Amgen Announces Positive Top-Line Results from Phase III RUTHERFORD?-2 Trial Of Evolocumab in Patients with Heterozygo?us Familial Hyperchole?sterolemia

Amgen has announced that the Phase III RUTHERFORD-2 (RedUction of LDL-C with PCSK9 InhibiTion in HEteRozygous Familial HyperchOlesteRolemia Disorder Study-2) trial evaluating evolocumab in combination with statins and other lipid-lowering therapies in patients with heterozygous familial hypercholesterolemia (HeFH) met its co-primary endpoints: the percent reduction from baseline in low-density lipoprotein cholesterol (LDL-C) at week 12 and the mean percent reduction from baseline in LDL-C at weeks 10 and 12.

The mean percent reductions in LDL-C, or "bad" cholesterol, were consistent with the results observed for the same doses in the Phase 2 RUTHERFORD trial for evolocumab compared to placebo.1

Evolocumab is an investigational fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces the liver's ability to remove LDL-C from the blood.2

The RUTHERFORD-2 trial evaluated safety, tolerability and efficacy of evolocumab in 329 HeFH patients on a stable dose of statin and other lipid-lowering therapies. Patients were randomized to one of four treatment groups to compare subcutaneous evolocumab (140 mg every 2 weeks or 420 mg monthly) with subcutaneous placebo (every 2 weeks or monthly).

Safety was balanced across treatment groups except for the following most common adverse events (= 2% in evolocumab combined group and = 2% compared to placebo): nasopharyngitis (8.6% evolocumab; 4.6% placebo), contusion (4.1% evolocumab; 0.9% placebo), back pain (3.6% evolocumab; 0.9% placebo), nausea (3.6% evolocumab; 0.9% placebo), influenza (3.2% evolocumab; 0.0% placebo), and myalgia (2.7% evolocumab; 0.0% placebo).

"Data from the RUTHERFORD-2 study suggest that evolocumab, when used as an add-on therapy to existing lipid-lowering medications, may offer a new treatment option for patients with heterozygous familial hypercholesterolemia," said Sean E. Harper, MD, executive vice president of R&D at Amgen. "The RUTHERFORD-2 study is the fifth pivotal LDL-C lowering study in our Phase III programme. The robust data from these five studies will form the basis of our global filing plan and we look forward to discussions with regulatory agencies."

Details of the Phase III RUTHERFORD-2 study results will be submitted to a future medical conference and for publication.

In a separate Phase III study that enrolled 164 patients with high cholesterol on statin therapy, 95% or greater of patients were able to self-administer at least one full home administration of evolocumab 420 mg subcutaneously by one injection with an automated mini-doser or by three injections with a standard spring-based autoinjector.

Reductions in LDL-C were comparable with both devices and consistent to those seen in the Phase II LAPLACE-TIMI 57 (LDL-C Assessment with PCSK9 MonoclonaL Antibody Inhibition Combined with Statin ThErapy -Thrombolysis In Myocardial Infarction-57) trial. Safety was balanced between the treatment groups and no new safety concerns were identified.

According to the Centers for Disease Control and Prevention, more than 71 million American adults have high LDL-C.3 Elevated LDL-C is recognised as a major risk factor for cardiovascular disease.4-5 Patients with familial hypercholesterolemia, an inherited condition that causes high levels of LDL-C levels beginning at birth, are at high-risk for cardiovascular events at an early age.6 Heterozygous familial hypercholesterolemia is one of the most common genetic disorders, affecting approximately one out of every 300 to 500 people worldwide.7

References

1. Raal F, et al. Low-Density Lipoprotein Cholesterol-Lowering Effects of AMG 145, a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease in Patients With Heterozygous Familial Hypercholesterolemia. Circ. 2012;126:2408-2417. 

2. Amgen Data on File, Investigator Brochure.

3. www.cdc.gov/mmwr/preview/mmwrhtml/mm6004a5.htm?s_cid=mm6004a5_w. Accessed January 2014.

4. www.heart.org/HEARTORG/Conditions/Cholesterol/WhyCholesterolMatters/Why-Cholesterol-Matters_UCM_001212_Article.jsp. Accessed January 2014.

5. World Health Organization. Global status report on noncommunicable diseases 2010. Geneva, 2011.

6. www.genome.gov/25520184. Accessed January 2014.

7. World Health Organization. Familial Hypercholesterolaemia Report 1998.