Over­wrought mar­ket­ing? Ads, not re­search, cre­ate some phar­ma best-sell­ers

An over­head light draw­ing at­ten­tion to his face, ac­tor Dan­ny Glover starts to cry, drop­ping his head in­to one hand — then, he abrupt­ly switch­es over to deep bel­ly laughs, be­fore re­sum­ing a straight face. “When I act, if I do this it’s to­tal­ly in my con­trol,” he says, get­ting to the point: “But for some­one with pseudob­ul­bar af­fect, choos­ing to cry or laugh may not be your de­ci­sion.”

The 60-sec­ond TV ad­ver­tise­ment, which ran wide­ly late last year, con­cerns a neu­ro­log­i­cal con­di­tion known by the acronym PBA, char­ac­ter­ized by in­ap­pro­pri­ate, un­con­trolled out­bursts of laugh­ing or cry­ing. Though no drug is men­tioned, the ad­ver­tise­ment is spon­sored by Avanir Phar­ma­ceu­ti­cals, an Al­iso Viejo, Calif., firm that launched Nuedex­ta, a pricey, brand-name med­i­cine that tar­gets the dis­or­der. The ad ends by re­fer­ring peo­ple to a web­site and toll-free num­ber for more in­for­ma­tion.

PBA is re­al, most­ly af­fect­ing peo­ple with neu­ro­log­i­cal con­di­tions such as mul­ti­ple scle­ro­sis, a re­cent stroke or Lou Gehrig’s dis­ease. It runs the spec­trum from mild to se­vere im­pair­ment. Be­cause the de­f­i­n­i­tion of the con­di­tion is am­bigu­ous, es­ti­mates of its preva­lence vary wide­ly. Some clin­i­cians say PBA is rel­a­tive­ly un­com­mon among their pa­tients, while Avanir sets the num­ber at near­ly 2 mil­lion.

But the ad cam­paign has helped fu­el the con­tro­ver­sy over how di­rect-to-con­sumer (DTC) ad­ver­tis­ing — typ­i­fied by ads that call on you to “ask your doc­tor” about a pos­si­ble treat­ment — takes niche med­i­cine and pro­motes its use for a broad range of pa­tients and fos­ters the use of pricey pre­scrip­tion prod­ucts when cheap­er ones might suf­fice.

“I sus­pect this dis­ease is be­ing re­de­fined to in­clude over­ly emo­tion­al peo­ple” through ad­ver­tis­ing, said Adri­ane Fugh-Berman, a doc­tor who teach­es at George­town Uni­ver­si­ty Med­ical Cen­ter and has in­ves­ti­gat­ed phar­ma­ceu­ti­cal mar­ket­ing prac­tices. The Unit­ed States is one of two coun­tries that al­lows ad­ver­tis­ing of pre­scrip­tion drugs.

Not so, says the com­pa­ny in a writ­ten state­ment out­lin­ing that its ef­forts are “fo­cused on rais­ing aware­ness about PBA to help peo­ple bet­ter un­der­stand the symp­toms of a con­di­tion that is of­ten over­looked, mis­un­der­stood and mis­di­ag­nosed.”

The case of Nuedex­ta is no­table be­cause of its price, more than $700 a month for a sup­ply of the twice-a-day pills. The drug is a com­bi­na­tion of two low-cost in­gre­di­ents — an over-the-counter cough med­i­cine and a gener­ic heart drug — that, pur­chased sep­a­rate­ly, would run rough­ly $20 a month based on on­line cost es­ti­ma­tors. To be sure, the com­par­i­son is ap­ples to or­anges be­cause the dosage of the heart drug is so much low­er in Nuedex­ta than is gen­er­al­ly avail­able on its own by pre­scrip­tion. Ex­perts say a do-it-your­self treat­ment would be dif­fi­cult and po­ten­tial­ly dan­ger­ous for a con­sumer to try to con­coct. “You’d have to get the ex­act dos­es right, and that would be tricky,” said Dr. Aiesha Ahmed, a neu­rol­o­gist at Penn State Her­shey Med­ical Cen­ter who has re­searched the preva­lence of PBA and its treat­ment op­tions.

The pill doesn’t cure PBA but must be tak­en for the rest of a pa­tient’s life to help re­duce the laugh­ing or cry­ing episodes. While it’s the on­ly Food and Drug Ad­min­is­tra­tion-ap­proved drug specif­i­cal­ly for PBA, doc­tors have suc­cess­ful­ly treat­ed the con­di­tion with sev­er­al al­ter­na­tives cost­ing far less — all an­ti­de­pres­sants.

“The cost for mix­ing two old drugs to­geth­er is un­con­scionable,” said Jer­ry Avorn, pro­fes­sor of med­i­cine at Har­vard Med­ical School and chief of the Di­vi­sion of Phar­ma­coepi­demi­ol­o­gy and Phar­ma­coeco­nom­ics at Brigham and Women’s Hos­pi­tal.

The strate­gic mar­ket­ing of Nuedex­ta is part of a broad­er trend in which even small phar­ma­ceu­ti­cal firms turn to high-cost air­waves to en­cour­age use of their prod­ucts. Phar­ma­ceu­ti­cal in­dus­try spend­ing on DTC tele­vi­sion ads has been on the rise — up 62 per­cent since 2012 to an es­ti­mat­ed $6.4 bil­lion in 2016 — even as TV ad­ver­tis­ing for oth­er prod­uct types stayed flat, ac­cord­ing to Kan­tar Me­dia, a con­sult­ing firm that tracks mul­ti­me­dia ad­ver­tis­ing. By last year, drug ads were the sixth-most-com­mon cat­e­go­ry of tele­vi­sion ad­ver­tise­ment — be­hind such things as cars and restau­rants — up from 12th just five years ago.

A num­ber of the ads, like Nuedex­ta’s, pro­mote med­ica­tion for rel­a­tive­ly un­usu­al con­di­tions, such as a sleep dis­or­der that af­fects on­ly peo­ple who are blind; or more com­mon con­di­tions, such as opi­oid-in­duced con­sti­pa­tion.

Drug­mak­ers de­fend the slew of ad­ver­tise­ments as ed­u­cat­ing pa­tients who may not un­der­stand they have a dis­ease or that their symp­toms can be treat­ed. The un­con­trolled laugh­ing or cry­ing of PBA “is quite de­bil­i­tat­ing,” and Nuedex­ta pro­vides sub­stan­tial re­lief for many, said Avanir’s chief med­ical of­fi­cer, Rick Mala­mut, a neu­rol­o­gist who re­cent­ly joined the com­pa­ny.

Avanir de­clined to say how much it is spend­ing to mar­ket Nuedex­ta. In jus­ti­fy­ing the price, Mala­mut said the com­pa­ny had in­vest­ed hun­dreds of mil­lions of dol­lars over 10 years on re­search be­fore win­ning FDA ap­proval in late 2010. More is now be­ing spent to re­search whether it — or oth­er Avanir prod­ucts — could help with oth­er neu­ro­log­i­cal con­di­tions.

“We un­der­stand the cost of med­ica­tion is bur­den­some for peo­ple with­out [in­sur­ance] cov­er­age,” he said, not­ing the com­pa­ny of­fers fi­nan­cial as­sis­tance to help such pa­tients.

Some ex­perts say the cost isn’t worth it: “If it were your loved one, there would prob­a­bly be a val­ue to pre­vent these episodes,” said Mark Pauly, a health econ­o­mist at the Whar­ton School of the Uni­ver­si­ty of Penn­syl­va­nia, of the bouts of laugh­ter and cry­ing. But, he added: “As a hard­heart­ed econ­o­mist, I have to ask if it’s worth $700 a month.”

Still, the mar­ket has proved lu­cra­tive. Nuedex­ta’s sales have risen from about $37 mil­lion in 2012 to $218 mil­lion last year, ac­cord­ing to Eval­u­atePhar­ma, which tracks phar­ma­ceu­ti­cal in­dus­try pric­ing and mar­kets.

Strate­gi­cal­ly Rais­ing A Drug’s Pro­file

The sto­ry of Nuedex­ta be­gan with Richard Smith, a neu­rol­o­gist whose Cen­ter for Neu­ro­log­ic Study was look­ing to de­vel­op a new treat­ment for Lou Gehrig’s dis­ease, al­so known as ALS. In the ear­ly 2000s, Smith com­bined dex­tromethor­phan — the main in­gre­di­ent in cough syrups such as Ro­bi­tussin — with quini­dine, a drug used to treat ir­reg­u­lar heart rhythms. The heart drug helps boost and main­tain lev­els of the dex­tromethor­phan in the blood­stream.

What his re­search team ob­served in pre­lim­i­nary stud­ies was that pa­tients “al­most im­me­di­ate­ly start­ed re­port­ing an ef­fect on PBA,” said Smith, in a tele­phone in­ter­view. The drug was even­tu­al­ly sold to Avanir. In Oc­to­ber 2006, the FDA re­spond­ed that the drug looked ap­prov­able, but in­ves­ti­ga­tors had “fun­da­men­tal ques­tions about both the ef­fec­tive­ness and safe­ty of the prod­uct.”

The com­pa­ny then low­ered the dose of the heart drug and per­formed an­oth­er clin­i­cal tri­al, which found the drug cut in half the num­ber of episodes of un­con­trolled laugh­ing or cry­ing by pa­tients who took it rather than a place­bo. It was not com­pared with oth­er treat­ments al­ready in use and the pa­tients in the study had ei­ther MS or ALS. It gained the FDA’s OK in late 2010.

Ear­ly on, Avanir ex­ec­u­tives were clear that they had big am­bi­tions for the new prod­uct. In 2013, then-CEO Kei­th Katkin tout­ed the drug as a “pipeline in a pill” to in­vestors, pre­dict­ing it could even­tu­al­ly be used in a host of con­di­tions, from pain re­lat­ed to MS to ag­i­ta­tion in pa­tients with de­men­tia.

Dur­ing and af­ter ap­proval of the drug, Avanir pro­vid­ed ed­u­ca­tion­al talks for doc­tors aimed at rais­ing the pro­file of the lit­tle-known con­di­tion and ex­pand­ing the use of their drug.

It made a pitch to con­sumers with a 2013 ad cam­paign on­line and on tele­vi­sion that di­rect­ed view­ers to a web­site. The cam­paign pro­duced “an over­whelm­ing” re­sponse, with “350,000 new unique vis­i­tors to the web­site or calls to the hot­line,” Kei­th A. Katkin, the chief ex­ec­u­tive at the time, told in­vestors that year.

That po­ten­tial — along with oth­er drugs in Avanir’s re­search labs — helped prompt Japan-based Ot­su­ka Hold­ings to pur­chase Avanir in 2014 for $3.5 bil­lion.

But af­ter mar­ket­ing sur­veys found that, still, on­ly about one-third of po­ten­tial pa­tients and pri­ma­ry care doc­tors who treat such pa­tients knew about PBA, Avanir de­cid­ed to en­list Glover’s celebri­ty fire­pow­er, said Lau­ren D’An­ge­lo, se­nior di­rec­tor of mar­ket­ing for Avanir.

The ad fea­tur­ing Glover, who doesn’t him­self have PBA or any per­son­al link to it, was on ca­ble and na­tion­al news pro­grams spo­rad­i­cal­ly in 2015 and through the end of De­cem­ber the fol­low­ing year. Glover’s pub­li­cist didn’t of­fer any ad­di­tion­al com­ment for this sto­ry.

The ad is “non-brand­ed” — mean­ing the drug is not men­tioned — and there­fore isn’t re­quired by the FDA to list side ef­fects and risks. In­stead, it sim­ply sug­gests pa­tients ask their doc­tor about treat­ment or go a web­site to find out more about PBA. Aware­ness among pri­ma­ry care doc­tors rose to 72 per­cent and 52 per­cent among pa­tients.

“It was an ex­treme­ly suc­cess­ful cam­paign,” D’An­ge­lo said. “We drove a lot of pa­tients in­to doc­tors’ of­fices. The chal­lenge was they did not ask for Nuedex­ta by name.” For sales, that was a prob­lem. In­stead of get­ting Nuedex­ta, some pa­tients were in­cor­rect­ly di­ag­nosed or pre­scribed an an­ti­de­pres­sant, she said.

So, in 2017, the drug­mak­er un­veiled a new ad­ver­tis­ing cam­paign.

This one, which is cur­rent­ly run­ning on prime-time TV, fea­tures a man in­ex­plic­a­bly burst­ing in­to tears at a child’s birth­day par­ty. It in­tends to move po­ten­tial cus­tomers be­yond “could you have PBA?” to “ask your doc­tor for Nuedex­ta.”

“We are mim­ic­k­ing what we want them to do, to ask about PBA and ask about Nuedex­ta,” said D’An­ge­lo.

And there’s good rea­son for this kind of mes­sag­ing. A 2016 poll, for in­stance, con­duct­ed by Med­scape, an on­line physi­cian ed­u­ca­tion web­site, found that 62 per­cent of physi­cians said they would or might pre­scribe an in­nocu­ous, even place­bo treat­ment to a pa­tient who didn’t need it but de­mand­ed it.

Some neu­rol­o­gists are fans of the drug. Ken­neth Heil­man, a pro­fes­sor of neu­rol­o­gy at the Uni­ver­si­ty of Flori­da School of Med­i­cine and a fel­low of the Amer­i­can Acad­e­my of Neu­rol­o­gy says Nuedex­ta “seems to con­trol [PBA symp­toms] very well.” He al­so doesn’t ob­ject to the ad­ver­tis­ing cam­paign, since it might be use­ful in alert­ing fam­i­ly physi­cians who don’t know about the dis­or­der. (Dr. Heil­man does not get any mon­ey from Avanir.)

Who Needs Nuedex­ta? Do You?

But PBA can be dif­fi­cult to di­ag­nose, be­cause symp­toms — cry­ing and emo­tion­al volatil­i­ty — can be at­trib­uted to oth­er con­di­tions, such as de­pres­sion. In­ap­pro­pri­ate laugh­ter or tears are rel­a­tive­ly com­mon in de­men­tia, re­ferred to mere­ly as “emo­tion­al la­bil­i­ty” in many oth­er coun­tries, but may not con­sti­tute a prob­lem that needs treat­ment. Many ex­perts wor­ry that “pa­tient aware­ness” and press­ing doc­tors to write pre­scrip­tions will lead to overuse.

On the PBA in­for­ma­tion­al web­site, cre­at­ed by Avanir, the com­pa­ny pro­vides a sev­en-ques­tion self-as­sess­ment.

The ques­tion­naire al­lows a range of an­swers about the fre­quen­cy of symp­toms, with test tak­ers able to re­spond nev­er, rarely, oc­ca­sion­al­ly, fre­quent­ly or most of the time. Ques­tions in­clude: “There are times when I feel fine one minute, and then I’ll be­come tear­ful the next over some­thing small or for no rea­son at all.” “I find my­self cry­ing very eas­i­ly.” “There are times when I won’t be think­ing of any­thing hap­py or fun­ny at all, but will sud­den­ly be over­come by fun­ny or hap­py thoughts.”

The scale au­to­mat­i­cal­ly awards sev­en points to those who take it — even when “nev­er” is the an­swer to all ques­tions. A score of 13 is need­ed to in­di­cate the po­ten­tial for PBA. A con­sumer an­swer­ing “nev­er” to one of the ques­tions, “rarely” to five and “oc­ca­sion­al­ly” to just one scores 14.

Ear­ly on, FDA re­view­ers raised ques­tions about this test and some ex­perts con­tin­ue to ex­press sim­i­lar con­cerns.

Di­ag­nos­ing who ac­tu­al­ly has a PBA con­di­tion re­quires ask­ing how it af­fects a per­son’s life, said Dr. Lau­ra Boy­lan, a neu­rol­o­gist and ad­junct pro­fes­sor at New York Uni­ver­si­ty School of Med­i­cine who treats pa­tients with psy­chi­atric con­cerns re­lat­ed to neu­ro­log­i­cal dis­eases.

While she ac­knowl­edged that PBA — which she says is more ac­cu­rate­ly called “patho­log­ic af­fect” — is un­der-rec­og­nized by the med­ical pro­fes­sion, she wor­ries about over­pre­scrib­ing: “I’m the kind of per­son who gets all teary at AT&T ads,” said Boy­lan. “I’m just like that and would not want to take a med­i­cine to stop that. What if we start giv­ing Nuedex­ta to peo­ple who are just emo­tion­al peo­ple?”


Kaiser Health News, a non­prof­it health news­room whose sto­ries ap­pear in news out­lets na­tion­wide, is an ed­i­to­ri­al­ly in­de­pen­dent part of the Kaiser Fam­i­ly Foun­da­tion.

Vas Narasimhan, AP Images

On a hot streak, No­var­tis ex­ecs run the odds on their two most im­por­tant PhI­II read­outs. Which is 0.01% more like­ly to suc­ceed?

Novartis CEO Vas Narasimhan is living in the sweet spot right now.

The numbers are running a bit better than expected, the pipeline — which he assembled as development chief — is performing and the stock popped more than 4% on Thursday as the executive team ran through their assessment of Q2 performance.

Year-to-date the stock is up 28%, so the investors will be beaming. Anyone looking for chinks in their armor — and there are plenty giving it a shot — right now focus on payer acceptance of their $2.1 million gene therapy Zolgensma, where it’s early days. And CAR-T continues to underperform, but Novartis doesn’t appear to be suffering from it.

So what could go wrong?

Actually, not much. But Tim Anderson at Wolfe pressed Narasimhan and his development chief John Tsai to pick which of two looming Phase III readouts with blockbuster implication had the better odds of success.

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Norbert Bischofberger. Kronos

Backed by some of the biggest names in biotech, Nor­bert Bischof­berg­er gets his megaround for plat­form tech out of MIT

A little over a year ago when I reported on Norbert Bischofberger’s jump from the CSO job at giant Gilead to a tiny upstart called Kronos, I noted that with his connections in biotech finance, that $18 million launch round he was starting off with could just as easily have been $100 million or more.

With his first anniversary now behind him, Bischofberger has that mega-round in the bank.

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Francesco De Rubertis

Medicxi is rolling out its biggest fund ever to back Eu­rope's top 'sci­en­tists with strange ideas'

Francesco De Rubertis built Medicxi to be the kind of biotech venture player he would have liked to have known back when he was a full time scientist.

“When I was a scientist 20 years ago I would have loved Medicxi,’ the co-founder tells me. It’s the kind of place run by and for investigators, what the Medicxi partner calls “scientists with strange ideas — a platform for the drug hunter and scientific entrepreneur. That’s what I wanted when I was a scientist.”

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Af­ter a decade, Vi­iV CSO John Pot­tage says it's time to step down — and he's hand­ing the job to long­time col­league Kim Smith

ViiV Healthcare has always been something unique in the global drug industry.

Owned by GlaxoSmithKline and Pfizer — with GSK in the lead as majority owner — it was created 10 years ago in a time of deep turmoil for the field as something independent of the pharma giants, but with access to lots of infrastructural support on demand. While R&D at the mother ship inside GSK was souring, a razor-focused ViiV provided a rare bright spot, challenging Gilead on a lucrative front in delivering new combinations that require fewer therapies with a more easily tolerated regimen.

They kept a massive number of people alive who would otherwise have been facing a death sentence. And they made money.

And throughout, John Pottage has been the chief scientific and chief medical officer.

Until now.

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Novotech CRO Ex­pands Chi­na Team as Biotech De­mand for Clin­i­cal Tri­als In­creas­es up to 79%

An increase in demand of up to 79% for clinical trials in China has prompted Novotech the Asia-Pacific CRO to rapidly expand the China team, appointing expert local clinical executives to their Shanghai and Hong Kong offices. The company is planning to expand their team by 30% over the next quarter.

Novotech China has seen considerable demand recently which is borne out by research from GlobalData:
A global migration of clinical research is occurring from high-income countries to low and middle-income countries with emerging economies. Over the period 2017 to 2018, for example, the number of clinical trial sites opened by biotech companies in Asia-Pacific increased by 35% compared to 8% in the rest of the world, with growth as high as 79% in China.
Novotech CEO Dr John Moller said China offers the largest population in the world, rapid economic growth, and an increasing willingness by government to invest in research and development.
Novotech’s 23 years of experience working in the region means we are the ideal CRO partner for USA biotechs wanting to tap the research expertise and opportunities that China offers.
There are over 22,000 active investigators in Greater China, with about 5,000 investigators with experience on at least 3 studies (source GlobalData).

On a glob­al romp, Boehringer BD team picks up its third R&D al­liance for Ju­ly — this time fo­cused on IPF with $50M up­front

Boehringer Ingelheim’s BD team is on a global deal spree. The German pharma company just wrapped its third deal in 3 weeks, going back to Korea for its latest pipeline pact — this time focused on idiopathic pulmonary fibrosis.

They’re handing over $50 million to get their hands on BBT-877, an ATX inhibitor from Korea’s Bridge Biotherapeutics that was on display at a science conference in Dallas recently. There’s not a whole lot of data to evaluate the prospects here.

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Servi­er scoots out of an­oth­er col­lab­o­ra­tion with Macro­Gen­ics, writ­ing off their $40M

Servier is walking out on a partnership with MacroGenics $MGNX — for the second time.

After the market closed on Wednesday MacroGenics put out word that Servier is severing a deal — inked close to 7 years ago — to collaborate on the development of flotetuzumab and other Dual-Affinity Re-Targeting (DART) drugs in its pipeline.

MacroGenics CEO Scott Koenig shrugged off the departure of Servier, which paid $20 million to kick off the alliance and $20 million to option flotetuzumab — putting a heavily back-ended $1 billion-plus in additional biobuck money on the table for the anti-CD123/CD3 bispecific and its companion therapies.

Den­mark's Gen­mab hits the jack­pot with $500M+ US IPO as small­er biotechs rake in a com­bined $147M

Danish drugmaker Genmab A/S is off to the races with perhaps one of the biggest biotech public listings in decades, having reaped over $500 million on the Nasdaq, as it positions itself as a bonafide player in antibody-based cancer therapies.

The company, which has long served as J&J’s $JNJ key partner on the blockbuster multiple myeloma therapy Darzalex, has asserted it has been looking to launch its own proprietary product — one it owns at least half of — by 2025.

FDA over­rides ad­comm opin­ions a fifth of the time, study finds — but why?

For drugmakers, FDA advisory panels are often an apprehended barometer of regulators’ final decisions. While the experts’ endorsement or criticism often translate directly to final outcomes, the FDA sometimes stun observers by diverging from recommendations.

A new paper out of Milbank Quarterly put a number on that trend by analyzing 376 voting meetings and subsequent actions from 2008 through 2015, confirming the general impression that regulators tend to agree with the adcomms most of the time — with discordances in only 22% of the cases.