Hyperlipidemia: CETP Inhibitors, PCSK9 Inhibitors, and More
Two events have conspired to delay—and perhaps demolish—development efforts for novel drugs indicated for the treatment of
high cholesterol and the reduction of atherosclerosis. The first was Pfizer's failure with its first-in-class CETP inhibitor
torcetrapib, which killed patients in clinical trials. The second was the ubiquitous use of statins, and their standout efficacy
and safety as a class. Roche's CETP inhibitor dalcetrapib, a drug with blockbuster status written all over it, according to
many analysts, was shuttered after a Phase III trial in May. At the time, Roche's chief medical officer and head of global
product development Hal Barron said "lowering cardiovascular risk beyond that which is achieved with intensive statin treatment
is a very challenging goal."
Merck is still working on its CETP inhibitor anacetrapib, but the excitement over this class of drugs has cooled, given the
need for extremely robust data proving efficacy and safety. Given that, Meekings at Thomson Reuters says anacetrapib could
still become a blockbuster several times over, but "it probably won't get approved before 2016." Lilly commenced Phase III
trials on its CETP inhibitor, evacetrapib, but it's behind Merck's drug and faces the same challenges.
In the meantime, a new class of monoclonal antibodies targeting Proprotein Convertase Subtilisin/Kexin type 9 and known as
PCSK9 inhibitors are entering later stages of development. The first of these, Regeneron/Sanofi's alirocumab, has recently
entered Phase III trials for hypercholesterolemia, or very high cholesterol levels in the blood. Administered subcutaneously,
alirocumab showed extremely good results in Phase II, and is already getting blockbuster whispers, according to Meekings.
A second PCSK9 inhibitor, Amgen's AMG 145, has also entered Phase III development. Like alirocumab, AMG 145 is being tested
with and without a statin, and for familial hypercholesterolemia in addition to general hypercholesterolemia. Adis Insight
predicts a January 2016 target approval date for both drugs, but gives AMG 145 a slightly higher chance of approval. "It remains
to be seen which drug will emerge as the dominant PCSK9," says Meekings. Thompson Reuters expects peak sales for both drugs
to reach $4 billion.
Orphan alert: mipomersen
Last year's orphan alert in the cholesterol space went to Aegerion Pharmaceuticals' lomitapide, which received a 13 to two
vote for approval from FDA's Endocrinologic and Metabolic Drugs Advisory Committee on October 17. A day later, the same committee
voted nine to six to approve Genzyme/Isis Pharmaceuticals' mipomersen (brand name Kynamro), an oligonucleotide antisense inhibitor
for the treatment of familial hypercholesterolemia. Analysts have been bullish on lomitapide for some time, and it's expected
to earn nearly half a billion dollars in annual sales. While the two drugs would compete in the familial orphan indication,
Sanofi/Isis, unlike Aegerion, is following the orphan indication with Phase III trials for hypercholesterolemia in patients
at risk for coronary heart disease, a decidedly un-orphan indication. "It will be interesting to see how mipomersen pivots
into the non-familial indication," says Meekings. More specifically, it will be interesting to see how Sanofi/Isis handles
the inevitable pricing issues that will arise as a result of crossing over from orphan to non-orphan indications.