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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.
JAK Program
Janus Kinase Inhibitors: Compelling Approach to Treat Inflammation, Myeloproliferative Disorders 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 inflammatory diseases, myeloproliferative disorders (MPDs) and malignancies. There are four known JAK enzymes: JAK1, 2, 3 and TYK2.
Potential Benefits
Program Status
We have two potent, selective, orally bioavailable candidates currently in clinical development - INCB18424 and INCB28050:
Our lead compound, INCB18424, is being developed for:
INCB28050, is being developed as our lead oral treatment for chronic inflammatory conditions
| 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 |
JAK Inhibition in Myeloproliferative Disorders: A Tutorial
2009 AACR TKI Resistance Poster
December 6, 2008 ASH Press Release
December 2008 ASH Presentation
October 26, 2008 ACR Press Release
June 12, 2008 EULAR Press Release
June 2, 2008 ASCO Press Release
December 10, 2007 ASH Press Release
December 2007 ASH Presentation
| 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.
Several additional lines of evidence implicate 11beta-HSD1 activity as a primary driver of insulin resistance and a critical point for disease intervention:
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
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:
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:
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 9, 2008 ADA Press Release
Oncology| 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.
Our lead compound: INCB7839
Clinical Status
Phase I completed in healthy volunteers:
A Phase II trial in HER2 positive breast cancer has begun and will be used to determine the effectiveness of INCB7839 in combination with Herceptin. Results from this trial are expected in the second half of 2009.
December 16, 2007 SABCS Press Release
December 2007 SABCS Poster 6064
December 2007 SABCS Poster 6065
December 2007 SABCS Poster 1117
| The relationship between insulin resistance, plasma insulin concentration, glucose intolerance, and hypertriglyceridemia is mediated to a significant degree by changes in daylong plasma free fatty acid concentrations. Pharmacological agents that possess the ability to normalize aberrant free fatty acid levels in insulin resistant patients offer a potentially powerful opportunity to fundamentally alter the course of several clinical syndromes, including type 2 diabetes. |
| Gerald M. Reaven Emeritus Professor of Medicine Stanford University School of Medicine |
Mechanism of Action
HM74A is a G-protein coupled receptor that is highly expressed in human adipose tissue. When activated, HM74A signaling reduces the amount of adipose tissue free fatty acids (FFA) released from triglycerides, a process known as ‘lipolysis’. Nicotinic acid, the broad-spectrum hyperlipidemic therapy, is believed to function at least in part through agonism of HM74A and subsequent lowering of plasma FFA.
Chronic elevation of FFA is a common problem in patients with type 2 diabetes (T2D) as they exhibit accelerated lipolysis and day-long elevations in plasma FFA concentrations. This affects blood glucose levels by attenuating insulin action in muscle and liver, and impairing pancreatic insulin secretion. Increased FFA can also affect the secretion of very low-density lipoprotein and lead to abnormal lipid levels in T2D patients.
Potential Benefits
Multiple lines of evidence indicate that HM74A-mediated inhibition of adipose tissue lipolysis may offer an attractive therapeutic intervention point in T2D and its associated co-morbidities. Lowering circulating FFA concentrations through administration of small molecule HM74A agonists has been shown to significantly attenuate key drivers of disease in T2D, dyslipidemia, and atherosclerosis. Although currently available HM74A agonists, including nicotinic acid in its various formulations, provide an important proof-of-concept in man for this therapeutic strategy, the compounds suffer from significant potency, pharmacokinetic and pharmacodynamic deficiencies that limit their utility as anti-hyperglycemia agents in the T2D patients. Specifically, approved dosing regimens of nicotinic acid are ineffective at improving insulin resistance and glycemia. This is likely a result of the propensity for FFA rebound excursions after dosing that occurs due to the relatively short circulating half-life of the compounds.. Furthermore, oral administration of these agents results in pronounced skin flushing that while harmless, affects virtually every patient taking therapeutic doses of these drugs and severely limits compliance.
A novel HM74A agonist that can effectively suppress FFA for longer periods during the day and improves glycemic control and hyperlipidemia without rebound and skin flushing has te potential to be an important therapeutic advance in T2D patients.
Clinical Status
Phase I clinical trials INCB19602:
Preliminary results from a 28-day Phase IIa trial in patients with type 2 diabetes not well-controlled on metformin monotherapy suggest that we will need to conduct a 3-month trial to determine HbA1c levels as the clinical endpoint and confirm whether this mechanism warrants further development as a treatment for type 2 diabetes.
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:
Potential Benefits
Our lead compound: INCB8696
Clinical Status
HIV
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.
Potential Benefits
CCR5 antagonists in HIV regimens may provide:
Our lead compound: INCB9471
Clinical Status
10-Day Phase I studies in healthy volunteers completed:
14-Day Phase IIa study completed:
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.
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