25 years ago this month, the FDA approved the drug. May 10, 2001. Around 70 days from submission to approval, the fastest oncology review on record at the time. The compound was called STI571. You probably know it as Gleevec.

Issue 005 found the Philadelphia chromosome target in 1960, and the BCR-ABL fusion protein it creates, characterized through the 1980s. It found Brian Druker in Oregon, and a chemist at a Swiss pharmaceutical company, working on a compound that nobody wanted to develop. It found the trial data: 53 of 54 chronic-phase CML patients with a complete hematologic response at daily doses of 300 mg or more.

The science said it could be done. The company that owned the compound said it was not worth doing.

This is what happened next.

Brian Druker arrived at Oregon Health Sciences University in 1993 with one obsession: BCR-ABL. He had been studying tyrosine kinases at Dana-Farber, and he was convinced that BCR-ABL's abnormal kinase activity was not just a marker of CML but its driver. If you could shut it off, you could stop the disease.

At Ciba-Geigy (later Novartis), a chemist named Nick Lydon was synthesizing protein kinase inhibitors. One compound, STI571, hit BCR-ABL with unusual precision. The mechanism was later shown to work by binding BCR-ABL in its inactive conformation, which is what gave it the selectivity that made the difference.

Druker and Lydon collaborated. In 1996, Druker's lab published in Nature Medicine: STI571 killed BCR-ABL-positive leukemia cells without harming normal cells. It did not harm normal cells. In the context of 1990s oncology, that sentence was outlandish.

Outlandish, given the era. In the mid-1990s, cancer treatment was generally a shotgun blast, not a guided missile. Cytotoxic chemotherapy killed dividing cells, cancerous and healthy alike. The idea that a small molecule could identify a specific molecular target, bind it selectively, and leave everything else alone was a theoretical promise, not an established clinical reality.

One of the most promising papers in cancer biology that decade. Novartis, which now owned the compound, said no.

Novartis's reluctance was not a conspiracy. It was a business calculation, and it is how the pipeline actually works under resource pressure. The specific reasons mattered:

Market. CML was rare. A drug for fewer than 10,000 new patients per year was not a priority for a company with hundreds of competing compounds and much larger potential markets.

Technical track record. Oncology had a long history of compounds that killed cells in culture and failed in animals or humans. Skepticism was not irrational.

Toxicity. Early animal studies of STI571 raised liver concerns at higher doses. The therapeutic window was unclear.

Manufacturing. Producing STI571 at clinical scale was technically demanding.

Competition. Other Novartis oncology compounds were judged to have better market prospects.

Institutional inertia. Large pharma moves slowly. Druker did not have a champion inside Novartis with the authority to move the compound forward against all of those concerns.

For 6 years, the compound sat.

From the trial side of the industry, this is not unusual.

The clinical research industry, in my experience, is about timing. The right series of events: a clear target, the incidence rate that makes a trial viable, the advocacy pressure that makes a sponsor move. The STI571 story is an extreme version of that, but the structure is familiar. The compound existed. The science existed. What was missing was the organizational will to run the trial.

Bandwidth matters too. The companies sponsoring these trials are sometimes small biotechs with 10 employees. That is why they hire CROs. The CRO model exists in part because sponsors do not always have the infrastructure to run a trial even when they have a compound worth running it on. In Novartis's case the infrastructure existed. What was missing was priority.

GCP defines the relationship between investigator and sponsor. An investigator (the physician or scientist running a trial) cannot file an Investigational New Drug application without the compound. The compound is the sponsor's property. The sponsor holds the IND. The investigator has no legal pathway to run a trial without the sponsor's agreement.

Druker was the investigator. Novartis was the sponsor. Under the IND framework from Issue 004, Druker could not file his own IND for a compound he did not own. He could advocate, publish, present data, and lobby. He could not compel.

This is often cited as the system protecting corporate over patient interests. What it actually reflects is the accountability structure. The sponsor is liable for the trial. The sponsor bears the regulatory responsibility. It is not an arbitrary power arrangement. It is a liability arrangement. If the trial harms patients, the sponsor answers for it.

The system has failure modes. STI571 is one. 6 years is too long. But the failure is not suppression by design. It is the gap between the science and the institutional will to act on it. Those are different problems with different solutions.

By the late 1990s, Druker had been advocating for years. He had allies inside Novartis, including Lydon. He had presented the data to Novartis executives. He had been told repeatedly that CML was not a priority.

What changed the timeline was not corporate. It was patients.

CML patient advocacy groups had been following Druker's work. They understood, with the clarity of having the disease, that STI571 was not a theoretical possibility. It was a compound that had already worked in a lab. They organized, petitioned, and publicly pressured Novartis. Patient letters, advocacy campaigns, and direct contact with Novartis leadership. The pressure was not subtle.

In parallel, Druker negotiated. He secured a small supply of compound for a Phase I trial. He agreed to bear the operational burden of running the trial. He used his own institutional resources at OHSU. The trial was approved, and patient advocacy had moved a corporate decision that the science alone could not.

Phase I enrollment opened in 1998.

The Phase I trial for STI571 (later imatinib, sold as Gleevec) enrolled CML patients who had failed or could not tolerate interferon, which was then the standard of care. These were patients without other options. The starting dose was 25 mg per day.

Standard oncology Phase I uses a 3+3 design. 3 patients per dose level. If none experience a dose-limiting toxicity, the dose escalates. If 1 of 3 does, 3 more are added. If 2 of 6 experience a DLT, escalation stops and the maximum tolerated dose is established.

STI571 was unusual from the first dose level.

White blood cell counts began to normalize at doses well below where the trial was designed to detect efficacy. Once daily doses reached 300 mg or more, 53 of 54 chronic-phase CML patients had a complete hematologic response. Most in the first month.

Druker called skeptics. Some did not believe him. He invited them to his clinic to see the patients.

Among the patients whose lives this data would eventually reach: Kareem Abdul-Jabbar, diagnosed with CML in 2008. He is still alive.

Here is the part of the Gleevec story that lives past Gleevec.

In my undergrad Cell Signaling class at the University of Lethbridge, my professor, a cell cancer researcher, put it this way. Why would we treat a cancer that doubles in 5 days the same way as one that doubles in 20 years? The question is not rhetorical. It is a paradigm indictment.

The range is real. Burkitt lymphoma doubles every 24 to 48 hours. Nearly every cell actively dividing. On the other end, indolent prostate cancer in older men may grow so slowly that active surveillance, watching it without treating it, outperforms intervention. The same word, cancer, covers both.

This is why there has never been a single cure for cancer. Cancer is more than 200 distinct diseases. Each has a different molecular driver, a different growth rate, a different set of vulnerabilities. Imatinib worked because CML had one specific, identifiable target. That is not true for most cancers.

The Druker story is one lock turning. There are many more.

Four facts worth having ready at any table.

MOMENT 1: Novartis declined a drug that would peak at over $5 billion a year. The compound was already in their lab. They said no for 6 years because CML was rare, the market was small, and other compounds looked more profitable. Patient advocacy changed their decision. The science did not.

MOMENT 2: Once Phase I reached 300 mg a day or more, 53 of 54 chronic-phase CML patients had a complete hematologic response. Most in the first month. The trial was designed to find the maximum tolerated dose. It found something rarer: a drug that worked so well it almost did not need a Phase III.

MOMENT 3: Druker's 1996 Nature Medicine paper, the one that showed a compound killing BCR-ABL cancer cells without harming normal cells, was written off by most of the oncology establishment as a cell culture artifact. It took 5 years of additional data, patient advocacy, and a Phase I result of 53 of 54 to change that consensus.

MOMENT 4: Under GCP, the sponsor holds the IND, not the investigator. Druker could not file his own application for a compound he did not own. What people call suppression was a bureaucratic and financial impasse: the scientist had no legal mechanism to compel the sponsor, and the sponsor had no financial incentive to move. Patient advocacy was the mechanism that worked.

Debby the Denier had been seeing the anniversary posts all week. 25 years of Gleevec. NPR. OHSU. People sharing their stories. Then her feed gave her something else.

One was a former pharma researcher at a whiteboard, explaining that pharma systematically suppresses treatments that threaten revenue. The Gleevec story, in that version, was a case study in suppression: Novartis knew, Novartis sat on it, patients suffered.

Debby watched twice. It felt true. She had just read about Novartis saying no for 6 years.

The full conversation, Sam walking Debby through the Toolkit and Rooty on the algorithm, lives in The Informed track this week. Read it there.

Send this to someone who thinks the system only moves for money. Patient advocacy moved it here.

Issue 007: STI571 from Phase I into Phase II and III, the FDA priority review, the roughly 70-day approval that set a record, and what the Gleevec story taught the FDA about accelerating access without compromising safety standards. Plus: IRIS, the randomized trial that confirmed what the Phase I already showed.

Issue 003b: The Skeptic's Toolkit. Ten questions for any health claim.
Issue 001: Distrust, Earned and Inherited. Why skepticism is rational.
Issue 004: The Research Pipeline. How a molecule becomes a medicine.

For educational purposes only. Nothing in this newsletter is medical advice. Talk to your doctor before making any health decision.

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