Pipeline

September 18, 2014
COMPOUND
TARGET
DISEASE
PHASE I
PHASE II
PHASE III
APPROVED
ONCOLOGY
Jakafi® ruxolitinib[a]
JAK1 / JAK2
Myelofibrosis

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

Jakafi is approved in the United States for the treatment of patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF (PPV-MF) and post-essential thrombocythemia MF (PET-MF). It is marketed by Incyte in the U.S. MF is a potentially life-threatening blood cancer and is characterized by bone marrow failure, enlarged spleen (splenomegaly) and debilitating symptoms. Jakafi is the first FDA-approved therapy for MF and was the first FDA-approved JAK pathway inhibitor for any indication.

Our collaboration partner, Novartis, received approval from the European Commission for the treatment of disease-related splenomegaly or symptoms in adult patients with primary MF (also known as chronic idiopathic MF), PPV-MF and PET-MF. Novartis also received approval for the product in more than 55 countries. Jakafi is marketed as Jakavi® outside of the United States.

In Phase III registration studies,[1,2] patients treated with Jakafi experienced significant reductions in splenomegaly and improvement in symptoms, while patients in the control arms (placebo or best available therapy) experienced progressive splenomegaly and worsening of MF-related symptoms. These results served as the basis for approval for Jakafi in the United States. 

Additionally, data from the Phase III studies showed improvements in overall quality of life measures in patients treated with Jakafi.  In long-term analyses of these trials, Jakafi was associated with durable spleen and symptom responses and improved survival.[3,4] Exploratory analyses of data collected in the ongoing Phase II trial suggest that ruxolitinib may reverse and/or stabilize bone marrow fibrosis.[5,6]

Jakafi can cause serious side effects including:

Low blood counts: Jakafi may cause your platelet, red blood cell, or white blood cell counts to be lowered. If you develop bleeding, stop taking Jakafi and call your healthcare provider. Your healthcare provider will perform blood tests to check your blood counts before you start Jakafi and regularly during your treatment. Your healthcare provider may change your dose of Jakafi or stop your treatment based on the results of your blood tests. Tell your healthcare provider right away if you experience unusual bleeding, bruising, fatigue, shortness of breath, or a fever.

Infection: You may be at risk for developing a serious infection while taking Jakafi. Tell your healthcare provider if you develop symptoms such as chills, nausea, vomiting, aches, weakness, fever, or painful skin rash or blisters.

The most common side effects of Jakafi include dizziness and headache.

These are not all the possible side effects of Jakafi. Ask your healthcare provider or pharmacist for more information. Tell your healthcare provider about any side effect that bothers you or that does not go away. 

Before taking Jakafi, tell your healthcare provider about all the medications, vitamins, and herbal supplements you are taking and all your medical conditions, including if you have an infection, have or had liver or kidney problems, are on dialysis, or have any other medical condition. Do not drink grapefruit juice while taking Jakafi.

Women should not take Jakafi while pregnant or planning to become pregnant, or if breast-feeding.

(Please see Full Prescribing Information for Jakafi).

References

  1. Verstovsek S, Mesa RA, Gotlib J et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807.
  1. Harrison C, Kiladjian JJ, Al-Ali HK et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787-98.
  1. Verstovsek S, Mesa RA, Gotlib J et al. Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I. Haematologica. 2013;98:1865-71.
  1. Cervantes F, Vannucchi AM, Kiladjian JJ et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood 2013;122:4047-53.
  1. Kvasnicka HM, Thiele J, Bueso-Ramos CE et al. Effects of five-years of ruxolitinib therapy on bone marrow morphology in patients with myelofibrosis and comparison with best available therapy. The 55th American Society of Hematology (ASH) Annual Meeting and Exposition, New Orleans, LA, USA. Blood. 2013;Abstract 4055.
  1. Kvasnicka HM, Thiele J, Bueso-Ramos CE et al. Effects of ruxolitinib therapy on megakaryocyte morphology and inflammatory bone marrow reaction in patients with myelofibrosis. The 55th American Society of Hematology (ASH) Annual Meeting and Exposition, New Orleans, LA, USA. Blood. 2013;Abstract 4056.
ruxolitinib[a]
JAK1 / JAK2
Polycythemia vera

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] Almost all patients with PV have dysregulated JAK signaling, with ~95% harboring the JAK2V617F mutation.[3] In an ongoing Phase II trial in patients with advanced PV resistant to or intolerant of hydroxyurea (http://www.clinicaltrials.gov/ct2/show/NCT00726232), ruxolitinib treatment for a median of 35 months achieved durable control of hematocrit without phlebotomy, reduction in splenomegaly, and reduction in PV-related symptoms.[4]

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; http://www.clinicaltrials.gov/ct2/show/NCT01243944) is being conducted under a Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA).

Another ongoing Phase III study in patients with PV, called RELIEF (Randomized switch study from hydroxyurea to ruxolitinib for RELIEF of polycythemia vera symptoms; http://www.clinicaltrials.gov/ct2/show/NCT01632904), is evaluating symptomatic benefit. The results of this study, which is fully enrolled, are expected to be submitted as a label update on symptomatic benefit.

References

  1. Leukemia & Lymphoma Society. Polycythemia Vera Facts. Available at http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/polycythemiavera.pdf. Accessed January 2014.
  2. Finazzi G, Barbui T. Evidence and expertise in the management of polycythemia vera and essential thrombocythemia. Leukemia. 2008;22:1494-1502.
  3. Vannucchi  AM, Guglielmelli P, Tefferi A. Advances in understanding and management of myeloproliferative neoplasms. CA Cancer J Clin. 2009;59:171-91.
  4. Verstovsek S, Passamonti F, Rambaldi A et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer. 2013 Oct 30. doi: 10.1002/cncr.28441.[Epub ahead of print].
ruxolitinib[b]
JAK1 / JAK2
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 in the growth and proliferation of pancreatic cancer cells and resistance to chemotherapeutic agents.[2-3]

Top-line results from RECAP (Phase II Study of Ruxolitinib Efficacy And Safety In Combination with Capecitabine for Subjects With Recurrent Or Treatment-Refractory Metastatic Pancreatic Cancer), a double-blind, placebo-controlled trial (http://clinicaltrials.gov/show/NCT01423604), showed a hazard ratio for overall survival of 0.47 favoring the ruxolitinib arm in a prospectively defined subgroup of the patients, pre-selected as most likely to benefit from JAK pathway inhibition. The subgroup of interest represented approximately half of the randomized study population.

The U.S. Food and Drug Administration (FDA) has granted orphan status for ruxolitinib for the treatment of pancreatic cancer. Additionally, the Phase III program, which is expected to begin enrollment in the first half of 2014, includes a Special Protocol Assessment (SPA) for a registration trial of patients who failed or were intolerant to first-line therapy and who are part of the subgroup that showed benefit in the RECAP trial. The Phase III program includes a second nearly identical Phase III trial.

References

  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 et al. Role of mononuclear cells and inflammatory cytokines in pancreatic cancer-related cachexia. Clin Cancer Res. 2005;11(16):5802-8.
  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):859-67.
ruxolitinib[b]
JAK1 / JAK2
Advanced malignancies

A Phase I trial to evaluate the safety and tolerability of ruxolitinib in combination with gemcitabine with or without nab-paclitaxel in patients with advanced solid tumors is ongoing (www.clinicaltrials.gov Identifier: NCT01822756).

ruxolitinib[b]
JAK1 / JAK2
Non-small cell lung cancer
ruxolitinib[b]
JAK1 / JAK2
Breast cancer
ruxolitinib[b]
JAK1 / JAK2
Colorectal cancer
INCB39110
JAK1
Advanced malignancies

We are conducting a Phase I safety study of our JAK1 inhibitor INCB39110 in combination with gemcitabine and nab-paclitaxel in patients with advanced solid tumor malignancies (www.clinicaltrials.gov identifier: NCT01858883). The first part of the study is a dose-optimization phase designed to find a tolerated regimen that includes the maximum tolerated dose of INCB39110 (within a defined pharmacologic range) in combination with doses of gemcitabine and nab-paclitaxel that have established safety and tolerability in subjects with advanced or metastatic solid tumors.

INCB39110
JAK1
Non-small cell lung cancer
INCB40093
PI3Kδ
B-lymphoid malignancies
INCB39110 & INCB40093
JAK1 & PI3Kδ
B-lymphoid malignancies

Our PI3Kδ inhibitor, INCB40093, is being studied in the first part of a Phase I dose-escalation trial in patients with previously treated B-lymphoid malignancies. The second part, which was initiated in January 2014, is a safety and efficacy study of INCB40093 in combination with the JAK1 inhibitor INCB39110 in the same patient group. (www.clinicaltrials.gov Identifier: NCT01905813)

INCB24360
IDO1
Metastatic melanoma

Indoleamine 2, 3-dioxygenase (IDO1) 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.[1] Preclinical studies have shown that inhibition of IDO1 increases the anti-tumor immune response and dramatically increases the efficacy of various chemotherapeutic agents.[2]

The Phase I dose-escalation trial of INCB24360, a novel, first-in-class, oral inhibitor of IDO1, 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.[3] A Phase I/II study of INCB24360 in combination with the anti-CTLA4 monoclonal antibody ipilimumab in patients with unresectable or metastatic melanoma was initiated in 2012 (www.clinicaltrials.gov Identifier: NCT01604889).

References

  1. Liu X, Newton RC, Friedman SM, Scherle PA. Indoleamine 2,3-dioxygenase, an emerging target for anti-cancer therapy. Curr Cancer Drug Targets. 2009;9:938-52.
  1. Muller AJ, DuHadaway JB, Donover PS et al. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med. 2005;11:312-9.
  1. Beatty GL, O’Dwyer PJ, Clark J et al. Phase 1 study of the safety, pharmacokinetics, and pharmacodynamics of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO1) INCB24360 in patients with advanced malignancies. J Clin Oncol. 2013;31(suppl; abstr 3025).
INCB24360[c]
IDO1
Non-small cell lung cancer
INCB24360[d]*
IDO1
Multiple cancers
INCB24360[e]*
IDO1
Multiple cancers
INCB24360[f]*
IDO1
Non-small cell lung cancer
INCB28060[g]
c-MET
Solid tumors

c-MET is a receptor tyrosine kinase cancer target normally activated by hepatocyte growth factor. 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.[1] We believe our lead c-MET inhibitor, INC280, has the requisite properties to overcome these limitations, including greater selectivity and improved potency, resulting in more effective inhibition of c-MET.[2] We have licensed to Novartis the worldwide rights to develop INC280.  

References

  1. Liu X, Newton RC, Scherle PA. Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. Trends Mol Med. 2010;16:37-45.
  1. Liu X, Wang Q, Yang G, et al. A novel kinase inhibitor, INCB28060, blocks c-MET dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3. Clin Cancer Res. 2011;17:7127-38.
INCB28060[g]
c-MET
Hepatocellular carcinoma

 c-MET is a receptor tyrosine kinase cancer target normally activated by hepatocyte growth factor. 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.[1] We believe our lead c-MET inhibitor, INC280, has the requisite properties to overcome these limitations, including greater selectivity and improved potency, resulting in more effective inhibition of c-MET.[2] We have licensed to Novartis the worldwide rights to develop INC280.

References

  1. Liu X, Newton RC, Scherle PA. Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. Trends Mol Med. 2010;16:37-45.
  1. Liu X, Wang Q, Yang G, et al. A novel kinase inhibitor, INCB28060, blocks c-MET dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3. Clin Cancer Res. 2011;17:7127-38.
INCB28060[g]
c-MET
Non-small cell lung cancer

c-MET is a receptor tyrosine kinase cancer target normally activated by hepatocyte growth factor. 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. [1] We believe our lead c-MET inhibitor, INC280, has the requisite properties to overcome these limitations, including greater selectivity and improved potency, resulting in more effective inhibition of c-MET.[2] We have licensed to Novartis the worldwide rights to develop INC280.

References

  1. Liu X, Newton RC, Scherle PA. Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. Trends Mol Med. 2010;16:37-45.
  1. Liu X, Wang Q, Yang G, et al. A novel kinase inhibitor, INCB28060, blocks c-MET dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3. Clin Cancer Res. 2011;17:7127-38.
INFLAMMATION
baricitinib[h]
JAK1 / JAK2
Rheumatoid arthritis

Our JAK1/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 with an ongoing open-label, long-term extension (JADA study; www.clinicaltrials.gov identifier: NCT01185353) in patients with rheumatoid arthritis on background methotrexate therapy. After 12 weeks, baricitinib significantly improved the signs and symptoms of rheumatoid arthritis versus placebo [1], and after 24 weeks, these responses were maintained or improved.[2] The 52-week results were presented at the 2013 Annual Meeting of the European League Against Rheumatism (EULAR) and indicated that the clinical improvements achieved at 24 weeks were maintained at 52 weeks.[3]

The Phase III program to evaluate baricitinib in patients with rheumatoid arthritis, conducted by Lilly, includes five ongoing trials (www.clinicaltrials.gov identifiers: NCT01885078; NCT01711359; NCT01710358; NCT01721057; NCT01721044).

References

  1. Keystone E, Taylor P, Genovese M et al. 12-week results of a phase 2b dose-ranging study of LY3009104 (INCB28050), an oral JAK1/JAK2 inhibitor in combination with traditional DMARDS in patients with rheumatoid arthritis. Ann Rheum Dis. 2012;71(Suppl3):152
  1. Genovese M, Keystone E, Taylor P, et al. 24-week results of a blinded phase 2b dose-ranging study of baricitinib, an oral janus kinase 1/ janus kinase 2 inhibitor, in combination with traditional disease modifying antirheumatic drugs in patients with rheumatoid arthritis. Arth Rheum. 2012;64(Suppl 10):S1049.
  1. Taylor P, Genovese MC, Keystone E et al. Baricitinib, an oral janus kinase inhibitor, in the treatment of rheumatoid arthritis: 52-week safety and efficacy in an open-label, long-term extension study. Ann Rheum Dis. 2013;72(Suppl 3):65.
baricitinib[h]
JAK1 / JAK2
Psoriasis

Eli Lilly and Company is evaluating our JAK1/JAK2 inhibitor baricitinib for treatment of patients with moderate-to-severe psoriasis. Lilly is currently conducting a randomized, double-blind, placebo-controlled Phase IIb trial (www.clinicaltrials.gov identifier: NCT01490632), the primary objective of which 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.

 

baricitinib[h]
JAK1 / JAK2
Diabetic nephropathy

Eli Lilly and Company is evaluating our JAK1/JAK2 inhibitor baricitinib for treatment of patients with diabetic nephropathy. Lilly is currently conducting a randomized, double-blind, placebo-controlled Phase IIb trial (www.clinicaltrials.gov identifier: NCT01683409) in patients with mild to moderate diabetic kidney disease.

a. Incyte: U.S. rights; Novartis: ex-U.S. rights   b. Incyte: U.S. rights   c. In combination with Merck's pembrolizumab  
d. In combination with MedImmune's MEDI4736  e. In combination with Bristol-Myers Squibb's nivolumab
f. In combination with Genentech's MPDL3280A  g. Novartis: worldwide rights  h. Lilly: worldwide rights  *trial not yet initiated