biology insight

chemistry platform

clinical expertise

virtual infrastructure

Corporate Presentation

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: "anticipate," "intend," "plan," "goal," "seek," "believe," "project," "estimate," "expect," "strategy," "future, "likely," "may," "should," "will" and similar references to future periods. Examples of forward-looking statements include, among others, statements we make regarding our future financial performance, business plans and objectives, timing and success of our clinical trials, our ability to obtain regulatory approval, the potential therapeutic benefits and economic value of our lead product candidate, potential growth opportunities, financing plans, competitive position, industry environment and potential market opportunities.

Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, projections, anticipated events and trends, the economy and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Our actual results and financial condition may differ materially from those indicated in the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause our actual results and financial condition to differ materially from those indicated in the forward-looking statements include, among others, the following: those related to our future financial performance, our ability to develop and maintain partnerships, our ability to identify and develop new products in a timely manner, the outcome, cost and timing of our product development activities and clinical trials, market acceptance of our targeted small molecule therapeutics and diagnostics, our ability to maintain, protect and enhance our brand and intellectual property, our ability to continue to stay in compliance with applicable laws and regulations, our ability to scale our business and make key hires and such other factors as discussed in a registration statement (including a prospectus) that we filed with the Securities and Exchange Commission (“SEC”) for our initial public offering as well as our other filings with the SEC.

Any forward-looking statement made by us in this presentation and the accompanying oral presentation is based only on information currently available to us and speaks only as of the date on which it is made. We undertake no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

2

• We build specific and potent inhibitors against validated and emerging

targets in areas of high unmet medical need

• Our collaboration with Array BioPharma affords a diverse and ambitious

pipeline

– LOXO-101, the only purpose-built TRK inhibitor in clinical development (Phase 1)

– 2 undisclosed programs ready for IND-enabling work

– RET, FGFR, FLT3, and 2 other (undisclosed) preclinical programs

• We hold worldwide commercial rights for our entire pipeline

• Our management team and advisors have deep oncology experience

• Well funded through significant clinical milestones and into 2017

3

Loxo Oncology is committed to the discovery, development, and commercialization of targeted cancer therapies with best-in-class

potential

Josh Bilenker, MDChief Executive Officer

Jennifer Low, MD, PhDChief Medical Officer

EVP, Research and Development

Dov Goldstein, MDActing Chief Financial Officer

Nisha Nanda, PhD VP of Development

Jacob Van NaardenVP of Corp Dev and Strategy

Sara Slifka Sr. Director of Operations

4

Management Team

5

Keith Flaherty, MD MGHBoard of Directors

Jeffrey A. Engelman, MD, PhD MGHScientific Advisor

Ross L. Levine, MD MSKCCResearch Affiliation

Ben Ho Park, MD, PhD JHUResearch Affiliation

David Solit, MD MSKCC

Research Affiliation

SAB Integral To Target Qualification

• Capital efficient approach to develop multiple small molecule therapeutics

• Mature chemistry library and structure-based approach demonstrated through

partnerships

– AstraZeneca, Biogen Idec, Celgene, Genentech, Novartis and Oncothyreon

• Array BioPharma track record: 20 INDs filed 15 in clinical development that

met safety and PK goals

6

• FTE support

• Loxo equity

• Back-end milestones

• Mid-single digit royalties

Array Loxo

• Validated chemistry access

• R&D capability through Phase 1 drug supply

• Multi-target exclusivity

• Worldwide commercial rights

Loxo Array BioPharma

Multi-Target Array BioPharma Collaboration

• Translocations increasingly described and validated as therapeutic targets in solid tumors: e.g. ALKand ROS1

• TRK translocations first described in 1982 in colon cancer over next ~25 years, TRK translocations identified in tumors such as thyroid cancer, secretory breast cancer, mesoblastic nephroma, pediatric leukemia, and congenital fibrosarcoma

• In last 2-3 years, expanded use of next-generation sequencing identifies TRK translocations in numerous additional solid tumors:

7

TRK: A Novel Translocation

Pulciani et al, Nature 300; 539-542 (1982)Vaishnavi et al, Nature Medicine 19; 1469-1472 (2013)

Nature Reviews Cancer November 2013: 13; 772.

• Glioblastoma

• Lung adenocarcinoma

• Melanoma

• Brain low-grade glioma

• Colon adenocarcinoma

• Head and neck squamous cell carcinoma

• Sarcoma

• Breast, invasive carcinoma

TRK Fusions Across Multiple Tumor Types Suggestive of Important Biology

Estimated frequency

Gene Fusion Cancer <4% 5-25% >25% Ref.

NTRK1 Papillary thyroid cancer 1

NTRK1 Spitz neoplasms nevi 2

NTRK1 Glioblastoma 3

NTRK1 Intrahepatic cholangiocarcinoma 4

NTRK1 Lung large cell neuroendocrine cancer 5

NTRK1 Sarcoma 6

NTRK2 Astrocytoma 7

NTRK3 Mammary analogue secretory carcinoma (MASC) of the salivary glands 8

NTRK3 Secretory breast carcinoma 9

NTRK3 Congenital mesoblastic nephroma 10

NTRK3 Papillary thyroid cancer (post-radiation exposure) 11

NTRK3 Acute myeloid leukemia 12

NTRK3 Breast invasive carcinoma 6

NTRK3 Papillary thyroid cancer 13

NTRK3 Skin cutaneous melanoma 6

NTRK1/2 Lung adenocarcinoma 6, 14

NTRK1/3 Colorectal cancer 6, 15

NTRK2/3 Brain low-grade glioma 6

NTRK2/3 Head and neck squamous cell carcinoma 6

NTRK1/2/3 Pontine glioma 16

8

1. Bongarzone et al, Clin Cancer Res 4; 223-228 (1998). Brzezianska et al, Mutation Research 599; 26-35 (2006). 2. Wiesner et al, Nature Communications 5; 3116 (2014). 3. Kim et al, PLoS One 9; 3 (2014). 4. Ross et al, The Oncologist 19; 235-242 (2014). 5. Fernandez-Cuesta et al, AACR 2014; Abstract 1531. 6. Stransky et al, Nature Communications 5; 4846 (2014). 7. Jones et al, Nature Genetics 45; 927-934 (2013). 8. Bishop et al, Human Pathology 44; 1982-1988 (2013). 9. Tognon et al, Cancer Cell 2; 367-376 (2002). 10. Argani et al, Modern Pathology 13; 29 (2000). Rubin et al, Amer J Path 153; 1451-1458 (1998). 11. Leeman-Neill et al, Cancer 120; 799-807 (2014). 12. Kralik et al, Diagnostic Pathology 6; 19 (2011). 13. Leeman-Neill et al, Cancer 120; 799-807 (2014). 14. Vaishnavi et al, Nature Medicine 19; 1469-1472 (2013). 15. De Braud et al, ASCO 2014; Abstract 2502. 16. Wu et al, Nature Genetics; online 6 April 2014.

Note: The above table shows estimated frequency of TRK fusions.

• Sympathetic nervous system development is orchestrated by neurotrophins (NT) and respective neurotrophin receptors

• 3 distinct receptor genes

– NTRK1 TRKA

– NTRK2 TRKB

– NTRK3 TRKC

• Normal function of TRK in adults

– TRKA Pain, thermoregulation

– TRKB Movement, memory, mood, appetite, body weight

– TRKC Proprioception

• Receptors and ligands commonly dysregulated in multiple tumor types

9

Neurotrophins and Tropomyosin Receptor Kinases: A Novel Oncogenic Target

LOXO-101 Highly Specific for TRK Receptors

LOXO-101 has favorable TRK inhibitor properties:

1. Low nM potency for TRKs

2. Limited inhibition of other kinases

3. >100x selective for other kinases

4. >1,000x selective for other off targets

LOXO-101 CEP-701 (lestaurtinib)

TRK A and TRK B1

101 Upstate kinase panel shown does not include TRK C. LOXO-101 shown to be equipotent for TRK C in other assays.

Excellent Pharmacologic Drug Properties

PROPERTY DESCRIPTION

Selectivity

Potency

Oral Bioavailability

Protein Binding

Safety

Dosing

Toxicity

11

TRK A, B, CLimited inhibition of other kinases

Low nM potency against TRK A, B, C(cell & enzymatic)

High, in 4 preclinical species

Moderate

No relevant hERG inhibitionNo preclinical QT findings

Phase 1: oral, continuous 28 day cycle

Wide safety margin at expected therapeutic doses.Animals show no body weight loss and no drug-related

deaths at high doses

Tumors showed responses at all doses

12

Days Post-Tumor Implant

Tu

mo

r V

olu

me (

mm

3)

0 7 14 21

0

1000

2000

3000

10 mg/kg BID

20 mg/kg QD

30 mg/kg BID

60 mg/kg QD

100 mg/kg BID

200 mg/kg QD

Vehicle Control

LOXO-101 Treatment

Demonstrated Anti-Tumor ActivityTRKA-Driven Mouse Model of Cancer

Note: Presented at 2014 EORTC-NCI-AACR Symposium. LOXO-101, a pan TRK inhibitor, For The Treatment Of TRK-driven Cancers. Bouhana et al. Abstract #391.

13

LOXO-101 Phase 1a Clinical Trial

• Dose escalation, designed to evaluate safety, pharmacokinetics, pharmacodynamics, and identify the Phase 2 dose of LOXO-101

• Four sites currently open (Sarah Cannon Research Institute, University of Pennsylvania, Massachusetts General Hospital, University of Colorado)

• Will be opening additional sites in transition to Phase 1b

• Expect dose selection for 1b expansion 2H 2015

LOXO-101 Phase 1a Clinical Trial

• Phase 1a initial clinical data accepted for poster presentation at AACR in Philadelphia, PA

– Experimental and Molecular Therapeutics session on 4/21/2015 from 1:00 PM - 5:00 PM ET in poster section 32

– Abstracts will be published online at 1:00 PM ET on March 18, 2015

14

15

LOXO-101 Phase 1b Clinical Trial

• Dose expansion phase begins with identification of an appropriate dose from Phase 1a

• Limit enrollment to specific NTRK biology hypotheses, across tumor types, with statistical flexibility to rapidly advance into Phase 2

• Expect 1b start 2H 2015

• Will provide update on clinical development plans in 2H 2015

• Future clinical data will be presented at a medical meeting if they support proof of concept for LOXO-101 in TRK altered patients

NTRK Fusions

Certain NTRK mutations

NTRK gene amplification

NTRK Biology Hypotheses

Trk protein overexpression

Trk autocrine/ paracrine signaling

Activity signal to support Phase 2

Loxo Pipeline Programs Where Chemistry Can Offer Best-In-Class Potential

• Focused on targets where Loxo can demonstrate clinical differentiation through better chemistry

• Will pare down list of Array exclusive targets to four, exclusive of TRK, in Jan 2016, with option on a fifth for an additional payment to Array

• Pipeline work started in earnest in 2Q 2014

• Pipeline consists of:

– Two undisclosed programs ready for IND-enabling work; confirmatory pre-IND work ongoing that could support a clinical program in the first half of 2016

– RET, FGFR, and FLT3; periodic medical meeting updates starting 2H 2015

– Two others undisclosed

16

Loxo Pipeline: Competitive Advantages

• Disclosed targets have preliminary clinical validation. Loxo advances program if:

– Loxo identifies compelling clinical and regulatory strategy

– Loxo SAB corroborates product profile thesis

– Array platform can deliver differentiated chemistry

• Structure-based approach enables rational drug design

• Early database hits in Array proprietary library of pharmacology-tested chemotypes

• Array prior work in adjacent kinome spaces

• Many targets offer opportunity to leverage LOXO-101 infrastructure and expertise

– Multiplex testing for oncogene fusion targets and other alterations

– Overlapping clinical investigator network

17

RET (REarranged during Transfection) Preliminary Validation and Loxo Opportunity

• Commercial and pipeline drugs are multikinase inhibitors

• Loxo dialing out undesirable off-targets and ensuring coverage of resistant clones

18DiscoveRx

Falchook et al. Journal Clinical Oncology 2014; online first

Clinical Validation Loxo Differentiation Opportunity

RET (REarranged during Transfection)Alterations in Cancer

19

Histology FusionsActivating Mutations

Breast cancer

Chronic myelomonocytic leukemia

Colorectal cancer

Myelofibrosis

Non-small cell lung cancer

Small cell lung cancer

Thyroid cancer

FGFR (Fibroblast Growth Factor Receptor) Preliminary Validation and Loxo Opportunity

20

Challenging to interpret clinical activity signals, given drug promiscuity and earlier-generation diagnostic tools

Recent clinical validation across multiple programsDienstmann et al. AACR 2014. Abstract CT325

Sequist et al. AACR 2014. Abstract CT326Bahelda et al. ASCO 2014. Abstract 2501Arkenau et al. ASCO 2014. Abstract 2620Nogova et al. ASCO 2014. Abstract 8034

Paik et al. ASCO 2014. Abstract 8035Kilgour et al. ASCO 2014. Abstract 11010

FGFR1-3 with improved kinome selectivity (e.g. VEGF, JAK, Aurora, CSF1R) and optimized oral pharmacology

1st Generation:FGFR1-3, VEGFR,

Off-targets

2nd Generation:FGFR1-3,

VEGFR-sparing

Loxo 3rd Generation Differentiation Opportunities

Improved isoform selectivity

FGFR (Fibroblast Growth Factor Receptor) Alterations in Cancer

Histology FusionsActivating Mutations

High Level Gene Amplification

Breast cancer

Bladder cancer

Cervical cancer

Endometrial cancer

Gastric cancer

Glioblastoma

Head/neck cancer

Lung cancer

Multiple myeloma

Ovarian cancer

Prostate cancer

21

FGFR1

FGFR2

FGFR3

FLT3 (Fms-Like Tyrosine kinase 3)Alterations in Cancer

Activating mutations

(20-35% of adult AML)

Common resistance mutations

(e.g. D835, F619)

22Stirewalt and Radich. Nature Reviews Cancer 2003; 3(9): 650-665

• FLT3-mutant AML confers adverse clinical prognosis

FLT3 (Fms-Like Tyrosine kinase 3)Preliminary Validation and Loxo Opportunity

23CR = Complete ResponseCRc = Composite Complete Response (CRi+CRp+CR)

• FLT3-WT & FLT3-ITD coverage• D835 & F691 escape mutant coverage• Spare KIT and other liability targets• No hERG liability (QTc risk)• Best-in-class oral pharmacology

• Pursue CRs• Explore use in earlier line settings• More tailored patient selection criteria• Combinations with emerging AML classes

Loxo Differentiation Opportunities Loxo Clinical Strategies

Precedent FLT3 Inhibitors Identify New Questions

• A decade of clinical development in FLT3 has led to promising rates of monotherapy CRc, but few monotherapy CRs

• Escape mutants have emerged clinically, and quickly, with precedent FLT3 inhibitors• Oral pharmacology (i.e. “target coverage”) must deliver on in vitro profile• Randomized Phase 3 trials ongoing

Capitalization and Milestones

• Shares Outstanding (9/30/2014)

– Basic: 16.6M

– Options: 1.5M ; $3.54 weighted average strike price

– Total FD: 18.1M

• Cash

– $118.6M cash on hand as of 9/30/2014

– Runway into 2017

24

2H 20151H 2015

April 2015 – LOXO-101 Phase 1a Data at AACR

2H 2015 – Initial Pipeline Preclinical Data and Timeline

Update

2H 2015 – Update on LOXO-101 Clinical Development Plans

Appendix

25

Agent Company Inhibitor Profile TRK Development

PLX7486 Daiichi Sankyo Flt3, cFMS

Phase 1 dose-findinggem/abraxane combo in pancreatic; Monotx TRK cohort included

DS-6051b Daiichi Sankyo ROS1Phase 1 dose-finding, TRK cohort included

RXDX-101 Ignyta ROS1, ALKPhase 1/2 dose-finding, TRK cohort included

MGCD516 MiratiRET, DDR, MET, AXL, VEGFRs, EPHA/B

Phase 1 dose-finding

Dovitinib NovartisFlt3, c-Kit, FGFR1-3, VEGFR1-3, PDGFR

Phase 2 in any activated pathway, including TRK

TSR-011 TesaroALK10X less for TRK

Phase 1/2a dose-finding,TRK cohort included

LOXO-101 CompetitionMulti-Kinase Inhibitors with TRK Cohorts

26