Review of Amgen Cholesterol Drug Favored by FDA Panel

An FDA regulatory panel has recommended approval of Amgen’s proposed choles-terol-lowering medication, evolocumab, to be marketed as Repatha. The panel’s 11 to 4 vote on June 10 suggests that the drug is likely to be ap-proved in the near future. ¹

Proposed indications for evolocumab include:

• Use in adults with primary hyper-lipidemia including heterozygous familial and nonfamilial hyperlip-idemia, as well as mixed dyslipidemia as an adjunct to dietary interventions for reducing low-density lipoprotein (LDL) cholesterol levels, total cholesterol levels, apolipoprotein B, and other unfavorable lipid parameters, as well as for increasing levels of the salutary biomarker high-density lipoprotein (HDL) cholesterol.

• Use in combination with statins and non-statin lipid-lowering therapies, such as ezetimibe.

• Use in statin-intolerant patients. Current FDA-approved treatments for primary or mixed dyslipidemias include atorvastatin, simvastatin, pitavastatin, lovastatin, fluvastatin, pravastatin, extended-release niacin, fenofibrate, rosuvastatin, atorvastatin/ezetimibe, and simvastatin/ezetimibe. For patients with homozygous familial hypercholes-terolemia (HoFH), oral lomitapide and injectable mipomersen are also avail-able for reduction of non-HDL cholesterol levels.

MECHANISM OF ACTION

The circulating protein proprotein convertase subtilisin/kexin type 9 (PCSK9) was initially considered a drug target due to literature reports of mutant indi-viduals with low PCSK9 activity having unusually robust cardiovascular health. For instance, African Americans with a nonsense allele encoding PCSK9 had, on average, 29% lower LDL cholesterol lev-els, and an aggregate 88% lower risk of developing coronary heart disease.

One woman in her early 20s who had a complete loss-of-function mutation for PCSK9 had an LDL cholesterol level of 15.5 mg/dL and an HDL cholesterol level of 54 mg/dL. Another woman in her early 30s had a heterozygous loss-of-function mutation for PCSK9, an LDL cholesterol level of 14 mg/dL, and an HDL cholesterol level of 65 mg/dL.

Mechanistically, the human monoclo- nal immunoglobulin G2 (IgG2) antibody evolocumab binds to the circulating PCSK9 protein, inhibiting it from binding to LDL receptors (LDLRs) on the surface of hepatocytes. These LDLRs serve to clear LDL cholesterol from the blood. By inhibiting PCSK9 activity, medications such as evolocumab increase LDLR levels on the surface of liver cells, increasing the intensity of LDLR-mediated LDL cholesterol clearance.

DOSING

Proposed dosing for evolocumab is 140 mg administered subcutaneously every 2 weeks, or 420 mg administered subcutaneously every month. Potential con- cerns with the monthly dosing option include a more limited opportunity for dosage titration in patients achieving very low LDL cholesterol levels.

PHARMACOLOGY AND PHARMACOKINETICS

The FDA’s briefing document suggests that no dosage adjustments will be nec-essary in geriatric patients or those with mild-to-moderate renal or hepatic impairment.²

Important pharmacokinetic considerations include a 20% increase in evo-locumab clearance rates when it is co-administered with statins, an estimated half-life of 11 to 17 days, and 2- to 3-fold accumulation with repeat dosing. The medication has limited tissue distri-bution, and a volume of distribution averaging 3.3 L. Maximum levels are achieved within 3 to 4 days, and bio-availability has been estimated at 72% following a single dose of evolocumab.

In efficacy studies, evolocumab-binding antibodies have developed in <1% of patients using the drug, but there have been no cases of neutralizing antibodies to evolocumab.

CLINICAL STUDIES

Clinical data are based on 5 short-term phase 2 trials, 1 long-term phase 2 trial, 4 short-term phase 3 trials, and 2 long-term phase 3 trials.

General efficacy statements noted in the FDA’s briefing document concerning the drug include:

• LDL cholesterol reduction of 55% to 75% within 1 week of starting ther-apy in patients with primary hyper-lipidemia, and a maximal response within 2 weeks of therapy.

• LDL cholesterol reduction of 31% within 12 weeks in patients with HoFH not receiving lipid apheresis.

• A lower rate of treatment response in HoFH patients receiving lipid apheresis versus patients not re-ceiving lipid apheresis over 24 weeks of evolocumab therapy (re-sponse rates of 20% with apheresis vs 25% without apheresis, respec-tively).

• A 6% greater reduction in LDL cho-lesterol among HoFH patients re-ceiving an intensified dosing regi-men of 420 mg every 2 weeks versus the usual dosage of 420 mg monthly.

WARNINGS AND PRECAUTIONS

In evolocumab trials, nonfatal serious adverse events (AEs) occurred in 3% of patients receiving active treatment ver-sus 2.4% of patients receiving placebo alone. These events included myocardial infarction, angina pectoris, and pneumonia, each of which occurred in 0.1% of patients receiving evolocumab.

Pancreatitis, appendicitis, pneumonia, and back pain were also reported. Cardiac disorders, increases in creatinine phosphokinase levels, and nausea were the most common serious AEs leading to treatment discontinuation.

In evolocumab monotherapy trials, the most common AEs of any severity were nasopharyngitis (5.9%), upper respiratory tract infection (3.2%), back pain (3.0%), and nausea (2.1%), each of which occurred in patients taking evolocumab at a modestly higher rate than in those taking placebo.

When taken with standard-of-care treatments, evolocumab was associated with slightly higher rates of arthralgia (3.4%), back pain (3.1%), myalgia (2.5%), and extremity pain (2.5%) versus pa-tients receiving only standard-of-care medications. Monthly evolocumab dosing increased the risk of nasopharyngitis, headache, and fatigue more than every-2-week dosing.

In early trials, neurocognitive AEs occurred in 11 patients, including 6 in control groups. In trials lasting up to 1 year, a total of 22 neurocognitive AEs were recorded, unrelated to the degree of LDL cholesterol reduction achieved.

In phase 3 trials, 0.1% of patients taking evolocumab developed renal disease or proteinuria, while no such cases were identified in control groups. These renal events may be more likely to occur in statin-intolerant patients and diabetics. In addition, a possible safety signal relat-ed to pancreatitis risk was detected.

Injection site reactions were reported at rates of 3.3% to 5.7%, varying by trial duration and design. A total of 5 cases of an-gioedema have been reported, all of which occurred in patients using evolocumab.

DRUG-DRUG INTERACTIONS

Studies of drug-drug or drug-food inter-actions have not been conducted with evolocumab. Due to the drug’s properties, no such interactions are expected. However, a 20% increase in the clearance of statins is a notable finding from pharma-cokinetic studies.

GENOTOXICITY AND TERATOGENICITY

Genotoxicity assays were not per-formed, as a DNA interaction with evolocumab was not expected, based on the drug’s mechanism of action. To assuage lingering carcinogenicity concerns, the manufacturer conducted a 2-year study in hamsters. No drug-related tumors were identified. Animal studies in hamsters and mon-keys showed no relationship between evolocumab exposure and fetal variations or malformations, even at supra-therapeutic doses. A total of 7 women became pregnant in all evolocumab re-search programs, and a total of 9 men fathered children. Among these 16 pregnancies, 1 of the 7 in the maternal exposure group and 3 of the 9 in the paternal exposure group resulted in a full-term birth without complications.

CONCLUSIONS

Given the favorable FDA panel opinion of evolocumab, Amgen is optimistic about the drug’s future.

“If approved, Repatha would provide patients and physicians with an impor-tant new treatment option for managing high cholesterol,” stated Sean E. Harper, MD, executive vice president of research and development for Amgen.³

The FDA is expected to act on Repatha’s biologics license application on August 27, 2015. RefeRences

1. Caffrey MK. FDA panel gives evolocumab green light, with advice on who gets it to follow. http://www.ajmc.com/newsroom/fda-panel-gives-evolocumab-green-light-with-advice-on-who-gets-it-to-follow. American Journal of Managed Care website. Published June 10, 2015. Accessed June 10, 2015.

2. FDA briefing document: June 10, 2015. FDA website. http://www.fda.gov/downloads/Advi-soryCommittees/CommitteesMeetingMaterials/ Drugs/EndocrinologicandMetabolicDrugsAdviso-ryCommittee/UCM450072.pdf. Accessed June 2015.

3. Amgen to discuss details of Repatha (evolo-cumab) biologics license application for the treatment of high cholesterol [press release]. http://www.amgen.com/media/media_pr_de-tail.jsp?releaseID=2058073. Thousand Oaks, CA: PRNewswire; June 10, 2015.

Download PDF: Review of Amgen Cholesterol Drug Favored by FDA Panel