Repatha by Amgen Inc

ON AUGUST 27, 2015, the FDA approved Repatha (evolocumab) for the treatment of primary hyperlipidemia in combination with dietary measures and maximally tolerated doses of statins. Use of Repatha is indicated in patients with heterozygous familial hypercholesterolemia (HeFH), patients with homozygous familial hypercholesterolemia (HoFH), and patients with clinical atherosclerotic cardiovascular disease who require additional low-density lipoprotein cholesterol (LDL-C) reduction.

Although Repatha has been shown to lower LDL-C, its effect on cardiovascular morbidity and mortality remains undetermined.^1,2

Mechanism of Action

Repatha contains a monoclonal immunoglobulin G2 antibody that binds to circulating protein known as proprotein convertase subtilisin kexin 9 (PCSK9). Normally, PCKS9 binds to and inhibits the activity of the LDL receptor (LDLR) on the surface of hepatocytes. By binding to PCSK9, Repatha prevents PCSK9 from inhibiting LDLR activity.

As a result, more LDLRs are available on hepatocytes to capture LDL-C from the blood, resulting in lower LDL-C levels.²

Pharmacology and Pharmacokinetics

After administration of a single dose of Repatha, maximal PCSK9 inhibition occurs within approximately 4 hours, with peak levels reached within 3 to 4 days. With multiple doses, Repatha trough concentrations accumulate 2- to 3-fold and steady-state trough levels are reached within approximately 12 weeks. Repatha has an effective half-life estimated at 11 to 17 days.²

Age, gender, race, creatinine clearance, and bodyweight had no clinically meaningful effects on the pharmacokinetics of Repatha. Although Repatha has not been studied in patients with severe renal impairment, because monoclonal antibodies are not eliminated renally, severe renal impairment should not affect Repatha exposure.

The dose of Repatha should not be adjusted in patients with mild to moderate hepatic impairment, although it is notable that exposure and maximum concentrations of Repatha were lower in these patients than in healthy patients.²

Dosage and Administration

Prefilled syringes of Repatha contain 1 mL of medication at a concentration of 140 mg/mL. Syringes are supplied either as ordinary prefilled syringes (1 per box) or as SureClick autoinjectors (1 to 3 per box).

Injections of Repatha are administered at a dose of either 140 mg every 2 weeks or 420 mg monthly (3 consecutive injections of 140 mg each administered over a 30-minute period) in patients with HeFH or clinical atherosclerotic cardiovascular disease.

However, only the monthly dosage regimen should be used in patients with HoFH.² Instruct patients to either store Repatha under refrigeration or to keep Repatha in its original carton at room temperature (no higher than 77°F) for up to 1 month.

If Repatha is refrigerated, it should be kept at room temperature for a minimum of 30 minutes before administration. After inspecting the solution for discoloration and particulates, the medication may be injected subcutaneously into the abdomen, thigh, or upper arm.

Patients should rotate the injection site with each injection. If a dose is missed, the missed dose may be administered late as long as consecutive doses are administered more than 7 days apart.²

Clinical Studies

Repatha has been evaluated in patients with clinical atherosclerotic cardiovascular disease, HeFH, and HoFH. Among patients with clinical atherosclerotic cardiovascular disease, 296 patients received Repatha in addition to high-dose statin therapy for 12 weeks.

Repatha reduced baseline LDL-C 71% more than placebo when administered every 2 weeks and 61% more than placebo when administered monthly. Similarly, in a 12-week study of 329 patients with HeFH, Repatha reduced baseline LDL-C levels 61% more than placebo when administered every 2 weeks and 60% more than placebo when administered monthly.

In 49 patients with HoFH, 12-week results were less dramatic, with baseline LDL-C levels reduced 31% more with monthly Repatha injections than with placebo. All of these results were highly statistically significant (P <.0001).²

Warnings and Precautions

Hypersensitivity reactions have been reported with Repatha, including serious allergic reactions that led to discontinuation of treatment. Local injection site reactions and allergic reactions occurred more commonly in patients receiving Repatha than placebo (3.2% vs 3.0%, and 5.1% vs 4.7%, respectively).²

Musculoskeletal adverse events (AEs), including back pain, arthralgia, and myalgia, occurred in 14.3% of patients receiving Repatha versus 12.8% of patients receiving placebo. However, it is notable that rhabdomyolysis is not listed as a potential AE in the Repatha package insert.

Although neurocognitive AEs have been reported, these occurred in less than or equal to 0.2% of patients receiving either Repatha or placebo.²

AEs occurring in more than 5% of patients receiving Repatha, and more frequently than in patients receiving placebo, were nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions.² SPT

References

• FDA approves Repatha to treat certain patients with high cholesterol [news release]. Silver Spring, MD: FDA; August 27, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm460082.htm. Accessed August 27, 2015.
• Repatha (evolocumab) injection [package insert]. Thousand Oaks, CA: Amgen Inc; 2015.