Jerome Check firmly believes that mifepristone, better known as the abortion pill, can extend and improve the lives of terminally ill lung cancer patients who have run out of treatment options.
He has enough circumstantial evidence of this that the U.S. Food and Drug Administration gave him permission to formally test the drug in 40 advanced-stage patients. His clinical trial is the first step toward getting mifepristone approved as a palliative therapy.
But Check has a problem.
The 72-year old Melrose Park infertility specialist can’t get oncologists to send him patients. After 2½ years, he has enrolled only two of the 40 he needs. Both are doing very well on their daily mifepristone pill.
Check’s problem doesn’t stem from skepticism about the potential benefits of the controversial drug, or his scientific credibility. The root of his trouble seems to be that he’s not an oncologist, and he has no “sponsor” – no deep-pocketed university, company, or institution to manage and finance his clinical trial.
He knew this would be an issue, but decided to go ahead because lung cancer is the nation’s leading cancer killer, ending 154,000 lives a year. And he isn’t getting any younger.
“I was naive. I thought people would look on clinicaltrials.gov,” Check said, referring to the government’s online catalog of human studies of experimental therapies. “I thought I’d have to turn people away.”
Check hopes his story will bring him patients or, better yet, an oncologist willing to take over. In any case, the tribulations of his trial show that in the arcane world of drug development, a good idea and good intentions are rarely enough.
Claire F. Verschraegen, an Ohio State University oncologist who has studied mifepristone, said, “It’s definitely an interesting drug. I appreciate his effort to push it forward. But trying to do it himself when he doesn’t have oncology training, it’s a slippery slope. I wish him luck, but I really think he needs to find a champion in oncology. He needs to go to a big cancer center.”
Cutting an immune-system brake
In medical school at what was then called Hahnemann University, Check thought he’d become an oncologist.
“But I lost a patient,” he recalled recently, sitting in the antiques-filled Tudor mansion that houses his Melrose Park clinic. “I was so devastated, I thought, ‘I can’t do this.’ So maybe do the opposite of death. Do life.”
Check and his wife, Diane, a medical technologist, estimate that 40,000 babies have been conceived with the help of their Cooper Institute for Reproductive Hormonal Disorders. It’s affiliated with Cooper Medical School of Rowan University, where he holds the title of division head of reproductive endocrinology and infertility.
In the mid-1990s, Check — who has a Ph.D. in reproductive biology as well as a medical degree — collaborated with Hungarian scientists to study why some women had repeated miscarriages.
The Hungarians had discovered a protein that brakes the immune system to keep it from attacking a fast-growing invader — the fetus. This protein is driven by progesterone, the hormone that surges to sustain a pregnancy.
Check wondered if cancer cells somehow produced the same protein to evade the body’s defenses. If so, maybe some cancers could be foiled by a drug that blocked progesterone, he wrote in a 2001 journal article laying out his theory.
As Check knew, the FDA had just approved such a drug: mifepristone.
The concept of indirectly curbing cancer by cutting an immune system brake is no longer speculative. That’s the basis of checkpoint inhibitors, the new class of drugs that has transformed the outlook for metastatic skin, lung, and kidney cancers.
Check’s work “is interesting because it piggybacks on a hot topic in immunotherapy,” said Langhorne oncologist Youval Katz, who worked in Check’s lab 20 years ago, before medical school.
Mifepristone also is interesting. Synthesized in 1980 by the French company Roussel-Uclaf, the compound dubbed RU486 became the world’s most controversial drug after it was developed to derail a pregnancy when used in combination with a second drug that causes contractions.
But while opponents kept the focus on abortion, proponents saw mifepristone as a potential wonder drug because it modifies two key hormone systems – cortisol as well as progesterone – that are crucial to many bodily processes.
That potential is now being investigated. Clinicaltrials.gov lists scores of current or recent studies of mifepristone to treat uterine fibroids, metabolic syndrome, psychotic depression, Alzheimer’s disease, alcohol addiction, cancers including breast, prostate and ovarian, and more.
So far, the only success story is Cushing’s syndrome. California-based Corcept Therapeutics spent $300 million to get mifepristone approved to treat patients with the rare metabolic disorder. (The product, Korlym, costs $550 for a 300-milligram tablet before discounts, compared with $80 for the 200-milligram abortion pill, Mifeprex, made by Danco Laboratories.)
Corcept is developing next-generation versions of mifepristone, as well as supplying Korlym free to Check’s trial and numerous others, said chief financial officer Charlie Robb.
“Corcept has always had more ideas than money,” Robb said. “For about 10 years, we’ve been supporting studies as best we can” by providing free pills.
Robb said Corcept will stick with Check for as long as his trial takes.
“He’s a credible researcher, and we thought his hypothesis was interesting,” Robb said. “Recruitment can be tough, especially in oncology. It just may be that he’s got an idea that’s not in the mainstream. We certainly have run into that ourselves.”
Amazing anecdotes aren’t enough
In 2004, during a routine gynecological checkup, a patient confided to Check that she had a very rare cancer of the thymus, an immune system organ in the neck. Her tumors were growing despite chemotherapy and radiation.
She became his first mifepristone patient. The FDA gave permission for “compassionate use” of Danco’s pills.
The patient’s tumors stabilized for more than two years – the second-longest survival ever recorded by the Thymic Cell Carcinoma Society, Check wrote in a 2010 journal article. Then, hoping to wipe out the cancer, she stopped mifepristone and had more radiation, which caused a fatal lung complication.
Over the next decade, Check treated 10 more patients who were dying of colon, brain, pancreatic and other cancers. They seemed to live longer than their oncologists expected, and their energy, appetite, and pain levels seemed to improve.
But there was no way to know whether this was luck, biased impressions, or actual benefits of mifepristone.
Consider the most remarkable case, an 80-year-old woman who happened to be Check’s mother-in-law. When the ex-smoker went to the emergency room in respiratory failure, X-rays revealed lung lesions typical of cancer. She refused surgery and chemo, but agreed to try mifepristone. After six weeks on the drug, the lesions were gone. Her lungs were still clear when she died five years later of a heart attack.
But she refused a lung biopsy, so her “probable” lung cancer diagnosis was never confirmed.
Check readily acknowledges such anecdotal cases prove nothing. That’s why he applied to the FDA to do the trial. His wife, a former clinical trials administrator, wrote the protocol.
He sees mifepristone as a “salvage” therapy for incurable cases. The trial, which is open to metastatic patients who have progressed despite at least two chemo regimens, aims to extend their expected median survival of 10 months to 16 months. Other goals are to show mifepristone can keep cancer stable for a median of 15 weeks — five weeks longer than with last-resort chemo — and improve quality of life.
If the benefits are more modest, however, it could leave doubts about mifepristone’s effectiveness.
Ambiguous results plagued small studies that tested mifepristone to control meningioma, a slow-growing brain tumor with progesterone receptors. While the tumors are not malignant, they can recur, defy surgery and radiation, and become lethal.
To settle the effectiveness question, meningioma researchers including Verschraegen, the Ohio State oncologist, did a costly, gold-standard study that randomly assigned patients to mifepristone or a placebo, then followed them until they died.
“It turns out if you look at the survival curve, people on placebo did better,” Verschraegen said.
Beating the odds
Although only two lung cancer patients have been treated in Check’s trial so far, both have beaten the survival odds. The names are not being disclosed because of the trial’s confidentiality requirement.
The first patient, a 71-year-old retired bus driver who lives in New York City, was diagnosed in 2013 with lung cancer that had spread to his bladder. Surgery and chemo helped for two years, when a small brain metastasis was detected. He wasn’t a candidate for a checkpoint inhibitor, so his oncologist suggested Check’s trial.
“In 2016, I started mifepristone,” said the patient, who drives to Melrose Park once a month for monitoring tests. “The lung lesions are stable. There’s no further evidence of metastases in the brain. I have no shortness of breath. No side effects whatsoever.”
The second patient, a 69-year-old woman from South Jersey, already had debilitating pulmonary disease from years of smoking when she was diagnosed with late-stage lung cancer in 2014. After chemo, two targeted drugs, and a checkpoint inhibitor failed to control it, her Voorhees oncologist, Trina Poretta, told her about the trial.
In April, with her cancer stable for more than 19 months, she said, “You take a pill once a day at the same time. That’s pretty much it. You can eat anything. I’ve had no headaches, no nausea.”
Although her cancer has not progressed, her pulmonary disease has worsened to the point where she is now receiving hospice care.
To boost recruitment, Check has given presentations at oncology conferences around the world, most recently in April in Chicago. He has networked at Cooper University Hospital, now affiliated with the eminent Texas cancer center, MD Anderson. His wife has sent letters to patient advocacy groups including the Lung Cancer Foundation of America.
The trial continues to languish, even though no one disparages his concept or efforts.
“He’s a brilliant man,” said Poretta, who is affiliated with Kennedy Cancer Center, now part of Jefferson Health in Philadelphia.
She said she hasn’t referred more patients because she hasn’t had suitable ones, and besides, patients don’t want to go very far for treatment.
Katz, the Langhorne oncologist who once worked in Check’s lab, echoed those reasons for not sending any patients.
Kim Norris, president of the Lung Cancer Foundation of America, said Check’s dilemma is not unusual: “Even in well-touted trials, patient accrual is an ongoing problem.”
Still, Check worries that Corcept, the FDA, or the review board that monitors the trial’s progress will pull the plug.
“I generally just do my work and avoid publicity,” he said. “But I’m afraid if I can’t enlist more patients … a drug that has almost no side effects and provides marked improved longevity and quality of life will be lost.”
How the abortion pill came to the U.S. market
1980: French drug company Roussel Uclaf synthesizes RU486, or mifepristone. The next year, endocrinologist Etienne-Emile Baulieu leads a successful study of its use as an abortion agent.
1988: France approves RU486 for abortion. Facing anti-abortion pressure, Roussel Uclaf’s board votes to stop distributing the drug. The French government orders distribution in the interests of public health.
1989: Abortion foes in Congress get the FDA to ban importation of RU486 for personal use.
1990: U.S. Rep. Ron Wyden introduces a bill to lift the import ban following testimony from scientists seeking to study non-abortion uses of mifepristone.
1992: Bill Clinton, who supports bringing mifepristone to the U.S., is elected president.
1994: Roussel Uclaf gives its U.S. patent rights to the Population Council, which plans to do clinical trials and make mifepristone in the U.S.
2000: The FDA approves mifepristone. The Population Council licenses the drug, branded Mifeprex, to Danco Laboratories, a single-product company immune to anti-abortion boycotts.