Slide 1: FY2022 R&D Meeting: Part I
FY2022 R&D Meeting: Part I December 15, 2022 NIPPON SHINYAKU CO., LTD.
Slide 2: Current and Future Treatment for Dravet Syndrome
Current and Future Treatment for Dravet Syndrome *presentation slides are unavailable
Slide 3: FY2022 R&D Meeting: Part II
FY2022 R&D Meeting: Part II December 15, 2022 NIPPON SHINYAKU CO., LTD.
Slide 4: Promoting patient-centric business activity
Promoting patient-centric business activity Three commitments to fulfill our corporate philosophy Continue to launch at least one unique product each year Generate at least 50% of consolidated sales from overseas Target at least more than twice in net sales and operating profit Corporate philosophy
Slide 5: Leveraging our acquired strengths
Leveraging our acquired strengths Leveraging our technical superiority 20 years of R&D activity in the field of nucleic acid, results to success of Nucleic developing the first nucleic acid drug acid discovered in Japan technology Viltepso Doing one’s all for individuals Generic name: Viltolarsen Pr
Slide 6: R&D strategy
R&D strategy We aim to become a company with a meaningful existence in the global healthcare field. 6
Slide 7: Research and Development Activities
Research and Development Activities
Slide 8: R&D approach
R&D approach As a slogan for our R&D division, we aim for “The creation of new drugs to be used worldwide.“ Therefore, we will continue to create highly unique and distinctive new drugs. With a sense of speed and to increase the probability of success in mind, research will be conducted to expand ou
Slide 9: Progress of nucleic acid DMD pipeline
Progress of nucleic acid DMD pipeline Program Target % of DMD patients Pre clinical PI PI／Ⅱ PII PIII Launch NS-065/NCNP-01 PIII Exon 53 8% (Viltolarsen) in progress NS-089/NCNP-02 Exon 44 6% NS-050/NCNP-03 Exon 50 4% NS-051/NCNP-04 Exon 51 13% Exon 45 Skipping Exon 45 8% Exon 55 Skipping Exon 55 2%
Slide 10: Progress of nucleic acid product (NS-065/NCNP-01)
Progress of nucleic acid product (NS-065/NCNP-01) Study no. Study description Estimated primary completion date* Study 202 P2, open Complete (Long-term study from Week 217, 16 patients 2021/11 P2 study (Study 201)) Study 502 Long-term follow-up (Registry from Study 2032/9 10 years, ~16 cases 202). S
Slide 11: Clinical study updates
Clinical study updates • NS-065/NCNP-01 phase 2 extension study • NS-089/NCNP-02 investigator-initiated clinical study 11
Slide 12: Clinical study updates
Clinical study updates • NS-065/NCNP-01 phase 2 extension study • NS-089/NCNP-02 investigator-initiated clinical study 12
Slide 13: NS-065/NCNP-01 phase extension study design
NS-065/NCNP-01 phase 2 extension study 【Study Design of Study 201 and 202】 Viltolarsen 40 mg/kg/wk n=6 Continue current dose Placebo Viltolarsen 40 mg/kg/wk Randomization n=2 n=2 Randomization 30-day follow-up Viltolarsen 80 mg/kg/wk n=6 Continue current dose Placebo Viltolarsen 80 mg/kg/wk n=2 n=2
Slide 14: TTSTAND CFB vs Natural History Controls
NS-065/NCNP-01 phase 2 extension study 【TTSTAND CFB vs Natural History Controls】 *P <0.05; †P <0.01; ‡P ≤0.001. CFB, change from baseline; DNHS, Duchenne Natural History Study（DMD natural history control group）; s, seconds; SE, standard error; TTSTAND, time to stand from supine; w, weeks. 14
Slide 15: TTRW CFB vs Natural History Controls
NS-065/NCNP-01 phase 2 extension study 【TTRW CFB vs Natural History Controls】 *P <0.05; †P <0.01; ‡P ≤0.001. CFB, change from baseline; DNHS, Duchenne Natural History Study（DMD natural history control group）; s, seconds; SE, standard error; TTRW, time to run/walk 10 meters; w, weeks. 15
Slide 16: TTCLIMB CFB vs Natural History Controls
NS-065/NCNP-01 phase 2 extension study 【TTCLIMB CFB vs Natural History Controls】 *P <0.05; †P <0.01; ‡P ≤0.001. CFB, change from baseline; DNHS, Duchenne Natural History Study（DMD natural history control group）; s, seconds; SE, standard error; TTCLIMB, time to climb 4 stairs; w, weeks. 16
Slide 17: Safety Assessment / Common TEAEs
NS-065/NCNP-01 phase 2 extension study 【 Safety Assessment / Common TEAEs (Preferred Term in ≥25% of Participants)】 Viltolarsen participants 40 mg/kg/wk 80 mg/kg/wk Total Participants with: (n = 8) (n = 8) (N = 16) Any TEAE, n (%) 8 (100) 8 (100) 16 (100) Any drug-related TEAE, n (%) 0 1 (13) 1 (6)
Slide 18: Conclusion
Conclusion • Participants treated with viltolarsen for an additional 192 weeks (up to 216 weeks or 4 years) showed maintenance of function over the first 2 years and significantly delayed disease progression over the following 2 years in timed function tests compared with CINRG DNHS controls, which
Slide 19: Clinical study update
Clinical study update • NS-065/NCNP-01 phase 2 extension study • NS-089/NCNP-02 investigator-initiated clinical study 19
Slide 20: NS-089/NCNP-02 Study design of Phase 1/2 Study
NS-089/NCNP-02 Study design of Phase 1/2 Study（First-in-human, Open label study) MDA, March 2022 Key inclusion Criteria Primary Objectives Secondary Objectives • Age : 4-17 years • Safety and • Dystrophin protein expression • Ambulant tolerability • Motor function assessments* • Amenable to exon • E
Slide 21: NS-089/NCNP-02 dystrophin in patient muscle
NS-089/NCNP-02 Study design of Phase 1/2 Study（First-in-human, Open label study) Amount of change in dystrophin in patient Amount of change in exon skipping muscle efficiency Dystrophin in patient muscle Exon skipping efficiency (mean %) (mean %) Baseline Week 25 Baseline Week 25 Baseline Week 25 Ba
Slide 22: Status of developing DMD pipelines
Status of developing DMD pipelines Development Contents stage Approved in NS-065/ Japan and US P3 study, Study 502 (long-term follow-up study), and Study 211 (study in NCNP-01 P3 study in ambulant and non-ambulant boys with DMD) in progress. progress Investigator-initiated clinical trial in Japa
Slide 23: Next-generation modalities
Next-generation modalities
Slide 24: Development of next-generation antisense nucleic acids
Development of next-generation antisense nucleic acids Improvement of the activity and specificity by designing single Novel sequence sequence in which has two target design method sequences Next-generation antisense nucleic acids Membrane- Synthesis of Improvement of permeable Stereoselective stere
Slide 25: Peptide-conjugated nucleic acid
Peptide-conjugated nucleic acid We are developing PPMO in which CPP is bound to morpholino nucleic acid as DDS technology to improve the pharmacokinetics of nucleic acid drugs by enhanced cell membrane permeability. As a result, we aim to improve the drug efficacy and reduce the frequency of adminis
Slide 26: Stereoselective synthesis
Stereoselective synthesis Conventional PMO (a mixture of stereoisomers) mirror B(n) ＊ ＊N Stereocontrol (single-stereoisomers) P N CH3 CH3 Monomer has chirality and PMO is a mixture of stereoisomer. ：monomer Stereocontrolled synthesis of optimized modified nucleic acids create new added value (such a
Slide 27: Novel sequence design method (NS-089/NCNP-02)
Novel sequence design method (NS-089/NCNP-02) Exon 44 Active sequence A Active sequence B When activity is enhanced by combining sequence A and sequence B Link sequence A and sequence B Strong skipping activity Skipping efficiency (%) is obtained. NS-089/NCNP- NS-089/ NCNP- Sequence Sequence A Seque
Slide 28: Several types of approach for DMD
Several types of approach for DMD
Slide 29: Nucleic acid drug (exon skipping)
Nucleic acid drug (exon skipping) Dystrophin mRNA Full 51 52 53 54 length Full-length Full-length mRNA Reading frame Protein production does not fit. Exon 52 51 52 53 54 Deletion No protein Deletion of exon 52 production Reading frame fits. mRNA Exon 52 51 54 Deletion mRNA lacking Slightly short but
Slide 30: Cell therapy CAP-1002
Cell therapy CAP-1002 Cardiosphere-derived cell therapeutic. Exosomes (extracellular vesicles) released from this drug are expected to reduce oxidative stress, inflammation, fibrosis, and increase cell energy and myocyte generation, resulting in reducing deterioration of motor and cardiac functions.
Slide 31: Cell therapy CAP-1002: HOPE-2 study + OLE study
Cell therapy CAP-1002:HOPE-2 study + OLE study DB Phase Gap Phase OLE Phase The Lancet, March 2022 WMS, October 2022 HOPE-2 DB: PUL scoring HOPE-2 DB+OLE: PUL scoring Key inclusion criteria Duration of treatment As a result, • Age: 10 years or older ・DB Phase: CAP-1002 or placebo CAP-1002 • Non-ambu
Slide 32: Gene therapy (our activity)
Gene therapy (our activity) Challenges of microdystrophin products: Serious adverse events associated with high-dose and systemic administration ※ enhancer and promoter work together to increase transcription (DNA to mRNA) Concept: Microdystrophin gene therapy with equivalent or higher efficacy and
Slide 33: Position within the three treatments
Position within the three treatments Advantage Disadvantage Nucleic acid drug ・Multiple doses are possible ・Target patients are limited (Exon skipping) ・Long-term safety and efficacy data are ・Therapeutic effects only towards available skeletal muscle Cell (exosome) ・Potentially effective not only f
Slide 34: 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
Slide 35: Nippon Shinyaku Co., Ltd. R&D Meeting
Nippon Shinyaku Co., Ltd. R&D Meeting December 15, 2022
Slide 36: Presentation
Presentation Moderator: I will now introduce today's speakers. From the left, Toru Nakai, President. Nakai: Hello. Thank you. Moderator: Kazuchika Takagaki, Director, Research and Development. Takagaki: Hello. Thank you. Moderator: Takanori Edamitsu, Director, Business Management and Sustainability.
Slide 37: Our identity is to create new medicines
Since our company was established, our identity has been to create new medicines. To us, that means we are pursuing our corporate philosophy, which is Helping People Lead Healthier, Happier Lives through the provision of high quality and distinctive products. To this end, all of our employees have t
Slide 38: Our R&D strategy
Our R&D strategy is to promote research and development with a sense of urgency in our four focus therapeutic areas of urology, hematology, intractable and rare diseases, and gynecology. Our approach is based on the three pillars of in-house drug discovery, in-licensing, and product lifecycle manage
Slide 39: R&D approach to creating unique drugs
Takagaki: Hello, I am Takagaki, Director, Research and Development. Our approach to research and development is to continuously create highly unique and distinctive new drugs to be used worldwide. With an eye to speeding up the development process and increasing the probability of success, we are co
Slide 40: DMD pipeline
Here is our DMD pipeline. We have viltolarsen, NS-065, targeting exon 53, NS-089 targeting exon 44, NS-050 targeting exon 50, NS-051 targeting exon 51 and exon 45 and exon 55 skipping agents. The percentage of DMD patients covered by viltolarsen is 8%, by exon 44 is 6%, by exon 50 is 4%, by exon 51
Slide 41: Progress of NS-065 viltolarsen
First, I would like to explain the current progress of NS-065, viltolarsen. At the top is Study 202, an extension study of Phase II study. This was completed in November 2021. The results will be presented later on. We also have Study 502, an extension study from Study 202. This is a long-term follo
Slide 42: Phase II extension study design
Now, I would like to continue with clinical study updates. First, I would like to explain the results of the Phase II extension study of NS-065, viltolarsen. Here is a description of the design of Study 201 and Study 202. In Study 201, viltolarsen at 40 mg/kg and 80 mg/kg was administered. Initially
Slide 43: Motor function results over four years
This slide shows the motor function results over the four-year period. The blue line is for the group that received viltolarsen, and the yellow line represents natural history data of DMD patients. This is a test of time to stand from supine, with seconds on the left side and speed on the right side
Slide 44: Time to run/walk 10 meters
Next is a study for time to run/walk 10 meters. The left side shows seconds, and the right side shows speed, which is still the same data described in a different way. The upper blue line is the viltolarsen group and the lower yellow line is the natural history data of DMD patients. 9
Slide 45: Time to climb four stairs
The next slide is data from a study of time to climb four stairs. The left side shows seconds, and the right side shows velocity, both of which also showed improvement followed by maintenance in the viltolarsen group. 10
Slide 46: Adverse events of phase II extension study
These are adverse events of phase II extension study. There have been eight cases reporting adverse events receiving the 40 mg/kg dose and eight cases on the 80 mg/kg dose. However, there was only one case reporting adverse events related to the drug receiving the 80 mg/kg dose. In this one case, th
Slide 47: Summary of Phase II extension study
This is a summary of Phase II extension study. When comparing patients receiving viltolarsen and natural history data of DMD patients, patients treated with viltolarsen showed maintenance of motor function over the first two years and showed a trend of delaying disease progression during the followi
Slide 48: NS-089/NCNP-02 investigator-initiated study
Next, I would like to talk about the results of the investigator-initiated clinical study for NS-089/NCNP-02. This is an investigator-initiated clinical study conducted by the National Center of Neurology and Psychiatry, NCNP. First, here is a design of the clinical study. The left side is part one,
Slide 49: Muscle biopsy results after part two
These are the results of muscle biopsy after part two. As for the mean change from baseline in dystrophin expression, a 10.27% increase of protein expression in the 40 mg/kg group and a 15.79% increase in the 80 mg/kg group were observed. Patients amenable to exon 44 skipping had a rather high basel
Slide 50: Status of developing DMD pipelines
Next, is the status of developing DMD pipelines. NS-065 or viltolarsen is approved in Japan and the US and are now undergoing Phase III trials. Regarding NS-089, investigator-initiated clinical trial in Japan have been completed and we are now conducting an extension study. Furthermore, we are now i
Slide 51: Next-generation technology
Next, I would like to talk about the next-generation technology. As for next-generation antisense nucleic acids, we are promoting the three approaches shown here. One is a novel sequence design method, in which a single sequence recognizes two target sequences to improve activity and specificity. Ne
Slide 52: Peptide-conjugated nucleic acid
Firstly, I would like to start off with an explanation of peptide-conjugated nucleic acid. This is a membrane-permeable peptide, linked with a morpholino nucleic acid. We are now realizing that the stability of PPMO is considerably influenced by not only the peptide and morpholino nucleic acid but a
Slide 53: Stereoselective synthesis
The next step is stereoselective synthesis. In this figure, “P”, the phosphorus with the red dot has a chiral center. It is just like a right-handed and left- handed relationship. However, the two molecules are different sterically. In PMO, there are 20 linkages of the phosphate moiety for 21 monome
Slide 54: New sequence design method
NS-089 is an example of our new sequence design method. A single antisense oligo binding to a single target sequence in exon 44 is usually selected. In the case of NS- 089, there were two target sequences or regions in exon 44 that caused activity, so we designed two antisense oligos for these targe
Slide 55: Exon skipping with nucleic acid medicine
I will continue with a description of various approaches in DMD. The first is exon skipping with nucleic acid medicine. I am sure you all know this already, but the picture at the top shows production of full-length proteins. The second is an example of deletion of exon 52, in which the protein read
Slide 56: Cell therapy CAP-1002
Next, here is an example of cell therapy CAP-1002. This is a cardiosphere-derived cell therapy. Exosomes or extracellular vesicles released from CAP-1002 are expected to reduce oxidative stress, inflammation, fibrosis, and increase cell energy and myocyte generation, resulting in reducing deteriorat
Slide 57: HOPE-2 Phase II trial data
This is some of the data from the HOPE-2 Phase II trial. Patients in this study were non-ambulant, so upper limb motor function are evaluated. The left side bar is a result of placebo group, and the right side bar is a result of CAP-1002 group. A statically significant improvement in upper limb moto
Slide 58: Gene therapy approach
Next is gene therapy. I would like to introduce our company's approach. We believe that the major issue with the current developing drug of microdystrophin for the treatment of DMD is that it is administered in very high doses and systemically. We consider this very problematic because of the potent
Slide 59: Position of the three treatments
Lastly, we have discussed the position of these three treatments. Nucleic acid drug, cell (exosome) therapy, and gene therapy (microdystrophin) each have their own advantages and disadvantages, and we believe that the best treatment can be achieved by combining them. In nucleic acid drug, multiple d
Slide 60: Combining treatments for DMD patients
What he said was that for those who are not eligible for exon skipping, gene therapy is the only way to go for now. However, for patients who are eligible for exon-skipping therapy, initially, the patient has a lot of stem cells or satellite cells, so in that case, it would be a good idea to prevent