Developing a new drug and ushering it through rounds of clinical trials usually takes a huge team of scientists and billions of dollars. I did it without the support of a drug company or a clinical trials group and for a fraction of the cost. My 23-year odyssey offers an intimate and detailed look into how that happened while offering lessons that may give today’s innovators and bureaucrats pause for reflection.
As a cancer specialist who likes to understand how things work, I was always on the lookout for new compounds that could fight cancer. In the early 1980s, my lab at the Manitoba Institute of Cell Biology at the University of Manitoba was conducting research on tamoxifen, a drug used to shrink estrogen-driven breast cancer. It works by preventing estrogen from latching onto a specific cell receptor so the hormone can no longer fuel the growth of breast cancer cells.
A new discovery that tamoxifen also homes in on another “anti-estrogen binding site” intrigued me. Wondering if blocking it could help tamoxifen shrink breast cancer, I started looking for compounds that could do just that.
As I describe in “Survival: A Medical Memoir,” my chronicle of the discovery and testing of DPPE, my colleague Asher Begleiter and I started with some off-the-shelf reagents to create tamoxifen-like molecules using standard organic chemistry techniques. On our second try, we created a creamy white powder that lacked one of tamoxifen’s three chemical rings. It didn’t prevent estrogen from binding to its receptor (which was good) but was as powerful as tamoxifen in its ability to latch onto this new antiestrogen binding site.
We called the compound DPPE, an acronym for its long chemical name. It later came to be known as tesmilifene. We turned it loose on a cell culture of estrogen-driven breast cancer cells. The results were unequivocal — DPPE slowed the growth of these cells; higher doses killed them, just as tamoxifen did.
DPPE patents were quickly filed and animal studies approved within one or two weeks. The human protocols required by the university ethics committee and health regulators got the go-ahead within 50 days. The entire regulatory process took just eight months from start to finish.
Although DPPE was an experimental treatment, the government of Manitoba took the unprecedented step of funding the early patient trials at a time of widespread budget austerity.
Those initial Phase 1 and Phase 2 studies first combined DPPE with other chemotherapy agents among individuals with late-stage cancers of various types, then concentrated on patients with metastatic breast and prostate cancer. The results showed such promise that they were published in the Journal of Clinical Oncology.
After 12 years of going it alone, we licensed DPPE to Bristol-Myers Squibb in 1996. Despite early success in a Phase 2 trial in advanced breast cancer, a follow-up Phase 3 study showed that DPPE didn’t appear to add any additional benefit to the chemotherapy drug doxorubicin against breast cancer. Bristol-Myers Squibb stopped the trial before it was scheduled to end and abandoned DPPE before we could measure its effect on survival, a prespecified outcome.
That was unfortunate, because 18 months later we learned that women who received DPPE plus doxorubicin lived 50 percent longer than women who received doxorubicin alone. Even so, Bristol-Myers Squibb didn’t want the drug back.
A Canadian company, YM BioSciences, retested DPPE in a US Food and Drug Administration-approved Phase 3 trial in more than 700 women with advanced aggressive breast cancer. That study, completed in 2007, showed no survival benefit among the women receiving DPPE. As is all too common with negative studies, the results of that trial were never published.
Could this happen today?
I don’t believe I could have developed DPPE today. The nurturing culture that propelled it forward in the 1980s and 1990s stands in stark contrast to the ever-increasing layers of institutional bureaucracy and risk-averse lawyers that now permeate biomedical research.
I often wonder how the pioneers in chemotherapy, whose breakthrough treatments have saved countless lives, would have fared had they been working within today’s research framework. It’s unlikely that Sidney Farber, regarded as the father of modern chemotherapy, would have been able to proceed as quickly as he did in 1948 — after discovering that folic acid stimulated the progression of leukemia — to administer the folic acid antagonist methotrexate to children with leukemia.
In 1965, Emil Frei and Emil Freireich got a quick green light to treat children with leukemia using a previously untested combination of four chemotherapy drugs, dubbed VAMP. In his highly acclaimed book “The Death of Cancer,” Vincent DeVita writes, “When changes [to VAMP] were agreed upon, they were put into practice the next day. Some aspect of VAMP — dosage or the interval of treatment, say — changed from week to week, all in an attempt to make it more effective.” Try doing that with the National Cancer Institute or FDA in 2016!
The relative lack of institutional and regulatory red tape during that golden period propelled innovation in ways that aren’t possible today. At the same time, lives were unnecessarily lost in the haste to offer new hope to patients because the “rules of the road” in cancer chemotherapy were still rudimentary. As time passed and lessons were learned, treatment protocols became ever more strict, to the point that bureaucracy now prevails in full force.
Has bureaucracy gone too far?
There is no question that oversight is essential to ensure high standards and patient safety. Yet today’s bureaucratic and legal maze has increased to such a degree that it is stifling innovation. Researchers and physicians commonly complain that inordinate paperwork, coupled with long delays in approval of laboratory and clinical protocols, severely hamper their progress.
Unless this changes, I fear that many of our best and brightest academics will depart our universities for the private sector, or leave science altogether. Yet, that need not happen. “Survival’s” story provides us with a lesson from the past, and it is this: If we can ratchet down bureaucracy to the still-workable and effective level that allowed me to develop DPPE thirty years ago, everyone will benefit.
Lorne J. Brandes, MD was senior oncologist at CancerCare Manitoba and professor of medicine at the University of Manitoba until his retirement in 2015. He is the author of “Survival: A Medical Memoir” (FriesenPress, 2016).
The comment that it takes billions of dollars to do trials for a new drug is a complete myth. I have worked on patent cases for numerous NDA lawsuits, and the usual cost of the actual, necessary trials to prove safety and efficacy in man and animals is in the ten to twenty million dollar range. The REST of that bloated figure that Big Pharma always touts as its “investment” goes to sham studies to invent new diseases and extend indications, and other patent-extending blockbuster maneuvers. Not to mention the HUGE expenditures on marketing pitches disguised as CME and symposia. Even then, the real budget to take a blockbuster like Vioxx to market was only in the $150-200 million range, NOT the billion dollars Merck asserted. And that included a ten million dolar launch party. The rest of the revenues makes up that 95-98% profit margin most blockbusters provide. What the Big Pharma snake oil peddlers spend for real research is a tiny fraction of what they spend for Marketing research and patent extension.