With all of the talk this week about new cholesterol drugs, it might be refreshing to slow down – practice slow medicine, slow journalism, slow breathing – and to do so to the words of Dr. Richard Lehman from his weekly journal review blog for The BMJ. This week he writes:
“While we are on the subject of surrogate end-points, let’s look at the latest paper to appear on the NEJM website, which is the second trial to reveal a small beneficial effect of ezetimibe when added to a simvastatin 40mg, this time in patients following an acute coronary event. After seven years, the benefit is tiny but just within the limits of statistical significance, with a hazard ratio of 0.94, 95% CI 0.89-0.99. Clinically this has no meaning at all since the same degree of LDL-C lowering could have been achieved by using 40mg of atorvastatin instead of simvastatin. But the NEJM greets it with a triumphalist commentary by two staff editors entitled “Proof That Lower Is Better—LDL Cholesterol and IMPROVE-IT“, ending with “Perhaps the LDL hypothesis should now be considered the ‘LDL principle.’” Well, IMPROVE-IT is a pretty shaky pedestal on which to mount a principle. The rush to proclaim it derives, I suggest, from the pharmaceutical industry’s desperation to repeat the success of statins with new blockbuster drugs based on the surrogate measure of LDL-C lowering. And it’s interesting that the NEJM goes out of its way to support this, while it prints a series of pieces denying the pervasiveness of industry influence.”
Regarding that same ezetimibe IMPROVE-IT trial, see the blog post this week by Stephen A. Martin, MD and Lisa Plymate, MD on the National Physicians Alliance website, “Separating Signal and Noise: How IMPROVE-IT’s Modest Results Became a “Home Run”.” Excerpts:
“Some observers found these results modest, small, and “very clinically marginal.” Though the study “technically” met a primary end point, that “just make[s] us want to look more closely” at the actual data. In essence, the signal is underwhelming.
Because that’s the noise. ….
Why all this noise over such a marginal result? Why the call for new guidelines—based only on this single non-peer reviewed pharma-funded trial? Because industry and its academic advocates need to claw back the guidelines to “lower is better.”
The inside baseball: If the guidelines aren’t changed, and if the FDA is more cautious about the limitations of surrogates like LDL, then new PCSK9 inhibitors, which also reduce LDL, may not be quickly approved and promulgated. …
Separating signal from noise is part of our job. In the case of ezetimibe and its future cousins, the signal is currently weak and the noise is strong. We need help from the medical, journalist, and regulatory communities to help us listen as best we can and make sure the public isn’t being sold a noisy tune.”
Now let’s leap to the PCSK9 inhibitor news of the week.
An FDA Advisory Committee recommended approval of alirocumab for hypercholesterolemia. A major study of the drug had been published in the New England Journal of Medicine in April. But in response to that published study, editorial writers in the NEJM wrote: “Lowering LDL Cholesterol Is Good, but How and in Whom?” Excerpt:
“…it would be premature to endorse these drugs for widespread use before the ongoing randomized trials, appropriately powered for primary end-point analysis and safety assessment, are available. Reports from several lipid treatment trials provide important object lessons in this regard. Two trials of niacin revealed lower levels of LDL cholesterol and lipoprotein(a) when niacin was added to statin therapy but no net clinical benefit and very worrisome signals of harm. A randomized, controlled trial of torcetrapib reminds us that “off-target” effects can scuttle a promising drug. And the recent long-awaited presentation of results of a trial in which ezetimibe was added to moderate-intensity statin therapy in high-risk patients showed only modest benefit, though with excellent safety.”
The New York Times reported on the 13-3 vote by the advisory committee to recommend approval of alirocumab. Excerpts:
Those who voted no said drugs should not be approved until clinical trials established their efficacy, and voiced the worry that people participating in the trials would drop out once the drugs were approved so they could be sure to get the medicine, not a placebo.
“We need clinical outcomes,” said Dr. Peter Wilson of Emory University. ….
Dr. Harlan M. Krumholz, a Yale cardiologist, worries that the patient population who take the drugs will expand beyond limited categories. Already, he said, the companies are conducting aggressive education campaigns and slipping brochures under doctors’ doors at medical meetings.
“We need to watch this carefully,” he said. “These drugs should be reserved for people who have no choice.”
But the panelists expressed concerns about whether cutting LDL truly makes patients’ lives better in the long term, warning the FDA that approving alirocumab could lead to widespread use of a treatment that isn’t fully understood. Many backed the antibody’s use in patients genetically predisposed to severely high LDL but hesitated to recommend it for larger populations. Only 7 of the experts were agreeable to approving the drug for patients who can’t tolerate statins, setting up a potential regulatory road block that could come back to haunt the developers, who have a lot riding on the fate of this therapy.
Martha Nason, PhD, a mathematical statistician at the National Institute of Allergy and Infectious Diseases, in Bethesda, Md., voted against approval, saying she wasn’t convinced that the LDL cholesterol was the right surrogate for this new class of drugs. …
Beyond safety and efficacy, one looming concern is the cost of these new biologic agents. The annual cost for PCSK9 inhibitors has been estimated at $7,000 to $12,000, according to a Health Affairs editorial. …”Even in a system that costs $4 trillion per year, a single therapy adding $100-$200 billion in costs annually is extraordinary,” it asserted.
Today, the FDA advisory committee will make a recommendation about a rival drug, evolocumab. FierceBiotech reminds readers that the makers of the two drugs want to “angle for a first-mover advantage that may give them a better position to work deals with payers who cover big patient populations.”
On Forbes.com, Matthew Herper had an industry analyst do the math:
There are 3.9 million Americans who: have a high risk of cardiovascular disease, are on a statin, and still have an LDL (bad cholesterol) of more than 100 milligrams per deciliter. Assuming that 25%-33% of these patients will be prescribe a PCSK9 and 60% of those will stick with it, Evans assumes 1.2 million to 1.6 million prescriptions of the drug annually. Moreover, he assumes that 10% of the 6.8 million Americans who are at high risk, take a statin, and have LDL’s above 70 mg/dL but below 100 mg/dL will be prescribed a PCSK9, and 60% will stick with it.
In total, that leads him to between 6.1 million to 6.5 million prescriptions for PCSK9 drugs. At a $340 per month price, this translates into $2.1 billion in sales. But they could be even higher if it turns out insurers really can’t prevent statin intolerant patients from getting the medicines.
In the vast heart disease empire (market), LDL, Lion King of the surrogates, still rules.
Boilerplate caveat: an FDA advisory committee’s advice is not binding on the FDA. What’s recommended is not always the same as the final FDA action.
Note: If you don’t know much about surrogate markers, you might learn from reading our primer, “Surrogate markers may not tell the whole story,” and its collection of links to other resources on the topic.
Addendum on June 10: An FDA advisory committee voted to recommend evolocumab for approval as a cholesterol-lowing, injectable biologic drug. MedPage Today reflected on the two days of meetings about the two cholesterol drugs:
“In opening remarks, James Smith, MD, MS, deputy director for the FDA’s Division of Metabolism and Endocrinology Products, cautioned, “In the excitement that surrounds the potential availability of a new class of drug, it is incredibly important for us to remember that relying on surrogates [such as LDL] to establish clinical benefits sometimes fails us,” he said. He pointed to torcetrapib as one example of a drug whose danger was narrowly averted by additional clinical data. In pre-approval outcomes trials, the drug was found to increase the risk of cardiovascular events and mortality. He gave a similar warning at Tuesday’s committee meeting for alirocumab.”