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Tale Of Two Heart Drugs Show Challenges And Rewards In R&D

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This article is more than 9 years old.

As I have been around for a while, I am often asked what has changed in R&D over the last 35 odd years. For me, I think the biggest changes – and challenges – have occurred on the Development side of the R&D equation. Yes, the Research (aka, Discovery) part is pretty hard. But the tremendous progress made in technologies and genomics have made the R&D world that I started in back in the 1970s look terribly antiquated. However, the Development side is what I find daunting; specifically, the need to demonstrate the value of your new medicine before seeking regulatory and marketing approval. This was borne out in two studies that emerged from the recent American College of Cardiology meeting.

The first case involves a new heart failure (HF) drug, LCZ696, from Novartis . This compound is a novel, first-in-class angiotensin receptor neprilysin inhibitor (ARNI) which was hypothesized to help HF patients by acting on multiple neurohormonal pathways in such a way to reduce the strain on the patient’s heart. To prove this theory, Novartis ran a major trial known as PARADIGM-HF, in which LCZ696 was tested against the well-established standard of care, enalapril, an ACE inhibitor. Novartis put its experimental medicine to a major test. It was betting that LCZ696 would not be just as good as standard treatment, but it would be better. Why? Because no one in medicine today would either prescribe a drug or reimburse its costs just because LCZ696 was “novel” or “first-in-class”. After all, enalapril is generic (i.e. cheap) and has been used by millions of patients for years. LCZ696 has to be superior to be a success.

Well, the Data Safety Monitoring Board (DSMB), responsible for following the patients in this study recently stopped this trial before it was due to end. The reason was that the drug significantly reduced cardiovascular mortality in HF patients in comparison to the gold standard. My fellow Forbes contributor, Larry Husten, put this result into context.

“The first thing to know is that a reduction in cardiovascular mortality is a really big deal. In heart failure….there have only been a few therapies to show this benefit…..And the presence of these established therapies makes it even harder to find new drugs with added benefit. As best I can recall, there’s never been a case in which another drug has been shown to be dramatically superior to one of these bedrocks of therapy.”

What Larry didn’t say was that this study was very risky and very expensive to carry out. In the past, Novartis – or any other company for that matter - would have taken a safer development path and compared its ARNI to placebo, and then apply for approval based on this result (assuming that it is safe and effective) . It would then be up to doctors to try this medicine in patients and determine if patients fared better on it than on other treatments. Such a plan isn’t acceptable any more. You really have to demonstrate that your novel, first-in-class drug is adding value by being superior to current therapy in order to gain acceptance. Novartis has done that with LCZ696 and, if the data hold up, it will have a wonderful new drug that will change medical practice – and be very profitable as well.

Unfortunately, at this same meeting, a sad story for heart patients unfolded. GSK announced results from a major study with its drug, darapladib, in patients with chronic coronary heart disease (CHD). Darapladib is a novel inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), which is implicated in the development and progression of atherosclerosis. GSK carried out a pivotal Phase 3 trial, called STABILITY, an outcomes study like PARADIGM-HF, in which almost 16,000 CHD patients were given either darapladib or placebo, on top of their usual heart medications (statins, blood pressure drugs, etc.). GSK believed that darapladib, by virtue of its novel action, would prevent atherosclerotic plaques from rupturing thus providing a significant reduction of heart attacks and strokes in these patients. The primary endpoint of the study was the time to occurrence of a major adverse cardiac event for the CHD patients. Unfortunately, after running this study for 3,7 years, no difference in cardiovascular events was seen in the darapladib treated groups. Despite some great science and its best intentions, as well as the investments of hundreds of millions of dollars, GSK’s efforts came up short.

Patient, physicians and payers are all demanding that new medicines deliver value over older or current therapies. Drug companies are setting out to do just that. However, running the types of studies that Novartis and GSK did are not trivial, are costly, take years to run and analyze, and there is no guarantee that they will be successful. You can’t simply measure biomarkers such as changes in blood pressure or lipid modulation to get a drug approved. You have to study the drug in a real world setting and show long-term benefits. This is probably the biggest change I’ve seen over the years and why the development of new drugs is far more difficult now than ever before. That’s not a bad thing. When your drugs works, as happened with Novartis, you create a major medical breakthrough and everyone benefits. But, there are going to be far more failures than successes. Drug R&D is pretty tough.