Product Pipeline

Click here to view the JakafiTM press release.
Click here to view the JakafiTM (ruxolitinib) Prescribing Information insert.

 JAK Program for Oncology and Inflammation

Janus Kinase Inhibitors: Compelling Approach to Treat Inflammation, Myeloproliferative Neoplasms and Cancer

Mechanism of Action

Janus kinases (JAK) are enzymes that mediate signaling of several important drivers of myeloproliferative neoplasms (MPNs), other hematological malignancies and inflammatory diseases. There are four JAK enzymes: JAK1, 2, 3 and TYK2.

• Aberrant activation of the JAK-STAT pathway has been documented in a variety of cancers.
• Known inflammatory cytokines, such as IL-6, IL-12, and IL-23, signal through JAKs to promote inflammation.

JAK Inhibition in Myeloproliferative Disorders: A Tutorial

Potential Benefits in Oncology Conditions

• Potential to be first targeted therapy for MPNs.
• Broad applicability in a number of malignant hematologic conditions and solid tumors.
• Convenient oral dosing.

Potential Benefits in Chronic Inflammatory Conditions

• Convenient oral dosing - current best-of-care anti-inflammatory therapies are injectable.
• Expected to be effective in patients naive and refractory to anti-TNF therapies.
• Broad applicability in a number of inflammatory conditions.

Program Status

We have two potent, selective, orally bioavailable candidates currently in clinical development - ruxolitinib (INCB18424) and LY3009104 (INCB28050).

Our lead oral compound, ruxolitinib, is being developed by us in the U.S. and by Novartis outside of the U.S. for:

• Myelofibrosis: Phase III development
• Polycythemia vera: Phase III development
• Trials in solid tumors/other hematologic malignancies: Phase I and II

LY3009104 is being developed by Lilly as an oral treatment for chronic inflammatory conditions.

• Rheumatoid Arthritis: Phase IIb trial

Additionally, we have completed Phase II trials for ruxolitinib in the following indications:

• Essential thrombocythemia (oral): Phase II development
• Psoriasis (topical): Phase II development

Resources

JAK Backgrounder

Myeloproliferative Neoplasms

June 11, 2011 EHA Press Release

2011 EHA Poster

June 4, 2011 ASCO Press Release

June 2011 ASCO COMFORT-I Presentation

June 2011 ASCO COMFORT-11 Presentation

JAK Inhibition in Myeloproliferative Disorders: A Tutorial

December 6, 2010 ASH Press Release

December 2010 ASH PV/ET Presentation

December 7, 2009 ASH Press Release

December 2009 ASH Presentation: A Phase II Study of INCB018424 (PV/ET) Presentation

December 2009 ASH Presentation: Significant Activity of JAK2 Inhibitor, INCB018424 (Leukemias) Presentation

December 2009 ASH Presentation: Long-Term Follow up and Optimized Dosing Regimen of INCB018424 (MF) Presentation

2009 ASH Poster

2009 AACR TKI Resistance Poster

2009 AACR Cachexia Poster

December 2008 ASH Presentation

2008 ASH Poster 1760

2008 ASH Poster 1762

2008 ASH Poster 2802

2008 ASH Poster 2804

June 2, 2008 ASCO Press Release

June 2008 ASCO Presentation

December 2007 ASH Presentation

2007 ASH Poster

Inflammation

November 10, 2010 ACR Press Release

November 2010 ACR Presentation

May 2010 SID Presentation

2010 SID Poster

October 26, 2008 ACR Press Release

October 2008 ACR Presentation

2008 ACR Poster

June 12, 2008 EULAR Press Release

June 2008 EULAR Presentation

c-MET Program for Solid Tumors

c-MET Receptor Kinase: Clinically Validated Cancer Target

Mechanism of Action

c-MET is a receptor tyrosine kinase that is a clinically validated cancer target. Dysregulation of the c-MET pathway triggers tumor growth, promotes the formation of new blood vessels that supply the tumor with nutrients, and causes cancer to spread to other organs. Dysregulation of the c-MET pathway is seen in many types of cancers, including kidney, liver, stomach, breast, and brain and correlates with poor prognosis.

Potential Benefits in Oncology

Several small molecule c-MET kinase inhibitors have demonstrated clinical efficacy in a number of cancers; however, we believe these molecules have limited potency and are relatively non-selective, which could lead to off-target toxicities.

We believe our lead c-MET inhibitor has the requisite properties to overcome these limitations, including:

• greater selectivity and
• improved potency, resulting in more effective inhibition of c-MET.

Program Status

We have an oral candidate, INCB28060, in Phase I clinical development for solid tumors. Worldwide rights to INCB28060 have been licensed to Novartis.

IDO Inhibitor: Potential to Increase Anti-tumor Immune Response

Mechanism of Action

Indoleamine 2, 3-dioxygenase is an immune regulatory enzyme that is normally expressed in tumor cells and in activated immune cells. It dampens the immune response and interferes with immune function by; depleting the amino acid, tryptophan, which is needed for immune cell activation and growth; increasing the local concentration of tryptophan metabolites which are toxic to the immune cells; and increasing the levels of regulatory T cells which further suppress the immune response.

Potential Benefits in Oncology

In a number of tumor types, IDO expression has been clearly associated with poor clinical outcomes and decreased overall survival. Pre-clinically, it has been shown that IDO inhibition, by increasing the anti-tumor immune response, dramatically increases the efficacy of various chemotherapeutic agents in controlling tumor growth. Together, these results suggest that the IDO pathway is a key regulatory element responsible for induction and maintenance of tumor immune tolerance.

Program Status

We have a novel, potent, selective inhibitor of the enzyme, IDO, INCB24360, in Phase I clinical development for solid tumors.