Loxo Oncology (LOXO) Issues Update, Commentary on Pipeline, FY15 Program

Loxo Oncology (Nasdaq: LOXO) provided updated 2015 program guidance and unveiled molecular targets for three of its active preclinical programs. The three targets disclosed are Rearranged during Transfection (RET), Fibroblast Growth Factor Receptor (FGFR), and FMS-Like Tyrosine kinase 3 (FLT3). In addition to these three programs, Loxo possesses well-vetted candidates for two other programs, not yet disclosed by target name, that are ready for IND-enabling work. Like Loxo's clinical program LOXO-101, these preclinical pipeline programs are the result of Loxo's collaboration with Array BioPharma. The Company will provide periodic data updates for its discovery pipeline at medical meetings, beginning in the second half of 2015.

"We are very excited about the progress we have made with Array as our partner, since filing our LOXO-101 IND and shifting preclinical resources towards our pipeline," said Josh Bilenker, MD, Chief Executive Officer. "We are pursuing drugs with best-in-class potential, ideally where clinical research has pointed to opportunities for rational drug design and distinct clinical development strategies to overcome limitations in earlier-generation drugs. For our RET, FGFR, and FLT3 programs, we set ambitious candidate profiles, informed by the exciting preliminary activity signals seen in the clinic for these targets."

Loxo continues to advance LOXO-101, a selective inhibitor of the TRK family of tyrosine kinase receptors. LOXO-101 is currently in a Phase 1 dose-escalation clinical trial, for which initial safety and pharmacokinetic data will be presented in April at the American Association of Cancer Research (AACR) 2015 Annual Meeting.

"For LOXO-101, we will soon turn our focus towards TRK-altered patients, as the dose escalation reaches biologically relevant levels," added Josh Bilenker. "Our clinical development opportunity is perhaps broader than we had planned, as recent publications have identified TRK alterations in many tumor types outside of lung cancer, such as head and neck, salivary, sarcoma, melanoma, colorectal and breast cancers."

"Loxo has made very exciting and rapid progress with LOXO-101 and its discovery efforts. The company is building a world-class and diverse pipeline, leveraging insights from its Scientific Advisory Board (SAB) and translating those into differentiated molecules with exciting clinical theses. The global cancer drug pipeline remains in need of well-designed RET, FGFR, and FLT3 inhibitors, as we learn time and again that only the most potent and selective inhibitors of oncogenes maximize single-agent benefit and best facilitate combination regimens," said Keith Flaherty, MD, Director and Chair of Loxo's SAB.

2015 Program Guidance

LOXO-101

LOXO-101 is a selective inhibitor of the TRK family of tyrosine kinase receptors.

• Initial Phase 1 safety and pharmacokinetic data for LOXO-101 will be presented as a poster at the AACR 2015 Annual Meeting in Philadelphia in April. The poster will be presented in the Experimental and Molecular Therapeutics session on Tuesday April 21, 2015 from 1:00 PM - 5:00 PM ET in poster section 32. Abstracts for AACR 2015 will be published online at 1:00 PM ET on March 18, 2015.
• In the second half of 2015, Loxo will provide an update on its clinical development plans for LOXO-101. Loxo will present future clinical data at a medical meeting if they support proof of concept for LOXO-101 in TRK altered patients.

Active Pipeline Programs

• In addition to the RET, FGFR, and FLT3 programs, Loxo possesses well-vetted candidates for two other programs, not yet disclosed by target name, that are ready for IND-enabling work. We are currently conducting confirmatory pre-IND work for these programs. With supportive data, we could initiate clinical programs for either of these programs in the first half of 2016.
• RET is a tyrosine kinase receptor that binds the glial cell line-derived neurotrophic factor (GDNF) ligand family and contributes to the development of the nervous system and kidneys. Kinase inhibitors with anti-RET activity have demonstrated preliminary anti-tumor activity in experimental trials enrolling lung and thyroid cancer patients with RET fusion proteins and RET mutations. We are designing a highly specific RET inhibitor that optimizes on-target potency for RET fusion proteins, mutations, and clinically-identified resistance mutations.
• The FGFR family of receptors consists of four isoforms with tyrosine kinase domains, numbered one through four (1-4), which play important roles in embryonic development and adult angiogenesis, hormone regulation, and renal function. Fusions, point mutations, and gene amplifications in individual isoforms of the FGFR family have been associated with distinct cancer types in patients, and preliminary anti-tumor activity has been demonstrated in genitourinary, lung, and breast cancers in experimental trials of kinase inhibitors with anti-FGFR activity. We are designing a highly specific FGFR inhibitor that optimizes on-target potency against FGFR. In addition, there may be a therapeutic index advantage—and therefore an opportunity for better target coverage—with an isoform-specific FGFR inhibitor, though the structural similarities of FGFR 1-3 create significant challenges for designing such an inhibitor.
• FLT3 is a tyrosine kinase receptor that plays an important role in the development of stem cells and the immune system. In acute myeloid leukemia (AML), so-called internal tandem duplication (ITD) mutations in FLT3 have been associated with poorer outcomes with standard therapies, and predict sensitivity to inhibition with kinase inhibitors with anti-FLT3 activity. Precedent FLT3 inhibitors have taught us much about how leukemia cells acquire resistance to FLT3 directed therapies. We are designing a highly specific FLT3 inhibitor that optimizes on-target potency for the FLT3-ITD mutations and clinically-identified resistance mutations.
• The Company will provide periodic data updates for its discovery pipeline at medical meetings, beginning in the second half of 2015.

Array Collaboration Update

• As per its collaboration agreement with Array BioPharma, Loxo initially held exclusivity for twelve undisclosed targets, excluding TRK. In January 2015, Loxo's exclusivity was reduced to seven targets, and will be further reduced to four targets in January 2016. Loxo has an option for a fifth target, which would trigger a milestone payment to Array.

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