Pipeline

Jakafi is a selective inhibitor of Janus kinases 1 and 2 (JAK1 and JAK2). These enzymes mediate signaling of several important drivers of myeloproliferative neoplasms (MPNs), other hematological malignancies and inflammatory diseases.

Jakafi is approved in the United States for the treatment of intermediate or high-risk myelofibrosis (MF) and marketed by Incyte in the U.S. (Please see Full Prescribing Information and Important Safety Information for Jakafi).

MF is a potentially life-threatening blood cancer and is characterized by bone marrow failure, enlarged spleen (splenomegaly) and debilitating symptoms. MF has a poor prognosis and limited treatment options.[1,2]

Our collaboration partner, Novartis, received approval from the European Commission for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. Novartis also received approval for the product in Canada. Jakafi is marketed as Jakavi® outside of the United States.

In Phase III registration studies,[3,4] patients treated with Jakafi experienced significant reductions in splenomegaly and improvement in symptoms and overall quality of life measures, while patients in the control arms (placebo or best available therapy) experienced progressive splenomegaly and worsening of MF-related symptoms.

References

1. The Leukemia & Lymphoma Society. Idiopathic Myelofibrosis. Available at http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/idiopathicmyelofibrosis.pdf. Accessed September 2011.

2. Mesa RA, Schwager S, Radia D, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res. 2009;33:1199-1203.

3. Verstovsek S, Mesa R, Gotlib J et al. Results of COMFORT-I, a randomized double-blind phase III trial of JAK1/2 inhibitor INCB18424 (424) vs placebo (PB) for patients with myelofibrosis (MF). The 47th Annual ASCO Meeting, Chicago, IL, USA. J. Clin. Oncol. 2011 Suppl [Abstract 6500].

4. Harrison CN, Kiladjian J, Al-Ali H et al. Results of a randomized study of the JAK inhibitor ruxolitinib (INC424) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PET-MF). The 47th ASCO Annual Meeting, Chicago, IL, USA. J. Clin. Oncol. 2011 Suppl [Abstract LBA6501].

Ruxolitinib is currently in development for the treatment of polycythemia vera (PV), a blood cancer characterized by the overproduction of red blood cells which increases blood viscosity and leads to elevated thromboembolic risk. Increased levels of white blood cells and platelets are also common. In advanced disease, patients frequently exhibit spleen enlargement and debilitating symptoms, including pruritus, night sweats, fatigue and muscle and bone pain.[1,2] In a Phase II trial in patients with advanced PV, ruxolitinib demonstrated long-term clinical activity, including reduction in spleen size, phlebotomy independence and improvements in blood counts and PV-related symptoms after a median follow-up of 21 months.[3] A global Phase III registration trial called RESPONSE (Randomized, open-label, multicenter phase III study of Efficacy and Safety in POlycythemia vera subjects who are resistant to or intolerant of hydroxyurea: JAK iNhibitor INC424 tablets versus best available care) is open for enrollment (for additional information go to: ClinicalTrials.gov identifier: NCTO1243944 or http://www.responsetrial.com)

A second study in PV patients, called RELIEF, evaluating symptomatic benefit is ongoing. This study is not required for FDA approval, but the results will be submitted to support labeling claims on symptomatic benefit in PV in the initial FDA application for the treatment of patients with PV. 

References

1. The Leukemia & Lymphoma Society. Polycythemia Vera. 2011. Available at http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/polycythemiavera.pdf. Accessed September 2011.
2. Finazzi G, Barbui T. Evidence and expertise in the management of polycythemia vera and essential thrombocythemia. Leukemia. 2008;22:1494-1502.
3. Verstovsek S, Passamonti F, Rambaldi A et al. Durable responses with the JAK1/ JAK2 inhibitor, INCB018424, in patients with polycythemia vera (PV) and essential thrombocythemia (ET) refractory or intolerant to hydroxyurea (HU). 52nd American Society of Hematology Annual Meeting. 2010 [Abstract 313].

Ruxolitinib is currently under investigation for the treatment of essential thrombocythemia vera (ET), a blood cancer characterized by the overproduction of platelets and thrombotic events. Patients experience debilitating symptoms, including headache, dizziness, and weakness.[1] In a Phase II trial in patients with advanced ET, ruxolitinib demonstrated long-term clinical activity, including improvements in blood counts and ET related symptioms after a median follow-up of 21 months.[2]
References

1. The Leukemia & Lymphoma Society. Essential or primary thrombocythemia. Available at http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/essentialprimarythrombocythemia.pdf. Accessed September 2011.
2. Verstovsek S, Passamonti F, Rambaldi A et al. Durable responses with the JAK1/ JAK2 inhibitor, INCB018424, in patients with polycythemia vera (PV) and essential thrombocythemia (ET) refractory or intolerant to hydroxyurea (HU). 52nd American Society of Hematology Annual Meeting. 2010 [Abstract 313].

Ruxolitinib is currently being evaluated in pancreatic cancer. Patients with pancreatic cancer often suffer from cachexia, which can have a significant impact on survival and performance status.[1] Dysregulated JAK-STAT activity (resulting from elevated levels of pro-inflammatory cytokines) is believed to play a key role in the development of cachexia, as well as the growth and proliferation of pancreatic cancer cells and resistance to chemotherapeutic agents.[2-3]

A Phase II trial of ruxolitinib in combination with capecitabine in patients with pancreatic cancer is underway, with a primary endpoint of overall survival. Secondary endpoints include tumor response rate, patient-reported quality of life measures, and pain status.

1. Bachmann J,  Ketterer K, Marsch C, et al. Pancreatic cancer-related cachexia: influence on metabolism and correlation to weight loss and pulmonary function. BMC Cancer. 2009,9:255 [open access].

2. Marc E. Martignoni M, Kunze P, Hildebrandt W, et al. Role of mononuclear cells and inflammatory cytokines in pancreatic cancer-related cachexia. Clin Cancer Res. 2005;11(16):5802-5808.

3. Okitsu K, Kanda T, Imazeki F, et al. Involvement of Interleukin-6 and Androgen Receptor Signaling in Pancreatic Cancer. Genes & Cancer. 2010;1(8):859-867.

Ruxolitinib is being studied in a variety of other hematologic malignancies and solid tumors, including two Phase I/II trials in adults with advanced hematologic malignancies (acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome and chronic myelogenous leukemia) and relapsed or refractory acute leukemia, and a Phase I/II trial in children with hematologic malignancies and solid tumors. A complete list of Incyte-sponsored studies and investigator-initiated trials can be found at www.clinicaltrials.gov.

c-MET is a receptor kinase cancer target. Dysregulation of the c-MET pathway occurs in many cancer types and correlates with a poor prognosis. Abnormal c-MET activity triggers tumor growth and formation of new blood vessels that supply the tumor with nutrients and causes cancer to spread to other organs. Several small molecule c-MET kinase inhibitors have demonstrated clinical efficacy in a number of cancers; however, many of these molecules have limited potency and are relatively non-selective, which could lead to off-target toxicities. We believe our lead c-MET inhibitor, INCB28060, has the requisite properties to overcome these limitations, including greater selectivity and improved potency, resulting in more effective inhibition of c-MET. We have licensed to Novartis the worldwide rights to develop INCB28060.

Indoleamine 2, 3-dioxygenase (IDO) is an immune regulatory enzyme that is normally expressed in tumor cells and in activated immune cells. It dampens the immune response through oxidation of tryptophan, thereby blocking T-cell activation and inducing T-cell apoptosis. This creates an environment in which tumor-specific cytotoxic T lymphocytes are rendered functionally inactive or are no longer able to attack a patient’s cancer cells. Preclinical studies have shown that inhibition of IDO increases the anti-tumor immune response and dramatically increases the efficacy of various chemotherapeutic agents.

The Phase I dose-escalation trial of INCB24360, a novel oral inhibitor of IDO, has achieved its objective in selecting a dose that is generally well-tolerated and potently inhibits the target as measured using two independent pharmacodynamic markers. “Pharmacodynamic assessment of INCB242360, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), in advanced cancer patients” was the subject of an oral presentation at the 2012 American Society of Clinical Oncology annual meeting. Click here  to learn more. 

The first Phase II study of INCB24360, which was initiated in 2012, is a randomized study in combination with ipilimumab in patients with metastatic melanoma (www.clinicaltrials.gov Identifier: NCT01604889).

Indoleamine 2, 3-dioxygenase (IDO) is an immune regulatory enzyme that is normally expressed in tumor cells and in activated immune cells. It dampens the immune response through oxidation of tryptophan, thereby blocking T-cell activation and inducing T-cell apoptosis. This creates an environment in which tumor-specific cytotoxic T lymphocytes are rendered functionally inactive or are no longer able to attack a patient’s cancer cells. Preclinical studies have shown that inhibition of IDO increases the anti-tumor immune response and dramatically increases the efficacy of various chemotherapeutic agents.

The Phase I dose-escalation trial of INCB24360, a novel oral inhibitor of IDO, has achieved its objective in selecting a dose that is generally well-tolerated and potently inhibits the target as measured using two independent pharmacodynamic markers. “Pharmacodynamic assessment of INCB24360, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), in advanced cancer patients” was the subject of an oral presentation at the 2012 American Society of Clinical Oncology annual meeting. Click here to learn more.

A Phase II trial evaluating INCB24360 as monotherapy in patients with ovarian cancer was initiated in 2012. (www.clinicaltrials.gov Identifier: NCT01685255)

We are currently conducting proof-of-concept studies of our proprietary JAK1 inhibitor, INCB39110, in myelofibrosis, rheumatoid arthritis and psoriasis. We believe these Phase I/II studies will enable us to further understand the therapeutic potential of JAK1 inhibition. (www.clinicaltrials.gov Identifier: NCT01633372)

Targets not yet disclosed.

Our JAK1 and JAK2 inhibitor, baricitinib has potential as a treatment for rheumatoid arthritis and autoimmune diseases and is licensed to Eli Lilly and Company under a worldwide license and collaboration agreement which includes certain follow-on compounds. Incyte has exercised its option to co-develop this compound in rheumatoid arthritis with Lilly and retains a significant interest in this program. Lilly conducted a six-month, double-blind Phase IIb study in patients with rheumatoid arthritis. The 24-week results were presented at the American College of Rheumatology annual meeting in November 2012. Click here to learn more.

The Phase III program to evaluate baricitinib in patients with rheumatoil arthritis, conducted by Lilly, started randomized treatments in November 2012. (www.clinicaltrials.gov Identifiers: NCT01711359; NCT01710358; NCT01721057; NCT01721044)

Eli Lilly and Company is looking at our JAK1 and JAK2 inhibitor (INC28050/LY3009104) for treatment of patients with moderate-to-severe psoriasis. Lilly is currently conducting Phase IIb trial with this compound (now called baricitinib). The primary objective of this study is to demonstrate that at least one of four dose groups is superior to placebo at week 12 in the treatment of patients with moderate-to-severe psoriasis as measured by the proportion of patients with at least a 75 percent improvement from baseline in Psoriasis Area and Severity Index (PASI) score.

Eli Lilly and Company is looking at our JAK1 and JAK2 inhibitor (INC28050/LY3009104) for treatment of patients with diabetic nephropathy. Lilly is currently conducting Phase IIb trial with this compound (now called baricitinib).

We are currently conducting proof-of-concept studies of our proprietary JAK1 inhibitor, INCB39110, in myelofibrosis, rheumatoid arthritis and psoriasis. We believe these Phase I/II studies will enable us to further understand the therapeutic potential of JAK1 inhibition. (www.clinicaltrials.gov Identifier: NCT01626573)

We are currently conducting proof-of-concept studies of our proprietary JAK1 inhibitor, INCB39110, in myelofibrosis, rheumatoid arthritis and psoriasis. We believe these Phase I/II studies will enable us to further understand the therapeutic potential of JAK1 inhibition. (www.clinicaltrials.gov Identifier:  NCT01634087)

Targets not yet disclosed.