Sales of Pfizer's Lipitor topped out at more than $10 billion before the drug finally lost patent protection. The next generation of cholesterol-lowering drugs are on their way, and it's clear they can improve on the effects of Lipitor and the other statins such as AstraZeneca's Crestor and Merck's Zocor, but that doesn't necessarily mean they'll reach the same sales levels.

Rare but important
Aegerion Pharmaceuticals 
gained Food and Drug Administration approval last week for Juxtapid, its treatment for homozygous familial hypercholesterolemia. Patients with the disease have mutations in both copies of a gene responsible for removing cholesterol from the blood stream.

While rare, homozygous familial hypercholesterolemia is an extremely serious disease where young patients have insanely high levels of cholesterol, which leads to premature cardiovascular issues and an early death.


Sanofi and Isis Pharmaceuticals are also developing a drug to treat homozygous familial hypercholesterolemia, Kynamro, which is currently under FDA review. The EU's Committee for Medicinal Products for Human Use recently rejected  the drug, but the FDA's advisory committee gave it a positive recommendation -- albeit a little muted -- so there's still hope that it could be approved stateside.

Having one mutated copy of the disease, called heterozygous, is far more common. Patients aren't nearly as sick, but still have unhealthy levels of cholesterol that is often not controlled by the current medications. Both Juxtapid and Kynamro have safety issues that might keep them from getting approved to treat heterozygous patients.

The masses
A new generation of drugs are targeting protein convertase subtilisin/kexin type 9, or PCSK9, which promotes the degradation of receptors that remove bad LDL cholesterol from the bloodstream. Inhibiting PCSK9 increases the receptors, thereby decreasing the level of cholesterol.

So far, the data looks pretty promising. Regeneron Pharmaceuticals and Sanofi are developing REGN727, which Sanofi calls SAR236553, reduced LDL cholesterol by 28.9% to 67.9% at different doses compared with a 10.7% reduction in patients receiving placebo. Amgen's  AMG 145 produced similarly striking results, reducing LDL levels by 66% in one trial and 51% in another.

Alnylam Pharmaceuticals  is also targeting PCSK9, but its drug, ALN-PCS, reduces the protein's function through RNAi, which degrades the RNA before it can be used to produce the protein. Regneron and Amgen's drugs inhibit the PCSK9 protein directly by binding an antibody to it.

Is lower cholesterol really better?
Or maybe the better question is: Can you prove it?

Drugs that treat homozygous familial hypercholesterolemia can get away with just showing that they reduce cholesterol levels to prove their worth. For drugs given to the masses, the Food and Drug Administration will want to see more than the results of a laboratory test. The agency requires drugmakers show the drugs reduce the level of heart attacks, strokes, and the like before they can be approved.

The problem for new drugs is that statins and healthier living has already reduced negative heart outcomes substantially. Proving that a drug can reduce them further has proven difficult. And it's unethical to run a trial that tests a drug against placebo unless you allow all patients to also be on a statin if they need it.

Merck, for instance tried to prove that its cholesterol and lipid drug, Cordaptive, combined with a statin could reduce negative outcomes compared to a statin alone, but the trial failed. Does the drug really not work? My guess is that it probably does; it increases good HDL cholesterol, reduces bad LDL cholesterol, and reduces lipid level after all. But proving that it reduces an already low level of negative events isn't easy.

Good investment?
I think going after heart drugs for the masses is probably not the wisest investment. I see the appeal -- $10 billion annually is an awfully big number -- but it costs an awful lot to run these large outcomes trials and to prove that a drug works, the trials might need to be even larger. And if the change is really that small, I'm not sure insurance companies are going to be willing to pay for it.

Homozygous familial hypercholesterolemia is an appealing alternative. There's money to be made in treating orphan diseases because drugmakers can charge so much; Juxtapid will reportedly cost between $200,000 and $300,000 per year. But they're not going to be a megablockbuster and perhaps not even a blockbuster at all if the market is split among multiple drugs.

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The article Better Than Lipitor! Higher Sales? originally appeared on Fool.com.

Fool contributor Brian Orelli has no positions in the stocks mentioned above. The Motley Fool has no positions in the stocks mentioned above. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.

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