IL-21 Acts on Tcells, B cells & NK cells
IL-21 Augments Therapeutic antibody-mediated tumor lysis

Interleukin 21 (IL-21)

IL-21 has demonstrated anti-tumor activity in Phase 2 clinical trials

Interleukin-21 (IL-21) is a cytokine with potential use in the treatment of cancer. ZymoGenetics is testing recombinant IL-21 in a Phase 2b clinical trial in collaboration with the NCIC Clinical Trials Group in Canada in patients with metastatic melanoma. Previously, the company demonstrated anti-tumor activity in a Phase 2a clinical trial in metastatic melanoma and in a Phase 2 clinical trial in combination with Nexavar® in metastatic renal cell carcinoma. In October 2005, the FDA granted IL-21 orphan drug status for the treatment of melanoma patients with advanced or aggressive disease. ZymoGenetics has worldwide development and commercialization rights to IL-21 after securing ex-North American rights from Novo Nordisk A/S in January 2009.

Background

Endogenous IL-21 is a potent regulator of key classes of immune cells, including cytotoxic T lymphocyte cells and natural killer cells. These cell types play critical roles in eliminating malignant and virally infected cells from the body. IL-21 also is important in boosting antibody response, another weapon in the body's fight against cancer. The combined biologic actions of IL-21 suggest that it may be an effective immunotherapy in the treatment of cancer, either alone or in combination with other anti-cancer drugs. Based on preclinical and early clinical trial data, IL-21 could potentially be better tolerated and more efficacious than other currently marketed immunotherapies for cancer, such as interleukin-2 (IL-2) and interferon-alpha.

Clinical Trials

ZymoGenetics is pursuing metastatic melanoma as the lead indication for IL-21. A Phase 1 monotherapy trial of IL-21 in patients with metastatic renal cell carcinoma and metastatic melanoma demonstrated a favorable safety profile for use in an outpatient setting and evidence of anti-tumor activity in both indications. Results from a Phase 2a open-label clinical trial in metastatic melanoma were presented at the American Society of Clinical Oncology 2010 annual meeting. The overall response rate was 23.1% in evaluable patients, and median progression-free survival was 4.3 months. Thirty-nine of the 40 patients were evaluable for response, and 9 of the 39 (23.1%) had a confirmed partial response as measured by RECIST (Response Evaluation Criteria In Solid Tumors). In addition, 16 of the 39 patients (41%) had stable disease, and 14 of 39 (36%) had progressive disease. Two patients had 100% shrinkage of tumor target lesions. The most common adverse events in the Phase 2a IL-21 trial were fatigue, rash, fever, myalgia, anorexia, chills and nausea. The NCIC Clinical Trials Group in Canada evaluated their historical Phase 2 melanoma trial results with patients matching the IL-21 clinical trial entry criteria, and in those 68 clinical trials, progression-free survival was 1.58 months. Dacarbazine has shown in patients with melanoma median progression-free survival of 1.5 months and an overall response rate of less than 15%. Based on these results, ZymoGenetics is continuing development of IL-21 in metastatic melanoma as a single agent in collaboration with the NCIC Clinical Trials Group in Canada. A Phase 2b clinical trial in metastatic melanoma was initiated in Q2 2010.

IL-21 Phase 2b Melanoma Clinical Trial Design: IL-21 vs. DTIC

Market Opportunity

Metastatic Melanoma

Metastatic melanoma now ranks as one of the most common cancers in the United States and Europe. In 2007, there were approximately 115,000 new cases of metastatic melanoma in the United States, Europe and Japan. Over the next ten years the number of newly diagnosed cases of metastatic melanoma is expected to increase by 32% in these markets.

Scientific Publications

Phase 2

  • ASCO 2010 Presentation: IL-21 Phase 2 Metastatic Melanoma Results (PDF)
  • ASCO 2010 Abstract: IL-21 Phase 2 Metastatic Melanoma Results (PDF)
  • ASCO 2009: IL-21 ASCO Renal Cell Cancer Results from a Phase 2 Clinical Trial (PDF)
  • 7th World Congress on Melanoma, Vienna, Austria, May 2009: IL-21 Metastatic Melanoma Phase 2 Interim Results (PDF)
  • Abstract for the 7th World Congress on Melanoma, Vienna, Austria, May 2009: IL-21 Metastatic Melanoma Phase 2 Interim Results (PDF)
  • EORTC-NCI-AACR 2008: Recombinant IL-21 in Combination with Sorafenib as Second- or Third-Line Therapy for Metastatic Renal Cell Carcinoma (mRCC): Interim Results from a Phase 2 Study (PDF)

Phase 1

  • iSBTC 2008: Recombinant Interleukin-21 Plus Sorafenib for Metastatic Renal Cell Carcinoma (mRCC): A Phase 1 Dose Escalation Study (PDF)
  • ASCO 2008: Efficacy and Safety of Recombinant Interleukin-21 (rIL-21) and Rituximab in Relapsed/Refractory Indolent Lymphoma (PDF)
  • AACR-NCI-EORTC 2007: Recombinant IL-21 (rIL-21) in Combination with Sorafenib: Preliminary Results from a Phase I/II Study in Patients with Metastatic Renal Cell Cancer (RCC) (PDF)
  • ASH 2007: Recombinant Interleukin-21 (rIL-21) Plus Rituximab Clinical Activity in a Phase 1, Dose-Finding Trial in Relapsed Indolent B Cell Lymphoma (PDF)
  • ASCO 2006: Recombinant Interleukin-21 (IL-21) Tolerability and antitumor activity following two 5-day cycles in patients with stage IV melanoma (MM) or renal cell carcinoma (RCC) (PDF)
  • ASCO 2005: Preliminary Tolerability and Anti-tumor Activity of Intravenous Recombinant Human Interleukin-21 (IL-21) in Patients With Metastatic Melanoma and Metastatic Renal Cell Carcinoma (PDF)

Preclinical

Press Releases