What are the requirements desired patients with MF? for future JAK inhibitors? Greatly needed needed Necessity 16% 36% Use
Slide 19: NS-018 - Treatment for myelofibrosis
NS-018 - Treatment for myelofibrosis - Development phase Preparing overseas PII Origin Nippon Shinyaku Mechanism of action JAK2 inhibitor Indications Myelofibrosis Dosage form Tablet Potent and highly selective JAK2 inhibitor High efficacy and safety are expected for myelofibrosis Feature patien
Slide 20: NS-580 - mPGES-1 inhibition
NS-580 - Treatment for endometriosis - By inhibiting mPGES-1 selectively, inhibits the production of PGE₂ 20
Slide 21: NS-580 - Treatment for endometriosis
NS-580 - Treatment for endometriosis - Development phase PII trial Origin Nippon Shinyaku Mechanism of Membrane-bound prostaglandin E action synthase-1 (mPGES-1) inhibition Indications Endometriosis Dosage form Oral agent Treatment for endometriosis without hormonal effect and with possible analge
Slide 22: NS-229 - Treatment for inflammatory diseases
NS-229 - Treatment for inflammatory diseases - Selective inhibitory effect on JAK1 compared to existing drugs The JAK family consist of four members (JAK1-3 and TYK2). JAK1 involves pathogenesis of inflammatory diseases through various cytokine signals JAK1 inhibitors launched for rheumatoid a
Slide 23: NS-229 - Treatment for inflammatory diseases
NS-229 - Treatment for inflammatory diseases - Development phase PI trial Origin Nippon Shinyaku Mechanism of action JAK1 inhibition Indications Inflammatory diseases Dosage form Oral agent Potent and highly selective JAK1 inhibitor Feature High efficacy and good safety profiles are expected in
Slide 24: R&D progress in nucleic acid drug
R&D progress in nucleic acid drug
Slide 25: History of research on nucleic acid drugs
History of research on nucleic acid drugs 1980 1990 2000 2010 2020 Application of DDS, Poly(I): 2009 2013 2020 Poly(C) Research on nucleoside synthesis Clinical trials of NS-9 DDS Development Nucleoside of the CEM synthesis method Commence NS-065/NCNP-01 co-development (viltolarsen) Launched with NC
Slide 26: Characteristics of nucleic acid drugs
Characteristics of nucleic acid drugs (1) Activates toward targets which were difficult to approach with exisiting modalities Direct linkage to genetic information (2) Highly selective Precise targeting to the target gene sequence (3) Development requires expertness Sequence design, nonclinical eval
Slide 27: Treatment for Duchenne muscular dystrophy
Treatment for Duchenne muscular dystrophy
Slide 28: Duchenne muscular dystrophy (DMD)
Duchenne muscular dystrophy (DMD) ・ Incidence: about 1/3,500 male births ・ Number of patients: approximately 3,500-5,000/Japan ・ Cause: dystrophin gene mutation ・ Progressive muscular atrophy ・ Onset around age 3 years ・ Difficult to walk at age 11-13 ・ Respiratory failure in the 20s Out of cell Cel
Slide 29: Viltepso (viltolarsen: NS-065/NCNP-01)
Viltepso (viltolarsen: NS-065/NCNP-01) Origin: Nippon Shinyaku National Center of Neurology and Psychiatry (co-development) Feature: Antisense nucleic acids with morpholino oligomer structure High exon 53 skipping activity PMO March 2020 manufacturing and marketing Phosphorodiamidate approval
Slide 30: Mechanism of antisense nucleic acid
Mechanism of antisense nucleic acid - Block the target sequence - DNA Antisense nucleic acids: single-stranded nucleic Transcription acid with 20-30 bases Targets mRNA mRNA Work inside of cell Inhibits binding of functional factors by ACGTTGCAT binding against target sequences Antisense nucleic acid
Slide 31: Principles of DMD exon skipping therapy
Principles of DMD exon skipping therapy Dystrophin mRNA Full 51 52 53 54 length Full-length The reading frame Full-length mRNA doesn't fit. protein production Exon 52 51 52 53 54 Deletion Deletion of exon 52 No protein Fit the reading frame mRNA production Exon 52 51 54 Deletion mRNA lacking Short b
Slide 32: Overview of the viltolarsen clinical trials
Overview of the viltolarsen clinical trials 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 (by NCNP*) Phase I investigator-initiated clinical trial (Japan) Application Launch Dose: 1.25, 5, 20 mg/kg for 12 weeks in Japan in Japan Phase 1/2 dose-ranging study (Japan) Dose: 40, 80 mg/kg for Applica
Slide 33: From the presentation of the PPMD Annual Meeting
From the presentation of the PPMD Annual Meeting (23-26 June, 2021) PPMD: Parent Project Muscular Dystrophy
Slide 34: Extension Study: Time to Stand from the floor
Extension Study (Interim; ～109 week) Time to Stand from the floor (change from baseline) w: week Calculation of TTSTAND velocity: rise/sec * P < 0.05; (P < 0.01; ± P ≤ 0.0001) The viltolarsen-treated group showed significant improvement in time to stand from the floor compared with the natural histo
Slide 35: Extension Study: 10m run/walk time
Extension Study (Interim; ～109 week) 10m run/walk time (change from baseline) Improvement Improvement w: week Calculation of TTRW speed: meter/sec * P < 0.05; P < 0.01; P ± 0.0001 The viltolarsen-treated group showed significant improvement in time to 10m run/walk compared with the natural history c
Slide 36: Extension Study: 6-Minute Walk Test
Extension Study (Interim; ～109 week) 6-Minute Walk Test (change from baseline) w: week *P<0.05. The viltolarsen-treated group showed significant improvement in walking distance compared with the natural history control group. PPMD Annual Meeting (June 23-26, 2021) 36
Slide 37: Summary of the presentations at PPMD Annual Meeting
Summary of the presentations at PPMD Annual Meeting (June 23-26, 2021) • viltolarsen was well tolerated. All adverse events were mild or moderate. • All 16 patients treated with viltolarsen showed significant dystrophin expression by Western Blot. • The exon skipping effect demonstrated by RT-PCR me
Slide 38: Phase III Confirmatory Trial (Global) design
Phase III Confirmatory Trial (Global) Design and evaluation items Viltolarsen Randomization 80 mg/kg/week Screening N=37 Viltolarsen 80 mg/kg/week N=74 Placebo N=37 Day -21 First Week 1 Week 48 Rollover study Week 96 day (RACER53-X) Study population Primary endpoint • DMD patients who can be treated
Slide 39: DMD pipeline
DMD pipeline © NIPPON SHINYAKU CO, LTD.
Slide 40: DMD pipeline
DMD pipeline *Approval on August 12, 2020 in the United States(Priority Review), Approval on March 25, 2020 in Japan (Conditional Early Approval System) , application on June 25, 2021 in China (priority review) NS-owned DMD pipeline can cover approximately 40% of all DMD patients. NCNP: National Cen
Slide 41: NS-089/NCNP-02
NS-089/NCNP-02 Development NCNP: Investigator initiated study in progress phase NS: Preparing PII trial in Japan and U.S. Mechanism of Exon 44 skipping action High skipping activity with a new sequence design method developed by NS Feature High safety confirmed in pre-clinical Expect remarkabl
Slide 42: Treatment for Fukuyama congenital muscular dystrophy
Treatment for Fukuyama congenital muscular dystrophy
Slide 43: Fukuyama congenital muscular dystrophy (FCMD)
Fukuyama congenital muscular dystrophy (FCMD) Characteristics ・Congenital muscular dystrophy ・1,000-2,000 patients ・Hereditary disease common in Japan ・Muscle atrophy and CNS abnormalities Symptoms ・Average age for sitting: 2 years ・Many patients are unable to walk and are more serious than DMD. ・Av
Slide 44: FCMD - Abnormalities in the causative gene (fukutin)
Fukuyama congenital muscular dystrophy - Abnormalities in the causative gene (fukutin) - Extracellular matrix Glycosylation modification Arq Neuropsiquiatr. Dystrophin 2009 Jun; 67(1):144- 168 Fukutin Abnormalities Abnormal α-DG with Failure to Vulnerable in the fukutin fukutin no glycosy- fix muscl
Slide 45: FCMD - Exon trapping inhibition
Fukuyama congenital muscular dystrophy - Exon trapping inhibition - Stop codon Normal fukutin splicing 8 9 10 Normal fukutin 8 9 10 protein Normal Exon trapping Transposon FCMD 8 9 10 splicing New exon11 FCMD FCMD fukutin The C-terminal 38 amino Stop codon 8 9 10 11 protein acid is converted to the
Slide 46: FCMD - Exon trapping inhibition
Fukuyama congenital muscular dystrophy - Exon trapping inhibition - • Multisequence antisense nucleic acid treatment suppressed aberrant splicing in patient cells and model mice, produced normal fukutin protein, and restored dystroglycan glycosylation. These results pave the way for the fundamental
Slide 47: Exon trapping
Exon trapping Stop codon 8 9 10 8 9 10 Exon trapping 8 9 FCMD New exon11 8 9 10 11 C-terminal 38 amino acids to Stop codon 129 transposon amino acids Abnormal protein Exon trapping: The presence of a strong splice acceptor site within the inserted retrotransposon, which results from the insertion of
Slide 48: FCMD - Exon trapping inhibition
Fukuyama congenital muscular dystrophy - Exon trapping inhibition - • In patients with FCMD, insertional mutations of the "moving gene" SVA retrotransposon into the downstream region of the fukutin gene have been observed. • Exon trapping (a process in which a copy of a DNA fragment called a retrotr
Slide 49: Development of next-generation antisense nucleic acids
Development of next-generation antisense nucleic acids
Slide 50: Development of next-generation antisense nucleic acids
Development of next-generation antisense nucleic acids We are working on the development of next generation antisense nucleic acids using the following three methods. Membrane-permeable Stereoselective synthesis peptide linkage Stereoselective synthesis allows Membrane-permeable peptide the synthesi
Slide 51: Membrane permeable peptide linkage
Next-generation antisense nucleic acids - Membrane permeable peptide linkage - PPMO in which CPP is bound to morpholino nucleic acid as DDS technology to improve the dynamics of nucleic acid drugs by enhanced cell membrane permeability ・improve the drug efficacy ・reduce the frequency of administrati
Slide 52: Stereoselective synthesis
Next-generation antisense nucleic acids - Stereoselective synthesis - <Conventional> Rp : Sp = ~ 1 : 1 Steric uncontrolled <Next Generation> * * Rp Sp Create new added value by controlling the stereochemistry of morpholinonucleic acid (Phosphorodiamidate morpholino oligomer) 52
Slide 53: Stereoselective synthesis
Next-generation antisense nucleic acids - Stereoselective synthesis - <Conventional> n-mer: a mixture of 2n-1 stereoisomers (21 mer: more than 1,000,000 isomers) <Next Generation> Completely single nucleic acid (21mer: 1/ 1,000,000) 53
Slide 54: Novel sequence design method
Next-generation antisense nucleic acids - Novel sequence design method - Conventional: One sequence acts on one target. Antisense nucleic acid mRNA Novel method: One sequence acts on two targets. Antisense nucleic acid mRNA Improve the activity and specificity of antisense nucleic acids by applying
Slide 55: Novel coronavirus infection - Nucleic acid drugs
Novel coronavirus infection - Nucleic acid drugs -
Slide 56: Novel coronavirus infection - Nucleic acid drugs
Novel coronavirus infection - Nucleic acid drugs - The types and structures of nucleic acids such as long-chain RNA and antisense nucleic acids (morpholino nucleic acids) will be studied to select the nucleic acids that effectively kill the novel coronavirus. The figure shows an example of the appli
Slide 57: Sequence screening of nucleic acid
Novel coronavirus infection - Sequence screening of nucleic acid - Step 1 • In vitro efficacy evaluation of uninfected experimental systems ✓ Step 2 • In vitro efficacy evaluation of infection experiments ✓ • In vivo efficacy evaluation of infection experiments Step 3 • In vitro and in vivo toxicity
Slide 58: Safe Harbor Statement
Safe Harbor Statement • Materials and information provided during this presentation may contain so-called “forward-looking statements.” These statements are based on current expectations, forecasts and assumptions that are subject to risks and uncertainties which could cause actual outcomes and resu