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Incyte's Product Pipeline

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.

Top JAK Program


Janus-associated Kinase Inhibitors: Compelling Approach to Treat Inflammation, Myeloproliferative Disorders and Cancer

Recent clinical data with an oral JAK inhibitor demonstrating dramatic efficacy and rapid onset of action in both rheumatoid arthritis and psoriasis represent a significant development
in our approach to treat these diseases. While the data are still early, I believe that JAK inhibition is one of the most exciting new therapeutic approaches for chronic inflammatory diseases.
Larry Moreland, M.D.
Professor of Medicine, University of Alabama
Director of the UAB Arthritis Clinical Intervention Program
Director of the UAB Pittman General Clinical Research Center


Multiple activating mutations in JAK2 have recently been identified in the majority of myeloproliferative disorders, including polycythemia vera, essential thrombocythemia
and primary myelofibrosis. Research results suggesting a causal role for these mutations in the pathogenesis of myeloproliferative disorders strongly support the development of JAK2 inhibitors as targeted drugs for these disorders - many of which can be life threatening and for which we lack effective therapies.
Ayalew Tefferi, M.D.
Professor in Hematology and Internal & Medicine
Mayo Clinic College of Medicine, Division of Hematology in the Department of Medicine


Mechanism of Action

Janus-associated kinases (JAK) are enzymes that mediate signaling of several important drivers of inflammatory diseases, myeloproliferative disorders (MPDs) and malignancies. There are four known JAK enzymes: JAK1, 2, 3 and TYK2.

  • Known inflammatory cytokines, such as IL-6, IL-12, and IL-23, signal through JAKs to promote inflammation.
  • Activating mutations of JAK2 are present in >90% of polycythemia vera and ~50% of essential thrombocythemia and myeloid metaplasia with myelofibrosis.
  • Aberrant activation of the JAK-STAT pathway has been documented in a variety of cancers.

Potential Benefits

  • Convenient oral dosing – current best-of-care therapies are injectable.
  • Expected to be effective in patients refractory to anti-TNF therapies.
  • Rapid onset of action based on data from early clinical studies.
  • Potential to be first targeted therapy for MPDs.
  • Broad applicability in a number of autoimmune diseases, malignant hematologic conditions and solid cancers.

Program Status

Multiple potent, selective, orally bioavailable candidates currently in preclinical development:

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

Lead compound selected, INCB18424:

  • GLP-safety studies successfully completed

Three clinical programs initiated in 2007:

  • Myelofibrosis (oral)
  • Psoriasis (topical)
  • Rheumatoid arthritis (oral)

Additional clinical trials for other indications underway and/or planned in 2008 include:

  • Multiple myeloma (oral)
  • Hormone refractory prostate cancer (oral)
  • Polycythemia vera and essential thrombocythemia (oral)
  • Psoriasis (oral)
The positive clinical results being seen with our JAK inhibitor 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

Data Presented At The American Society of Hematology 49th Meeting Demonstrate That Incyte's Novel JAK Inhibitor, INCB18424, Provides Rapid and Profound Clinical Benefits in Myelofibrosis Patients

ASH Presentation

JAK Backgrounder

ASH Poster



Top

Diabetes

11 Beta-HSD1

 
11beta-HSD1 is a significant and promising new therapeutic target for the metabolic syndrome. Current therapies, particularly for diabetes, fail to prevent disease
progression long term, demonstrating a clear need for more effective, broad spectrum approaches to treatment. By inhibiting cortisol production in key tissues, inhibitors of 11beta-HSD1 have the potential to directly and profoundly improve insulin resistance, thus targeting the fundamental underlying cause of type 2 diabetes and cardiovascular disease.
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

Three-month efficacy study in patients with type 2 diabetes expected to follow in first half of 2008.

Incyte Reports Positive Proof-of-Concept Results For INCB18424, Its Lead JAK Inhibitor, and INCB13739, its Lead 11beta-HSD1 Inhibitor, September 25

11-beta HSD1 backgrounder

June 7, 2006 press release

HM74A (to come)



TopHIV


CCR5 Antagonists: A Next Generation in HIV Therapy  

On March 17, 2008, Incyte announced its decision to not initiate two six-month Phase IIb trials for its lead CCR5 antagonist, INCB9471, in treatment-experienced HIV patients.

While we continue to believe INCB9471 has the potential to be the best-in-class CCR5 antagonist, given the rapid growth in our pipeline, we believe it is essential that we focus our resources on programs that have the greatest near-term value. Because development of the CCR5 antagonist is one of our more expensive, time and labor intensive programs, and is now our only HIV product, we are currently looking to out license the program.

Mechanism of Action
Human immunodeficiency virus (HIV) enters T-cells by binding to CD4 and one of two obligate co-receptors: CCR5 or CXCR4.

  • CCR5 antagonists block entry of HIV that binds exclusively to CCR5 (R5 tropic virus).
  • Over 85% of patients starting HIV therapy have only R5 tropic virus detectable in blood.
  • About 50 to 60% of highly treatment-experienced patients still have only R5 tropic virus detectable in blood.

Potential Benefits
CCR5 antagonists in HIV regimens may provide:

  • Substantial benefit in patients with R5 tropic virus.
  • Immunologic benefit in all subjects based on increasing CD4 cell counts.
  • Safe addition to therapy, complementary to drugs with other modes of action.
  • Less risk of developing drug resistance.

Our lead compound: INCB9471

  • Potential to be best-in-class.
  • Potent antiviral compound with excellent pharmacokinetics.
  • Allows for once daily use without boosting with ritonavir, a compound associated with cardiovascular risk.
  • Potential for use in first and second line regimens.
  • Long half-life expected to provide more effective antiviral activity even if doses are occasionally missed.

Clinical Status
10-Day Phase I studies in healthy volunteers completed:

  • Single doses of INCB9471 studied up to 300 mg.
  • Multiple doses up to 200 mg once daily for 10 days of dosing.
  • Very well-tolerated with no dose-limiting toxicity identified.

14-Day Phase IIa study completed:

  • Includes treatment-naïve and treatment-experienced patients not currently on HIV therapy.
  • R5 tropic HIV/naïve to CCR5 antagonists with viral load >10,000 copies/ml.
  • Impressive and sustained antiviral effect demonstrated with multiple once daily doses of INCB9471 as monotherapy.
  • Well-tolerated at all doses tested.

Phase IIa Study Results Demonstrate that Once-Daily 200 mg Dosing of INCB9471 Provided Potent and Prolonged Antiviral Activity in HIV-Infected Patients, July 24

Data Presented at the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy Demonstrate That INCB9471 is a Potent, Selective Inhibitor of the HIV-1 Virus with Excellent Pharmacokinetics Suitable for Once-Daily Dosing, September 18

Required drug interaction studies expected to be completed in first half of 2008.

On March 17, 2008, Incyte announced its decision to not initiate two six-month Phase IIb trials for its lead CCR5 antagonist, INCB9471, in treatment-experienced HIV patients. Incyte is actively seeking to out license the program.

Our follow-on CCR5 antagonist: INCB15050

  • The single-and multiple dose portions of a Phase I trial are complete.
  • Like INCB9471, INCB15050 has the potential to be a once-a-day therapy for HIV-infected patients.

TopOncology


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.

Phase Ib/IIa trial in refractory cancer patients (breast, colorectal, head and neck, prostate, non-small cell lung) is ongoing.

The first of two planned Phase II trials in breast cancer has initiated.

Data Presented at the 30th San Antonio Breast Cancer Symposium Supports Further Development of INCB7839 As A New Oral Treatment For Breast Cancer, December 16

SABCS Poster 6064

SABCS Poster 6065

SABCS Poster 1117


Top Inflammation

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 is currently underway.

 

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