The genomics and proteomics revolution has produced thousands of new targets for drug discovery. Designing molecules with novel mechanisms is sexy and can be very rewarding but is risky and time consuming, though some would say this novelty and pursuit of innovation is the embodiment of the biotech industry. But the pursuit of innovation requires a large investment in research to define a target’s role in human biology, to validate its relevance in human disease. Even after this early validation, there is no guarantee that modulation of this target will result in an effective treatment in humans.
There is another path. Through years of research, many drug targets have already been validated. Academic and industry researchers alike have published peer-reviewed papers on many of the most interesting targets. A review of the scientific literature can provide an enormous amount of information on important targets. For even more highly validated targets, companies can look to the competition. Has the molecule entered clinical studies, if so, what stage? The farther along a molecule has progressed, the more the target has been de-risked. No longer does a company talk about “first in class,” the goal is to be “best in class”.
A first in class drug provides the manufacturer with a period of market exclusivity free of competition from similar drugs. Companies that pursue the development of a more validated target with a “follow-on” drug will face competition immediately upon approval even as the development risk has been reduced. To compete, they must differentiate their products. The benefits of being first to market, however, may be offset by the risk of developing drugs with novel mechanisms of action and unproven targets.
According to Tufts Center for the Study of Drug Development (CSDD), the average time to market entry of follow-on drugs has decreased to 1.3 years in the 1990s from 5.1 years in the 1960s. This is a very short time for a drug to be on the market before competition arrives. Although competition does not necessarily lead to price reduction, it can have a deliterious effect on market share. Moreover, an analysis by McKinsey & Company showed that “fast-followers”, those who arrive on the market between 2-5 years after the first drug, actually fared better than the innovators, with significantly higher median sales. Surprisingly, follow-on drugs coming to market even 15 years after the innovators were just as successful as the first drugs.
The fact is first-in-class drugs may not ultimately be the best-in-class drugs on the market. With the incredible pace of scientific research, each passing day leads to an increase in the understanding of a drug target- knowledge that may benefit the follow-on drug makers. While the innovator drug is in development, makers of follow-on drugs have the ability to survey the competitive landscape and decide on a project based on its scientific and financial merits. They can also glean information from drugs in development ahead of them, giving them the chance to improve on the first-in-class drug even before it hits the market.
Innovator drugs also end up paving the way for the follow-on drugs. They may face increased scrutiny from the FDA with their novel mechanism of action. Provenge is a good example: as a cancer vaccine, it was certainly in a class of its own. Dendreon (NASDAQ:DNDN), the drug’s maker, needed to assuage the FDA’s concerns on issues such as how the drug prolonged survival without shrinking tumors. But with its approval, future cancer vaccine makers will know what to expect when presenting their data to the FDA, and the FDA will be experienced in the handling of cancer vaccines.
Even after navigating regulatory hurdles, makers of innovator drugs must educate patients, physicians, and payers on the merits of their drugs, in essence, creating a new market that follow-on drugs can exploit. Before Viagra came along, the world had never heard of erectile dysfuntion drugs. Heavy advertising and other promotions by Pfizer (NYSE:PFE) made Viagra a household name. Even so, the follow-on drug, Cialis, from Lilly (NYSE:LLY), eventually overtook Viagra in market share due to its improved convenience. In another example, Lovastatin heralded the market for the class of cholesterol lowering drugs known as statins in 1987 while Lipitor was not approved until 1997, but today, Lipitor is the world’s best selling drug.
What is the most exciting class of drugs in development today? Some would say Phosphoinositide 3-Kinase(PI3K) inhibitors. This is not a new target; the first paper on PI3K was published in 1990 and an inhibitor was identified in 1993. Such targeted therapies have made it easier for companies to make follow-on compounds quickly. Once a target has been validated, future competitors know exactly what to pursue. This is especially true with today’s popular kinase inhibitors, where compounds usually act on the target’s ATP binding site.
In December 2006, the first PI3K inhibitor, BEZ235, from Novartis (NYSE:NVS) entered the clinic; since then, at least ten more have joined it. Though none of these have yet to pass Phase II development, new generations of inhibitors are already close behind. That is the speed of follow-on drug development today.
The data show that it is financially more advantageous to pursue a follow-on drug than attempt to pave the way with an innovator drug and novel mechanism of action. This does not mean the end of innovative medicine, for there can be no follow-on drug without the initial pioneering drug to follow. What it shows is the follow-on drug strategy is a very good one and is well suited for managing the risks of drug development. It is also of benefit to patients, as drug makers attempt to improve on their predecessors with each new compound they put into the clinic, aiming for the best-in-class drug.
Disclosure: Long NVS