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Take a Grain of Salt (Or Two) With New Cholesterol Drug Predictions

Xconomy National — 

My mother always warned me never to start a column with a reference to management consultants. Sorry, Mom. Cover your eyes. But anyone else with personal health or personal finance interest in the latest cholesterol-fighting drugs, read on.

Two years ago, three McKinseyites published a study about forecasts for drug sales. The upshot: To predict future blockbusters, you might as well start throwing darts.

Ladies and gentlemen, get your darts ready. Today and tomorrow a panel of experts who advise the FDA will convene in a hotel ballroom outside Washington, DC, to jawbone about two anti-cholesterol drugs, and they are largely expected to recommend FDA approval, which would come in July and August.

The drugs, evolocumab (Repatha) from Amgen (NASDAQ: AMGN) and alirocumab (Praluent) from Regeneron Pharmaceuticals (NASDAQ: REGN) and Sanofi (NYSE: SNY), could also reach blockbuster status—$1 billion in annual sales—in fast fashion. That’s a lot of cart-before-horsing, but the two drugs’ safety and efficacy record in clinical trials does seem to make approval a good bet.

The big sales, though? For context, here from pharma data provider IMS Health (NYSE: IMS) are the top drug launches since 2010, based on their first 12 months of U.S. sales.

TOP DRUG LAUNCHES, 2010-PRESENT
(source: IMS Health)

Brand Name Disease Company Date of
Launch
First-Year
Revenue ($)
Sovaldi HCV Gilead Sciences 12/2013 7.6 B
Harvoni HCV Gilead Sciences 10/2014 5.4 B
Olysio HCV Johnson & Johnson 12/2013 1.9 B
Tecfidera MS Biogen 4/2013 1.6 B
Incivek HCV Vertex Pharmaceuticals 5/2011 1.4 B

Just to show how quickly fate can change, telaprevir (Incivek) was off the market in three years, and simprevir (Olysio), after a booming 2014, was singled out last month by owner J&J as having “negative impact” on the company’s worldwide growth in the first quarter of 2015. Both those beatings came at the hands of the top two drugs on the launch chart, Gilead’s sofosbuvir (Sovaldi) and combination offering Harvoni, which promised cures and were priced accordingly; the hepatitis C world has been an extreme theme-park ride for all involved.

A mercurial market could await the drugs in discussion this week, too. They are the first two entrants from the next generation of cholesterol-lowering treatments that work by blocking a protein discovered 12 years ago called PCSK9. (It stands for proprotein convertase subtilisin/kexin Type 9; you’ll be quizzed on this tomorrow.)

Statins such as atorvastatin (Lipitor) have been the most lucrative drugs of all time, and there are a lot of people out there who aren’t helped by them (more on this in a minute). So why wouldn’t these two new drugs bust out of the gate? Let’s ask the McKinsey consultants, who pored over drug forecasts and launches from 2002 to 2011: “Most consensus forecasts were wrong, often substantially… and accuracy remained an issue even several years post-launch.”

“Furthermore,” they wrote, “a significant number of consensus forecasts were overly optimistic by more than 160 percent of the actual peak revenues of the product.”

Analysts at Leerink Partners late last year said the market for PCSK9-inhibitors for cardiovascular disease could reach nearly $11 billion at its peak, with alirocumab and evolocumab, the two drugs in this week’s spotlight, each nabbing 40 percent.

The stakes are high enough that Regeneron and Sanofi paid $67.5 million in 2014 for a voucher that let them speed up the FDA review of alirocumab by a few months, a sign that the partners believed those few months—and a slight head start against Amgen—could return to their bottom line more than the outlay. (With the voucher, which is part of an FDA program to encourage drug development for tropical and rare pediatric diseases, Regeneron and Sanofi jumped the alirocumab review ahead of evolocumab by one month.)

Even more bullish than the analysts and companies themselves, but for different reasons, are the drug-purchasing middlemen who have made it their mission to force down prescription drug prices. Test case number one was in hepatitis C, where the middlemen—Express Scripts (NYSE: ESRX) and CVS Health (NYSE: CVS) are the two largest—played Gilead (NASDAQ: GILD) and AbbVie (NYSE: ABBV) off each other for lower prices and have boasted of their success.

Now the purchasers, officially known as pharmacy benefit managers, are sounding the alarm over the cost of PCSK9 drugs. In a much-discussed February blog post in Health Affairs, CVS officials said the class of drugs—which in a few years could also include a candidate from Pfizer that’s currently in Phase 3 trials—“will likely be the highest selling class of medications in history.”

EvaluatePharma predicted last September, however, that it would take four full years for alirocumab and evolocumab to reach the $1 billion sales mark.

That wouldn’t be shabby, but it wouldn’t match the hype built up around these two products.

What’s going on? Statins are now generic and cheap, and it seems most of the older people you know are gobbling them like candy. Why do we need more expensive alternatives?

Some background first: Late last year, the U.S. Centers for Disease Control and Prevention reported that in 2011-2012, nearly 28 percent of Americans age 40 and over used a cholesterol-lowering drug. In the same period, 13 percent of Americans 20 and over were found to have high cholesterol.

Yet heart disease is the cause of 1 in 4 American deaths.

It’s not clear PCSK9 inhibitors will make a big dent. Assuming evolocumab and alirocumab are approved, they’ll first be used for the 620,000 Americans with an inherited version of extremely high cholesterol called familial hypercholesterolemia that statins can’t help with. About one million more Americans who don’t have that particular genetic factor still have extreme cholesterol levels that statins can’t reduce enough. Beyond these patient groups, a certain slice of people with high cholesterol—estimates range from 5 to 20 percent—can’t take statins because of side effects that range from muscle pain and damage to liver problems.

These few million people are the obvious future recipients of the new drugs. (Although insurance companies and their purchasers will be vigilant in making sure statin-intolerant people are in fact statin-intolerant: “Pharmacy benefit managers will attempt to limit that number, based on clinical guidelines and expert opinion,” wrote the CVS/Caremark officials in February. “They will likely require laboratory tests to show evidence of muscle inflammation or liver damage before allowing treatment for those with statin intolerance.”)

Beyond those special populations, however, it’s unclear how deeply into a more general population the drugs will penetrate. “The broader question is, ‘Should we be routinely adding PCSK9 inhibitors to statin therapy in everybody to reduce risk?'” said University of Iowa cardiologist Jennifer Robinson, who is leading the study of alirocumab, during an interview at a cardiology conference last month. “I think we’re going to have to wait for the cardiovascular outcome trials.”

And those trials, which both Sanofi/Regeneron and Amgen are running, won’t divulge their data until late 2017 or early 2018.

Let’s dig into the biology a little. Remember all that talk about good cholesterol and bad cholesterol? The bad stuff is LDL, the low-density lipoproteins. When they hang around in the bloodstream, they clog arteries. Our bodies have trouble breaking down LDL, which is a big reason 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: 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.

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  • Jerry Jeff

    Thanks, Alex. Great article.