Biologics Legislation Will Speed Progress

Scott Gotlieb, deputy commissioner for medical and scientific affairs at the Food and Drug Administration
Resident Fellow Scott Gotlieb, M.D.
In the mid-1990s, a big trial compared two protein drugs being used to re-open the blocked arteries of heart attack victims. The trial showed that the newer of the two drugs was saving the life of one extra patient for every hundred patients treated. Yet the government was flummoxed when physicians immediately started using the better drug--despite the fact that it cost 10 times as much as the other drug. Some payers questioned whether the superior drug--tPA--was really worth the extra cost.

It begged the most uncomfortable question of all: Which 1% of their heart attack patients should doctors have sacrificed in the name of cost containment?

The competition between the older drug, streptokinase, and its newer rival, tPA, for the minds of doctors and the hearts of their patients should be a cautionary tale for politicians who expect big savings to come from a pathway for developing copy-cat or "generic" versions of today's protein-based or "biological" drugs. While a legislative path for the abbreviated approval of biologics may open the door to faster copies of the current crop of protein drugs, the most enduring effect of the legislation may be to accelerate the development of much-improved second- and third-generation versions of today's medicines.

Reminiscent of the battle between streptokinase and tPA, competition between enhanced versions of existing biologic drugs is just getting underway. Sheltered from competition from follow-on drugs, incremental innovation in the form and function of existing biologics, or "large molecules" as they have come to be called in the industry lexicon, has been slower to develop than competition between tweaked versions of "small molecule" or "pill-form" drugs.

In the biologics world--especially with the simpler proteins--the focus of intellectual property creation was often on the target, not the molecule. But with IP on the targets set to expire, the focus is going to increasingly shift to finding better molecules. And there is good reason tobelieve the pace of incremental innovation in the biologics space--and the therapeutic importance of even seemingly small changes made to existing protein drugs--could dwarf the kinds of benefits seen from tweaks made to small molecules.

For one thing, the changes you can make to proteins, turning small improvements into significant therapeutic advances, pales in comparison to what you can do to small molecule drugs. Even small alterations in the purity, potency and half-life or "durability" of a protein product can have significant impacts on their effectiveness. Given the success of drugs like Aranesp (a long-acting version of the red-blood-cell-stimulating protein epogen), no one in the industry is likely to dismiss the value of second-generation protein products. Amgen developed Aranesp by changing the amino acid backbone of the first-generation epogen molecule and adding sialic acid to it--enabling less frequent dosing.

The burgeoning market for improved and longer-acting versions of insulin products, like those made by Novo Nordisk and Eli Lilly, is also proof of the value of follow-on innovation in the protein space. Proponents of "generic" biologics argue that today's absence of lower-cost, "generic" versions of ordinary insulin is due to the lack of legislation for enabling the quick approval of such copies and the Food and Drug Administration's lack of guidance to generic drug makers on how to abbreviate the process for developing these proteins.

Truth is, there is little interest in making follow-on copies of basic, short-acting insulin (the patent on insulin has long expired) because all of the growth in the insulin category is with the tweaked versions of the protein, which cannot be copied. If generic drug makers wanted to knock off copies of ordinary insulin, the process for seeking approval of regular insulin is about as easy and clear as it gets due to good surrogates of safety and effectiveness.

The future of protein products rest not with the copies of today's drugs, but with altogether better versions of these products. The companies best positioned to take advantage of this innovation may be those that combine small-molecule expertise with protein know-how, and those that can work across traditionally separated functions to design better protein molecules.

The orientation in development of protein drugs in the future will not just be around the target, but the large molecule. The therapeutic fields and diseases that will be open to these drugs will also continue to expand. While today's protein drugs are focused largely at treating cancer and inflammation, new therapeutic fields will be increasingly amenable to protein products, including gastroenterology, metabolic diseases and especially the neurosciences.

In general, large molecules--while inconvenient to patients because of their injectable dosing--are nonetheless often more specific for their targets than small-molecule drugs and do not undergo complicated metabolism in the body. Thus, the proteins can often have fewer side effects than pills aimed at the same target, and sometimes, higher potency.

Some copies of old protein products will continue to have a place in the therapeutic armamentarium, but more likely, new and better versions of these original proteins will begin to take their place. The march of medical progress has been paved by incremental improvements to existing drugs that led to steady gains against disease. The continued evolution of protein drugs is not likely to be any different.

Genentech's Genentech drug tPA decimated the market for streptokinase because if offered a clear advantage in a lethal disease. The two were arguably different proteins but with a common therapeutic purpose. The fact that many protein drugs target serious problems makes it all the more likely that even small advantages will rapidly shift prescribing.

Legislation to expose today's biologics to easier competition, after legitimate patents have expired, is going to accelerate development of improved products, not just lower-cost, copycat versions of outdated proteins. Those making static assumptions against today's standards of care about how much savings this legislation is likely to bring are losing sight of the competition and progress they will have unleashed.

Scott Gottlieb, M.D., is a resident fellow at AEI.

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