Slide 1: Information Meeting on ZELBORAF and cobas BRAF V600 Mutation Test
Information Meeting on ZELBORAF® and cobas® BRAF V600 Mutation Test CHUGAI PHAMACEUTICAL CO., LTD. Roche Diagnostics K.K. April 2, 2015
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation may include forward-looking statements pertaining to the business and prospects of Chugai Pharmaceutical Co., Ltd. (the “Company”). These statements reflect the Company’s current analysis of existing information and trends. Actual results may differ from
Slide 3: Overview of ZELBORAF
Overview of ZELBORAF® Takahiro Mizui ZELBORAF Lifecycle Leader CHUGAI PHARMACEUTICAL CO., LTD.
Slide 4: Outline of ZELBORAF
Outline of ZELBORAF® ZELBORAF® is a small molecule compound that selectively inhibits oncogenic BRAF kinase, developed by F. Hoffmann-La Roche Ltd. and Plexxikon Inc. Nonproprietary name： Vemurafenib (JAN) Structural formula Molecular weight： 489.92 Chemical name： N-{3-[5-(4-Chlorophenyl) -1H-
Slide 5: Development history of ZELBORAF
Development history of ZELBORAF® Month/Year Global Japan Roche and Plexxikon Started Phase I Nov/2006 study (PLX06-02 [BRIM1]) Started Phase II study (NP22657 Sep/2009 [BRIM2]) Started Phase III study (NO25026 Jan/2010 [BRIM3]) Approval for the patients with Aug/2011 unresectable or metastat
Slide 6: Selectivity against V600 mutated BRAF kinase (in vitro)
Selectivity against V600 mutated BRAF kinase (in vitro) Kinase inhibitory activity of vemurafenib Kinase inhibitory activity of vemurafenib against various kinases against V600 mutated BRAF kinases Kinase IC50 （nmol/L） BRAF ATP IC50 Source BRAF V600E 8 mutation （μmol/L） （nmol/L） CRAF 16 V600E* B
Slide 7: Mechanism of antitumor activity of vemurafenib in mutant BRAF V600 tumor cells
The mechanism of antitumor activity of vemurafenib in tumor cells with mutant BRAF V600 Normal signaling Signaling in tumor cells with Inhibitory activity of vemurafenb via RAS-BRAF1） mutant BRAF V6002, 3） against the tumor cells Growth factor with mutant BRAF V6003-5） RAS-GTP Receptor tyrosine kina
Slide 8: Description
Description Regulatory classification Powerful drug, Prescription-only drug* * Caution - Use only pursuant to the prescription or directions of a physician, etc. Storage Store at room temperature; protect from moisture (ZELBORAF should be stored in its original PTP packaging) Expiration date 2
Slide 9: Indications
Indications 【INDICATIONS】 Unresectable melanoma with BRAF mutation ＜Precautions related to INDICATIONS＞ 1. ZELBORAF should be administered only in patients confirmed to be BRAF mutation-positive through tests by an adequately experienced pathologist or test facility. The test should be conducted usi
Slide 10: Dosage and administration
Dosage and administration 【DOSAGE AND ADMINISTRATION】 The usual adult dosage of vemurafenib is 960 mg administered orally twice daily. ＜Precautions Related to DOSAGE AND ADMINISTRATION＞ 1. If an adverse reaction occurs, the dose should be modified with reference to Table 1. However, if cutaneous squ
Slide 11: Conditions for approval
Conditions for approval 1. A drug risk management plan should be prepared and appropriately implemented. 2. Because the number of patients in Japanese clinical trials is very limited, postmarketing drug use surveillance of all patients receiving ZELBORAF should be conducted until data for a set numb
Slide 12: cobas BRAF V600 Mutation Test
cobas® BRAF V600 Mutation Test Toru Ogawa Manager, Molecular Diagnostics Roche Diagnostics K.K. 11
Slide 13: Companion Diagnostics
Companion Diagnostics ”cobas® BRAF V600 Mutation Test” is a companion diagnostic for “Zelboraf ®” RUO; Research Use Only IVD; in vitro diagnostics CoDx; Companion Diagnostics identify patients who are most likely to benefit from a particular therapeutic product identify patients who are likely t
Slide 14: cobas BRAF V600 Mutation Test to aid selection of patients for Zelboraf
cobas® BRAF V600 Mutation Test To aid in the selection of patients for therapy with Zelboraf ® Zelboraf®? Unresectable Malignant Melanoma cobas® BRAF V600 Mutation Test Only cobas® BRAF Mutation Test can be used for the identification of patients for therapy with Zelboraf®. 13
Slide 15: Extracts from Package insert
Extracts from Package insert cobas® BRAF V600 Mutation Test 【intended use】 Detection of BRAF V600 mutations in DNA extracted from formalin-fixed, paraffin-embedded human melanoma tissue （an aid in selecting melanoma patients whose tumors carry the BRAF V600E mutation for treatment with vemurafenib
Slide 16: Reagents and System for Diagnostics
Reagents and System for Diagnostics cobas® DNA Sample Preparation Kit(FFPE) cobas® BRAF V600 cobas® 4800 System Mutation Test z480 DNA Extraction Reagent for Amplification System and Detection 15
Slide 17: cobas BRAF V600 Mutation Test Specification
cobas® BRAF V600 Mutation Test Specification cobas® BRAF V600 Mutation Test Detection of BRAF V600 mutations in DNA extracted from formalin-fixed, Intended Use paraffin-embedded human melanoma tissue （an aid in selecting melanoma patients whose tumors carry the BRAF V600E mutation for treatment with
Slide 18: Detection of exon 15, codon 600 in BRAF gene
Detection: The detection of exon 15, codon 600 in BRAF gene 1 2 3 13 14 15 BRAF gene Exon Intron codon 600 Most of malignant melanoma is the mutation of codon 600 V(Val) to E(Glu), D(Asp), and K(Lys). cobas BRAF V600 mutation kit could cross react to D and K in addition to E. Roche Diagnostics Docum
Slide 19: 4 key steps
4 key steps Step 1 Step 2 (1) H&E staining & tumor content determination Macro-dissect, if < 50% tumor content by Sample Genomic DNA area Preparation DNA isolation quantification Kit Step 4 Step 3 Standardized reporting Automated PCR setup analysis Harkanwal Halait, et al, Diagn Mol Pathol Volume 21
Slide 20: Report
Report Test results are automatically reported. Basic information Date, Lot... Control result Measurement result 19
Slide 21: Doing now what patients need next
Doing now what patients need next 20
Slide 22: ZELBORAF tablet Postmarketing safety measures
ZELBORAF® tablet Postmarketing safety measures Shin Yoshida Pharmacovigilance Department CHUGAI PHARMACEUTICAL CO., LTD. 21
Slide 23: Contents
Contents 1. Reasons for implementing safety measures 2. Safety measures based on post-approval commitments (PACs) – Implement safety measures on the basis of the risk management plan (RMP) – Implement postmarketing surveillance for all patients treated 3. Other approaches for safety measures 4. Summ
Slide 24: Reasons for implementing safety measures
1. Reasons for implementing safety measures Only a very small number of patients were studied in Japanese clinical trials. • Only 11 patients received the clinical dose during the Japanese Phase I/II clinical trial. Therefore, it is necessary to identify demographic characteristics of patients giv
Slide 25: Reasons for implementing safety measures: Package Insert warnings
1. Reasons for implementing safety measures Package Insert: WARNINGS 【WARNINGS】 Zelboraf should be administered only in patients who are deemed suitable for treatment, in a medical facility adequately equipped to deal with emergencies, and under the supervision of a physician who is knowledgeable an
Slide 26: Safety measures based on PACs
2. Safety measures based on PACs Implement safety measures on the basis of the RMP RMPs should be planned and appropriately implemented. Implement postmarketing surveillance for all patients treated Only a very small number of Japanese patients were treated during the clinical trials. Therefore,
Slide 27: Safety measures based on PACs: RMP safety specification
2. Safety measures based on PACs RMP Safety specification Important identified risks •Squamous-cell carcinoma •Secondary malignancies other than squamous-cell carcinoma •Liver disorder •Photosensitivity •QT interval prolongation •Skin disorder •Hypersensitivity •Eye disorder (Uveitis, etc.) Importan
Slide 28: Safety measures based on the RMP: activities
2. Safety measures based on PACs -Implement safety measures on the basis of the RMP RMP Pharmacovigilance activities Risk minimization activities 1) Collection and evaluation of individual cases 2) Research report (literature, etc.) Routine Routine •JPI creation (revision) 3) Report on safety action
Slide 29: Pharmacovigilance activities: EPPV
2. Safety measures based on PACs -Implement safety measures on the basis of the RMP Pharmacovigilance activities: EPPV Approval 6 months after Product Delivery launch product launch 2 weeks after delivery MR visit, briefing, Requests for cooperation, and regular and request for (once/2 weeks) provis
Slide 30: Risk minimization activities: Information provision
2. Safety measures based on PACs -Implement safety measures on the basis of the RMP Risk minimization activities: Information provision Materials for healthcare professionals Materials for patients 29
Slide 31: Postmarketing surveillance for all patients treated
2. Safety measures based on PACs -Implement postmarketing surveillance for all patients treated To determine the following items under the conditions of actual clinical use of Zelboraf during a long-term follow-up period (24 months) Surveillance • Incidence of ADRs objectives • Unlabeled ADRs • Over
Slide 32: Other approaches for safety measures
3. Other approaches for safety measures Confirmation of requirements for institutions/physicians planning to use Zelboraf Careful selection of patients for treatment Use of Zelboraf Emergency Contact Card 31
Slide 33: Confirmation of requirements for institutions/physicians
3. Other approaches for safety measures Confirmation of requirements for institutions/ physicians planning to use Zelboraf Institution requirements 1. Understand and cooperate with the safety measures specified for Zelboraf. 2. Be able to appropriately provide urgent transportation and emergency tre
Slide 34: Careful selection of patients for treatment
3. Other approaches for safety measures Careful selection of patients for treatment All patients who will use Zelboraf should be enrolled before drug administration Confirm patient eligibility Raise precautions by informing the prescribing physician about the package insert contents if necessary All
Slide 35: Use of Zelboraf Emergency Contact Card
3. Other approaches for safety measures Use of Zelboraf Emergency Contact Card This card must be shown when Zelboraf is dispensed. Physicians are requested to provide patients with this card when Zelboraf is prescribed. [Front: ADRs that need to be reported at onset] [ Back：Emergency contact details
Slide 36: Summary
4. Summary • Reasons for implementing safety assurance measures Only a very small number of patients were studied in clinical trials in Japan. Serious ADRs may occur. • Approaches for safety assurance Safety measures based on PACs Implement safety measures on the basis of the RMP Implement p
Slide 37: Overview of melanoma and clinical trials of vemurafenib
Overview of melanoma and clinical trials of vemurafenib Naoya Yamazaki, M.D., Ph.D. Chief, Dept. of Dermatologic Oncology National Cancer Center Hospital, Japan 36
Slide 38: Characteristics of main skin cancer
Characteristics of main skin cancer Usually caused by UV ray exposure and occur frequently on the face in the elderly Basal cell Rarely spread to other parts of the body and become life- carcinoma threatening Generally treated by surgical excision Malignant growth of epidermal keratinocytes
Slide 39: Number of New Cases/Deaths of Melanoma by Race/Ethnicity
Number of New Cases/Deaths of Melanoma by Race/Ethnicity Male (person/100,000・year) Female 27.7 16.7 All Races 4.1 1.7 32.3 20.0 White 4.6 2.0 1.0 1.0 Black 0.5 0.4 1.5 Asian / 1.2 0.4 Pacific Islander 0.3 4.1 American Indian / 4.0 1.7 Alaska Native 0.8 4.8 4.6 Hispanic 1.1 0.6 31.2 19.1 Non-Hispani
Slide 40: Number of deaths of melanoma patients in Japan
Number of deaths of melanoma patients in Japan （Total number of deaths from 1972-2013） 700 Male （8,448） Female （7,548） 600 Total （15,996） Number of deaths 500 400 300 200 100 （year） 0 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1
Slide 41: Incidence rates of melanoma by Stage
Incidence rates of melanoma by Stage (UICC, 2002) Unresectable Stage 11% Tis 18% Stage Ia 9% Stage Ib Stage Ⅱa Stage Ⅱb Resectable 8% 13% Stage Ⅱc Stage Stage Ⅲa 4% Stage Ⅲb Stage Ⅲc 9% 9% Stage Ⅳ 10% 9% Fujisawa Y. et al., Skin Cancer 2008;195-204 40
Slide 42: Treatment algorithm for melanoma: Clinical practice guideline (Japan)
Treatment algorithm for melanoma： Clinical practice guideline for skin cancer (Japan) Prophylaxis Clinical findings/Dermoscopy Difficulties in Biopsy Risk factor clinical diagnosis Screening Diagnosis Histology NCCN Preoperative test Target of chemotherapy No distant metastasis Distant metastasis DT
Slide 43: Overall survival rate of melanoma by Stage
Overall survival rate of melanoma by Stage Melanoma is extremely resistant to chemotherapy. The response rate of DTIC (Dacarbazine), standard treatment for progressive melanoma, is 10-20%. Melanoma is resistant to radiotherapy in general. Survival curve by Stage (UICC, 2002) in Japanese melanoma
Slide 44: Histological subtypes of melanoma
Histological subtypes of melanoma (Clark’s classification) Nodular melanoma：NM Superficial spreading melanoma：SSM Acral lentiginous melanoma：ALM Lentigo maligna melanoma：LMM Atypical melanocyte (individuality) Alveolar of atypical melanocyte Atarashii hifukagaku version 2 (Nakayama shoten) 2011, p45
Slide 45: Incidence rate according to types of melanoma
Incidence rate according to types of melanoma NM SSM ALM LMM Mucosal Japan1） 11.5％ 25.7％ 49.0％ 10.0％ 3.8％ 0 20 40 60 80 100 （％） 1.0％ US2） 14.0％ 63.0％ 12.0％ 9.0％ 0 20 40 60 80 100 （％） 1） Japanese Classification of Skin Cancer version 2 (KANEHARA & Co., LTD) 2010, p178-179 2） Fujisawa Y. et al. Nihon
Slide 46: Oncogenic mutation of melanoma
Oncogenic mutation of melanoma Major signaling pathways in melanoma and oncogenic mutation frequency1) Growth Factors GNAQ mutated 50％ of RTK uveal melanoma GPCR Cell Membrane 30-50％ Loss α γ PTEN RAS β Cytoplasm NRAS 15％ mutated PI3K GEFT RAF BRAF 50-70％ mutated （Japan：30-40%）2，3) RAC RHO Akt1 30
Slide 47: Treatment algorithm for melanoma: Clinical practice guideline (Japan)
Treatment algorithm for melanoma: Clinical practice guideline for skin cancer (Japan) Prophylaxis Clinical findings/Dermoscopy Difficulties in Biopsy Risk factor clinical diagnosis Screening Diagnosis Histology NCCN Preoperative test Target of chemotherapy No distant metastasis Distant metastasis Ni
Slide 48: Overseas Phase III study (NO25026 BRIM3)
Phase III study (NO25026[BRIM3]) Overseas Phase III study (NO25026[BRIM3]) Study design Vemurafenib Previously untreated PD 960mg, b.i.d., p.o. patients with unresectable （n=337） Stage III or Stage IV R melanoma positive for 1:1 BRAF V600 mutation*1） Dacarbazine (DTIC)*2） （n=675） 1,000mg/m2, i.v.,
Slide 49: Patient Characteristics
Phase III study (NO25026[BRIM3]) Patient Characteristics DTIC （n=338） Vemurafenib （n=337） Male 181 （54％） 200 （59％） Median age (range) 52.5 （17-86） 56.0 （21-86） Metastatic Classification IV：M1a 40 （12％） 34 （10％） IV：M1b 65 （19％） 62 （18％） IV：M1c 220 （65％） 221 （66％） Unresectable StageIIIC 13 （4％） 20 （6％
Slide 50: Progression-free survival
Phase III study (NO25026[BRIM3]) PFS (at the time of primary analysis) 1.0 Number of events Vemurafenib （n=275） 104 （37.8％） DTIC （n=274） 182 （66.4％） Progression-free survival 0.8 HR 0.26 （95％CI 0.20-0.33） p＜0.0001, Unstratified log-rank test 0.6 0.4 0.2 1.61 5.32 0 0 1 2 3 4 5 6 7 8 9 10 11 12 (mont
Slide 51: Overall survival
Phase III study (NO25026[BRIM3]) OS (at the time of primary analysis) Number of events Vemurafenib （n=336） 43 （12.8％） DTIC （n=336） 75 （22.3％） 1.0 HR 0.37 （95％CI 0.26-0.55） p＜0.0001, Unstratified log-rank test 0.8 Overall survival 0.6 0.4 0.2 7.75 9.23 0 0 1 2 3 4 5 6 7 8 9 10 11 12 (month) Time n at
Slide 52: Best overall response rate, Duration of response
Phase III study (NO25026[BRIM3]) Best overall response rate, Duration of response (at the time of primary analysis) DTIC Vemurafenib p-value （n=220） （n=219） （Schouten χ2 test） Responders 12 106 Response rate ＜0.0001 5.5％ （2.8-9.3） 48.4％ （41.6-55.2） （95％CI） CR 0 （0.0％） 2 （0.9％） PR 12 （5.5％） 104 （47.5
Slide 53: Best tumor response
Phase III study (NO25026[BRIM3]) Best tumor response (at the time of primary analysis) Vemurafenib （n=209） Metastatic Classification （％） Unresectable Stage IIIC n=219 in Diameters of Target Lesions 250 IV：M1a Responders (n) 106 200 Change from Baseline IV：M1b Response rate (％) 48.4 150 IV：M1c CR (
Slide 54: Summary of safety
Phase III study (NO25026[BRIM3]) Summary of safety (at the time of primary analysis) DTIC Vemurafenib （n=282） （n=336） Any AEs 253 （89.7％） 326 （97.0％） AEs of Grade 3 and above 86 （30.5％） 168 （50.0％） AEs of Grade 4 22 （7.8％） 13 （3.9％） AEs of Grade 5 6 （2.1％） 6 （1.8％） Serious AEs 45 （16.0％） 110 （32.7％）
Slide 55: Adverse events (incidence: ≥10%)
Phase III study (NO25026[BRIM3]) Adverse events (incidence: ≥10%) DTIC （n=282） Vemurafenib （n=336） All Grades ≥ Grade 3 All Grades ≥ Grade 3 Total Pts with at Least one AE 253 （89.7％） 86 （30.5％） 326 （97.0％） 168 （50.0％） Nausea 115 （40.8％） 5 （1.8％） 101 （30.1％） 4 （1.2％） Fatigue 87 （30.9％） 5 （1.8％） 112
Slide 56: Conclusions: NO25026 BRIM3
Phase III study (NO25026[BRIM3]) Conclusions：NO25026[BRIM3] Vemurafenib demonstrated superior benefit across the clinically relevant efficacy endpoints of OS, PFS and BORR compared with dacarbazine in previously untreated patients with unresectable Stage III or Stage IV melanoma positive for BRAF
Slide 57: Japanese phase I/II study (JO28178)
JPN Phase I/II study (JO28178) Japanese phase I/II study (JO28178) Study design Efficacy analysis populations: 8 pts Unresectable melanoma with in Step2 BRAF V600 mutations*1） （n=11） Safety analysis populations: 11 pts in Step 1 and 2 Step1 Step2 Vemurafenib Vemurafenib *1） Determined by cobas® 48
Slide 58: Patient characteristics (Steps 1, 2)
JPN Phase I/II study (JO28178) Patient characteristics (Steps1, 2) Step1 （n=3） Step2 （n=8） Male 2 （66.7％） 1 （12.5％） Median age (range) 51.0 （38-68） 45.0 （23-62） Disease Stage n=2 n=7 at relapse III － 1 （14.3％） IV 2 （100.0％） 6 （85.7％） Histological SSM 1 （33.3％） 2 （25.0％） subtypes LMM － 1 （12.5％） ALM
Slide 59: Summary of efficacy (Steps 1, 2)
JPN Phase I/II study (JO28178) Summary of efficacy (Steps1, 2) IRC assessment Efficacy analysis population (n) 8 Responders (n) 6 CR 0 Best overall response PR 6 (n) SD 1 NE 1 Duration of response Median* （day） ［95％CI］** 59.0 ［56.0-NR］ Time to response Median* （day） ［95％CI］ 29.0 ［27.0-29.0］ PFS Medi
Slide 60: Summary of safety (Steps 1, 2)
JPN Phase I/II study (JO28178) Summary of safety (Steps1, 2) Vemurafenib （n=11） Patients experience any AEs 11 （100％） AEs of Grade 1 11 （100％） AEs of Grade 2 7 （63.6％） AEs of Grade 3 3 （27.3％） AEs of Grade 4 and above － Serious AEs 1 （9.1％） AEs that led to discontinuation － AEs that led to dose modi
Slide 61: Adverse events (incidence: ≥10%) (Steps 1, 2)
JPN Phase I/II study (JO28178) Adverse events (incidence: ≥10%) (Steps1, 2) All Grades ≥ Grade 3 All Grades ≥ Grade 3 Number of patients 11 Pyrexia 3 （27.3％） － 3 （27.3％） experiencing AEs （100.0％） Nasopharyngitis 3 （27.3％） － 10 Arthralgia － Milium 3 （27.3％） － （90.9％） Insomnia 3 （27.3％） － Myalgia 7 （6
Slide 62: Conclusions: JO28178
JPN Phase I/II study (JO28178) Conclusions：JO28178 This study investigated the efficacy and safety of vemurafenib 960 mg orally administered twice daily to Japanese patients with unresectable melanoma with BRAF V600 mutations. An objective response was confirmed by the IRC in 6 patients in Step
Slide 63: Contacts
Contacts CHUGAI PHARMACEUTICAL CO., LTD. Corporate Communications Dept. Media Relations Group Tel: +81 (0)3-3273-0881 Fax: +81 (0)3-3281-6607 e-mail: pr@chugai-pharm.co.jp Koki Harada, Hiroshi Araki, Sachiyo Yoshimura, Chisato Miyoshi Investor Relations Group Tel: +81 (0)3-3273-0554 Fax: +81 (0)3-32