This Is No Fish Story

When big fish Johnson & Johnson announced plans to swallow little fish Centocor in July, it was more than just a typical transaction in biotechnology’s food chain. It marked, at least indirectly, the latest chapter in one of biotech’s most intriguing and edifying shaggy-dog stories.

Centocor, based in Malvern, Pa., had always been one of those “coulda, shoulda” players in the biotech world. In the game early, well-capitalized and with good scientific talent, the company always seemed poised to join the first echelon of biotech startups. But it never quite made the ranks of the Amgens and Genentechs.

In August of 1998, Centocor received approval from the Food and Drug Administration (FDA) to market a product called Remicade for the treatment of Crohn’s disease, a debilitating intestinal disorder. The company now seems well-positioned to win approval also to market the drug as a treatment for rheumatoid arthritis. If approved, Remicade would compete against Enbrel, a similar product for treating rheumatoid arthritis that is manufactured by Seattle-based Immunex and which won FDA approval last September.

The testimonials that have rained down on these two drugs, especially in terms of the rheumatoid market, rate right up there on the Hosanna Scale. Analysts and physicians predicted a “potential blockbuster.” One doctor was quoted in The Wall Street Journal as saying: “In my 25 years of doing studies of rheumatoid arthritis medications, I’ve never seen clinical data this good.” Remicade figured as a key factor in Johnson & Johnson’s decision to acquire Centocor.

Yet how many people remember where this success story began? The drugs took the Jerry Garcia route to the marketplace-and what a long, strange trip it’s been. Remicade and Enbrel have their origins in two of the sorriest chapters of the early history of biotechnology: tumor necrosis factor and monoclonal antibodies.

In 1975, in work that later resulted in a Nobel prize, Cesar Milstein and Georges Kohler of Cambridge University demonstrated that the laboratory-induced fusion of an immortal cancer cell with an antibody-spewing B cell could create a hybridoma, a living antibody-producing machine. Because each B cell produces a unique antibody with a specific biological task, the resulting hybridoma cell churns out the same one-of-a-kind, or monoclonal, antibody molecules. Biotech startups like Centocor, which began operations in
1979, were formed to exploit the breakthrough.

Following a much-publicized early success in the treatment of a lymphoma case at Stanford University Medical Center, monoclonals made their debut as the industry’s magic bullet du jour.Optimism so outdistanced discipline that one academic scientist told me at a meeting several years ago that monoclonals that had not even been properly characterized in the lab were being used in clinical trials-trials that failed, one after another. Too much promise and not enough rigor doomed monoclonals to an unkind fate.

Meanwhile, back in 1975 again, Elizabeth Carswell, Lloyd Old and their colleagues at Sloan-Kettering Research Institute in New York reported the discovery of a molecule that caused tumors to melt away in mice. Dubbed tumor necrosis factor, or TNF, the molecule incited the usual riot among investors and the usual hype from companies. In short order, the TNF gene was cloned, the protein mass-produced and an ugly truth unearthed:At doses humans could tolerate, patients derived no benefit whatsoever. By 1990, TNF had joined monoclonal antibodies in the pile of spent bullets in the war on cancer.

And now we arrive at one of the most interesting tensions in biotechnology: the always-yawning gap between pharmacological aspiration and biological reality. Although no one appreciated it in the early days, TNF is one of the body’s baddest actors when it comes to inflammation. Only in the late 1980s (and only, it should be noted, out of pure academic interest) did researchers discover that rheumatoid arthritis arises from a cascade of inflammatory proteins that collect in the joints, among which perhaps the worst of the bunch is-you guessed it-TNF. Separate research established that Crohn’s disease was also caused by an excess of the factor.

From that biological insight, it was a logical next step to suggest that a monoclonal antibody that neutralized TNF might short-circuit the ravages of rheumatoid arthritis and Crohn’s disease.Though Centocor’s earlier attempts to turn anti-TNF monoclonals into a viable drug to treat sepsis had failed, the company’s experience positioned it perfectly to develop monoclonals against TNF to treat rheumatoid arthritis and Crohn’s disease.

Henry Adams, in his autobiography The Education of Henry Adams, makes the wise point that any path that arrives at the destination is the right one. But it’s hard to square that haphazard form of navigation and everything it implies-luck, happenstance, accident, misdirection and perseverance-with the linear and often unforgiving thinking that goes into business plans, revenue streams and burn rates. The TNF story is a reminder that, for every success like Remicade, there are an awful lot of little white crosses on the side of the road.