FDA of­fi­cials: There was “no sci­en­tif­ic ba­sis” for Duchenne drug OK as Sarep­ta com­plained of “dire fi­nan­cial” con­di­tion

Janet Wood­cock

Two se­nior FDA of­fi­cials mount­ed a ve­he­ment as­sault on Janet Wood­cock’s de­ci­sion to push through an ap­proval of Sarep­ta’s Duchenne mus­cu­lar dy­s­tro­phy drug Ex­ondys 51. New doc­u­ments post­ed by the FDA, in­clud­ing a round of mem­os on the is­sue in Sep­tem­ber, warned FDA Com­mis­sion­er Robert Califf that he was al­low­ing an ap­proval even though Wood­cock had not con­sid­ered all the analy­sis they had done to un­der­score the com­pa­ny’s weak case, adding that there was no sci­en­tif­ic ba­sis to con­clude that the drug was rea­son­ably like­ly to ben­e­fit pa­tients.

The agency has al­ready post­ed some of the mem­os of­fered up in the lead-up to the ap­proval de­ci­sion, along with Califf’s de­ci­sion that he would de­fer to Wood­cock, who over­ruled the agency’s re­view­ers as well as Lu­ciano Bo­rio and El­lis Unger, the act­ing chief sci­en­tist and di­rec­tor of the Of­fice of Drug Eval­u­a­tion at the FDA. But these mem­os from Sep­tem­ber hit hard on their con­clu­sion that Wood­cock was de­vi­at­ing wide­ly from the agency’s stan­dards for an ap­proval in al­low­ing Ex­ondys 51 on the mar­ket af­ter the biotech had pro­vid­ed on­ly a “mere scin­til­la” of ev­i­dence of ef­fi­ca­cy.

Robert Califf

In a memo to Califf on Sep­tem­ber 14, Unger wrote that he had con­duct­ed an analy­sis of the ev­i­dence on dy­s­trophin pro­duc­tion, which Wood­cock did not take in­to con­sid­er­a­tion be­fore reach­ing her de­ci­sion:

I think it will be im­por­tant for the reg­u­la­to­ry record to re­flect that there was no sci­en­tif­ic ba­sis un­der­ly­ing the con­clu­sion of “rea­son­ably like­ly” in this case. This was sim­ply a judg­ment call by Dr. Wood­cock. (Dr. Wood­cock might have al­so tak­en the po­si­tion that, in this des­per­ate pa­tient pop­u­la­tion, any dy­s­trophin pro­duc­tion would suf­fice as a ba­sis for ac­cel­er­at­ed ap­proval, but she didn’t state this.)

In Unger’s opin­ion, the FDA al­so need­ed to more care­ful­ly con­sid­er the im­pact the de­ci­sion on eteplirsen would have on oth­er rare dis­ease drug ap­pli­ca­tions:

We all agree that each sit­u­a­tion must be eval­u­at­ed on its own mer­its; how­ev­er, I fail to see how DMD dif­fers in­trin­si­cal­ly from oth­er rare neu­ro­log­i­cal dis­eases, e.g., Alexan­der dis­ease, Cana­van dis­ease, Ear­ly in­fan­tile GM1 gan­gliosi­do­sis, Krabbe dis­ease, Metachro­mat­ic leukody­s­tro­phy, Nie­mann–Pick dis­ease, Pelizaeus–Merzbach­er dis­ease, Pompe dis­ease, Sand­hoff dis­ease, and X- linked adrenoleukody­s­tro­phy. Based on what you have writ­ten in your draft memo, it is not clear to me why a stan­dard of any in­crease in the sur­ro­gate end­point wouldn’t ap­ply for these dis­eases.

“Per­haps grant­i­ng ac­cel­er­at­ed ap­proval to drugs that show a mere scin­til­la of an ef­fect on a sur­ro­gate end­point rep­re­sents a stroke of bril­liance – one that will stim­u­late in­vest­ment in the de­vel­op­ment of drugs for these dis­or­ders. But in my opin­ion, this ap­proach should re­ceive broad­er pub­lic (and FDA) in­put be­fore be­ing im­ple­ment­ed.

Unger al­so not­ed:

Her (Wood­cock’s) is­suance of a de­ci­sion­al mem­o­ran­dum pri­or to care­ful con­sid­er­a­tion of my fi­nal re­view rep­re­sents a crit­i­cal de­vi­a­tion from pro­to­col….

Un­aware of my fi­nal con­clu­sions on this mat­ter, Dr. Wood­cock did not re­but the above rea­son­ing. As I not­ed (and the SDR Board ap­peared to agree), she pro­vid­ed no co­gent ra­tio­nale for her de­ci­sion that the bare­ly de­tectable amount of dy­s­trophin pro­duced is “rea­son­ably like­ly to pre­dict clin­i­cal ben­e­fit.

Calif, though, had al­ready made up his mind the day be­fore:

I have con­clud­ed that al­though I be­lieve that both views are ra­tio­nal and re­flect ex­tra­or­di­nary ded­i­ca­tion to the top­ic, there is no ba­sis up­on which I should over­rule Dr. Wood­cock’s de­ci­sion, and that ad­di­tion­al ex­ter­nal re­view is not in­di­cat­ed.

Lu­ciano Bo­ria, the act­ing chief sci­en­tist, al­so crit­i­cized Califf for fail­ing to grap­ple with the “mi­nus­cule” amount of da­ta that Sarep­ta had of­fered. In a memo dat­ed Sep­tem­ber 14, Bo­rio wrote Califf:

(Y)our draft de­ci­sion­al memo seems to down­play the sig­nif­i­cance of the very small amount of dy­s­trophin re­port­ed in the eteplirsen NDA (see, e.g., pages 4-5 of your draft de­ci­sion­al memo). In fact, your draft de­ci­sion­al memo nev­er once cites the 0.3% in­crease in dy­s­trophin pro­duc­tion shown by Study 301 (or the 0.93% de­tect­ed in Stud­ies 201/202). In­stead, your draft de­ci­sion­al memo at­trib­ut­es the sci­en­tif­ic dis­agree­ment to: (1) a lack of con­sen­sus on the ap­pro­pri­ate thresh­old for clin­i­cal ben­e­fit both with­in CDER and in the sci­en­tif­ic lit­er­a­ture, and (2) con­cerns re­gard­ing the cor­re­la­tion be­tween dy­s­trophin pro­duc­tion and clin­i­cal out­comes in Study 201/202. To me, the crux of the dis­agree­ment is not whether there is an ap­pro­pri­ate thresh­old, but whether such a minis­cule (sic) amount of dy­s­trophin is rea­son­ably like­ly to pre­dict clin­i­cal ben­e­fit. Your draft de­ci­sion­al memo does not ad­dress that is­sue. In my view, it is not suf­fi­cient to say that no thresh­old has been es­tab­lished and that, there­fore, any in­crease in dy­s­trophin pro­duc­tion is rea­son­ably like­ly to pre­dict clin­i­cal ben­e­fit.

In the months ahead of the show­down in­side the FDA, reg­u­la­tors re­peat­ed­ly ex­pressed their will­ing­ness to help speed the work they asked for to pro­vide ad­di­tion­al ev­i­dence of dy­s­trophin pro­duc­tion, which pro­voked Sarep­ta’s Shamim Ruff, their head of reg­u­la­to­ry af­fairs, to fret about the “dire fi­nan­cial con­straints” the com­pa­ny was forced to deal with as a re­sult of the de­lays at the FDA.

“We must start the process by June 6, 2016,” Ruff wrote.”There is no room for flex­i­bil­i­ty with this date due to our dire fi­nan­cial con­straints as a re­sult of the on­go­ing de­lays.”

Here’s a look at all the doc­u­ments re­leased by the FDA:

Albert Bourla appears before the Senate Committee on Finance for a hearing on prescription drug pricing on Capitol Hill in Washington, DC, February 26, 2019. Chris Kleponis for CNP via AP Images

UP­DAT­ED: Pfiz­er CEO Al­bert Bourla is back in the M&A game, but why is he pay­ing $11.4B for Ar­ray?

Pfiz­er $PFE has cut short its time on the side­lines of bio­phar­ma M&A.

Mon­day morn­ing the phar­ma gi­ant un­veiled an $11.4 bil­lion deal to ac­quire Ar­ray Bio­Phar­ma, beef­ing up its on­col­o­gy work and adding a new re­search hub in Boul­der, Col­orado to its glob­al op­er­a­tions.

At $48 a share, Ar­ray $AR­RY in­vestors will be get­ting a 62% pre­mi­um off the Fri­day close of $29.59.

Pfiz­er, which has strug­gled to gain all the up­side promised in past buy­outs like Medi­va­tion, high­light­ed the ac­qui­si­tion of 2 ap­proved drugs in the deal — Braftovi (en­co­rafenib) and Mek­tovi (binime­tinib).

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Gene ther­a­py R&D deals turn red hot as Big Phar­ma steps up to play

This September will mark the 20th anniversary of the death of Jesse Gelsinger, a young man suffering from X-linked genetic disease of the liver. He was killed in a gene therapy study conducted by Penn’s James Wilson, and the entire field endured a lengthy deep freeze as the field grappled with the safety issues inherent in the work.

Some thought gene therapy R&D would never survive. But it did. And this year marked a landmark approval for Zolgensma, a new gene therapy for spinal muscular atrophy Novartis priced at $2.1 million.

“Gene therapy is the hottest item on the block now. But there was a time when we first got into this trial, where there wasn’t a person in the world who believed that gene therapy would work. We have to remember that,” noted gene therapy investigator Jerry Mendell told SMA News Today.

We’re still right on the pioneering frontier when it comes to getting approvals for gene therapies and launching marketing campaigns with the European green light for bluebird's leading program last Friday underscoring the nascent nature of the field. But gene therapy R&D is booming, and has been for several years now.

The rapid growth of gene therapy clinical development is well known, but we decided to put some numbers on it, to quantify what’s going on. DealForma chief Chris Dokomajilar took a lot over the past 10 years, as the number of deals, R&D partnerships and buyouts steadily gained steam, spiking last year and on track to maintain the surge in 2019.

The upfronts and totals for the dollars on deals so far in 2019 is already close to the 2018 mark, underscoring a new phase of negotiations as the major players step up to gain a piece of the late-stage and commercial action.

Once again, we’re looking at an “overnight” biotech success story, decades in the making.

At some point, that may start to brake the numbers we’re seeing. But for now, as rivals line up to compete for frontline prominence across a range of diseases, the arrows are all pointed north.

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A uni­corn stalks Wall Street in search of IPO cash; CASI Phar­ma in-li­cens­es CD19 ther­a­py from Chi­na’s Ju­ven­tas

→ A herd of up­start biotechs will look to Wall Street for some ma­jor wind­falls this week as a burst of new of­fer­ings con­tin­ues to feed cash in­to the R&D sys­tem. To­day we learned that Bridge­Bio will look to raise in the neigh­bor­hood of $225 mil­lion by of­fer­ing 15 mil­lion shares for $14 to $16 each. And they have a string of joint bookrun­ners: J.P. Mor­gan, Gold­man Sachs, Jef­feries, SVB Leerink, KKR, Piper Jaf­fray, Mizuho Se­cu­ri­ties, BMO Cap­i­tal Mar­kets and Ray­mond James. If suc­cess­ful, Bridge­Bio will emerge with a mar­ket cap of around $1.7 bil­lion. There are 5 biotechs look­ing to IPO this week, in­clud­ing Akero and Pre­vail.

UP­DAT­ED: Sanofi Gen­zyme deserts gene ther­a­py de­vel­op­er Voy­ager Ther­a­peu­tics

While gene ther­a­py com­pa­nies re­joice as the sec­tor gains trac­tion with ap­provals and a flur­ry of M&A ac­tiv­i­ty, one play­er is feel­ing the heat.

Back in 2015, Voy­ager Ther­a­peu­tics joined forces with Sanofi Gen­zyme in a deal worth up to $845 mil­lion ($100 mil­lion up­front + a po­ten­tial $745 mil­lion in mile­stones) to co-de­vel­op gene ther­a­pies for se­vere cen­tral ner­vous sys­tem dis­or­ders. But two years lat­er, the French drug­mak­er re­treat­ed, elect­ing to not pick up the op­tion to work on Voy­ager’s Parkin­son’s dis­ease pro­gram. (Last year, the FDA dis­ap­point­ed Voy­ager, telling the com­pa­ny that it was not open to an ac­cel­er­at­ed fil­ing on the Parkin­son’s drug on the ba­sis of Phase II da­ta — in­stead of re­quir­ing an ad­di­tion­al piv­otal study.)

In­vestors fret as VBI's hep B vac­cine fails key sec­ondary PhI­II study goal

Sobered by mount­ing costs, Dy­navax $DVAX last month made the de­ci­sion to fo­cus all its re­sources on its 2017-ap­proved he­pati­tis B vac­cine Hep­lisav-B, which ri­vals and su­per­sedes the ef­fi­ca­cy and con­ve­nience pro­file of GSK’s $GSK es­tab­lished En­ger­ix-B. The Cal­i­for­nia-based com­pa­ny will be on the look­out for an­oth­er com­peti­tor — VBI Vac­cines, which on Mon­day un­veiled late-stage da­ta on its hep B vac­cine: Sci-B-Vac.

John Oyler, Founder & CEO of BeiGene, at the US-China Biopharma Innovation and Investment Summit in Shanghai on October 23, 2018; Credit: Endpoints News, PharmCube

UP­DAT­ED: As Bris­tol-My­ers/Cel­gene tie up loose ends, BeiGene pock­ets $150M from PD-1 breakup

As soon as Bristol-Myers Squibb announced its $74 billion buyout for Celgene, BeiGene emerged as a prominent example of a player whose pact with the big biotech could sour, as its PD-1 candidate seems to overlap with Opdivo. After six months of suspense, the partners say they are finally bringing the 2-year-old deal to an amicable end.

BeiGene $BGNE gets $150 million for the termination in addition to full global rights to tislelizumab. In 2017 Celgene had paid $263 million in upfront license fees to develop the PD-1 inhibitor for solid cancers in the US, Europe, Japan and the rest of the world outside Asia. It also threw in a $150 million equity investment in exchange for BeiGene handling its commercial operations — think Abraxane, Revlimid and Vidaza — in China.

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Exterior of the 1 million square foot Discovery Labs in Upper Merion, PA (PR Newswire)

Philadel­phia cham­pi­ons life sci­ences 'co-work­ing,' re­viv­ing for­mer GSK cam­pus in $500M makeover

In a boost to Philadel­phia’s thriv­ing life sci­ences scene, a for­mer Glax­o­SmithK­line cam­pus and a near­by site has been turned in­to what its de­vel­op­er calls “the largest cowork­ing ecosys­tem” for health­care com­pa­nies in the coun­try.

The Dis­cov­ery Labs, a com­pa­ny spawned by MLP Ven­tures, has se­lect­ed two lo­ca­tions in the King of Prus­sia area as the $500 mil­lion test case for its strat­e­gy of ac­quir­ing and con­vert­ing old phar­ma­ceu­ti­cal R&D fa­cil­i­ties world­wide. The sites add up to 1.64 mil­lion square feet.

Gene ther­a­pies seize the top of the list of the most ex­pen­sive drugs on the plan­et — and that trend has just be­gun

Anyone looking for a few simple reasons why the gene therapy field has caught fire with the pharma giants need only look at the new list of the 10 most expensive therapies from GoodRx.

Two recently approved gene therapies sit atop this list, with Novartis’ Zolgensma crowned the king of the priciest drugs at $2.1 million. Right below is Luxturna, the $850,000 pioneer from Spark, which Roche is pushing hard to acquire as it adds a gene therapy group to the global mix.

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Ted Love. HAVERFORD COLLEGE

Glob­al Blood Ther­a­peu­tics poised to sub­mit ap­pli­ca­tion for ac­cel­er­at­ed ap­proval, with new piv­otal da­ta on its sick­le cell dis­ease drug

Global Blood Therapeutics is set to submit an application for accelerated approval in the second-half of this year, after unveiling fresh data from a late-stage trial that showed just over half the patients given the highest dose of its experimental sickle cell disease drug experienced a statistically significant improvement in oxygen-wielding hemoglobin, meeting the study's main goal.

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