Incyte: Drug Discovery: Product Pipeline

Incyte's Product Pipeline

Potential for Near and Long-Term Value

Incyte's vision is to become a leading drug discovery and development company by building a proprietary product pipeline of novel small molecule drugs. We have an experienced team with prior success in bringing important new drugs to market. We believe we have the resources, experience and drive to improve the lives of patients and build sustainable value for our shareholders.

JAK Program

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

Over the past 18 months, nearly 150 MF patients have been enrolled in the Phase II trial, INCB18424-251. Important and previously unachievable clinical benefits observed in this
study include striking improvement in splenomegaly and the debilitating constitutional symptoms that plague the majority of these patients. INCB18424 treatment improves the systemic inflammatory state which we know characterizes advanced MF. INCB18424 results in prompt and sustained reductions in the markedly elevated levels of a broad range of pro-inflammatory cytokines that we have now documented in MF patients. Additionally, regardless of an MF patient's diagnostic subgroup or the presence or absence of JAK2 mutations which occur in subsets of MF patients, the vast majority of patients entering this trial remain on study, many for a year or more, with durable and robust clinical benefit.

Srdan Verstovsek, M.D., Ph.D.
Associate Professor, Leukemia Department, Myeloproliferative Disorders Program Leader
University of Texas M.D. Anderson Cancer Center
Principal Investigator for Phase II Trial
ASH, December 2008

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.
Activating mutations of JAK2 are present in >90% of polycythemia vera patients and ~50% of essential thrombocythemia and myelofibrosis patients.
Known inflammatory cytokines, such as IL-6, IL-12, and IL-23, signal through JAKs to promote inflammation.

Potential Benefits in Oncology and Chronic Inflammatory Conditions

Potential to be first targeted therapy for MPNs.
Convenient oral and topical dosing - current best-of-care anti-inflammatory therapies are injectable.
Expected to be effective in patients refractory to anti-TNF therapies.
Broad applicability in a number of malignant hematologic conditions, solid cancers and autoimmune diseases.

Program Status

We have two potent, selective, orally bioavailable candidates currently in clinical development - INCB18424 and INCB28050:

>100x selectivity against a broad panel of kinases.
10-40x selectivity over the JAK3 enzyme.

Our lead compound, INCB18424, is being developed for:

Myelofibrosis (oral): Phase III development
Polycythemia vera and essential thrombocythemia (oral): Phase II development
Psoriasis (topical): Phase II development

INCB28050 is being developed as an oral treatment for chronic inflammatory conditions

Currently in a six-month Phase II trial in rheumatoid arthritis

The positive clinical results being seen with our JAK inhibitors in multiple diseases including myelofibrosis, rheumatoid arthritis and psoriasis, as well as the strong scientific basis
for the therapeutic potential of JAK inhibition in oncology and chronic inflammatory conditions make JAK-STAT mechanism one of the most exciting areas of drug development. Incyte's JAK inhibitor program could significantly expedite our transformation to a successful biopharmaceutical company.

Kris Vaddi, Ph.D.
Vice President, Preclinical Biology

It's incredibly exciting to be involved in a company that has so many potential opportunities to make a meaningful difference in patients' lives. We're particularly encouraged to see the
early efficacy with our JAK inhibitor in both myelofibrosis and rheumatoid arthritis as well as topically in psoriasis and look forward to learning where else this new class of compounds may be clinically important.

William Williams, M.D.
Vice President, Exploratory Development

JAK Backgrounder

Myeloproliferative Neoplasms

JAK Inhibition in Myeloproliferative Disorders: A Tutorial

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

June 2, 2008 ASCO Press Release

June 2008 ASCO Presentation

December 2007 ASH Presentation

2007 ASH Poster

Inflammation

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

Sheddase Program

Sheddase Inhibitors: Novel Intervention in a Proven Pathway

Currently approved agents that target the EGFR/HER pathway have shown limited activity in treating solid tumors. While the reasons for this are still emerging, this limited efficacy in
metastatic disease may relate to the fact that existing treatments inhibit only one or two of the HER pathways. I believe new agents in development that target multiple HER pathways or target these pathways through novel mechanisms such as inhibition of ligand shedding and receptor cleavage are likely to lead to superior clinical outcomes, especially when used in combination with current therapies.

Allan Lipton, M.D.
Medical Oncology and Hematology
Milton S. Hershey Medical Center
Penn State University College of Medicine

Mechanism of Action

Epidermal growth factor receptor (EGFR) signaling pathways consist of four known cellular receptors: HER1 (also known as EGFR), HER2, HER3, and HER4. Normally, these HER pathways are tightly regulated. In cancer, signaling through these pathways can increase, resulting in growth, proliferation, migration, and survival of cancer cells. This correlates with disease progression and poor prognosis.

Sheddases are enzymes, specifically ADAM enzymes 10 and 17, that promote growth activity through all four HER pathways. Several marketed therapies that target individual EGFR family members have demonstrated that inhibition of HER signaling is an effective mechanism for treating certain solid tumors.

Potential Benefits

Sheddase inhibition blocks two different pro-oncogenic mechanisms, generation of active EGFR ligands and generation of a constitutively active HER2 kinase.

Inhibition of additional and/or common HER pathways is expected to be synergistic with currently approved EGFR inhibitors and improve patient outcomes.
Sheddase can activate HER3 through generation of the HER3 ligand, heregulin. As this pathway is involved in resistance to current EGFR targeted therapies, decreasing the activity of this pathway with inhibitors of sheddase may be beneficial.

Our lead compound: INCB7839

Novel, potent, orally bioavailable.
In preclinical models: single agent efficacy; synergistic with other EGFR therapies; and synergistic with chemotherapy.

Clinical Status

Phase I completed in healthy volunteers:

INCB7839 was well-tolerated.
In a dose-dependent manner, INCB7839 decreased HER2 ECD levels, a clinically relevant biomarker.

An ongoing Phase II trial (Study INCB7839-202) in HER2 positive breast cancer to determine the effectiveness of INCB7839 in combination with Herceptin is underway.

Study INCB7839-202 was initiated as a single-arm, dose-escalation trial of INCB7839 plus trastuzumab in women with HER2 positive metastatic breast cancer, naïve to chemotherapy. Three doses of INCB7839 were studied (100 mg, 200 mg, 300 mg BID) with an expansion group at the 300 mg dose. Trastuzumab was administered on a Q3 week schedule. Pharmacokinetics, plasma HER2 ECD levels and p95HER2 expression in primary tumor tissue were assessed in addition to clinical response and safety. The study was expanded to evaluate the addition of docetaxel to the INCB7839-plus-trastuzumab treatment regimen.

Thus far, 66 HER2-positive breast cancer patients have been enrolled in the study. Key findings include:

Treatment with INCB7839 results in a dose-dependent reduction in plasma HER2 ECD.
ORR was 41% versus 12% based on an intent-to-treat analysis (ITT) and the median PFS was 178 days versus 94 days for the p95HER2-positive and p95HER2-negative patients, respectively. This contrasts with the results of prior published studies conducted in the absence of INCB7839 where the ORR was lower and the PFS was shorter in p95HER2+ patients.
INCB7839 has been generally well-tolerated. Apart from thrombotic events, observed in 17% of patients, the frequency of adverse events and serious adverse events observed is similar to what is expected with trastuzumab alone.
Of the 66 patients, 20 patients were enrolled in a group that received docetaxel in addition to the INCB7839 plus trastuzumab regimen. Preliminary data, irrespective of p95 status, demonstrate that the ORR in this group was 50% (N=20) and 57% (N=17), based on ITT and per protocol analyses, respectively.
The combination of INCB7839 with trastuzumab and docetaxel has also been generally well tolerated.

June 6, 2010 ASCO Press Release

June 2010 ASCO Poster

December 12, 2009 SABCS Press Release

December 2009 SABCS Clinical Poster

December 2009 SABCS Preclinical Poster

December 2007 SABCS Poster 6064

December 2007 SABCS Poster 6065

December 2007 SABCS Poster 1117

11 Beta-HSD1 Program

The concept of 11beta-HSD1 inhibition as a potential therapy for humans has moved a substantial stride forward today with the publication of a Phase II trial of INCB13739 in patients with
type 2 diabetes inadequately controlled on metformin. We already know that inhibition of this enzyme is beneficial for rodents with metabolic disease, but what remained crucially unknown was whether the concept was useful in humans and whether the expected endocrine effects of loss of glucocorticoid regeneration in the splanchnic bed would lead to unacceptable side effects. The present data not only show INCB13739 produces a significant lowering of HbA1c, fasting blood glucose, insulin resistance and cholesterol levels without weight gain, but reassure that the endocrine changes appear relatively mild. Crucially, there were no changes in plasma cortisol in the morning and salivary cortisol at night, underlining the compensatory nature of the endocrine changes. Moreover, plasma testosterone levels in males and in females examined and the androgenic target sex hormone-binding globulin were unaltered. Thus, major short-term endocrine side effects appear unlikely with INCB13739 therapy, although these clearly need to be scrutinized in longer-term trials. These encouraging findings should reassure of the value of further studies.

Jonathan Seckl, M.D., Ph.D.
Moncrieff-Arnott Professor of Molecular Medicine Centre for Cardiovascular Science;
The Queen's Medical Research Institute, Edinburgh

Mechanism of Action

11beta-HSD1 is an enzyme that converts the biologically inactive steroid cortisone into the potent biologically active hormone cortisol, which is known to act as a functional antagonist of insulin action in multiple target tissues.

Liver: cortisol reduces insulin's ability to suppress glucose production.
Muscle: cortisol reduces insulin's ability to promote glucose uptake.
Adipose: cortisol blocks insulin's ability to suppress free fatty acid release.

Several additional lines of evidence implicate 11beta-HSD1 activity as a primary driver of insulin resistance and a critical point for disease intervention:

11beta-HSD1 is upregulated 3-5 fold in obese humans.
Adipose-specific overexpression of 11beta-HSD1 by 2-3 fold in transgenic mice produces a phenotype closely resembling human type 2 diabetes.
Reduction of intracellular cortisol levels in the rodent as a result of pharmacologic inhibition of 11beta-HSD1 can reverse manifestations of the metabolic syndrome including obesity, diabetes, dyslipidemia and atherosclerosis.

Potential Benefits

By reducing the insulin resistance caused by intracellular cortisol, an 11beta-HSD1 inhibitor may be useful as a treatment for type 2 diabetes and also in allied conditions such as dyslipidemia, cardiovascular disease, obesity and hypertension.

Our lead compound: INCB13739

Potent, selective oral compound with excellent pharmacokinetic profile.
Completely inhibits the production of intra-adipose and intra-hepatic cortisol by 11beta-HSD1, while maintaining normal systemic cortisol levels, which are essential for immune function and response to stress.

Clinical Status

Very well-tolerated in single- and multiple-dose-ranging Phase I studies.

Phase IIa adipose and liver pharmacodynamic activity study in obese/insulin resistant subjects completed:

First compound publicly shown to completely inhibit 11beta-HSD1 activity in both adipose tissue and liver; a required characteristic to truly test the clinical value of 11beta-HSD1 inhibition.

Phase IIa results from a twenty-eight day study conducted in 2007 demonstrated clinical improvement in six key endpoints for type 2 diabetes and metabolic disease:

Fasting Plasma Glucose
EGP (Glucose production)
Rd (Glucose uptake)
LDL Cholesterol
Total Cholesterol
Triglycerides

Positive results from a three-month Phase IIb efficacy study were presented at the ADA 69th Scientific Session demonstrating that INCB13739 significantly improved glycemic control, insulin sensitivity and total cholesterol in patients with type 2 diabetes. (See ADA press release for complete results.)

October 2009 EASD Presentation

June 6, 2009 ADA Press Release

June 2009 ADA Poster

11-beta HSD1 Backgrounder

June 9, 2008 ADA Press Release

June 2008 ADA Presentation

June 7, 2006 Press Release

CCR2 Program

CCR2 Antagonists: A Promising Target for Inflammatory Diseases

CCR2 is a chemokine receptor that is involved in the trafficking of inflammatory monocytes. These monocytes are believed to play critical roles in the pathogenesis of inflammatory diseases,
including multiple sclerosis. Based on the published preclinical data on CCR2, an oral CCR2 antagonist may have the potential to provide significant therapeutic effects in MS, and not cause overt immunosuppression.

Israel F. Charo, M.D., Ph.D.
Professor of Medicine, University of California, San Francisco

Mechanism of Action

CCR2 antagonists prevent blood monocytes from entering tissue and becoming inflammatory macrophages:

The severity of inflammation in a number of disease states correlates with the number of macrophages in tissue.
In multiple sclerosis (MS), activated macrophages accumulate in the lesions and are associated with destruction of the myelin sheath.
In autoimmune nephritides, macrophages are implicated in lupus renal pathology.

Potential Benefits

Novel mechanism.
Potential for efficacy with minimal immunosuppression.

Our lead compound: INCB8696

Selective compound with excellent pharmacokinetic properties.
Convenient oral dosing.

Clinical Status

Phase 1 trial in healthy volunteers has been completed.

This program is now partnered with Pfizer.

November 21, 2005 Press Release