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New Drugs Online Report for evolocumab
Generic Name:
Trade Name: Repatha SureClick 
Synonym: AMG 145 
Entry Type: New molecular entity  
Development and Regulatory status
UK: Launched 
EU: Launched 
US: Approved (Licensed) 
UK launch Plans: Available only to registered users
Actual UK launch date: July 2015 
Sep 15: Amgen files an application in the US for a licence variation to allow administration of the monthly 420mg dose as a single SC injection [19]. 
14/09/2015 11:16:09
Sep 15: Amgen has launched Repatha in Europe at a fraction of its cost in the US (£340 a month in the UK (= $6,780 a year), so substantially lower than its US list price of $14,100 [18]. 
03/09/2015 12:32:20
Aug 15: US FDA approved evolocumab injectionis for use in addition to diet and maximally-tolerated statin therapy in adults with heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH) or clinical atherosclerotic cardiovascular disease [17].  
28/08/2015 11:23:36
Jul 15: Reptha SureClick launched in the UK [16]. 
12/08/2015 11:37:20
Jul 15: Approved in EU [15]. 
22/07/2015 09:35:17
Jun 15: The U.S. Food and Drug Administration (FDA)’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted 11-4, recommending Repatha be approved for primarily heterozygous familial hypercholesterolemia (FH). The FDA will make a decision on Praluent on in August 2015 [14].  
12/06/2015 10:57:06
May 15: EU positive opinion for use in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet: (a) in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin, or (b) alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contra-indicated. Also positive opinion for adults and adolescents aged 12 years and over with homozygous familial hypercholesterolaemia in combination with other lipid-lowering therapies [13]. 
22/05/2015 13:44:45
Nov 14: FDA has accepted the BLA application and will issue a decision by Aug 27, 2015 [10]. 
10/11/2014 17:45:31
Oct 14: Amgen files a patent-infringement lawsuit to prevent the manufacture, use and sale of Sanofi and Regeneron´s PCSK9 antibody, alirocumab [9]. 
20/10/2014 10:35:55
Sep 14: Filed to the EMA seeking approval for the treatment of high cholesterol. [7] 
03/09/2014 15:04:59
Aug 14: Biologics License Application (BLA) submitted to US FDA for evolocumab, seeking approval for the treatment of high cholesterol. The BLA contains data from approximately 6,800 patients, including>4,500 patients with high cholesterol in 10 Phase 3 trials. The Phase 3 studies evaluated the safety and efficacy of evolocumab in patients with elevated cholesterol on statins with or without other lipid-lowering therapies; patients who cannot tolerate statins; patients with heterozygous familial hypercholesterolemia (HeFH); and patients with homozygous familial hypercholesterolemia (HoFH), a rare and serious genetic disorder.[6] 
29/08/2014 09:10:24
Trial or other data
Jun 16: NICE issues TA394. Evolocumab is recommended for primary hypercholesterolaemia/mixed dyslipidaemia if dosage is 140mg 2 weekly, low-density lipoprotein concentrations are persistently above those specified in the guidance despite maximal tolerated therapy and it is provided at an agreed discount [22]. 
23/06/2016 11:40:58
May 16: NICE issues draft guidance recommending Repatha and Praluent for people who cannot get their cholesterol under control using standard treatments, so long as the lower price is in place. It earlier approved Repatha for much more limited use. Sanofi and Regeneron put a list price of about $5,780 on Praluent when they took it to the UK, as did Amgen with Repatha. That is less than half of the roughly $14,000 they have on the drugs in the US. NICE notes that both drugs are relatively expensive, costing over £4000 per patient per year compared with about £350 for ezetemibe [21]. 
13/05/2016 10:25:55
Nov 15: Preliminary NICE guidelines reject Repatha. NICE says there have been no clinical trials to measure its direct effect on CV events, and that the question of whether reducing LDL cholesterol with Repatha would reduce angina, heart attacks and strokes remains unanswered. The review committee also cited several limitations in the company analysis. It was concerned that Amgen had estimated the risks of CVD using the Framingham risk equations, which have been shown to overestimate CVD risk in a UK population, instead of the NICE-recommended and UK-validated QRISK2 assessment tool, and concluded that the degree of uncertainty in the cost-effectiveness evidence was too high [20]. 
18/11/2015 15:38:41
Mar 15: Two reports published in NEJM describe results of three long-term studies. One trial, entitled Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM), was a double-blind, randomized, controlled trial of alirocumab (150 mg administered subcutaneously every 2 weeks) versus placebo for 78 weeks in 2341 patients at high risk for cardiovascular events who were already receiving the maximum tolerated doses of statins. Two other trials, entitled Open-Label Study of Long-Term Evaluation against LDL Cholesterol 1 (OSLER-1) and OSLER-2, used a randomized, open-label design in a total of 4465 patients with various degrees of cardiovascular risk. Evolocumab, administered subcutaneously at a dose of 140 mg every 2 weeks or 420 mg monthly, was added to standard therapy and compared with standard therapy alone over a period of approximately 1 year; the two OSLER trials were analysed together. Both the ODYSSEY LONG TERM trial and the OSLER trials included a mix of patients with cardiovascular disease, cardiovascular risk factors, or heterozygous familial hypercholesterolemia, and both included patients with elevated LDL cholesterol values despite statin use. As compared with placebo or standard therapy, the intervention reduced LDL cholesterol levels by an average of 61 to 62%. As with statins, levels of apolipoprotein B, non–high-density lipoprotein (HDL) cholesterol, and triglycerides were lowered by treatment, and levels of apolipoprotein A1 and HDL cholesterol were increased. However, unlike with statins, significant reductions in lipoprotein(a) were also observed [11]. 
16/03/2015 17:59:31
Sep 14: RUTHERFORD-2 published in The Lancet [7]. 
03/10/2014 15:42:42
Apr 14: In the RUTHERFORD-2 study in 329 HeFH patients on a stable dose of statin and other lipid-lowering therapies , the mean % reduction from baseline in LDL-C at weeks 10 and 12 were 60% for evolocumab 140 mg every two weeks and 66% for evolocumab 420 mg monthly vs placebo (p<0.001). [5] 
02/04/2014 11:52:40
Jan 14: Results reported from the PIII RUTHERFORD-2 (RedUction of LDL-C with PCSK9 InhibiTion in HEteRozygous Familial HyperchOlesteRolemia Disorder Study-2) trial. The study met its co-primary endpoints: % reduction from baseline in LDL-C at week 12 and mean % reduction from baseline in LDL-C at weeks 10 and 12. 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 1 of 4 treatment groups: evolocumab (140mg every two weeks or 420mg monthly) with subcutaneous placebo (every two weeks or monthly). Safety was balanced across treatment groups except for the following most common AEs (≥ 2% in evolocumab combined group and ≥ 2% vs placebo): nasopharyngitis (8.6% evolocumab vs 4.6% placebo), contusion (4.1 vs 0.9%), back pain (3.6 vs 0.9%), nausea (3.6 vs 0.9%), influenza (3.2 vs 0%), and myalgia (2.7 vs 0%). In a separate PIII study that enrolled 164 patients with high cholesterol on statin therapy, 95% of patients were able to self-administer at least one full home administration of evolocumab 420mg subcutaneously by one injection with an automated mini-doser or by three injections with a standard spring-based autoinjector [4].  
04/02/2014 18:03:43
Jan 13: NCT01763918 (RUTHERFORD-2) is a PIII double-blind, randomized, placebo-controlled, multicentre study to evaluate safety, tolerability and efficacy of AMG 145 on LDL-C in 300 subjects with heterozygous familial hypercholesterolemia. The primary outcome is % change from baseline in LDL-C at 12 weeks. The study starts Feb 13 and is due to complete Dec 13 [3]. 
10/01/2013 11:34:43
Nov 12: Results from the RUTHERFORD study released; a double-blind, placebo-controlled phase II RCT that evaluated AMG 145, dosed subcutaneously Q4W, in 168 pts with an LDL-C >100 mg/dL who were on a stable dose of statin, with or without ezetimibe. Pts were randomized to three treatment groups: AMG 145 at 350 mg, AMG 145 at 420 mg or placebo administered subcutaneously every four weeks. The primary endpoint was percentage change from baseline in LDL-C, measured by preparative ultracentrifugation, at week 12. Treatment with AMG 145 every four weeks (Q4W) resulted in a significant LDL-C decrease versus placebo in HeFH patients on lipid-lowering therapy (statins with or without ezetimibe). At week 12, LDL-C reduction, measured by preparative ultracentrifugation, was 43% and 55% with AMG 145 350 mg and 420 mg, respectively, compared to a 1% increase with placebo (p<0.001 for both dose groups). At week 12, treatment with AMG 145 350 mg and 420 mg Q4W resulted in 70% and 89% of pts reaching LDL-C levels of <100 mg/dL and 44% and 65% achieving <70 mg/dL, respectively, compared to 2% and 0% of placebo subjects, respectively. Favorable reductions in total cholesterol, non-HDL-C, Lp(a) and ApoB were consistent with the reductions in LDL-C [2]. 
07/11/2012 10:40:40
Evidence Based Evaluations
NICE TA  https://www.nice.org.uk/guidance/ta394 
NTAG  http://ntag.nhs.uk/docs/app/NTAG Appraisal document Evolocumab.pdf 
NTAG  http://ntag.nhs.uk/docs/rec/NTAG Decision Summary Evolocumab Repatha.pdf 
NICE scope  http://www.nice.org.uk/guidance/indevelopment/gid-tag498/documents 
Available only to registered users
BNF Category:
Lipid-regulating drugs (02.12)
Pharmacology: Fully human monoclonal antibody to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), a negative regulator of the LDL receptor.  
Epidemiology: Heterozygous familial hypercholesterolaemia (a form of primary hypercholesterolaemia) affects an estimated 1 in 500 people, totalling 106,000 in England (although only 15–17% are diagnosed) [12].  
Indication: Heterozygous familial hypercholesterolaemia 
Additional Details: in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL‑C goals with the maximum tolerated dose of a statin 
Method(s) of Administration
Company Information
Name: Amgen 
US Name: Amgen 
Further Information
Anticipated commissioning route (England) CCG 
High cost drug list? Yes - Likely
In NICE timetable: Yes 
When: Apr / 2016 
Note: www.nice.org.uk/guidance/indevelopment/gid-tag498 
Implications Available only to registered users