FDA tells Sprout Phar­ma, like it or not the black box on Ad­dyi stays, but we will di­lute the warn­ing

When the con­tro­ver­sial first drug for low sex­u­al de­sire in women was fi­nal­ly grant­ed ap­proval in 2015, crit­ics ac­cused the FDA of bow­ing to pres­sure from ad­vo­cates by sanc­tion­ing the use of a drug that was found to be mar­gin­al­ly ef­fec­tive in clin­i­cal tri­als, and dan­ger­ous when tak­en with al­co­hol. On Thurs­day, the agency re­buked the mak­er of the drug, Ad­dyi, by re­fus­ing to en­ter­tain the com­pa­ny’s quest to dis­card the black box warn­ing car­ried by the treat­ment, but agreed to damp­en the strong warn­ing on the ba­sis of post­mar­ket­ing da­ta.

Ad­dyi, known chem­i­cal­ly as flibanserin, is de­signed for pre­menopausal women whose lack of sex­u­al de­sire caus­es dis­tress. Pa­tients who took Ad­dyi in a clin­i­cal tri­al had an in­crease of about one sex­u­al­ly sat­is­fy­ing event per month, ver­sus those giv­en a place­bo.

The pink pill — nick­named the “fe­male Vi­a­gra” — has lit­tle in com­mon with the Pfiz­er $PFE block­buster, which was ap­proved decades ago as the pi­o­neer­ing erec­tile dys­func­tion treat­ment. While Vi­a­gra im­pacts blood flow and is tak­en as-need­ed, Ad­dyi was de­signed to ac­ti­vate sex­u­al im­puls­es in the brain and must be tak­en every day.

In par­tic­u­lar, Ad­dyi’s la­bel car­ries a black box warn­ing, high­light­ing the risk of po­ten­tial­ly dan­ger­ous low blood pres­sure and faint­ing, no­tably when tak­en with al­co­hol.

On Thurs­day, the reg­u­la­tor made clear that Ad­dyi’s la­bel must be mod­i­fied to clar­i­fy there is still a con­cern about con­sum­ing al­co­hol close in time to tak­ing Ad­dyi, but that it does not have to be avoid­ed com­plete­ly. Af­ter an­a­lyz­ing da­ta from post­mar­ket­ing stud­ies, the FDA said the warn­ing in­side the black box should re­flect that women should dis­con­tin­ue drink­ing al­co­hol at least two hours be­fore tak­ing Ad­dyi at bed­time or to skip the dose that evening and that women should not con­sume al­co­hol at least un­til the morn­ing af­ter tak­ing Ad­dyi at bed­time.

The reg­u­la­tor has prover­bial­ly put its foot down and is com­pelling Ad­dyi mak­er Sprout Phar­ma­ceu­ti­cals to make the change af­ter the two par­ties were un­able to reach an agree­ment. “We work dili­gent­ly with com­pa­nies to make la­bel­ing up­dates but oc­ca­sion­al­ly are un­able to reach an agree­ment. In those rare cas­es…we have im­por­tant au­thor­i­ties to com­pel com­pa­nies to make safe­ty la­bel­ing changes that are crit­i­cal for the safe use of an ap­proved prod­uct,” the agency said in a state­ment.

Cindy Eck­ert and Robert White­head

Click on the im­age to see the full-sized ver­sion

The founders of Sprout Phar­ma­ceu­ti­cals have long had a strained re­la­tion­ship with the FDA. Chief Cindy White­head (now Cindy Eck­ert) co-found­ed the com­pa­ny with her then-hus­band Robert White­head in 2011, af­ter sell­ing an­oth­er drug com­pa­ny they had spawned to­geth­er af­ter it was is­sued mul­ti­ple FDA warn­ings re­lat­ed to its mar­ket­ing tac­tics.

Sprout pur­chased flibanserin from Ger­many’s Boehringer In­gel­heim, which orig­i­nal­ly de­vel­oped it and took it to the FDA, on­ly to be de­nied ap­proval in 2010. Un­der Sprout, the drug was eval­u­at­ed in ad­di­tion­al stud­ies, but the FDA re­ject­ed it again in 2013. In­censed by the re­jec­tion, Sprout — with the sup­port of some women’s groups —  ag­gres­sive­ly lob­bied the FDA to get the drug across the fin­ish line, by ac­cus­ing the US agency of gen­der bias (a charge the reg­u­la­tor de­nied).

The FDA fi­nal­ly ap­proved the treat­ment — with a boxed warn­ing — on Au­gust 19, 2015, the very next day Sprout an­nounced it was be­ing sold to Valeant (now Bausch Health) for a tidy $1 bil­lion. The hon­ey­moon didn’t last long — in 2017, an em­bat­tled Valeant re­turned Sprout to its orig­i­nal own­ers.

Last month, Sprout is­sued a cheer­ful press re­lease, sug­gest­ing post­mar­ket­ing da­ta in­di­cat­ed that treat­ment with Ad­dyi did not re­sult in faint­ing or hy­poten­sion that re­quired med­ical at­ten­tion. But the FDA took is­sue with that as­sess­ment, say­ing the safe­ty pre­cau­tions built in­to the tri­al did not al­low for an ad­e­quate as­sess­ment of this risk. “For ex­am­ple, women with low blood pres­sure while ly­ing down…were not per­mit­ted to stand up to have blood pres­sure mea­sure­ments tak­en or had to have re­peat­ed blood pres­sure mea­sure­ments while ly­ing down un­til they were high enough for the women to safe­ly stand up. As a re­sult, the da­ta col­lect­ed had miss­ing or de­layed blood pres­sure mea­sure­ments from these women while stand­ing.”

The reg­u­la­tor was al­so not sat­is­fied with how the post­mar­ket­ing tri­als were con­duct­ed, point­ing out that in one tri­al, there were “miss­ing or de­layed mea­sure­ments for blood pres­sure from when the women were first lay­ing down to when they stood up that are crit­i­cal in de­ter­min­ing the risk of hy­poten­sion and syn­cope when tak­ing Ad­dyi and al­co­hol to­geth­er.” The agency al­so flagged that many more women had miss­ing or de­layed blood pres­sure mea­sure­ments when they took Ad­dyi and al­co­hol to­geth­er, com­pared to when they con­sumed al­co­hol or Ad­dyi alone.

Al­to­geth­er, the “pat­tern of the miss­ing or de­layed mea­sure­ments” pro­vides fur­ther ev­i­dence of an in­ter­ac­tion be­tween Ad­dyi and al­co­hol that can en­hance the risk of hy­poten­sion and faint­ing, the agency un­der­scored.

Sprout must com­ply with the FDA’s la­bel­ing de­ci­sion or risk mon­e­tary fines and/or en­force­ment in the form of prod­uct seizure and in­junc­tion. The com­pa­ny has un­til April 16 to ap­peal.

End­points News has con­tact­ed Sprout for com­ment.

Im­age source: Allen G. Breed AP

Brian Kaspar. AveXis via Twitter

AveX­is sci­en­tif­ic founder fires back at No­var­tis CEO Vas Narasimhan, 'cat­e­gor­i­cal­ly de­nies any wrong­do­ing'

Brian Kaspar’s head was among the first to roll at Novartis after company execs became aware of the fact that manipulated data had been included in its application for Zolgensma, now the world’s most expensive therapy.

But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

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We­bi­nar: Re­al World End­points — the brave new world com­ing in build­ing fran­chise ther­a­pies

Several biopharma companies have been working on expanding drug labels through the use of real world endpoints, combing through the data to find evidence of a drug’s efficacy for particular indications. But we’ve just begun. Real World Evidence is becoming an important part of every clinical development plan, in the soup-through-nuts approach used in building franchises.

I’ve recruited a panel of 3 top experts in the field — the first in a series of premium webinars — to look at the practical realities governing what can be done today, and where this is headed over the next few years, at the prodding of the FDA.

ZHEN SU — Merck Serono’s Senior Vice President and Global Head of Oncology

ELLIOTT LEVY — Amgen’s Senior Vice President of Global Development

CHRIS BOSHOFF — Pfizer Oncology’s Chief Development Officer

A premium subscription to Endpoints News is required to attend this webinar. Please upgrade to either an Insider or Enterprise plan for access. Already have Endpoints Premium? Please sign-in below. You can contact our Subscriptions team at help@endpointsnews.com with any issues.

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As­traZeneca’s Imfinzi/treme com­bo strikes out — again — in lung can­cer. Is it time for last rites?

AstraZeneca bet big on the future of their PD-L1 Imfinzi combined with the experimental CTLA-4 drug tremelimumab. But once again it’s gone down to defeat in a major Phase III study — while adding damage to the theory involving targeting cancer with a high tumor mutational burden.

Early Wednesday the pharma giant announced that their NEPTUNE study had failed, with the combination unable to beat standard chemo at overall survival in high TMB cases of advanced non-small cell lung cancer. We won’t get hard data until later in the year, but the drumbeat of failures will call into question what — if any — future this combination can have left.

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UP­DAT­ED: Pay­back? An­a­lysts say Sarep­ta was blind­sided by an FDA re­jec­tion dri­ven by reg­u­la­to­ry re­venge

In one of the least anticipated moves of the year, the FDA has rejected Sarepta’s application for an accelerated approval of its Duchenne MD drug golodirsen after fretting over safety issues.

In a statement that arrived after the bell on Monday, Sarepta explained the CRL, saying:

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Levi Garraway. Broad Institute via Youtube

Roche raids Eli Lil­ly for its next chief med­ical of­fi­cer as San­dra Horn­ing plans to step down

We found out Monday morning where Levi Garraway was headed after he left Eli Lilly as head of oncology R&D a few days ago. Roche named Garraway as their new chief medical officer, replacing Sandra Horning, who they say is retiring from the company.

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Af­ter a posse of Wall Street an­a­lysts pre­dict a like­ly new win for Sarep­ta, we're down to the wire on a crit­i­cal FDA de­ci­sion

As Bloomberg notes, most of the Wall Street analysts that cover Sarepta $SRPT are an upbeat bunch, ready to cheer on the team when it comes to their Duchenne MD drugs, or offer explanations when an odd setback occurs — as happened recently with a safety signal that was ‘erroneously’ reported last week.

Ritu Baral Cowen
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FDA de­ci­sion on Ver­tex's CF triple will come just ahead of planned CEO shake­up

Vertex has clinched a priority review for the all-important cystic fibrosis triple that will blaze the trail for treating a large group of patients unhelped by its current drugs.

FDA regulators have set a PDUFA date of March 19, 2020, just a year after the Boston biotech posted positive Phase III results showing that people with two F508del mutations experienced statistically significant improvements in lung function after a 4-week regimen of VX-445, tezacaftor and ivacaftor. After reviewing 24-week data among patients with one F508del mutation and one minimal function mutation — and thoroughly comparing the VX-445 triple with another combo featuring VX-659 on scores like safety, drug-drug interactions, and photosensitivity — Vertex ultimately went with VX-445.

An MIT spin­out kills one of its ‘liv­ing ther­a­peu­tics’ af­ter flunk­ing an ear­ly-stage study — shares rout­ed

Just a few weeks after bagging $80 million in a deal to collaborate with Gingko Bioworks on its special blend of engineered bacteria used for “living therapeutics,” little Synlogic in Boston $SYBX is tossing one of its two clinical programs after watching an early-stage study go down in defeat.

Their Phase Ib/IIa study for SYNB1020 to counter the accumulation of ammonia in the body, a condition called hyperammonemia or urea cycle disorder, floundered at the interim readout, forcing the biotech to kill it and reserve its cash for pipeline therapies with greater potential.

Elan­co to buy Bay­er's an­i­mal health busi­ness for $7.6B, as deal­mak­ing gath­ers steam in the sec­tor

Last week, Elanco explicitly dodged answering questions about its rumored interest in Bayer’s animal health business in its post-earnings call. On Tuesday, the Eli Lilly spinoff disclosed it was purchasing the German drug maker’s veterinary unit in a cash-and-stock deal worth $7.6 billion. 

Elanco $ELAN has been busy on the deal-making front. In April, it laid out plans to swallow its partner, Kansas-based pet therapeutics company Aratana $PETX. A July report by Reuters suggested a potential Bayer deal was being explored, and Bloomberg last week said the deal was imminent, citing sources.