Loxo Oncology — Investor Presentation (January 2018)
45 slides from Loxo Oncology's investor presentation, Jan 8, 2018
Slide 1: Forward Looking Statements
Forward Looking Statements This presentation and the accompanying oral presentation contain “forward-looking” statements within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by words such as: "anti
Slide 2: Pipeline of Highly Selective Drug Candidates for Genetically Defined Cancers
Pipeline of Highly Selective Drug Candidates for Genetically Defined Cancers 1 Program Indication Stage of Development Eligible US patients/yr1 Preclinical Phase 1 Phase 2 Marketed Status Larotrectinib (LOXO-101) TRK fusion cancers Rolling NDA initiated Dec 2017 Completion of NDA submission expected
Slide 3: Pipeline of Highly Selective Drug Candidates for Genetically Defined Cancers
Pipeline of Highly Selective Drug Candidates for Genetically Defined Cancers alterations Program S309 of Baveloveneett Eligible US Indication Preclinical Phase i Phase2 Marketed Status Patients/yr* Larotrectinib (LOXO-101) TRK fusion cancers Rolling NDA initiated Dec 2017 Pha Gate oe Completion of N
Slide 4: Bayer Global Partnership for TRK Franchise
Bayer Global Partnership for TRK Franchise 5 Global partnership with Bayer to develop and commercialize larotrectinib and LOXO-195, announced November 14, 2017 Up to $1.55B in upfront, regulatory, and commercial milestones with $825M achievable by end of 2019 $400M upfront; $650M in milestones assoc
Slide 5: TRK Fusions Found in Diverse Cancer Histologies
TRK Fusions Found in Diverse Cancer Histologies 6 Brain cancers (glioma, GBM, astrocytoma) Salivary (MASC) Lung cancer Secretory breast cancer Melanoma Colon Sarcoma (multiple) Infantile fibrosarcoma Gliomas Thyroid cancer Congenital nephroma Sarcoma (multiple) Common cancer with low TRK fusion freq
Slide 6: Larotrectinib
Larotrectinib Larotrectinib is the first and only selective pan-TRK inhibitor in clinical development Highly potent against TRKA, TRKB, TRKC 5–11 nM IC50 in cellular assays Highly selective Development timeline March 2015: 1st TRK fusion patient treated July 2016: breakthrough therapy designation Fe
Slide 7: Larotrectinib TRK Fusion Development Program
Larotrectinib TRK Fusion Development Program 8 N=55 TRK fusion patients n=8 n=12 n=35 TRK fusion status determined by local CLIA (or similarly accredited) laboratories Primary endpoint Best objective response rate (ORR) RECIST v1.1 per investigator assessment Secondary endpoints Duration of response
Slide 8: Clinical Activity of Larotrectinib in Patients with TRK Fusion Cancers (ASCO 2017)
Clinical Activity of Larotrectinib in Patients with TRK Fusion Cancers (ASCO 2017) 9 *Includes unconfirmed responses with confirmatory scans pending (4 PR, 1 CR). All remain in response and ongoing on study. Enrolled patients with confirmatory response data available (n=50) All enrolled patients (n=
Slide 9: Efficacy Regardless of Age, Tumor Type, NTRK Gene Fusion Partner
Efficacy Regardless of .. 10 Age Tumor Type NTRK Gene Fusion Partner Hyman et al. ASCO 2017. Abstract LBA2501. April 2017 data cut-off date
Slide 10: Duration of Larotrectinib Therapy (ASCO 2017)
Duration of Larotrectinib Therapy (ASCO 2017) 11 93% of responding patients and 75% of all patients remain on treatment or underwent surgery with curative intent 0 3 6 9 12 Overall treatment duration (months) 15 18 21 24 27 Treatment after progression Treatment after surgery Time to first response S
Slide 11: Adverse Events (ASCO 2017)
Adverse Events (ASCO 2017) 12 Treatment-emergent AEs (%)* Treatment-related AEs (%) Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 3 Grade 4 Total Fatigue 15 18 5 – 38 1 – 18 Dizziness 22 4 2 – 27 1 – 20 Nausea 20 5 2 – 26 2 – 18 Anemia 8 9 9 – 26 3 – 10 Vomiting 18 6 – – 24 – – 13 Increased AST 16 4 3
Slide 12: Independent Review Committee Results
Independent Review Committee Results Announced October 18, 2017 NDA/MAA dataset includes adult and pediatric TRK fusion patients enrolled in the three ongoing larotrectinib clinical trials Intent to treat (ITT) principle First 55 TRK fusion patients with RECIST-evaluable disease enrolled, regardless
Slide 13: Larotrectinib Regulatory Timing
Larotrectinib Regulatory Timing Breakthrough therapy designation (BTD) granted in July 2016 BTD indication: “For the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following pr
Slide 14: Larotrectinib Regulatory Timing
Larotrectinib Regulatory Timing * Breakthrough therapy designation (BTD) granted in July 2016 + BTD indication: “For the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed followin
Slide 15: LOXO-195: Structurally Distinct, Similarly Selective
LOXO-195: Structurally Distinct, Similarly Selective 16 LOXO-195 Larotrectinib TRKB TRKB TRKA TRKA
Slide 16: Mutations that limit drug binding are the most common form of acquired resistance
Mutations that limit drug binding are the most common form of acquired resistance; often the oncogene-addicted tumor remains addicted to the same oncogene 667C 595R larotrectinib Rationale for LOXO-195 Solvent front Activation loop 17 Larotrectinib bound to ATP-binding pocket of TrkA: Steric hindran
Slide 17: LOXO-195 to Address TRK Acquired Resistance (ASCO 2017)
LOXO-195 to Address TRK Acquired Resistance (ASCO 2017) 18 TRKA G595R Tumor type Fusion Resistance mutation Colorectal TPM3-NTRK1 TRKA G595R Colorectal LMNA-NTRK1 TRKA G595R NSCLC TPR-NTRK1 TRKA G595R Sarcoma TPM3-NTRK1 TRKA G595R IFS ETV6-NTRK3 TRKC G623R Cholangio LMNA-NTRK1 TRKA F589L* + GNAS Q22
Slide 18: LOXO-195 Clinical Development
LOXO-195 Clinical Development Phase 1/2 trial enrolling Next clinical data update expected in 2018 Plan to address patients with TRK fusion cancers harboring solvent front mutations, xDFG mutations, and gatekeeper mutations Loxo Oncology is well-positioned to be the first oncology company to simulta
Slide 19: LOXO-195 Clinical Development
CC EE EEE LOXO-195 Clinical Development + Phase 1/2 trial enrolling + Next clinical data update expected in 2018 * Plan to address patients with TRK fusion cancers harboring solvent front mutations, xDFG mutations, and gatekeeper mutations + Loxo Oncology is well-positioned to be the first oncology
Slide 20: RET (REarranged during Transfection)
RET (REarranged during Transfection) Adapted from Mulligan, Nature Reviews Cancer (2014) 14: 173-185; Besset, JBC 2000 275: 39159-39166 Wild-type RET Extracellular mutation C634R Intracellular mutation M918T Oncogenic fusion KIF5B-RET CCDC6-RET ~60% medullary thyroid cancer ~2% NSCLC, 10-20% papilla
Slide 21: M918T Clinically Validated in MTC
M918T Clinically Validated in MTC EXAM Phase 3 Trial, cabozantinib vs. pbo Source: Schlumberger, ASCO 2015 ITT Population HR 0.15 p<0.0001 HR 0.67 p=0.1875 22
Slide 22: Multikinase Inhibitors Have Clinically Validated RET Fusions in NSCLC
Multikinase Inhibitors Have Clinically Validated RET Fusions in NSCLC 23 Drug Publication N RECIST ORR1 Median PFS Issues Cabozantinib Initial data: ASCO 2015 Follow-up data: Lancet Oncol 2016 16 25 38% (6/16) 28% (7/25) 7m 5.5m Frequent AEs and dose reductions Lenvatinib ESMO 2016 25 16% (4/25) 7.3
Slide 23: Repurposed RET Inhibitors: Poor RET Coverage in Humans
Cabozantinib Vandetanib Lenvatinib Alectinib *cellular (phospho-RET) inhibitory concentration corrected for human plasma protein binding and published human PK RET KDR/VEGFR2 MET/ALK/ROS Other kinases FGFR1-3/EGFR MKI Approved Dose Toxicities Cabozantinib 140 mg QD Diarrhea, PPE, weight/appetite, fa
Slide 24: Multikinase Liabilities On Display
Multikinase Liabilities On Display 25 Excerpt from commentary “ ”
Slide 25: RET: Product Profile Goals
RET: Product Profile Goals Potent against RET fusions and mutations Superior RET inhibition in pharmacodynamic models Tumor regression in in vivo models Activity against predicted acquired resistance mutations, such as V804M and V804L Avoid off-targets such as VEGFR, Aurora kinase, FGFR, EGFR, MET E
Slide 26: LOXO-292: Potent and Selective RET Inhibition
RET LOXO-292 LOXO-292: Potent and Selective RET Inhibition Rationally designed, informed by proprietary crystallography insights Highly selective Fusion- and mutation-independent RET inhibition e.g. KIF5B-RET, CCDC6-RET C634W, M918T, V804L/M (gatekeeper—acquired resistance) Favorable drug-like prope
Slide 27: LOXO-292: Log-Scale Cell Line Selectivity
LOXO-292: Log-Scale Cell Line Selectivity 28 No RET alteration (n=83) RET alteration (n=4) Insensitive Sensitive Cabozantinib Vandetanib LOXO-292 10 100 1000 Cell Count EC50 (nM) Brandhuber et al. EORTC-NCI-AACR 2016. Abstract 441.
Slide 28: LOXO-292 Phase 1 Trial Design
LOXO-292 Phase 1 Trial Design 29 Advanced RET-altered solid tumor Any prior TKIs that inhibit RET MTD/ recommended expansion dose 5. Advanced RET-altered solid tumor, any of: Disease not measurable Other RET-altered tumors RET mutation-neg. MTC Any prior TKIs that inhibit RET 1. Advanced RET-fusion
Slide 29: LOXO-292 Phase 1 Study in Progress (IASLC 2017)
LOXO-292 Phase 1 Study in Progress (IASLC 2017) 28 patients enrolled to 4 dose levels (first patient dosed May 2017) No dose limiting toxicities (DLTs) PK dose proportional and consistent with significant RET target engagement 30 Cellular (phospho-RET) IC50/IC90 corrected for human plasma protein bi
Slide 30: Patient 1: CCDC6-RET Fusion
Patient 1: CCDC6-RET Fusion 63-year old woman with advanced NSCLC: prior surgery, radiation, and chemotherapy After identification of CCDC6-RET fusion, received RXDX-105 for 7 months and then progressed First LOXO-292 patient treated with RET fusion lung cancer, on Phase 1 trial (20 mg QD) Confirmed
Slide 31: Patient 2: KIF5B-RET Fusion
Drilon et al. IASLC 2017. Abstract 10955. September 27, 2017 data cut-off date Drilon et al., Cancer Discovery 2017 Sep;7(9):963-972, Published OnlineFirst June 3, 2017 Patient 2: KIF5B-RET Fusion 40-year old woman, never-smoker, with advanced NSCLC: 3 lines of chemotherapy, whole brain radiation, a
Slide 32: Patient 2: Pharmacokinetics at Current Dose
Cellular (phospho-RET) IC50/IC90 corrected for plasma/brain protein binding and estimated CNS penetration LOXO-292 in Plasma (ng/mL) Time (hours) Plasma IC50 Plasma IC90 Brain IC50 Brain IC90 Patient 2: Pharmacokinetics at Current Dose Patient experienced dramatic clinical improvement Neurologic sym
Slide 33: Patient 2: Systemic Tumor Response
Pre-treatment LOXO-292 at 2 mo. Patient 2: Systemic Tumor Response 34 Drilon et al. IASLC 2017. Abstract 10955. September 27, 2017 data cut-off date
Slide 34: Patient 2: Intracranial Tumor Response
Pre-treatment LOXO-292 at 3 mo. Patient 2: Intracranial Tumor Response 35 Drilon et al. IASLC 2017. Abstract 10955. September 27, 2017 data cut-off date
Slide 35: Patient 2: Intracranial Tumor Response
Pre-treatment LOXO-292 at 2 mo. Patient 2: Intracranial Tumor Response 36 Drilon et al. IASLC 2017. Abstract 10955. September 27, 2017 data cut-off date
Slide 36: IASLC 2017 Presentation Conclusions
IASLC 2017 Presentation Conclusions LOXO-292: RET inhibition in ongoing Phase 1 trial already greater than multikinase (MKI) inhibitors Well-tolerated with no DLTs Biologically relevant doses Proof of concept anti-tumor efficacy in patients with RET-fusion NSCLC Heavily pre-treated and MKI-experienc
Slide 37: LOXO-292 Clinical Development
LOXO-292 Clinical Development Dose escalation ongoing By dose cohort 4, IC90 target coverage in patients Next clinical data update expected in first half 2018 38
Slide 38: LOXO-292 Clinical Development
CC EEE ee LOXO-292 Clinical Development + Dose escalation ongoing - By dose cohort 4, IC90 target coverage in patients + Next clinical data update expected in first half 2018
Slide 39: C481S: Emerging, Class-wide Acquired Resistance
C481S: Emerging, Class-wide Acquired Resistance Irreversible BTK inhibitors all bind to BTK cysteine at position 481 A mechanism of acquired resistance has emerged called a C481S mutation that may explain 60-70% of progression events (cysteine mutates to serine)1 Likely to occur across all irreversi
Slide 40: LOXO-305 Shows Equal Affinity Against WT and Mutant BTK
LOXO-305 Shows Equal Affinity Against WT and Mutant BTK 42 Irreversible BTK inhibitors display a drop-off between BTK WT and BTK C481S LOXO-305 is equipotent against BTK WT and BTK C481S Log [LOXO-305] M LOXO-305 BTK IC50 = 1.0nM LOXO-305 BTK C481S IC50 = 0.8nM Binding affinity (LanthaScreen™) Log [
Slide 41: LOXO-305 is Highly Selective
LOXO-305 is Highly Selective 468 Kinases Screened 43 All enzyme hits with IC50 <0.1µM shown BTK
Slide 42: LOXO-305: Next Steps
LOXO-305: Next Steps Attractive drug-like properties In vitro ADME Animal pharmacokinetics Preliminary animal toxicology Currently completing pre-IND work Planning IND submission and clinical trial initiation in 2018 Opportunity for patient enrichment in Phase 1 As more patients are treated with irr
Slide 43: 2018 Milestones
2018 Milestones 45 PROGRAM UPDATE GUIDANCE Larotrectinib (LOXO-101, TRK) Complete rolling NDA submission with U.S. FDA Early 2018 MAA submission with EMA* 2018 Integrated TRK fusion clinical data update(s) 2018 LOXO-195 (TRK) Clinical data update from ongoing Phase 1/2 trial 2018 LOXO-292 (RET) Clin
Slide 44: Financials and Capitalization
Financials and Capitalization NASDAQ: LOXO Shares Outstanding*: 29.9M basic, 3.2M options ($24.32 weighted avg strike price) Cash, cash equivalents, and investments*: $405.3M** Bayer partnership milestones Up to $1.55B in upfront, regulatory, and commercial milestones $400M upfront $450M in mileston
Slide 45: Financials and Capitalization
Financials and Capitalization NASDAQ: LOXO + Shares Outstanding*: 29.9M basic, 3.2M options ($24.32 weighted avg strike price) * Cash, cash equivalents, and investments*: $405.3M** + Bayer partnership milestones — Up to $1.55B in upfront, regulatory, and commercial milestones + $400M upfront + $450M