why, despite all the statin use, heart disease is still such a big killer in the United States.
PCSK9 turns out to be LDL’s co-conspirator. Our liver cells have a bunch of receptors on their surface that catch free-floating LDL, shuttle it inside the cell for destruction, then come back out to the surface to catch more, like tiny garbage trucks going back and forth to the dump.
PCSK9 binds to those receptors, too, triggering the same trip to the dump. But when PCSK9 is on board, the garbage trucks are destroyed within the cell, instead of dumping their load and coming back for more. Cells end up with fewer and fewer LDL receptors, which means more and more free-floating LDL.
The underlying biology also explains why statins can only do so much. In a talk last year before the National Lipid Association, Jonathan Cohen, a researcher at University of Texas Southwestern Medical Center who helped uncover the relationship between PCSK9 and cholesterol levels, said statins stimulate LDL receptors in the liver—a good thing—but they also stimulate another protein that works with PCSK9 to speed up the destruction of those receptors. “Statins are intrinsically self-limiting”—after a certain point, taking more statins doesn’t equal more cholesterol reduction, he said.
The PCSK9 inhibitors prevent PCSK9 from latching on to the LDL receptors, which means the receptors can do more work removing bad cholesterol from the blood. How much more? In data presented earlier this year, patients taking evolocumab or alirocumabin combination with a statin had their LDL reduced by about 60 percent compared to patients taking a statin-placebo combination.
The drugs might lower bad cholesterol, but do they prevent heart disease? That’s an important question, but for the purposes of getting approved, it doesn’t matter. The FDA says a drug in this space doesn’t need to show “outcomes”—that is, a lower rate of disease—to be approved. This comes straight from documents the agency used to prepare its expert advisers this week:
Historically, a change in LDL-C has been considered sufficient to establish the effectiveness of a lipid-altering drug intended for use to reduce cardiovascular risk, without any regulatory requirement to demonstrate evidence for benefit in a CV outcomes trial, provided the reduction is sufficiently robust and the product (or its class) does not have safety issues that raise concern that risk exceeds benefit.
In other words, the agency wants to see a significant reduction in LDL and manageable safety. But doctors, patients, and insurers want to see the outcomes trial data, which is why at least a few analysts are calling for a more subdued launch than one might expect. Amgen and Sanofi/Regeneron aren’t required by the FDA to run those trials, but they’re doing so anyway. Amgen said Friday it has enrolled about 27,500 people for its study and data will be available by 2017. Sanofi/Regeneron are enrolling 18,000 people, with data due in early 2018.
So far, the two drugs have been tested in more than 10,000 people and haven’t triggered major safety alarms, although there are questions about memory loss and other neurological effects because PCSK9 is abundant not only in the liver but also in the brain.(What it does there, no one can say for sure.)
Questions, yes, because of the biological mystery, but not red flags. A metastudy of PCSK9 inhibitors published this April in the Annals of Internal Medicine declared them safe and effective.
While cautiously optimistic about the results so far, two top cardiologists—both helped write the latest U.S. guidelines for clinical practice in heart disease prevention—cautioned this year in the New England Journal of Medicine that previous tests of cholesterol-lowering treatments have faltered or stalled at advanced stages. Perhaps most notorious (not to mention expensive) was Pfizer’s torcetrapib in 2006, when Phase 3 data showing higher risk of death was “totally unexpected and disappointing” to the head of the study’s oversight committee.
Safety isn’t the only sticking point. Statins are convenient little pills, but more than half of patients stop taking them within the first year.
What’s going to happen with evolocumab and alirocumab, which must be injected once or twice a month for a lifetime? For people at high risk of heart disease who haven’t seen benefit from statins—or who experience bad side effects from statins—the inconvenience will probably be tolerable. But for others?
Finally, there’s the matter of price. As noted, the pharmacy benefit managers have already fired warning shots across the bow: $10,000-a-year drugs that must be taken for a lifetime will have to prove their mettle to reach larger populations. That burden of proof wasn’t in place when Gilead’s Sovaldi launched, and only later did payers manage to restrict access more tightly. “Sovaldi was widely prescribed, more than expected, and budgets were busted,” says Roger Longman, who runs the pharmaceutical reimbursement consultancy Real Endpoints.
Longman also points out that the biggest drug buyer of all has yet to weigh in: The U.S. Medicare system. Once the FDA rules, Medicare and the state plans, known as the Centers for Medicare & Medicaid Services, will follow. They could cover exactly the patient groups the FDA approves the drugs for, or they could choose a small subset. They could also play the exclusivity game like Express Scripts and CVS have done in hepatitis C. “One of the wild cards [for the PCSK9 markets] is the willingness of plans to exclude competitors in the same category,” Longman says.
More offerings—and more chance for price wars—could be on their way. Pfizer’s bococizumab is in Phase 3, with data due perhaps next year. Anti-PCSK9 pills are on a farther horizon, and an RNA interference drug, which stops production of PCSK9, entered Phase 1 late last year.
Meanwhile, Roger Newton, the man who created the best-selling statin Lipitor, is working on a pill that lowers LDL without the statin-related side effects. Newton’s Esperion Therapeutics (NASDAQ: [[ticker:ESPR]]) said last month it hopes the pill can start Phase 3 trials before the end of 2015.
Barring a big upset either this week in committee or when the FDA gives a full review, high-risk patients such as those with inherited high cholesterol should soon have at least two drugs available for their ailment. Beyond that, however, we’ll have to wait a few years to see if the breathless forecasts for those drugs can beat the odds and actually hit their marks.
