Surprise as Amgen pips Regeneron/Sanofi to first PCSK9 inhibitor approval

While all eyes were on the US market, Amgen has clinched victory over Regeneron/Sanofi in the race to be first to approval with a PCSK9 inhibitor in another major territory, the EU.

Just days ahead of the US PDUFA date for Regeneron/Sanofi's rival product Praluent (alirocumab), the European Commission has granted marketing authorization for Amgen's Repatha (evolocumab) for the treatment of patients with uncontrolled cholesterol who require additional intensive low-density lipoprotein cholesterol (LDL-C) reduction.

Amgen first nosed ahead in the EU when Repatha was granted a positive opinion by the EU's CHMP at its May meeting. This put it well ahead of Praluent, which was only accepted for review by the EMA in January 2015.

However, the two products are much closer together in the US, where despite being filed for approval later (December 2014), Regeneron's product is expected to be approved first thanks to the purchase of a priority review voucher for $67.5m from Biomarin in July 2014; this has reduced its review time from 10 to six months. The FDA is expected to decide on the BLA for Praluent by 24 July, followed shortly by a decision on Repatha BLA by 27 August.

Datamonitor Healthcare's Dr Aine Slowey commented: "This decision on Repatha by the European Commission, although expected, has taken everyone by surprise given its proximity to the deadline for the FDA's decision on Praluent. The timings of both of these decisions could offer some insight in to the future leading markets of the two PCSK9 inhibitors. Repatha's first-to-market status and broad label are likely to allow the drug to gain considerable uptake in Europe, while Praluent's expected approval in the US will allow the drug to be prescribed to high risk patients in this market."

Evercore ISI analyst Mark Schoenebaum said the EU decision on a broad label in line with the CHMP opinion says little as to what stance the FDA will take on the labelling for both products. "We think that today's decision has very little read across to the US. That said, we are bullish on Amgen/Regeneron receiving a broad label in the US."

Analysts at Deutsch Bank were also positive. "While approval was expected, the key unknowns for the drug were around the broadness of the label. The EC approved Repatha for: HeFH, statin intolerant, HoFH in combo with other agents, and in patients who are not achieving goal LDL-C with current treatments (statin or others). We see this broad labeling as encouraging. While EC labeling may not translate directly to the FDA, it is a positive sign that a regulatory body assigned a broader label before outcomes trials read out."

PCSK9 inhibition is a new strategy in cholesterol management and is set to be welcomed by doctors with patients needing greater reductions in their LDL-cholesterol levels. Both monoclonal antibodies can cause steep declines in LDL cholesterol that translate to cardiovascular benefits despite slightly higher adverse event rates, and their relative side-effect profiles are expected to play a part in therapy decisions and so their clinical data have been compared closely.

However, their relative costs are now expected to come under close scrutiny. No pricing information is available yet for Repatha.

indication

Specifically, the EC has approved Repatha for:

• The treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial [HeFH]) or mixed dyslipidemia, as an adjunct to diet: 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 alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.
• The treatment of adults and adolescents aged 12 years and over with homozygous familial hypercholesterolemia (HoFH) in combination with other lipid-lowering therapies.

It notes that the effect of Repatha on cardiovascular morbidity and mortality has not yet been determined.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that regulates the recycling of LDL-receptors on the surface of liver cells and decreases the ability of the liver to clear LDL from the blood. By binding to PCSK9 evolocumab increases liver levels of LDL receptor thereby reducing serum LDL-cholesterol levels.

Amgen notes that more than 60% of high-risk patients in Europe are still unable to adequately lower their LDL-C levels with statins or other currently approved lipid-lowering agents. Among very high-risk patients, the percentage is increased to more than 80%. It added that the health care cost of CVD in the EU is approximately €106bn per year.