The

treating

drug

BY A L E X A N D R A S I F F E R L I N

PHOTO-ILLUSTR ATION BY TIME

FORGET WRINKLES. BOTOX IS NOW BEING USED TO TREAT

MIGRAINES, DEPRESSION, TWITCHING EYES, OVERACTIVE

BLADDERS, SWEATY PALMS AND MORE. SOME CALL IT A

MARVEL OF MEDICINE; OTHERS CAUTION THE RISKS ARE STILL

UNKNOWN. INSIDE THE EXPLODING BUSINESS AND

STRANGE SCIENCE OF BOTOX

that’s

Medicine

everything

40 Time January 16, 2017

uring a recenT Therapysession, one of Dr. Norman

Rosenthal’s regulars said he was consider-ing suicide. It wasn’t the first time the pa-tient had entertained the thought, and eventhough he was on antidepressants and alwayskept up with his appointments, Rosenthal, alicensed psychiatrist with a private practicein North Bethesda, Md., wanted to offer hispatient something else.

“I think you should get Botox,” Rosenthaltold him. “You should schedule an appoint-ment on your way home.”

It was peculiar advice coming from ashrink, but not without precedent. In 2014,Rosenthal, a clinical professor of psychiatryat Georgetown University School of Medi-cine, and Dr. Eric Finzi, an assistant pro-fessor of psychiatry at George WashingtonSchool of Medicine, published a study show-ing that when people with major depressiongot Botox, they reported fewer symptoms sixweeks later than people who had been givenplacebo injections. “I’m always on the look-out for things that are unusual and interest-ing for depression,” says Rosenthal, who iswidely considered an expert on the condi-tion. “I’ve found Botox to be helpful, but it’sstill not mainstream.”

It’s also not approved by the U.S. Foodand Drug Administration (FDA) for depres-sion, not that that stops doctors from pre-scribing it that way. Such off-label use ofBotox, like that of any FDA-approved drug,is legal in the U.S. That’s because once a drughas been approved by the FDA for a condi-tion, licensed physicians are legally allowedto prescribe it for any medical issue theythink it could benefit, regardless of whether

D

Botox was invented as a drug to treat crossed eyes. Today it’s used on a wide range of disorders—someapproved, some not. Here’s what to know:

Botox FAQ

it’s been proved to work for that condition.Now, thanks in large part to off-label

use, Botox—the wrinkle smoother that ex-ploded as a cultural phenomenon and med-ical triumph—is increasingly being draftedfor problems that go far beyond the cosmetic.The depression suffered by Rosenthal’s pa-tient is just one example on a list that in-cludes everything from excessive sweatingand neck spasms to leaky bladders, pre-mature ejaculation, migraines, cold handsand even the dangerous cardiac condition ofatrial fibrillation after heart surgery, amongothers. The range of conditions for whichdoctors are now using Botox is dizzying, re-flecting the drug’s unique characteristics asmuch as the drug industry’s unique strate-gies for creating a blockbuster.

Botox is a neurotoxin derived from thebacterium Clostridium botulinum. Ingested incontaminated food, it can interfere with keymuscles in the body, causing paralysis andeven death. But when injected in tiny dosesinto targeted areas, it can block signals be-tween nerves and muscles, causing the mus-cles to relax. That’s how it smooths wrinkles:when you immobilize the muscles that sur-round fine lines, those lines are less likely tomove—making them less noticeable. It’s alsowhy it’s FDA-approved to treat an overactivebladder: Botox can prevent involuntary mus-cle contractions that can cause people to feellike they have to pee even when they don’t.

In 2015, Botox, produced by pharmaceu-tical maker Allergan, generated global reve-nue of $2.45 billion—more than half of whichcame from therapeutic rather than cosmeticuses. That noncosmetic revenue is likely toballoon in the years ahead as doctors try out

‘I meet withphysicians

who are usingthe toxin

everywhere—for diseasesyou would

never knowabout.’

MIN DONG,Harvard Medical School

1

WHAT IS BOTOX?

Botox comes from abacterium called Clostridiumbotulinum that can causesevere food poisoning ifeaten. When the drug isinjected, it delivers a tinydose of toxin that blockscommunication betweennerves and muscles.

2

DOES INSURANCECOVER IT?

Not for wrinkles. Somecompanies will cover it forFDA-approved medical usesif other therapies have notworked. Out of pocket, itcan cost $350 to $500 perinjection. Most treatmentsrequire multiple shots.

3

IS IT SAFE?

The FDA requires Botox tobear a black-box warning—an alert that the drug maycome with major risks—butmost experts agree it’s safewhen used correctly forapproved conditions. Still,serious side effects havebeen reported.

41

BOTOXBY THENUMBERS

In the 28 yearssince Botox wasapproved, the drug’spopularity—and thenumber of ailmentsit treats—hasskyrocketed

Botox for even more off-label uses and as Al-lergan conducts studies of its own.

“In the majority of these cases, it’s thedoctors at the front line who start usingBotox off-label, and then we see the treat-ment of things we never expected the toxinto work for,” says Min Dong, a researcher atHarvard Medical School who studies botu-linum toxins in the lab and has no financialties to Allergan. “I meet with physicians whoare using the toxin everywhere—for diseasesyou would never know about.”

The potential of the drug is enormous, butit isn’t without risks. Most of the experts Ispoke with agree that in small doses, Botox issafe when administered by a licensed profes-sional, but not everyone agrees that its safetyextends to all of its newer off-label uses.

In recent years, a number of high-profilelawsuits have been brought against Aller-gan in which plaintiffs claimed that off-label uses—for ailments including a child’scerebral-palsy symptoms, for instance, or anadult’s hand tremors—resulted in lasting del-eterious side effects. Still, the drug’s accep-tance in a growing number of doctors’ officesworldwide, and its revenue growth, show nosigns of slowing.

It’s a remarkable arc for a drug that onlya few years ago was associated with Holly-wood cocktail parties where guests camefor Bellinis and left with a forehead full ofBotox injections. It highlights the advancesthat can occur when physicians, seeking newtherapies for their patients, explore creativenew uses for approved drugs—basically, real-world experiments that take place largely be-yond the reach of federal regulators. That,in turn, raises questions about the risks ofdeploying medicines in ways that have notbeen fully vetted. But it happens all the time.

The drug has come a long way since itsability to smooth facial wrinkles was first dis-covered, by accident. In the 1970s, ophthal-mologist Dr. Alan B. Scott started studyingthe toxin as a therapy for people with a medi-cal condition that rendered them cross-eyed.“Some of these patients that would comewould kind of joke and say, ‘Oh, Doctor, I’vecome to get the lines out.’ And I would laugh,but I really wasn’t tuned in to the practical,and valuable, aspect of that,” Scott told CBSin 2012. Scott named the drug Oculinumand formed a company of the same name in1978. In 1989 he received FDA approval forthe treatment of strabismus (the crossed-eyedisorder) and abnormal eyelid spasms.

Two years later, Allergan bought Oculi-num for $9 million and changed the drug’sname to Botox. At the time, Allergan wasprimarily an ocular-care company thatsold products like contact-lens cleanersand prescription solutions for dry eyes,bringing in about $500 million in annualsales. Allergan says it saw Botox as a drugfor a niche population: it’s estimated that 4%of people in the U.S. have crossed eyes, forwhich the drug was initially approved, andAllergan made about $13 million in sales fromthe drug by the end of 1991.

In 1998, David E.I. Pyott became CEOof Allergan. He was enthusiastic aboutBotox’s wrinkle-reducing potential, hesays, and pushed the company to con-duct a series of studies on the matter. In2002, Botox earned FDA approval for so-called frown lines—wrinkles betweeneyebrows—marking the first time a phar-maceutical drug was given the green lightfor a strictly cosmetic purpose. In 2001,the year before Botox was approved forwrinkles, it generated about $310 millionin sales. By 2013, the year it was approvedfor overactive bladder, Allergan reportednearly $2 billion in revenue from Botox.

In just over a decade, the number of peo-ple in the U.S. receiving cosmetic botulinumtoxin type A injections—mostly from Botoxbut also from another brand called Dys-port, which commands less than 10% of themarket—exploded. From 2000 to 2015, useof the toxins for wrinkles increased 759%. Itbecame a cultural phenomenon too, spawn-ing Botox parties, Simpsons jokes, even greet-ing cards. In 2008, Sex and the City characterSamantha famously quipped, “I don’t reallybelieve in marriage. Now Botox, on the otherhand, that works every time.”

But today it’s the medical uses of the drugthat are the great moneymaker, in part be-cause doctors are getting a better handle onhow to use it. Botulinum toxin type A is oneof seven neurotoxins produced from Clos-tridium botulinum. Contracting botulism isbad news: it can cause blurred vision, per-sistent trouble swallowing and worse. In onerecent case, close to 30 people were hospital-ized in Ohio in 2015 after attending a churchpotluck. One person died. The outbreak wasultimately attributed to a potato salad madefrom improperly home-canned potatoesthat were harboring the bacteria. Given itslevel of toxicity, some countries have evenexplored its potential use as a bioweapon.

With Botox, however, the dose makes

12.2billionNumber of Botoxdoses administeredin the pastquarter-century

800Number of patentsheld by Allergan forcurrent and potentialBotox applications

SOURCE: ALLERGAN

In 1991, Allerganpaid $9 million for asmall company thatmade Botox

In 1998, Botoxglobal revenue was$125 million

By 2015globalrevenuehits$2.45billion

RevenuefromBotox

$2B

1

01990 ’10 ’152000

$2.45billion

$13million

42 Time January 16, 2017

WHATBOTOX ISUSED FOR

Best known forreducing facialwrinkles, Botoxis approved bythe FDA for theconditions below.The drug now bringsin significantlymore revenue for itsnoncosmetic uses.

Strabismus(crossed eyes)

Blepharospasm(eyelid spasms)

Cervical dystonia(severe neckspasms)

Severe underarmsweating

Upper-limbspasticity

Chronic-migraineprevention

Overactive bladder

Lower-limbspasticity

Some facialwrinkles

FDA -APPROVEDRigorous clinicaltrials were requiredbefore Botox wasdetermined to besafe and effective forthese uses:

the poison. In medicine, it’s used in suchsmall amounts that most experts deemit safe. “It’s fascinating,” says Dong, theHarvard researcher. “These are the mosttoxic substances known to man, and theyare also the most useful toxins used inmedicine right now.”

Botox works by temporarily immobiliz-ing muscle activity. It does this by block-ing nerve-muscle communication, whichmakes the injected muscles unable to con-tract. Paralyzing muscle activity is how Botoxcan steady a straying gaze, eliminate an eye-lid spasm or stop signaling from nerves thatstimulate sweat in a person’s armpit.

Botox has also been shown to preventchronic migraines, but there, it’s unclearexactly why Botox works. (For doctors,reaching a firm understanding of howBotox prevents migraines will be tricky,since they don’t know for certain whatcauses the severe headaches in the firstplace.) “There were multiple clinical trialsfor migraines, and most of them failed,”says Dr. Mitchell Brin, senior vice presidentof drug development at Allergan and chiefscientific officer for Botox. “It took a longtime to figure out where to inject and howmuch.” Today people who receive Botoxfor migraine prevention get 31 injections indifferent spots on their head and neck. Theeffects of Botox can last about three to sixmonths depending on the condition.

The use of Botox for migraines was, likemany other new applications for the drug,a kind of happy accident. A Beverly Hillsplastic surgeon observed that people whogot Botox for wrinkles were reporting fewerheadaches, paving the way for studies aboutmigraines. Similarly, doctors in Europe wereintrigued when they noticed that their pa-tients who got Botox for facial spasms weresweating less than usual.

“It’s pure serendipity,” says Brin.

Though people ofTen associaTe phar-maceutical discovery with giant industriallaboratories and expansive, rigorous clinicaltrials, the mission creep for Botox—as withmany other drugs that have received govern-ment approval for one specific use—has beendriven by off-label use.

In the case of Botox, doctors who experi-ment off-label say they do so because they’relooking for better treatment options for theirpatients. “In my 30 years of medical practice,Botox is one of the most impactful treatmentsI had ever seen,” says Dr. Linda Brubaker,

dean and chief diversity officer of the LoyolaUniversity Chicago Stritch School of Medi-cine, who independently studied Botox foroveractive bladder before the FDA approvedit for that condition in 2013.

Many of the women she saw in her prac-tice didn’t want to take drugs for the disor-der over the long term. Brubaker found thatabout 70% of women she treated with Botoxreported an average of three leaks a day, com-pared with the average of five leaks a day atthe start of the study. “It’s a very rewardingoption for them,” she says.

It’s true that Botox’s ever expanding useshave been largely physician-driven. Butdrugmakers are also often aware of off-labeluses long before those uses are officially rec-ognized by the FDA; that’s how Botox endedup being approved for wrinkles, after all.

Some industry insiders say it’s not un-usual, if still legally murky, for drug-companyrepresentatives and doctors to share infor-mation with one another about the differentways an approved drug may be used. If a doc-tor notices that, say, a treatment for crossedeyes also “takes the lines out,” he may men-tion it to the representative from whom hebuys the drugs. That rep may share that withanother of his clients, and so on.

U.S. pharmaceutical companies areprohibited from marketing a drug for un-approved purposes until they’ve submittedproof to the FDA of its efficacy and gotten theagency’s green light. If they skip that step,they’re breaking the law, and the penaltiescan be steep.

In 2010, Allergan pleaded guilty andagreed to pay $600 million to resolve alle-gations that it unlawfully promoted Botoxfor conditions—including headaches, pain,spasticity and juvenile cerebral palsy—thatat the time were not approved by the FDA. Inone of the complaints, prosecutors said thatAllergan “illegally, vigorously and withoutany thought to the possible negative healtheffects to which it subjected patients, pro-moted off-label uses of Botox.” The U.S.Department of Justice also argued that Al-lergan exploited on-label uses for cervicaldystonia—a disorder characterized by ex-treme neck-muscle contractions—to “growoff-label pain and headache sales.” Prosecu-tors also argued that Allergan paid doctorsto give presentations and trainings to otherphysicians about Botox uses that at the timewere off-label.

As part of the settlement, Allergan agreedto plead guilty to one criminal misdemeanor

43

Severely coldhands

Lockjaw

Back pain

Cleft-lip scars

Painful sex

Depression

Prematureejaculation

Parkinson’s-diseasesymptoms

Drooling

Anal fissures

Teeth grinding

OFF - LABELOnce a drug hasbeen approvedfor one condition,doctors can useit for any disorderthey think it canhelp. Here arejust a few usesdoctors haveembraced:

misbranding charge and pay $375 million.The company acknowledged that its mar-keting of Botox led to off-label uses of thedrug. Allergan also agreed to pay $225 mil-lion to resolve civil charges alleging that themarketing of Botox had caused doctors to filefalse reimbursement claims, though Aller-gan denied wrongdoing. The company saidin a statement that the settlement was in thebest interest of its stockholders because itavoided litigation costs and “permits us tofocus our time and resources on . . . develop-ing new treatments.”

As with any drug, Allergan is legally re-quired to make known Botox’s most severepotential side effects, and in 2009 the FDArequired Botox to bear a black-box warning—the strongest type of warning label given toany drug—cautioning that there was evi-dence the drug had been linked to seriousside effects. With Botox, this includes effectsspreading from the injection site to otherparts of the body, causing muscle weakness,double vision and drooping eyelids.

In physicians’ offices—where patientstypically don’t see the box the vials arepacked in and therefore may be unaware ofthe black-box warning—the onus is on doc-tors to outline the potential risks with anypatient choosing to try Botox for any condi-tion, FDA-approved or not.

Ray Chester, an attorney in Austin whohas represented several plaintiffs in lawsuitsagainst Allergan, says that just about all thecases he has handled involved off-label use ofthe drug. In 2014 a New York couple arguedthat Botox, which they chose to try off-labelto treat their son’s cerebral-palsy symptoms,caused life-threatening complications. Thefamily was awarded $6.75 million by a jury.Allergan, which initially planned to appeal,ended up privately settling the case with thefamily, and the terms of the settlement havebeen kept confidential.

Though the off-label use of drugs makesmany experts—including some at the FDA—uncomfortable, the practice is de rigueur inmedicine. It’s how doctors learned that Lyr-ica, which is approved to treat nerve pain,can treat anxiety, and how they learned thatfinasteride, a drug that treats enlarged pros-tates, can reduce male baldness.

“A separate balancing of risks and benefitsis necessary for each intended use of a drug,even once it is approved, to ensure the ben-efits of using the product to treat a particulardisease or condition outweigh the risks,” saysFDA press officer Sarah Peddicord.

That’s why for any off-label uses thatAllergan wants to market to doctors and thepublic—depression, cold hands, atrial fibril-lation in heart-surgery patients—the com-pany must conduct its own clinical trials toshow its efficacy and safety.

Allergan does not disclose its research-and-development budget for Botox specifi-cally, but the company’s annual R&D bud-get is about $1.5 billion. “This drug is notdone in terms of its different applications,”says Allergan’s Brin. “It still has many dif-ferent, exciting, meaningful opportunitiesfor patients.”

The sTudies using BoTox for depression,like other research into Botox’s off-label po-tential, were so encouraging that they caughtthe attention of Allergan. In Rosenthal andFinzi’s research, 74 people with major de-pressive disorder were randomly assignedto receive Botox injections or a placebo. Sixweeks later, 52% of the people who receivedBotox experienced a drop in reported symp-toms, compared with 15% of the people givena placebo. “Over 50% of people responding isa high number,” says Finzi. “These are peoplewho have already tried other treatments, andthey are significantly depressed.”

Now Allergan hopes to replicate thefindings on a larger scale, and the companyis currently running its own Phase 2 clini-cal trial. If its results are in line with Rosen-thal and Finzi’s, it would be huge, pavingthe way for Botox to obtain official approvalfor the drug as a depression treatment. Thatwouldn’t change anything for doctors, ofcourse—they can already prescribe it off-label, and some do, with great results—butit would allow Allergan to begin marketingBotox for depression, a change that coulddramatically increase its adoption and sales.

Still, Botox’s use for depression raisesa question that confounds some research-ers. In some cases, how Botox works is ev-ident: the toxin can block the signals be-tween nerves and muscles, which is why itcan help calm an overactive bladder, say, ora twitching eye, or the facial muscles thatmake wrinkles more apparent. In othercases, however (with migraines as well aswith depression), scientists are flummoxed.They may have noticed that the drug worksfor a given condition, but they aren’t al-ways sure why—in sciencespeak, they don’tknow what the mechanism is.

With depression, Rosenthal and Finzithink it may relate to what’s known as

‘A balancingof risks andbenefits isnecessary

for eachintendeduse of a

drug, evenonce it is

approved.’SARAH PEDDICORD, FDA

44 Time January 16, 2017

the facial-feedback hypothesis, a theorystemming from research by Charles Darwinand further explored by the American philos-opher and psychologist William James. Thetheory posits that people’s facial expressionscan influence their mood. Lift your face intoa smile and it may just cheer you up; if youcan’t frown or furrow your brow in worry,perhaps you won’t feel so anxious or sad.

But it could be something else altogether.In 2008, Matteo Caleo, a researcher at theItalian National Research Council’s Instituteof Neuroscience in Pisa, published a contro-versial study showing that when he injectedthe muscles of rats with Botox, he found evi-dence of the drug in the brain stem. He alsoinjected Botox into one side of the brain inmice and found that it spread to the oppositeside. That suggested the toxin could accessthe nervous system and the brain.

“We were very skeptical,” says EdwinChapman, a professor of neuroscience atthe University of Wisconsin–Madison,after reading Caleo’s study. But in August2016, Chapman and his graduate studentEwa Bomba-Warczak published a studyin the journal Cell Reports showing simi-lar spreading effects in animal cells in thelab. For Chapman, it explained what hewas hearing anecdotally from doctors: thatBotox might be influencing the central ner-vous system and not just the area where it’sbeing injected.

Ironically, it’s the off-target effects ofBotox that have some researchers most ex-cited. “Botox may be working in a way that isdifferent from what we think,” says Bomba-Warczak. “It may be even more complex.”

Chapman and Bomba-Warczak both thinkBotox is safe when used correctly, but theysay their inboxes quickly filled with mes-sages after their study was published. “Wewere startled by the number of people whofeel they were harmed by these toxins,” saysChapman. “We feel these were pretty safeagents. Now it seems that for some people,they believe the toxin can sometimes causesomething that may be irreversible. Andthat’s a total mystery.”

Allergan says Botox is well estab-lished as a drug and that the benefits andrisks of toxins are well understood. “Withmore than 25 years of real-world clinicalexperience . . . approximately 3,200 articlesin scientific and medical journals, market-ing authorizations in more than 90 marketsand many different indications, Botox andBotox Cosmetic are [among] the most widely

researched medicines in the world,” an Aller-gan rep wrote in an emailed statement.

Even if Botox’s mechanism isn’t alwayswell understood and some of its off-labeluses are still unproven, interest in the drugisn’t likely to wane. “Botox is a big cash cowfor the physicians’ practices,” says RonnyGal, an investment analyst at Sanford C.Bernstein who has watched the drug closelyfor more than a decade. “When I talk to phy-sicians, they say, ‘Botox is not a problem. Itworks and gives you the result you want.’ If itworks for depression and atrial fibrillation,it could be massive.”

In november, the FDA held a two-dayhearing asking for expert comment on theagency’s rules concerning off-label druguse and marketing. Some said the prac-tice paves the way for scientific progressand gives doctors and their patients muchneeded alternatives for hard-to-treat med-ical conditions. Others said that off-labeldrug use is primarily financially motivatedand that it poses a serious threat to publichealth, particularly when drugs are used ex-perimentally on children.

Off-label use is a topic the FDA has beeneyeing for some time. “There have been manyinstances where unapproved uses of a drug,even when commonly accepted by the medi-cal community, have later been shown to beunsafe or ineffective or both—sometimeswith devastating consequences to publichealth,” says the FDA’s Peddicord.

It’s unclear how the FDA’s focus will pivotwith the next Administration. President-elect Donald Trump has pledged that in hisfirst 100 days, he would be “cutting the redtape at the FDA,” and insiders have specu-lated that a Trump Administration wouldloosen the agency’s already limited oversighton off-label use.

But even if the laws remain unchanged, aslong as off-label uses are permitted by law,expect doctors to keep pushing the bound-aries of Botox’s applications—sometimes inthe name of medical progress and sometimeswith remarkable results.

Norman Rosenthal, the Maryland psychi-atrist who recommended Botox for his sui-cidal patient, says he’s seen the upside first-hand. The patient, persuaded by Rosenthal,did indeed get Botox shots on his foreheadand between his brows. Days later, Rosenthalgot an email from the patient. It was a thank-you note. Finally, the patient wrote, he wasfeeling better. •

‘Botox maybe working

in a way thatis differentfrom whatwe think.It may be

even morecomplex.’

EWA BOMBA-WARCZAK, University ofWisconsin–Madison