AMG 714, formerly known as HuMax-IL15™, is a fully human, high-affinity neutralizing antibody against Interleukin 15 (IL-15), a cytokine that appears early in the inflammation process. The recruitment of inflammatory T-cells by IL-15 is a contributor to the progress of several autoimmune diseases. In pre-clinical studies, AMG 714 has been shown to block important steps in the inflammatory cascade, including the release of TNF-a, a cytokine known to play a crucial role in the disease processes of rheumatoid arthritis (RA), psoriasis and Crohn’s Disease. AMG 714 also has potential utility in other inflammatory diseases such as inflammatory bowel disease, lupus and multiple sclerosis among others.  A Phase II study of AMG 714 in rheumatoid arthritis patients has been completed.

Development of AMG 714 is carried out under an agreement with Amgen.  In July 2003, Amgen exercised its commercialization options for both the AMG 714 antibody program and the IL15 receptor program. Amgen is responsible for further development of AMG 714.

In March 2006, Amgen announced it has reformulated AMG 714 in a more commercially productive cell line and the antibody is undergoing preclinical testing.  A Phase I study with the new formulation was started in 2006. Further development of AMG 714 is dependent upon results of the Phase I study.

Rheumatoid Arthritis   

Previous Clinical Studies

Phase II Results
In June 2006, Amgen published results in a Phase II study to treat patients with active RA who had previously failed treatment with at least one disease modifying anti-rheumatic drug (DMARD).  At week 14, 54% of patients receiving 280 mg of AMG 714 achieved ACR20, 29% achieved ACR50 and 14% achieved ACR70.  Response rates in patients who received placebo were 38%, 21% and 12%, respectively.  Levels of acute phase reactants decreased significantly with the 280 mg dose of AMG 714 compared with placebo beginning at week 4 and these levels remained significantly decreased for the remainder of the study.

AMG 714 was well tolerated by patients in the study and the safety profile was similar to that of placebo, with doses up to 280 mg being well tolerated.

Although the primary efficacy endpoint was not met, the overall clinical results suggest efficacy of AMG 714 in the treatment of DMARD-refractory RA.  These data demonstrate pharmacological activity of AMG 714 and suggest that inhibiting IL-15 with AMG 714 may be an important treatment strategy for RA and other inflammatory conditions.

A total of 180 patients were enrolled in the Phase II study with 114 patients evaluable for efficacy and 179 evaluable for safety.  Initially, patients were randomly assigned to receive one of four doses of AMG 714 (40, 80, 160 or 280 mg) or placebo every 2 weeks for 12 weeks.  Following a protocol amendment, additional patients were randomly assigned to receive 280 mg of AMG 714 or placebo twice monthly.  The primary endpoint of the study was proportion of patients achieving ACR20 at week 14.

Phase I/II Results
The Phase I/II clinical trial of AMG 714 was a dose escalation study to determine safety and preliminary efficacy.  Thirty RA patients initially received a single subcutaneous infusion of one of six doses (0.15, 0.5, 1, 2, 4 and 8 mg/kg) or placebo. Following satisfactory safety review, all patients received four doses at weekly intervals, including the placebo patients. However, the 0.15 mg/kg cohort was not extended into repeat dosing, and the 8 mg/kg cohort continued on 4 mg/kg. Patients were followed for 4 weeks after the last repeat dose.

After repeat doses, 15 of 24 patients (63%) achieved ACR20 response, 9 (38%) achieved ACR50  and 6 (25%) ACR70.  ACR70 was achieved in every multiple dose cohort.  The industry recognized ACR20 score indicates a 20 percent reduction in swelling of the diseased joints, while an ACR70 score represents a 70 percent reduction in the affected areas.

Safety data showed that AMG 714 at single doses up to 8 mg/kg and repeat doses up to 4 mg/kg is a well-tolerated treatment in patients with active RA.

Selected Scientific References:

Villadsen, L.S., Schuurman, J., Dam, T.N., Dagnaes-Hansen, F., Skov, L., Rygaard, J., Voorhorst-Ogink, M.M., Gerritsen, A.F., Van Dijk, M.A., Parren, P.W.H.I., Baadsgaard, O., and Van de Winkel, J.G.J. Resolution of psoriasis upon blockade of interleukin-15 biological activity. J. Clin. Invest.; 2003 (112): 1571-1580.

McInnes, I.B., and Liew, F.Y. Interleukin-15: a proinflammatory role in rheumatoid arthritis synovitis. Immunology Today; 1998 (19):75

McInnes, I.B., Al-Mughales, J., Field, M., Leung, B.P., Huang, F.P., Dixon, R., Sturrock, R.G., Wilkinson, P.C., and Liew, F.Y. The role of interleukin-15 in T cell migration and activation in rheumatoid arthritis. Nature Medicine; 1996 (2): 175-182.