Catalyzing Precision Medicine with Integrated Rx/Dx in Oncology. Jefferies Healthcare Conference June 8 th, 2016

Transcription

1 Catalyzing Precision Medicine with Integrated Rx/Dx in Oncology Jefferies Healthcare Conference June 8 th, 2016

2 Safe Harbor Statement This document contains forward-looking statements, as that term is defined in Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, about Ignyta, Inc. ( us or the Company ). Statements that are not purely historical are forward-looking statements. These include statements regarding, among other things: Ignyta s corporate and scientific vision and goals, including our ability to reduce the size of tumors and to eradicate residual disease; the clinical and/or non-clinical data or plans underlying entrectinib or any of our other development programs; our ability to design and conduct development activities for entrectinib and our other development programs; our ability to develop or access companion diagnostics for our product candidates; our ability to obtain and maintain intellectual property protection for our product candidates; our ability to adequately fund our development programs; our ability to obtain regulatory approvals in order to market any of our product candidates; and our ability to successfully commercialize any approved products. Forward-looking statements involve known and unknown risks that relate to future events or the Company s future financial performance, some of which may be beyond our control, and the actual results could differ materially from those discussed in this document. Accordingly, the Company cautions investors not to place undue reliance on the forward-looking statements contained in, or made in connection with, this document. Important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, include, among others, the potential for results of past or ongoing clinical or non-clinical studies to differ from expectations or previous results; the interpretation of data from our clinical and non-clinical studies; our ability to initiate and complete clinical trials and non-clinical studies; regulatory developments; the potential advantages of our product candidates; the markets any approved products are intended to serve; and our capital needs; as well as those set forth under the headings Special Note Regarding Forward-Looking Statements, Risk Factors and Management s Discussion and Analysis of Financial Condition and Results of Operations contained in the Company s Form 10-K filed with the Securities and Exchange Commission ( SEC ) on March 14, 2016, and similar disclosures made in the Company s Form 10-Q filings and other SEC filings and press releases. The forward-looking statements contained in this document represent our estimates and assumptions only as of the date of this document, and we undertake no duty or obligation to update or revise publicly any forward-looking statements contained in this document as a result of new information, future events or changes in our expectations. Third-party information included herein has been obtained from sources believed to be reliable, but the accuracy or completeness of such information is not guaranteed by, and should not be construed as a representation by, the Company. 2

3 Ignyta Case Report: Mr. Z Nov 2013 March M patient with metastatic, first diagnosed in November pack-year smoking history Prior therapies carboplatin/pemetrexed pembrolizumab docetaxel vinorelbine ECOG performance status of 2 Required supplemental O 2 Significant pain and dyspnea due to widely metastatic disease Staging head CT also revealed numerous (15 to 20) asymptomatic brain metastases In hospice Identified to have tumor harboring SQSTM1-NTRK1 fusion Enrolled in Ignyta s STARTRK-1 study at MGH in March

4 Clinical Response to Entrectinib, Ignyta s Lead Program, in a 46 year-old Male Patient with NTRK1-Rearranged Baseline Day 26: - 47% response Day 317: - 79% response Images courtesy of A. Shaw, MD, PhD and A. Farago, MD, PhD (MGH); Note: Individual results may not be representative of results in other patients. 4

5 Complete Response of All Brain Metastases in 46 Year-Old Male Patient with NTRK1-Rearranged Baseline (15-20 mets) Day 26 (CR) Day 155 (CR) Images: Farago and Shaw, MGH Note: Individual results may not be representative of results in other patients. CNS complete response persists at Day 317 5

6 Key Investment Highlights Ignyta s vision is to catalyze precision medicine for the benefit of cancer patients everywhere, with an integrated approach to "Rx/Dx" in oncology Integrated approach to Rx/Dx development - CAP-accredited, CLIA-certified, QSR-compliant diagnostic lab with multi-modality assays - Internal Dx allows Ignyta to illuminate the molecular drivers of cancer and quickly advance the most appropriate molecularly targeted therapies to address them Robust pipeline of molecularly targeted therapies - 3 potentially first-in-class or best-in-class clinical stage programs Entrectinib: In global Phase 2, potentially registration-enabling study Additional Phase 1 programs (RXDX-105, taladegib) with demonstrated clinical responses - Preclinical program (RXDX-106) at the nexus of molecularly targeted and immuno-oncology Multiple near-term catalysts to drive value - Utilizing basket study designs for resource-efficient clinical development plans to generate multiple clinical data readouts in next 12 months, while building long-term value for patients and stockholders Experienced management team - Breadth and depth of expertise in clinical/preclinical development, regulatory affairs, commercial, and other key technical and business disciplines 6

7 Management Team Brings to Ignyta Experience from Leading Organizations and Institutions Jonathan Lim, M.D. Chairman, CEO, and Co-Founder Zachary Hornby Chief Operating Officer Igor Bilinsky, Ph.D. SVP, Research Ops. & GM, I-O Jacob Chacko, M.D. Chief Financial Officer Val Harding, Ph.D. SVP, Chemistry, Mfg. & Controls Will McCarthy Chief Business Officer Pratik Multani, M.D. Chief Medical Officer Former Chair, CEO of Eclipse; CEO at Halozyme; McKinsey; NIH post-doc at Harvard/Dana Farber; Surgical resident at NYH-Cornell/Memorial Sloan Kettering; Board member at UCSD Moores Cancer Ctr. Former Senior Director of Business Development at Fate Therapeutics; Director of BD at Halozyme; Marketing at Neurocrine; L.E.K. Consulting; Shire (TKT); Harvard Business School. Former SVP of Corporate Development at Vical; VP Business Development and Special Operations at Halozyme; CEO of Androclus Therapeutics; Boston Consulting Group; MIT. Former Vice President at TPG Capital; McKinsey; Marshall Scholar at Oxford University; UCLA Medical School; Harvard Business School. Former VP, Product Differentiation/VP, Drug Product Design/VP, Pharmaceutical Development, in addition to numerous other leadership roles at Pfizer. Former VP of Corporate and Business Development at Foundation Medicine; Exec Dir of BD and Sr. Director of Marketing at Halozyme; IMS Health, Deloitte Consulting; London Business School. Former CMO at Fate; VP, Clin. Dev. at Kalypsys; CMO at Kanisa; VP, Clin. Dev. at Salmedix; Sr. Director of Medical Research at Biogen Idec; MD, MS at Harvard; Residency, MGH; Oncology, Dana Farber. 7

8 Robust Pipeline of Molecularly Targeted Therapies 1 In-licensed from Nerviano Medical Sciences (NMS); 2 In-licensed from Eli Lilly and Company; 3 Acquired from Cephalon, a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. 8

9 Commercial Opportunity Is Substantial for These Three Clinical Stage Assets ~175k patients annually in the U.S. could benefit from entrectinib, RXDX-105, and taladegib Indication Alteration/Mechanism NTRK 1 fusions NTRK 2 fusions NTRK 3 fusions ROS 1 fusions *2.2M non-melanoma skin cancers, of which 80% is BCC (1.76M); labcc is 1% of BCC (9.5% not candidates for surgery/radiation); mbcc is 0.55% (95% not candidates for surgery/radiation), yielding 10,868 patients in U.S.; Hh alterations include Hh (OE of SHh, IHh, DHh), PTCH1 (SNP/Del), SMO (SNP/OE); **Assumes 100% of patients are addressable, rather than 90%, due to lack of patient selection in BCC; Note: table does not include ~70k patients for oral taladegib as combo or ~70k patients for topical taladegib; % s in red not included in Total Addressable Patients due to multiple other approved products; Assumes ~7.5% of PTC patients referred to med onc; Ignyta-generated data from multiple publicly available third party sources. ALK fusions RET fusions BRAF fusions BRAF mutations Hh alter'ns / gene express. signature * Estimated U.S. Total Patients/Yr. for entrectinib Estimated U.S. Total Patients/Yr. for RXDX-105 Estimated U.S. Total Patients/Yr. for taladegib Advanced basal cell carcinoma* 90%** ,900 Bladder 1% 1% 2-10% ,900 Breast - secretory carcinoma 92% 1% Breast - NOS 2% 4-10% ,300 Cholangiocarcinoma 4% 9% 2% CNS 1-5% - - 1,000 Colorectal 1% 1% 1-2% 1-2% <1% <1% 9% 3-4% 6,700 13,400 4,700 Gallbladder/Biliary 4% GBM 1-3% 1% 2% 3-10% 350-1,100 Head and Neck 4-22% ,500 Kidney 2-8% - - 4,600 Liver 2-3% Lung adenocarcinoma ~1% <1% <1% 1-2% 3-7% 1-3% 4% 2-6% 3,000 1,700 4,900 Lung squamous cell 8-31% ,200 Medulloblastoma 5-33% Melanoma 1% 46% 2-6% ,100 Melanoma - Spitz 16% 3% 1% 3% Ovarian 9% - - 1,800 Pancreatic 3% 1-24% ,300 Prostate 1% 1% 4% - 2,350 10,000 Salivary gland - MASC % Sarcoma 1-9% 2-11% 2-3% 1-5% 2-6% 2, Stomach 5% - - 1,000 Thyroid - PTC 5-13% 2-14% 7% 6% 2% 59% 2-3% 900 2,600 1,800 Uterine endometrial 7% - - 3,800 Total Addressable Patients 4, ,500 4,300 2,900 2,700 4,500 14, ,000 15,500 21, ,000 9

10 Ignyta s Dx Capabilities Enable Leadership in Precision Medicine Clinical Sites Specimens Ignyta Central Lab Platform Output RNA Prep Trial Enrollment FFPE NGS CLIA CAP Gene Rearrangements to NTRK1, NTRK2, NTRK3, ROS1, ALK STARTRK-2 (second of the "Studies of Tumor Alterations Responsive to Targeting Receptor Kinases. ) 10

11 Ignyta s Integrated Rx/Dx Precision Medicine Vision: Molecularly Targeted Therapies for Cancer Patients Molecularly targeted therapies/ cancer immunotherapies Molecularly targeted/ CSC therapies Molecularly Targeted Therapies for Cancer Patients *TYRO3, AXL, MER TBA: to be announced 11

12 Entrectinib: A Potential First-in-Class Trk Inhibitor in Potentially Registration-enabling Phase 2 Study Potent, selective, orally available ATP-competitive inhibitor of 5 oncogenic drivers Target TrkA TrkB TrkC ROS1 ALK IC50* (nm) In vitro: inhibition of targets and downstream effectors in the PLCγ, MAPK and PI3K/AKT pathways In vivo: complete tumor growth inhibition and regression in multiple xenograft models FDA orphan drug designation for, CRC and neuroblastoma, and rare pediatric disease designation for neuroblastoma; EMA orphan drug designation for neuroblastoma Composition of matter patent issued in US and allowed in Europe, with commercial protection out to 2029 (excluding PTE) * Biochemical kinase assay 12

13 Phase 1 Studies Updated data as of March 7, 2016 ALKA STARTRK-1 Dosing: intermittent and continuous Dosing: continuous NTRK1/ROS1/ALK alterations NTRK1/2/3, ROS1 or ALK alterations Italy US, EU, Asia 54 patients 65 patients Total clinical experience: 119 patients 45 patients treated with RP2D*: 600 mg PO once daily Phase 2-eligible population : 25 patients - NTRK1/2/3-, ROS1-, or ALK-rearranged solid tumor - Naïve to prior Trk/ROS1/ALK inhibitors, as applicable - Treated at or above RP2D* Response Evaluation - RECIST v1.1, locally assessed and confirmed: 24 patients - Volumetric assessment: 1 patient with primary brain tumor** *RP2D = Recommended Phase 2 Dose ** RECIST criteria not validated in primary brain tumors (FDA-AACR Brain Tumor Endpoints Workshop 2006) 13

14 Treatment-Related Adverse Events at RP2D >10% incidence; grades according to NCI CTCAE v4.0 Adverse Events (AEs) at the RP2D (n=45) No cumulative toxicity No renal toxicity No QTc prolongation No hepatic toxicity No AEs > Grade 4 All AEs reversible with dose modification Adverse Event Term, n (%) Grades 1-2 Grade 3 Total Dysgeusia 21 (47) 21 (47) Fatigue/Asthenia 17 (38) 1 (2) 18 (40) Constipation 10 (22) 10 (22) Weight Increased 8 (18) 1 (2) 9 (20) Diarrhea 7 (16) 1 (2) 9 (18) Nausea 8 (18) 8 (18) Myalgia 7 (16) 7 (16) Paresthesia 7 (16) 7 (16) Dizziness 6 (13) 6 (13) Peripheral Sensory Neuropathy 4 (9) 2 (4) 6 (13) Anemia 2 (4) 3 (7) 5 (11) Dysphagia 4 (9) 1 (2) 5 (11) Vomiting 5 (11) 5 (11) ( 10% incidence, grades per NCI CTCAE v4.0, data as of March 7, 2016) 14

15 Antitumor Activity in ALK and ROS1 Inhibitor-Naïve Patients with NTRK1/2/3, ROS1, or ALK Gene Rearrangements 30 Best Response in TKI Treatment-Naïve NTRK-, ROS1-, and ALK-rearranged Tumors (n=24) 20 PD 10 % tumor reduction PR Fusion Confirmed Responses (n) ORR (%) NTRK1/3 3/3 100% ROS1 12/14 86% ALK 4/7 57% CR 15

16 Antitumor Activity in ALK and ROS1 Inhibitor-Naïve Patients with NTRK1/2/3, ROS1, or ALK Gene Rearrangements 30 Best Response in TKI Treatment-Naïve NTRK-, ROS1-, and ALK-rearranged Tumors (n=24) 20 PD 10 % tumor reduction PR Fusion Confirmed Responses (n) ORR (%) NTRK1/3 3/3 100% 1 additional patient with NTRK+ astrocytoma SD by RECIST (not validated for primary brain tumors) 45% by exploratory 3-D volumetric assessment CR 16

17 Antitumor Activity in ALK and ROS1 Inhibitor-Naïve Patients with NTRK1/2/3, ROS1, or ALK Gene Rearrangements MASC Astrocytoma RCC Melanoma Unknown Primary CRC CRC Time on Study (months) TKI Treatment-Naïve NTRK-, ROS1-, and ALK-rearranged Tumors (n=25) X X X X X X.. X X. NTRK ongoing off study ROS1 X ALK time to response progression by RECIST, continued due to clinical benefit The median duration of response has not been reached (95%CI: 6 months, NR) Data cutoff 07 March

18 CNS Involvement in Solid Tumor Malignancy Brain metastases % of all patients with cancer -lung (up to 50%) -breast -melanoma Primary brain tumors -astrocytoma (NTRK2 fusions: 3%) -glioblastoma (NTRK1 fusions: 1-2%) -pediatric gliomas (NTRK3 fusions: 7%) Optimal therapy would proactively address both systemic and CNS disease 1 Fokas et al, BBA - Reviews on Cancer Chi et al, Cancers

19 Entrectinib: More Potent and CNS-Penetrant than Crizotinib ROS1+ patient treated with entrectinib Baseline Day 50 Images courtesy of MJ. Ahn, MD, Samsung Medical Center 19

20 Entrectinib in ROS1-Rearranged Cancer High potency (IC nm), with ability to cross the BBB to address CNS disease Well tolerated ROS1 Patients Best Response (%) - No responders have discontinued due to tolerability Overall response rate (ORR) of 86% (12/14 patients) - In, ORR of 85% (11/13 patients) Based on clinical experience to date, compares favorably to crizotinib s 72% investigatorassessed ORR* One additional response in melanoma Two complete responses Rapid responses (after 1 month of treatment) 0% change (ROS1 patient) Durable responses; median duration of response not reached * Based on a study of 50 patients 20

21 Entrectinib in NTRK-Rearranged Cancer We believe entrectinib is the most potent Trk inhibitor in clinical development - Potent activity against 3 primary mechanisms of resistance to other clinical stage Trk inhibitors Safety experience of ~120 patients (~3x more patient data than any other Trk inhibitor of which we are aware) - No cumulative, renal, or hepatic tox, or QTc - No responders have discontinued due to tolerability Responses in 100% (5/5) of NTRK+ patients - Rapid (1 month of treatment) and prolonged ( >1 year) responses - Responses in five different histologies, adult and pediatric patients - 3 out of 4 patients with NTRK fusions on continuous daily dosing remain on study mcrc NTRK Patients - Best Response (%) Astrocytoma* RECIST v1.1 Infantile Fibrosarcoma** MASC * response by 3-D volumetric assessment (courtesy of P. Brastianos MD, MGH) ** estimated from radiology assessment CNS activity in 100% (3/3) of NTRK+ patients with CNS disease - Demonstrated consistent and robust CNS activity - 3/5 of NTRK+ patients treated in Phase 1 or compassionate use setting had primary or metastatic CNS disease 21

22 STARTRK-2: Entrectinib Global Phase 2 Basket Study 22

23 RXDX-105 Is a Potent RET Inhibitor with Activity against BRAF and Other Kinases RXDX-105 is a multikinase inhibitor with potent activity against RET and BRAF Biochemical In vitro Anti-proliferative Assay Kinase IC 50 (nm) RET 0.33 CCDC6-RET 0.33 NCOA4-RET 0.41 PRKAR1A-RET 0.81 RET (M918T) 4.34 RET (V804M) IC 50 (nm) LC2/ad Lung adenocarcinoma CCDC6-RET TT Thyroid cancer RET C634W RXDX Alectinib Cabozantinib

24 RXDX-105 Phase 1 Dose-Escalation Study Updated data as of May 25, 2016 Total Phase 1 clinical experience: 55 patients Patients treated at clinically relevant doses (275 mg and 350 mg, fed): 20 patients Patients with actionable RET or BRAF alterations: 11 patients 24

25 RXDX-105 Exposure Has Reached Levels Expected To Be Efficacious in RET and BRAF Driven Tumors Plasma Concentration (ng/ml) Time (h) PK Data: BSA-normalized Day 15; Linear exposure plot 350 mg (Fed), N=6 275 mg (Fed), N= mg, N=7 200 mg, N=7 150 mg, N=3 100 mg, N=3 75 mg, N=3 40 mg, N=3 20 mg, N=3 RET Target Concentration BRAF Target Concentration 25

26 Treatment-Emergent Adverse Events in All Phase 1 Patients Generally well-tolerated. All AEs reversible with dose reduction or holiday No treatment-related AEs > Grade 4 Four DLTs (all resolved with dose interruption): G3 maculopapular rash (200 mg), G3 fatigue (275 mg), G3 diarrhea (275 mg Fed), G3 hyperbilirubinemia (350 mg Fed) Three treatment-related SAEs: G2 headache, G3 hyperbilirubinemia, G3 DRESS syndrome Note: Data as of May 3 rd, Most Common (>15%) Treatment-Emergent AEs in All Phase 1 Patients (N=55), N (%) Grade 2 Grade 3 Any Grade Fatigue 23 (42) 2 (4) 25 (46) Rash 17 (31) 2 (4) 19 (35) Nausea 17 (31) 2 (4) 19 (35) Vomiting 17 (31) 2 (4) 19 (35) Diarrhea 12 (22) 5 (9) 17 (21) Decreased Appetite 14 (26) 1 (2) 15 (27) Constipation 14 (26) 1 (2) 15 (27) Anemia 7 (13) 8 (15) 15 (27) Muscle Spasms 14 (26) 0 14 (26) Abdominal pain 10 (18) 3 (6) 13 (24) Hypokalemia 9 (16) 3 (6) 12 (22) Hypertension 9 (16) 1 (2) 10 (18) Dyspnea 9 (16) 1 (2) 10 (18) Hypoalbuminemia 7 (13) 2 (4) 9 (16) 26

27 RXDX-105 Preliminary Anti-Tumor Activity Note: Phase 1 was an all-comers dose escalation study. 55 patients were treated in the Phase 1 portion of the study; 20 were treated at the clinically relevant doses of 275 mg and 350 mg, Fed condition. Of those, 11 patients had an actionable RET or BRAF alteration. Data as of May 25, 2016, for tumor response and duration of therapy in these patients are displayed above. 27

28 RET M918T Medullary Thyroid Cancer Patient 51M with Medullary Thyroid RET M918T Baseline Dose: 350 mg (fed) Prior therapies: vandetanib, cabozantinib, sorafenib, MGCD516 - No prior PR/CR, but 30 months of SD on cabozantinib Response: First restaging scan (Cycle 2) showed a 38% decrease in target lesion (upr) End of Cycle 2 Status: Patient continues on treatment with confirmatory scan at Cycle 4 in June Data as of May 25,

29 BRAF V600E Ovarian Cancer Patient 68F with serous ovarian CA BRAF V600E Dose: 350 mg (fed) Prior therapies: carbo/taxol, gemcitabine/carboplatin, topotecan, Response: 26% reduction in baseline tumor measurements at C2 and C4 scans Status: Patient continues on study in Cycle 5 Images provided by MSKCC Data as of May 25,

30 Patient with BRAF D594G Mutation 58F with metastatic BRAF D594G mutation Baseline 6 Weeks Later Dose: 275 mg (fed) Prior therapies: pemetrexed, cisplatin, bevacizumab, cobimetinib, vinorelbine, and gemcitabine Response: Scans taken 4 weeks after last dose (six weeks from baseline); showed 28% reduction in tumor burden Status: Patient treated for 2 weeks; taken off study due to idiosyncratic drug-reaction (DRESS syndrome) Images provided by Drilon (MSKCC) Data as of May 25,

31 Patient with KRAS Mutation 75F with metastatic, first diagnosed in 2007 Dose: 275 mg (fed) Prior therapies: multiple lines of chemotherapy and 6 years of erlotinib Molecular analysis of tumor from her initial diagnosis revealed KRAS G12C mutation Response: At Cycle 2, the patient had 40% reduction in her target lesion, which was confirmed at Cycle 3 Status: patient is still on study at 10+ cycles Baseline End of Cycle 2 Data as of May 25,

32 Non-Small Cell Lung Adenocarcinoma Opportunity RXDX-105 is a potent RET and BRAF inhibitor Clinical activity also seen outside of these targets Clinical activity observed Patient with mutant KRAS Patient with BRAF D594G mutation; typically non responsive to pure BRAF inhibition Source: Gerber et al, 2014 Suggests potential as both a targeted RET/BRAF inhibitor and MKI in Potent inhibitor 32

33 Amended RXDX-105 Phase 1b Basket Study Design RET, BRAF and Baskets Study : Phase 1b Basket Study Tumor samples for CDx analysis tested locally Separate by solid tumor type and molecular alteration RET+ BRAF+ RET+ Other histologies RET+ Other Non-Squamous Squamous BRAF+ BRAF+ CRC BRAF+ Other histologies Baskets RET Baskets Objective Preliminary demonstration of efficacy BRAF Baskets Exploration of efficacy in unselected population 33

34 Summary of RXDX-105 Clinical Experience RXDX-105 appears safe and well-tolerated to date 55 Phase 1 patients with advanced or metastatic solid tumors Achieved efficacious exposure, based on RET- and BRAF-driven PDX models RP2D selected and being further evaluated in Phase 1b study, which is open to enrollment RXDX-105 has demonstrated preliminary clinical activity in patients with cancers harboring activating BRAF- and RET- alterations Unconfirmed PR (38% reduction) at Cycle 2 in a medullary thyroid cancer patient with the RET M918T mutation 26% reduction in target lesions in an ovarian cancer patient with BRAF V600E mutation and 28% reduction in target lesions in a BRAF D594G patient Confirmed PR (40% reduction) in a patient with positive for KRAS G12C who continues on treatment after 10 cycles of therapy Further development ongoing Phase 1b study includes baskets for RET- or BRAF-driven tumors as well as baskets for patients with unselected lung cancer Ph 1b basket study interim data, 4Q16 34

35 Key Investment Highlights Ignyta s vision is to catalyze precision medicine for the benefit of cancer patients everywhere, with an integrated approach to "Rx/Dx" in oncology Integrated approach to Rx/Dx development - CAP-accredited, CLIA-certified, QSR-compliant diagnostic lab with multi-modality assays - Internal Dx allows Ignyta to illuminate the molecular drivers of cancer and quickly advance the most appropriate molecularly targeted therapies to address them Robust pipeline of molecularly targeted therapies - 3 potentially first-in-class or best-in-class clinical stage programs Entrectinib: In global Phase 2, potentially registration-enabling study Additional Phase 1 programs (RXDX-105, taladegib) with demonstrated clinical responses - Preclinical program (RXDX-106) at the nexus of molecularly targeted and immuno-oncology Multiple near-term catalysts to drive value - Utilizing basket study designs for resource-efficient clinical development plans to generate multiple clinical data readouts in next 12 months, while building long-term value for patients and stockholders Experienced management team - Breadth and depth of expertise in clinical/preclinical development, regulatory affairs, commercial, and other key technical and business disciplines 35