[ed. note: Michael Jorrin, who I call “Doc Gumshoe,” writes for us a couple times a month on health and medical issues — he is a longtime medical writer (not a doctor), he chooses his own topics, and his past articles can be found here.]
Flub Number One is the puncture of the “female Viagra” hot-air balloon, to which I say, “So be it!”
Flub Number Two is the failure of Eli Lilly’s evacetrapib, one of a new class of drugs to treat hyperlipidemia, on which high hopes were riding. To that unfortunate outcome I say, “Too bad, but what can we learn from it?”
And the Big Question Mark has to do with CRISPR gene editing, a topic that has many scientific brains quivering with excitement. My question, which I will explore in this piece, is “What will that actually mean for health care?”
So, on to the first flub. On August 18th, 2015, the FDA disregarded my careful and intelligent advice, which I had set forth in my Doc Gumshoe blog on July 2nd, and approved flibanserin, the so-called “female Viagra,” which was trade-named Addyi. My reasons for opposing the approval were, as I said then …
“I think FDA approval of this drug would do more harm than good, and I hope the FDA resists the pressure that is being placed on it and rejects the application.
The drug is flibanserin, which was initially developed by Boeringer Ingelheim, who dropped it after the FDA rejected it twice – first in 2010 and then again in 2013. A very small company, Sprout Pharmaceuticals, then acquired the rights to flibanserin. Since then, Sprout has mounted a campaign to persuade the FDA that flibanserin should be approved based more on the “fairness” issue than on efficacy and safety.
The “fairness” issue can be stated simply, although somewhat moronically in my view: There are a couple of dozen drugs approved by the FDA that improve sexual performance in men, but there are no FDA drugs that do the same for women. That constitutes gender discrimination. Therefore flibanserin must get FDA approval, regardless of its efficacy and safety data.
Sprout has organized and backed a pressure group called “Even the Score” whose mission has been to mount a campaign whose theme is that the lack of a drug that improves women’s sexual desire is a glaring example of the FDA’s gender bias. And, of course, the phrase “Viagra for women” is the slogan that sums it up.”
Well, the FDA went ahead and approved it anyway. But their approval was more than a bit tentative. Here’s part of the warning label in the patient PI:
The FDA was perhaps making a show of giving in to Sprout’s propaganda campaign, but the patient PI looks to me like the “bacio di morte,” although the immediate outcome for Sprout was far from fatal. A day after the FDA’s approval of Addyi, Sprout Pharmaceuticals was purchased by none other than Valeant Pharmaceuticals International (VRX) for One Billion U. S. Dollars. Sprout took the loot to the bank, and thereafter grief was visited upon Valeant.
Valeant’s first step was to double Sprout’s proposed $400 per month charge for the magic pills to $800 per month, as per their usual practice. Since then, Valeant’s stock has fallen about 85%, President J. Michael Pearson is out, and his couple of billions in stock is worth bubkas. Only 4000 prescriptions for Addyi were filled in the six months after FDA approval. It’s not hard to figure out why. The benefits in terms of improvement in sexual satisfaction are very small, the limitations on life-style are considerable, and the risks are truly serious. Valeant should have paid attention to the data, but that’s not their strong suit.
The diminished promise of CETP inhibitors
It’s no doubt quite unfair to refer to the failure of the evacetrapib clinical trial as a “flub.” Evacetrapib was one of Eli Lilly’s (LLY) top prospects, and with good reason. It further lowered LDL-cholesterol (LDL-C) in persons who had already attained good LDL-C levels with statin treatment, and, in addition, it more than doubled HDL-cholesterol (HL-C) levels, which statin treatment only affects minimally. The failure of that trial was a surprise and disappointment to the cardiovascular community. Dr Peter Libby, who is about as famous as cardiologists get, was quoted in the Times as saying “All of us would have put money on it. It was the great hope.”
The evidence that lowering LDL-C leads to a reduction in cardiovascular events is about as good as this type of evidence gets: a reduction of about 40 mg/dL in LDL-C reliably lowers the risk of an acute coronary event by about 20%. Depending on baseline levels, high-dose statin treatment can lower LDL-C levels by 50% or more, with concomitant reductions in cardiac risk. However, with statin treatment, LDL-C levels seldom go much below about 70 mg/dL, and cardiac risk does not disappear.
Many clinicians have sought to further reduce cardiovascular risk by adopting strategies to increase the levels of HDL-C through some other means, such as fibrates and nicotinic acid, both of which are severely limited by adverse effects. The association of a beneficial role of high-density lipoprotein (HDL) with reduced incidence of cardiovascular disease (CVD) is almost as strong as that for LDL-C and CVD, although more recent. The standard explanation for this relationship is that the HDL particles are the key players in reverse cholesterol transport, meaning that they gather up cholesterol in the circulation from low-density-lipoprotein (LDL) particles, and transport them back to the liver for elimination.
At the risk of going over old ground, I want to be clear about the terminology used to describe cholesterol and cholesterol transport. Low-density lipoprotein (LDL) is not the same as the cholesterol transported by low-density lipoprotein, which I scrupulously designate as LDL-C. Same thing with high-density lipoprotein (HDL) and high-density lipoprotein cholesterol (HDL-C).
Recent findings about cholesterol metabolism and transport muddy the waters considerably. Although the observation certainly holds true that higher levels of HDL-C relative to LDL-C are linked with better cardiac health, the mechanisms that affect the formation of HDL-C are highly complex, and it is not clear that introducing agents that affect these mechanisms will have a predictable outcome.
The two players in overall cholesterol metabolism that are central to the potential effectiveness of CETP inhibitors are cholesteryl ester and cholesteryl ester transfer protein (CETP). Cholesteryl ester is a molecule consisting of cholest