Statement on FOURIER Analysis Published in BMJ Open
Amgen disagrees with the analysis of Repatha (evolocumab) published in BMJ Open by Erviti et al. and we stand behind the integrity and validity of the FOURIER trial and results. As mentioned in the BMJ Open manuscript, there are a number of limitations to the Erviti et al. analysis resulting in an incomplete assessment of the FOURIER data and a flawed conclusion.
We stand confident in the prospectively defined clinical trial event adjudication process that was applied to FOURIER and believe that the most rigorous classification process for adjudication was used by the TIMI Study Group. This process was based on the uniform Standardized Data Collection for Cardiovascular Trials Initiative established by the Food and Drug Administration, as well as guidance from other regulatory agencies and was consistent with the adjudication process used in other cardiovascular outcomes trials. Adjudication was performed by an independent Clinical Endpoints Committee (CEC), thereby ensuring all CV events were captured, accounted for, and not duplicated. The CEC was blinded to study treatment and had access to all information within each adjudication package that would not have been contained in a clinical study report narrative, enabling them to make a more accurate determination of the cause of death.
Treatment guidelines and recommendations across the world recommend PCSK9i mAbs, like Repatha, due to their demonstrated safety profile, efficacy and data from CV outcomes trials as a preferred therapy for patients with established ASCVD who need to intensify their lipid lowering therapy.
We stand behind the robust body of evidence supporting the safety and efficacy profile of Repatha, which has been used in 1.7 million patients worldwide since 2015 and has been studied in more than 51,000 patients through clinical studies. Our confidence in Repatha was recently reaffirmed by the publication of the FOURIER-OLE results in Circulation, which included more than 8 years of clinical trial follow-up.
Read the rebuttal published in BMJ Open by the TIMI Study Group here.
References:
- Erviti J, et al. BMJ Open 2022;12:e060172. doi:10.1136/bmjopen-2021-060172
- Sabatine M et al. NEJM 2017; 376: 1713-1722
- Lloyd-Jones DM. et al. JACC. 2022; https://doi.org/10.1016/j.jacc.2022.07.006
- Mach F et al. EHJ 2020; 41:111-188
- Data on File, Amgen; 2022
Repatha Indications in the US:
Repatha® is indicated:
- In adults with established cardiovascular disease to reduce the risk of myocardial infarction, stroke, and coronary revascularization
- As an adjunct to diet, alone or in combination with other low-density lipoprotein cholesterol (LDL-C)‑lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL‑C
- As an adjunct to diet and other LDL-C-lowering therapies in pediatric patients aged 10 years and older with HeFH, to reduce LDL-C
- As an adjunct to other LDL‑C-lowering therapies in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH), to reduce LDL‑C
The safety and effectiveness of Repatha® have not been established in pediatric patients with HeFH or HoFH who are younger than 10 years old or in pediatric patients with other types of hyperlipidemia.
Repatha US Important Safety Information
Contraindication: Repatha® is contraindicated in patients with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients in Repatha®. Serious hypersensitivity reactions including angioedema have occurred in patients treated with Repatha®.
Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema, have been reported in patients treated with Repatha®. If signs or symptoms of serious hypersensitivity reactions occur, discontinue treatment with Repatha®, treat according to the standard of care, and monitor until signs and symptoms resolve.
Adverse Reactions in Adults with Primary Hyperlipidemia: The most common adverse reactions (>5% of patients treated with Repatha® and more frequently than placebo) were: nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions.
From a pool of the 52-week trial and seven 12-week trials: Local injection site reactions occurred in 3.2% and 3.0% of Repatha®-treated and placebo-treated patients, respectively. The most common injection site reactions were erythema, pain, and bruising. Hypersensitivity reactions occurred in 5.1% and 4.7% of Repatha®-treated and placebo-treated patients, respectively. The most common hypersensitivity reactions were rash (1.0% versus 0.5% for Repatha® and placebo, respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus 0.2%), and urticaria (0.4% versus 0.1%).
Adverse Reactions in the Cardiovascular Outcomes Trial: The most common adverse reactions (>5% of patients treated with Repatha® and more frequently than placebo) were: diabetes mellitus (8.8% Repatha®, 8.2% placebo), nasopharyngitis (7.8% Repatha®, 7.4% placebo), and upper respiratory tract infection (5.1% Repatha®, 4.8% placebo).
Among the 16,676 patients without diabetes mellitus at baseline, the incidence of new-onset diabetes mellitus during the trial was 8.1% in patients treated with Repatha® compared with 7.7% in patients that received placebo.
Adverse Reactions in Pediatric Patients with HeFH: The most common adverse reactions (>5% of patients treated with Repatha® and more frequently than placebo) were: nasopharyngitis, headache, oropharyngeal pain, influenza, and upper respiratory tract infection.
Adverse Reactions in Adults and Pediatric Patients with HoFH: In a 12-week study in 49 patients, the adverse reactions that occurred in at least two patients treated with Repatha® and more frequently than placebo were: upper respiratory tract infection, influenza, gastroenteritis, and nasopharyngitis. In an open-label extension study in 106 patients, including 14 pediatric patients, no new adverse reactions were observed.
Immunogenicity: Repatha® is a human monoclonal antibody. As with all therapeutic proteins, there is potential for immunogenicity with Repatha®.