A recent FDA advisory panel recommended the approval of 2 new agents in a novel class of cholesterol lowering drugs known as PCSK-9 inhibitors. What makes this remarkable is that these drugs illustrate all the promise and pitfalls of modern pharmaceutical development.
First, a little science. The target of the new drugs – a protein named proprotein convertase subtilisin/kexin type 9 (PCSK-9) – was discovered in 2001. Two years later, investigators reported that “gain-of-function” mutations in the gene that codes for PCSK-9 were associated with familial hypercholesterolemia and high rates of atherosclerotic vascular disease. Mutations of the gene that led to reductions in the function of PCSK-9 were associated with low LDL-cholesterol levels, and a lower incidence of vascular disease. That made the compelling case that PCSK-9 had a counter-regulatory function in LDL-cholesterol metabolism, so that interfering with its function would lead to lower cholesterol levels.
The pharmaceutical industry used this insight to design drugs based on monoclonal antibodies that specifically target PCSK-9. Early clinical trials found the agents to be safe and effective at lowering LDL-cholesterol levels, even in individuals who had persistently elevated levels on high dose statins. It was on the basis of these trials that the advisory panel recommended approval. Larger clinical trials are now underway to determine the impact of the drugs on clinical endpoints such as heart attack and death.
So what’s not to like? On the face of it, this is the story of a remarkable achievement of rapidly turning a “bench” discovery into a “bedside” tool by utilizing modern molecular genetics.
Here’s the rub. We are about to have a new “genie” released from the bottle. Because these agents are “biologics,” they must be administered by injection, and (like other biologics) they are likely to be very expensive. Among the as-yet unanswered questions are:
- How do these agents “fit in” with statin treatment? Should they be reserved for patients who “fail” statin treatment, and if so, what exactly constitutes a statin failure? Does it get added to statins or replace it?
- Should they be used only for patients with familial hypercholesterolemia? What about other high risk populations?
- How much money are these drugs worth? The recent controversies over the pricing of anti-cancer drugs is soon to play out in the cardiovascular field
All this boils down to the fact that we have a potentially wonderful new tool, but have no idea how best to use it or how much we should be willing to pay for it, or even if it improves clinical outcomes. This seems to me to be the problematic paradigm of new medical technology, and a significant driver of our ever-higher health care costs.
What do you think?