Clinical Trials

Date: 2015-09-30

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in The New English Journal of Medicine

Company: Amgen (USA - CA) AstraZeneca (UK)

Product: brodalumab (AMG 827)

Action mechanism: monoclonal antibody. Brodalumab is a highly-selective human monoclonal antibody that binds to and blocks signaling via the interleukin-17 (IL-17) receptor. The IL-17 pathway plays an important role in inducing and promoting inflammatory disease processes. Blocking inflammatory signaling at the IL-17 receptor may be beneficial in the treatment of moderate to severe plaque psoriasis, psoriatic arthritis, and potentially other immune-mediated diseases. In April 2012, Amgen and AstraZeneca have announced an agreement to jointly develop and commercialize five monoclonal antibodies from Amgen\'s clinical inflammation portfolio (AMG 139, AMG 157, AMG 181, AMG 557 and brodalumab - AMG 827). With oversight from joint governing bodies, Amgen leads clinical development and commercialization for brodalumab (Phase 3 for moderate-to-severe plaque psoriasis and psoriatic arthritis, Phase 2 for asthma) and AMG 557/MEDI5872 (Phase 1b for autoimmune diseases such as systemic lupus erythematosus). AstraZeneca , through its biologics arm MedImmune, leads clinical development and commercialization for MEDI7183/AMG 181 (Phase 2 for ulcerative colitis and Crohn\'s disease), MEDI2070/AMG 139 (Phase 2 for Crohn\'s disease) and MEDI9929/AMG 157 (Phase 2 for asthma).

Disease: psoriasis

Therapeutic area: Autoimmune diseases - Dermatological diseases

Country: Australia, Austria, Canada, Czech Republic, France, Hungary, The Netherlands, Poland, Portugal, Spain, USA

Trial details: AMAGINE-2 is a Phase 3 study that assessed the safety and efficacy of brodalumab given at two doses every two weeks via subcutaneous injection compared with Stelara and placebo in patients with moderate-to-severe plaque psoriasis. The study also assessed the safety and efficacy of four maintenance regimens of brodalumab. The primary endpoint comparing 210 mg of brodalumab as well as a pre-specified weight-based analysis group with Stelara was the proportion of patients achieving total clearance of skin disease, as measured by PASI 100 at week 12. When comparing brodalumab with placebo, the primary endpoints included the proportion of patients achieving at least a 75 percent improvement from baseline in disease severity (PASI 75) at week 12, and the achievement of clear or almost clear skin, according to the sPGA (0 or 1) at week 12. The study began with a 12-week, double-blind, active comparator- and placebo-controlled induction phase, where patients were randomized in a 2:2:1:1 ratio to receive brodalumab (210 mg or 140 mg), Stelara (per the labeled dose), or placebo. At week 12, patients originally randomized to either brodalumab arm were re-randomized 2:2:2:1 into the maintenance phase to receive brodalumab 210 mg or 140 mg at four different maintenance regimens. Patients originally randomized to Stelara continued to receive the same treatment, and those originally randomized to receive placebo began 210 mg of brodalumab every two weeks. At week 52, patients entered the long-term extension portion of the study, and those who were originally randomized to receive Stelara began receiving 210 mg of brodalumab every two weeks. All other patients continued on treatment with brodalumab at the same dose they were being treated with at week 52. Patients may be enrolled in the study for up to 271 weeks (approximately five years). Amgen will continue to collect efficacy and safety data during this long-term exposure period. (NCT01708603) The AMAGINE program is comprised of three pivotal Phase 3 studies designed to assess the efficacy and safety of brodalumab in patients with moderate-to-severe plaque psoriasis. Top-line results from AMAGINE-1, comparing brodalumab with placebo, were released in May 2014 . Top-line results from AMAGINE-3, comparing brodalumab with Stelara and placebo, were announced in November 2014. AMAGINE-2 and AMAGINE-3 are identical in design.  

Latest news:

• • On September 30, 2015, AstraZeneca announced that the New England Journal of Medicine (NEJM) has published positive results from two pivotal, multi-centre, Phase III studies –AMAGINE-2 and AMAGINE-3 – demonstrating that treatment with brodalumab resulted in significant clinical improvements in patients with moderate to severe psoriasis and was superior to both placebo and ustekinumab, a leading approved treatment for psoriasis (Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis. N Engl J Med 2015; 373:1318-1328 October 1, 2015 DOI: 10.1056/NEJMoa1503824). Previous results from the two studies have been reported in November 2014 (see below for AMAGINE-2 and AMAGINE-3). The studies were funded by AstraZeneca and Amgen, the former sponsor of the brodalumab programme. AstraZeneca recently announced it has entered into a collaboration with Valeant Pharmaceuticals, granting Valeant an exclusive license to develop and commercialise brodalumab. Regulatory submissions in the United States and European Union for brodalumab in moderate to severe psoriasis are planned for the fourth quarter of 2015.
• • On November 25, 2014, Amgen and AstraZeneca announced that AMAGINE-2™, a pivotal, multi-arm Phase 3 trial evaluating two doses of brodalumab in more than 1,800 patients with moderate-to-severe plaque psoriasis, met its primary endpoints when compared with both Stelara® (ustekinumab) and placebo at week 12. Brodalumab 210 mg given every two weeks and the brodalumab weight-based analysis group were each shown to be superior to Stelara on the primary endpoint of achieving total clearance of skin disease, as measured by the Psoriasis Area Severity Index (PASI 100). When compared with placebo, a significantly greater proportion of patients treated with brodalumab achieved at least a 75 percent improvement from baseline in disease severity at week 12, as measured by the Psoriasis Area Severity Index (PASI 75). A significantly greater proportion of patients treated with brodalumab also achieved clear or almost clear skin at week 12 compared with placebo, according to the static Physician Global Assessment (sPGA 0 or 1).
• Results showed that 44.4 percent of patients in the brodalumab 210 mg group, 33.6 percent of patients in the brodalumab weight-based group, 25.7 percent of patients in the brodalumab 140 mg group, 21.7 percent of patients in the Stelara group and 0.6 percent of patients in the placebo group achieved total clearance of skin disease (PASI 100). In addition, 86.3 percent of patients in the brodalumab 210 mg group, 77.0 percent of patients in the brodalumab weight-based group, 66.6 percent of patients in the brodalumab 140 mg group, 70.0 percent of patients in the Stelara group and 8.1 percent of patients in the placebo group achieved PASI 75. All key secondary endpoints comparing brodalumab with placebo were met. The first key secondary endpoint comparing PASI 100 for brodalumab (140 mg) with Stelara at week 12 was numerically greater but not statistically significant (p=0.078). The remaining secondary endpoints against Stelara were also numerically greater (all nominal p-values were less than 0.05), but could not be deemed statistically significant due to the sequential testing method.
• The most common adverse events that occurred in the brodalumab groups (more than 5 percent of patients in either group) were common cold, upper respiratory tract infection, headache and joint pain. Serious adverse events occurred in 1.0 percent of patients in the 210 mg group, 1.2 percent of patients in the weight-based group, and 2.1 percent of patients in the 140 mg group compared with 1.3 percent for Stelara and 2.6 percent for placebo during the placebo-controlled period. There was one (0.2 percent) fatal event of stroke in the brodalumab 210 mg group during the 12-week placebo-controlled induction phase, deemed by the study investigator as unrelated to treatment. \"These results confirm our belief that targeting the IL-17 receptor to inhibit inflammatory signaling can have significant benefit for psoriasis patients,\" said Briggs W. Morrison , M.D., executive vice president of Global Medicines Development at AstraZeneca . \"We look forward to sharing detailed results from the AMAGINE program in upcoming scientific forums.\"
• AMAGINE-2 is the third and final pivotal study in the Phase 3 psoriasis program and data from these studies will form the basis for global regulatory filings, planned in 2015.

Is general: Yes