With high costs and razor-thin success margins, pharmaceutical companies have been slow to bring drugs to treat cardiovascular diseases to market, putting the industry at a crossroads that has experts concerned.
The number of drugs approved for cardiovascular purposes in the U.S. has been flagging for years. Cardiovascular treatments approved since 2012 made up only 6% of all new drugs during that time frame, down from 13% in the mid-1990s, according to a 2017 study from the American College of Cardiology. The slump is occurring even though cardiovascular disease is listed by the World Health Organization as the number one cause of death globally.
Cursed by success
Pharmaceutical companies are shying away from innovating the kinds of drugs that once dominated the space due to cost, difficulty, trial enrollment requirements and the efficacy of existing drugs on the market.
"We've made a lot of progress in a lot of the major areas such that the amount of additional benefit that might be achieved with a new agent is going to be challenging to prove," said Kim Eagle, director of the Frankel Cardiovascular Center at the University of Michigan. "So in areas where we've got good therapies that are tolerated, it's hard to imagine a large market that one would have to go after."
For decades, statins have been the standard of care to lower cholesterol and prevent plaque buildup in the arteries. Pfizer Inc.'s blockbuster Lipitor is the best-selling drug of all time, but other successful statins include Merck & Co. Inc.'s Zocor and AstraZeneca PLC's Crestor. The arrival of generics has toppled the profits of these drugs in recent years but has also brought down their cost.
Developing a new drug to stand up to statins has become almost impractical, according to experts. Requirements for cardiovascular trials are extremely rigorous, and the chance of success over current treatments is slim. Pfizer proved this in 2006 when a Phase 3 trial for its cholesteryl ester transfer protein, or CETP, inhibitor cholesterol drug torcetrapib was halted for insubstantial efficacy over statins. Other failures include Eli Lilly and Co.'s evacetrapib and Roche Holding AG's dalcetrapib.
CETP inhibitors are drugs designed to raise levels of high-density lipoprotein cholesterol, known as "good" cholesterol. It was thought that raising these levels while lowering levels of low-density lipoprotein, or "bad," cholesterol would reduce cardiovascular risks.
Merck was the only company to find relative success with CETP inhibitors when in 2017 its drug anacetrapib demonstrated a reduction in heart attacks — but the drugmaker did not push toward regulatory approval, reflecting the same tepidity seen across the industry.
A new (pricey) player
PCSK9 inhibitors, a new class of genetic cholesterol fighters, on the other hand, have been shown in trials to greatly outstrip statins in their effectiveness against high cholesterol. PCSK9s entered the market in 2015 with Sanofi and Regeneron Pharmaceuticals Inc.'s Praluent and Amgen's Repatha.
The problem with PCSK9s, however, is the drugs' price tags. The personalized treatments each fetch about $14,000 a year per patient, putting them in a pricing space well outside the Institute for Clinical and Economic Review's recommendations. Although PCSK9s are more powerful and have fewer side effects, the cost leaves statins on top of the cholesterol market.
"PCSK9s clearly work, but the current formulations are expensive to make, and the companies need to recover the costs of development," said cardiologist Douglas Mann, editor-in-chief of the Journal of the American College of Cardiology: Basic to Translational Science. "We have these new therapies, and they make a clear difference, but then who pays for them? And how do we come up with a reasonable way of funding these expensive new therapies that clearly save lives? It's a difficult conundrum."
The high cost of developing these drugs is driving pharma companies away from the traditional cardiovascular space. Companies are instead opting for clinical trials in cancer, for instance, despite the smaller market, because of lower costs and regulatory incentives not available in cardiology. A Phase 3 trial for a cardiovascular drug can cost up to $47,000 per patient, according to a study from the American Heart Association — which can add up to half a billion dollars as cardiovascular trials often enroll anywhere from 5,000 to 15,000 patients.
Pharmaceutical companies are not completely giving up on cardiovascular drugs but are instead looking at simpler ways to move the products through regulatory agencies.
SGLT2 inhibitors are one of the newest developments in the cardiovascular space, but these drugs approach the medical issue from a different drug class altogether: diabetes management. The U.S. Food and Drug Administration approved Boehringer Ingelheim Corp. and Eli Lilly's diabetes drug Jardiance for a second indication at the end of 2016 for its cardiovascular benefits. The drug had already been on the market to treat diabetes for two years, but in later studies it showed efficacy in combating cardiovascular disease.
These new drugs come at a price of $4,800 a year and target a smaller, high-risk market.
"[SGLT2 inhibitors] are new therapies that are not going to be inexpensive, but they clearly prolong life," Mann said. "They have striking benefits for heart failure, and diabetes is a space that for many years had really no impact on cardiovascular outcomes, but they changed that."
Anti-inflammatory drugs are another promising development featured in a landmark 2017 study called CANTOS from Novartis AG. In Phase 3, the study showed that canakinumab reduced the risk of a cardiovascular event. But experts agree that anti-inflammatory drugs will be similarly cost-prohibitive when compared with statins.
"Some of the human antibodies used for inflammatory disorders may find a role in cardiovascular disease, but they're very expensive again," Eagle said. "Whether they'll find the light of day in the market is hard to tell."
Optimistic for an upward trajectory
Mann suggested that innovation in cardiovascular treatment is at a remarkable time, but patients have yet to see the benefit because of the existing pricing system.
"I think it's a challenge for all of us in healthcare to figure out how to rein in healthcare costs, but particularly developing new drugs in the cardiovascular space, we're going to have to be more innovative in our approach to the way we do it," Mann said. "My hope is that we'll continue to have blockbuster drugs like PCSK9 or SGLT2 that are really favorable and impacting lives. I just think it will be slower than it was in the past because of the overall cost."
Efforts put forth now will ultimately make for important strides in cardiovascular disease treatment and prevention, Eagle said — and the market should catch up.
"As we get more narrow in our lanes in terms of defining patients better, it'll be a little more hit or miss developing and funding new agents that may have a pretty big effect in a fairly small group of patients," Eagle said.