Medicine Hunters Part 1
Eros Dervishi for STAT

PHILADELPHIA — What propelled Kaylene Sheran up to the microphone was an overwhelming exhaustion of surgery. At 19, she’d had so much of her surface excised that she was sometimes surprised to have any skin left. It was true of many others in the room. They grew tumors the way some people grew freckles — not in great constellation-like splashes, but in a creeping multitude. The more frequently they checked, the more basal cell carcinomas they’d find.

Sheran didn’t count how many skin cancers she’d had. It would’ve taken too long, and the number would’ve been too scary. In a sense, she’d grown up as much in the dermatologist’s chair as she had at her parents’ house in East Boston. When she was little, the doctor would put her to sleep for the surgeries. She had nightmares of the anesthesiologist’s mask, of going under and never waking up. When she got older, the clinician would inject the area with a numbing agent that didn’t actually make her numb; she’d stay painfully alert as they sliced away tumors with a scalpel.

Those nicked-off bits of her were frozen and inspected under the microscope. If the edges were healthy, her doctor could patch her up; if the borders were cancerous, he’d take off the temporary gauze and keep cutting. Sometimes, she stayed all day. Even then, it wouldn’t be long before she was back. “I’m kind of in a battle with my own body,” she said.

That’s why Sheran was here, on a sunny June day, in the windowless ballroom of an airport hotel, where a Stanford dermatologist named Dr. Jean Tang was presenting with the patience of a schoolteacher and the conviction of a priest. As an emissary of a company called PellePharm, Tang was exhorting the assembled crowd to volunteer for a trial that involved daubing their faces with a new experimental drug: patidegib.

The occasion was the 2019 national conference of the Gorlin Syndrome Alliance: the rare moment when people with this genetic disorder were not the exception but the rule. They came mostly for the solidarity. When else could they find themselves in a throng that truly understood the terror of their never-ending surgical whack-a-mole? Where else were they to swap tips and tricks about their other possible symptoms — the predisposition to heart tumors that weren’t cancerous, the trend of brain tumors that were, the skeletal abnormalities, the aching jaw cysts?

But they were also abuzz about this gel, a possible avenue away from surgery. “Our golden moment,” Julie Breneiser, the alliance’s executive director, called it. Tang showed them slides of tumors shrunken to almost nothing. She interpreted graphs demonstrating just how few new tumors sprouted on those who’d smeared themselves with the goop.

“Instead of 10 surgeries, maybe one surgery a year,” Tang said. “How many of you would say that’s meaningful? Raise your hands.”

In a single motion, like some giant, many-armed being, the room raised all of its hands.

Sitting toward the front, Sheran couldn’t stop her mind from drifting back a few years, to the last time she’d taken this class of chemo. It was a daily pill called Erivedge. She was going into her senior year of high school. At first, she didn’t see much difference. Then, her carcinomas began to melt away. She lost much of her hair, felt shooting pains in her legs — and still it was the best period of her life.

That ended one afternoon in 2018, when her pharmacy called to say that the amount she needed to pay for the drug was going up. Her next refill, instead of costing nothing, would require a payment of nearly $4,000. It was $4,000 she didn’t have.

She counted down the days until she ran out of pills and watched, powerless, as her face and shoulders once again began bubbling with tumors. For more than a year now, she’d been back under the knife. That meant she was as interested in PellePharm as PellePharm was in her.

Gorlin - Kaylene Sheran
Kaylene Sheran at a park near her home in East Boston, Mass. Kayana Szymczak for STAT

“… None of this would be possible if we don’t get 150 patients,” Tang was saying. So far, the clinical trial had only 35. “Please step up. … Do it for the community. Do it for our children.”

It was an alluring pitch. Patidegib was chemically similar to Erivedge but supposedly safer: By rubbing the stuff on to skin, the thinking went, you could avoid the taste loss, hair loss, and muscle cramps that came when you swallowed it — reactions that kept some from taking the pills.

Yet behind such sound arguments lay a distinctly American epic, at once inspiring and troubling. The main ingredient in patidegib had emerged, like some shaggy, half-mythical folk hero, from the mountains of the West. It was a troublemaker at first, the culprit behind an epidemic of one-eyed sheep. Then, it became a savior, a potential panacea against a litany of cancers, sending pharma executives scrambling through national forests in a wild botanical gold rush. But, as with many heroes viewed in retrospect, this one’s legacy is complicated. To scientists, it’s still an exuberant story of discovery against the odds. To patients like Sheran, it’s a story tempered with worry: Every side effect, it seems, has been prepared for except financial toxicity.

What is to some an unimaginable amount of money is to others a fair return on a risky investment. That was what troubled Sheran as she stood up and moved toward the microphone. She’d seen how stratospheric prices had eroded public trust in medicine makers, but also how they needed the public’s participation to test their drugs. Her question for PellePharm was a wake-up call for the whole industry. If she volunteered to rub this gel into her face — and if it worked — would she be able to afford the treatment she’d helped usher into the world?

Medicine Hunters Breaker

If you’d wound back the clock by 60 years, clambered up to one of Idaho’s alpine meadows, and presented Sheran’s dilemma to the shepherds working there, they wouldn’t have believed it. They’d seen the effect of these chemicals firsthand, and it was the opposite of desirable — the kind of thing you might pay to be rid of, the mountain sheep-keeper’s equivalent of a rat problem or toxic spill. They didn’t know what caused the problem at first. All they knew was that certain ewes were giving birth to one-eyed lambs.

Often, the single eyeball stared unnervingly out from the middle of the face, sometimes with a fleshy forehead proboscis above it — a nose at once displaced and deformed. There were other issues, too: a lower jaw missing, a skull oddly domed. It happened enough for the shepherds to give the syndrome a name. To them, the affected lambs were “monkey-faced.”

They killed and buried the ones that were born alive. Owners feared that rumors might sink the value of their flocks. “They thought it was a genetic problem, so all the ranchers kept their mouths shut,” said Kip Panter, who used to direct the U.S. Department of Agriculture’s poisonous plant lab, in Logan, Utah. “Nobody wanted to admit that they had a gene floating around that caused this Cyclops lamb.”

By 1955, so many newborns were affected — in some flocks, the rate was as high as 25% — that the ranchers called for government help. It came in the form of a USDA animal nutritionist named Lynn James. The son of hardscrabble cattle-breeders, he’d grown up branding Herefords and fixing snow-broken fences in the Utah rangeland near the Idaho line. “I used to say to my dad, ‘What in the world did my forefathers do that caused them to run away to this Godforsaken area?’” his son Mark recalled. “It’s just miles of sagebrush.”

The trouble, it turned out, wasn’t lurking in the mothers’ genes. When James and his boss trucked the ewes down to their lab, introduced them to a dashing ram, and then pampered them through pregnancy with the choicest alfalfa and a daily half-pound of barley, they generally gave birth to healthy, two-eyed lambs.

Gorlin
A cyclopic lamb from a 2009 U.S. Department of Agriculture study. Poisonous Plant Research Lab/USDA

There had to be something else — something external — giving rise to this mystery among the sheep. So, like an old-fashioned anthropologist, James moved in with them. It wasn’t out of character. Later, whenever dogs got through the fence behind his lab, he’d take Mark and a shotgun and sleep in the bed of his pickup parked within the earshot of the sheep’s nighttime stirrings, close enough to keep the livestock safe. “I consider him to be the last of the pioneers,” said Mark, who grew up to be an attorney in Salt Lake City.

For three summers, James camped in the upland pastures, hounding the sheep, watching as they chomped through stands of grass and moved on to what remained. He collected sprigs of the plants they ate — wild buckwheat, Indian paintbrush, broad tongue, mule ear.

Eventually, the team zeroed in on a single weed: a tall, white-flowered stalk that grew in dense patches, as if a farmer had taken a wrong turn and seeded a mountain pass with corn. Cow cabbage, it was called, or Veratrum californicum, or corn lily. When James ground the stuff into a noxious pesto and force-fed it to pregnant ewes, sure enough, some gave birth to one-eyed, proboscis-weighted lambs.

Federal chemists set upon the cow cabbage to extract its poisons. The chief molecular culprit they named cyclopamine. Case closed. James, who died in 2018, always kept some one-eyed sheep heads in preservative by his desk, which he used to warn visiting school groups about the perils of drugs.

Cyclopamine, meanwhile, became the stuff of textbooks — and that’s where Philip Beachy found it. In the 1990s, Beachy’s Johns Hopkins lab members had been doing what developmental biologists do, prodding at molecules, flicking on and off genes the way you might the light switches in a new apartment to suss out the circuitry. When he shut off one gene in particular, he found himself raising a litter of Cyclops-mice-to-be. That sent him to his bookshelf, where he found a picture of Idaho’s one-eyed lambs and put two and two together — a realization that would have profound implications for cancer patients generally, and especially those with Gorlin syndrome. Cow cabbage, it seemed, could gum up the workings of the hedgehog genes.

Lynn James at work
Lynn James (right) with one of his colleagues at the U.S. Department of Agriculture Poisonous Plant Research Laboratory in Logan, Utah. Courtesy Mark F. James
Lynn James
James walking in the part of Utah where he grew up, near Park Valley. Courtesy Mark F. James

These weren’t just any old genes. The proteins they code for act as embryonic engineers, turning raw cellular material into brain or eye or bone. The job is as crucial as it is complex. Each of us starts out as a ball of undifferentiated cells, a tiny speck of primordial mass tasked with assembling itself into a four-limbed, brain-bearing individual. “If you melted down fingers and looked at every single molecule in them, they’d basically all be pretty much the same,” said Matthew Scott, emeritus professor of developmental biology at Stanford. “It’s the same materials that built them. What’s different is the architect.”

Hedgehog proteins are among the star employees at your inner architecture firm. When an embryonic cell’s hedgehog genes turn on and dispatch their signature proteins, these molecules can direct the surrounding cells to change identities or grow, forming an organ here, an appendage there. They help shape bodies as we know them, from the armored segments of a fly to the sea urchin’s dome, from the lattice-like feathering on a bird to the sculpting of every person’s face.

When these genes and proteins aren’t working right, the results are etched into an organism’s most basic architecture. Fiddle with the hedgehog genes in fruit flies and their larvae become spiky — hence the name. In us, the changes look a little different. Sheran could see hints in family photos from her father’s side: a pattern of larger-than-average heads, unusually jutted brows, distinctive spaces between teeth, and strangely frequent skin cancers.

How hedgehog genes were connected to Gorlin syndrome was only understood because other families with the condition had, in the 1980s and ’90s, given away bits of their bodily fluids to researchers. One of them was a University of California, San Francisco, physician — and eventual PellePharm co-founder — named Dr. Ervin Epstein.

The scion of a dermatological dynasty in the Bay Area, he’d grown up in a household where treating rashes and carcinomas was the norm. From his father, he’d inherited an obsession with skin surgery — but in its transmission, the fascination had acquired a mutation of sorts, a rare-disease twist. He was less interested in bread-and-butter excisions than in why those with Gorlin needed so damn many of them. The question sent him on the road. He crisscrossed the country, collecting blood, comparing the Gorlin-affected to their relatives who’d been spared, hunting for a telltale difference in their genes.

In a nursing home somewhere along the New England coast, he found a wizened matriarch he’d been hoping to meet; she’d had something like 10 children, about half of them with Gorlin. But the in-house phlebotomist couldn’t get a sample: She stuck her and stuck her and announced that the veins were just too small. “I said to myself, ‘I’ve come 3,000 miles to draw blood on her and others. This is really important,’” Epstein remembered. “The little old lady was willing to let me try” — and by a stroke of luck, the needle got where it needed to go. He still jokes about how triumphant he felt.

It was painstaking work. He estimates that he visited some 50 people, asking if he could poke their veins. Once, as he prepared to fly the fruits of his research back to California, he found himself being questioned by airport security: He’d been transferring human blood from glass vials to more durable plastic ones over the bathroom sink.

In 1992, some Yale scientists beat him to a preliminary answer, identifying a region of DNA where Gorlin patients were lacking some sort of tumor-blocker. Epstein kept on probing his blood samples, hoping to precisely pinpoint the missing piece. He’d been searching for almost 10 years when, in the fall of 1995, he got a call out of the blue from an insect-symmetry researcher he’d never met. It was Matt Scott, at Stanford, who’d heard of Epstein’s travels, through the scientific grapevine. “He said, ‘I think I have the gene you’re looking for,’” Epstein recalled.

It was one of the hedgehog genes. Normally, our cells keep their body-shaping chemical signals under lock and key. When we’re embryos, the hedgehog genes spring open the bolt to unleash them. Then, once our symmetry is established and we’ve been adorned with fingers and toes, the latch largely snaps shut, the proteins’ work done. There are exceptions, our ever-growing skin chief among them. In most tissues, though, the hedgehog genes shut off.

Not so in Gorlin syndrome. That was why patients like Sheran got so many tumors. The lock controlling their hedgehog proteins was missing. If the one-eyed lambs had gotten too little of these cellular signals, these patients were getting too much. In the developing sheep, growth was stunted; in these families, it continued uncontrolled.

In other words, the poison that had given rise to these profit-sapping birth defects among livestock began to look like an auspicious ingredient for cancer drugs.

Medicine Hunters Breaker

Arare disease conference can feel a bit like a city square on market day. Old friends meet and swap news. Deals are negotiated and decisions made. Whatever the world has to offer seems to be on view — and at the Gorlin Syndrome Alliance meeting, what the world had to offer was mostly hedgehog inhibitors. You could learn about a fungus-killing compound repurposed as an experimental hedgehog inhibitor. You could discuss whether lidocaine patches work to quell the cramps that come with Erivedge, an oral hedgehog inhibitor.

You could see a PellePharm executive exchanging business cards with a dermatologist, talking about patidegib, yet another hedgehog inhibitor. “If there are a certain number of patients who could come out of the effort, then we could determine whether it’s worth the investment,” the executive said.

In some ways, since they’d started in 2001, such meetings had reduced the need for Epstein-style scavenger hunts. Instead of showing up to nursing homes and houses scattered across the U.S., scientists looking for volunteers could simply come here, the American Mecca of Gorlin syndrome. One cancer researcher, Addy Alt-Holland of Tufts University School of Dental Medicine, had designed a whole study — about the molecules emitted from Gorlin patients’ skin — based almost exclusively on the samples she collected at these gatherings. “Are you ready to sweat?” she cried, as her husband dragged around a 45-pound duffel bag of gauze swatches and consent forms.

Addy Alt-Holland
Addy Alt-Holland, a professor of endodontics at Tufts University, registers volunteers willing to give sweat samples at the Gorlin Syndrome Alliance conference. Mark Makela for STAT
Gorlin Syndrome Alliance National Conference
Kate Holmes, 38, places a bandage of her sweat into a plastic bag for Alt-Holland’s study. Mark Makela for STAT

To recruit for a trial like PellePharm’s, though, even this fruitful ground wasn’t quite fruitful enough. Of the estimated 10,000 Americans with Gorlin syndrome, around 45 or so had shown up. Some of them weren’t eligible: If you didn’t grow skin cancers at an alarming rate, then it would be hard to measure whether the new gel was having an effect. Some — especially those with the severest cases — might not be willing to stop using their creams and hedgehog-inhibiting drugs for the length of the trial. Others, already swamped with appointments, might not have time for the extra doctor visits a study requires.

Sheran, it seemed, was the perfect candidate: plagued by carcinomas, no longer taking Erivedge, and deeply interested in a drug that could taper her reliance on painful procedures. She’d already had more than a lifetime’s worth.

Kaylene Sheran
A photo of Sheran taken before she had surgery at Boston Children’s Hospital to remove a tumor, called a cardiac fibroma, from her heart in March 2004. Courtesy Kaylene Sheran

When she was born in September 1999, she was legally blind: no peripheral vision in her right eye, no vision at all in her left. By the time she was 4, she had a non-cancerous tumor lurking in her chest. Before the surgeons wheeled her away, her mother threw a little party in the hospital. As Mary Sheran put it, “I basically said, ‘Well, if this is the end, I want my kid to have friends around.’”

That would be just one in an endless string of interventions. She remembers them with an awful clarity. Most vivid are the Novocain needles and slices and stitches of skin surgery, repeated ad nauseum; she can recite the steps like the lines of a poem. There were the oral surgeries for which she was kept awake, so painful she felt physically sick. There were the months she spent in the hospital for digestive issues triggered by growths in her jaw, still movie-like in her mind.

Once, a doctor tried inserting a drainage tube into a jaw cyst, only for it to fall out again and again: while she was selling Girl Scout cookies, eating mac and cheese, attending school. When she got to kindergarten, kids kept looking at her funny, and her parents got her a prosthetic so she’d fit in — “just the shell of an eye,” she said, which had to be sucked out each night with a suction.

“One day I just woke, up, I was like, ‘I’m sick and tired of wearing this prosthetic eye, it’s painful. … I don’t care what people think anymore.’ I was sick and tired of disguising myself.”

When Sheran received the call about the unexpected change in the cost of refilling her Erivedge prescription, the memory of all those medical insults contributed to her alarm. “They sounded so sure that I would pay the $4,000: ‘Do you want to pay with your credit card or do you want to send a check in the mail?’” Sheran recalled. She already had trouble affording the parade of specialists her condition required, which cost her $60 a pop. Her mother — who’s been, at different times, a teacher, a correctional officer, and an overnight attendant at a homeless shelter — often works two jobs to make ends meet.

What Sheran had understood from the pharmacy agent on the phone was that the amount she’d have to pay for the drug was going from zero to nearly $4,000 a month. Blue Cross Blue Shield of Massachusetts, her family’s insurer at the time, tells a different story.

“I do think there was some confusion in the communication. It is understandable; these things are very, very complicated,” said Dr. Katherine Dallow, the company’s vice president of clinical programs and strategy. She explained that Sheran’s mother’s employer had switched the coverage it provided to its workers, from a plan with a low annual deductible to one in which that number was around $4,000 a year. “This kind of situation happens every day,” Dallow said.

Frantic to keep taking her medication, Sheran tried two tacks: Massachusetts’ public insurance and financial assistance offered by Genentech, the company behind Erivedge. The first might have disqualified her from the second, but the point was moot. She gave up on MassHealth, she said, when the program started sending her bills, and on Genentech’s assistance because she worried that she’d still be left owing untenable amounts. (“We do our best to ensure price doesn’t prevent our medicines from getting to people who need them,” a Genentech spokeswoman said in an email, listing a number of patient assistance programs.)

There may have been other ways to get this cost reimbursed, Dallow said, had Sheran known about them. But underlying all of the discussions Sheran had in the wake of that unexpected phone call was an anxiety so basic it was almost primal. The pharmacy said her refill would cost around $4,000, and she simply didn’t have that kind of money.

Kaylene Sheran
Sheran at home. Kayana Szymczak for STAT

It was this toxic brew of genetic mutations, insurance changes, miscommunications, and egregious drug prices that brought Sheran’s skin cancers back. No surprise there, perhaps: The cost and complexity of our health care machine worsen illnesses all the time. “We’re all trying to get creative about ways to lessen that burden,” Dallow said. “But there are only a few levers that you can pull.”

To Sheran, PellePharm’s plea for volunteers represented something patients don’t often find in the American health care machine: a lever.

Medicine Hunters Breaker

She used the lever gently at first, walking up to the microphone and asking how much the experimental gel might eventually cost. As a Stanford dermatologist and one of PellePharm’s founders, Dr. Jean Tang was sympathetic.

“The worst of all things is to have a drug that works — all this energy, all this effort, all this hope — and it’s unaffordable and people can’t get it,” she said. “That would be terrible. A lot of people are thinking about it; I hope they’re thinking about it in the right way.” But she couldn’t answer Sheran’s question, and urged her to ask a PellePharm executive instead.

Sheran took Tang’s advice. She found a PellePharm exec and explained again that she didn’t want a false sense of hope. If and when the drug hit the pharmacy, she asked, how much would it cost? “They were like, ‘We won’t know that until years from now,’” she said. (“We have not set a price for patidegib,” PellePharm CEO Dr. Sanuj Ravindran explained after the conference. “But we’re working on that now. It is our goal to make the drug as widely accessible as possible.”)

Sheran stayed calm. She thanked the executive for his time. But inside, she felt a wave of shock. How could they not be prepared for this question?

Ultimately, the makers of patidegib wanted the same outcome as her. They wanted their drug to beat back patients’ tumors — a vision so alluring it had sent them back to the land of Lynn James, back into the valley of the one-eyed sheep. It had convinced them to convert lab chemists into cow-cabbage harvesters. It had convinced them to bet millions on a molecule that other companies had already tried in a plethora of other cancers. Now, in the space of a few minutes, with just a few words, PellePharm — desperate to recruit people like Sheran — had lost her trust.

She would have given up on the clinical trial altogether if it weren’t for a friend of hers: a straight-talking, 59-year-old community advocate from Florida who wasn’t afraid of a little confrontation.

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  • If anyone participates in a clinical trial and the drug is eventually successful, the drug company should give people in the trial a lifetime prescription for that drug.

    After all, the drug company is going to make a lot of money off the backs of these volunteer if the drug succeeds. Why participate in a trial if you can’t afford to use it?

    • Worked on a CF drug years ago with sites in Canada.
      It was required that the drug, if approved, would be supplied to study participants for life, for free otherwise this drug study would not be done in Canada.