It’s the new old story. Cancer researchers identify a potential molecular target inside tumors. An entrepreneurial scientist and his firm develop a proprietary method for developing drugs aimed at the target. A first candidate enters clinical trials and the initial results seem promising. Hopes — and the company’s stock price — soar.

Then, the results of the pivotal Phase III trials come in. It turns out the new drug is no better than what is already on the market. And that, as community oncologists are all too painfully aware, is none to good.

In late December Palo Alto-based Telik, Inc. was the latest company to complete this cycle of hope and despair when its TLK-256 (Telcyta) became the latest failed entry in the targeted therapies market.

Since the arrival of Herceptin for one form of breast cancer and Gleevec for chronic myelogenous leukemia, the cancer therapeutics world has pinned its hopes for new drugs on molecules that attach themselves to specific targets inside fast-multiplying cancer cells. A generation of basic science research into the mechanics of cancer cell replication has identified a host of possible molecular targets for arresting mutant cell growth. Translational scientists in the public and private sectors have identified or designed small molecule drugs and monoclonal antibodies for attacking these targets.
But just because scientists have identified a possible target — usually because it is overrepresented on the surface or inside a cancer cell — that doesn’t mean that inhibiting the target will cause the cell to die or stop growing. In the parlance of the drug developers (at least those who’ve experienced enough failures to know), it’s the difference between identifying a potential target and validating an actual target.

A brief review of the science behind TLK-256 shows why it had generated so much excitement among its developers and investors. The drug was elegantly designed to be like a time bomb attached to a guided missile. Once inside the body, the drug selectively attached itself to a variant of the protein glutathione S-transferase known as GST P1-1, which is over-represented in many drug-resistant cancer cells.

But TLK-256 itself wasn’t the cell killer. It was a so-called pro-drug that was rationally designed to release a fragment that would destroy the host cell only after it bound to GST P1-1. The relatively mild side effects that came from this delayed action made it an ideal complement to existing chemotherapy regimens.

So why didn’t it work? I’m sure scientists will be asking themselves the same question for years. The drug was active in vitro. Early safety and efficacy trials were promising. But the pivotal 520-patient non-small cell lung cancer trial that compared the drug to gefitinib (Genentech’s Iressa), another targeted drug that has had only marginal effects on lung cancer, failed to show a statistically significant increase in survival.

Another trial in 440 women with ovarian cancer compared TLK-256 to liposomal doxorubicin or topotecan. It also failed to improve survivability.

Unfortunately, scientists who hope to get answers to the question of what went wrong will have to wait a while. Successful trials get submitted to the Food and Drug Administration as part of a New Drug Application. Once approved, the gleeful academic researchers who conducted the trials eagerly publish their results.

But failure is an intellectual orphan. These trial results will probably remain buried at the FDA in a locked file cabinet labeled “proprietary business information.” Meanwhile, the company executives’ initial comments to the press cast almost no light on the situation. They attempted to deflect concerns about the company’s long-term prospects by casting aspersions on the conduct of the trials and the reading of the CAT scans.

With the incoming Democrats in Congress promising to force Medicare to negotiate lower drug prices, there’s been a lot of talk lately about how price controls will choke off pharmaceutical innovation. Richard Epstein, a law professor at the University of Chicago and a senior fellow at the Hoover Institution, is out with a new book that blames “excessive government regulation” for the dearth of new drugs coming out of industry’s labs.

Meanwhile, patient advocacy groups including the Abigail Alliance are pushing for earlier and easier FDA drug approvals for dying cancer patients. Under their proposed scheme, the Phase I/II trials that appeared to show that TLK-256 was effective against lung cancer would have been sufficient to make it an FDA-approved drug.

But if the Telcyta tale teaches us anything, it is that legitimate progress in cancer chemotherapeutics comes slowly. Brilliant scientific theories can only be corroborated through the painstakingly accurate application of controlled clinical trials with the statistical power to show significance. And sharing information, not hasty regulatory decisions based on fragmentary evidence, is the best way to expedite progress.

Merrill Goozner is a contributing editor to Bay Area Oncology News.

Posted on January 19, 2007 03:45 PM