Now that Sarep­ta has bolt­ed out of the barn, the FDA wants to shut the door

John Jenk­ins, Di­rec­tor, Of­fice of New Drugs

Now that the FDA has capped Sarep­ta’s long and con­tro­ver­sial cam­paign to win an ap­proval for its Duchenne mus­cu­lar dy­s­tro­phy drug with an ac­cel­er­at­ed ap­proval, FDA of­fi­cials would like to send a very clear mes­sage to any oth­er biotech look­ing to slug their way for­ward us­ing the same tac­tics: For­get about it.

In a pre­sen­ta­tion at a sum­mit meet­ing of the Na­tion­al Or­ga­ni­za­tion of Rare Dis­eases on Tues­day, John Jenk­ins, di­rec­tor of the of­fice of new drugs at the Cen­ter for Drug Eval­u­a­tion and Re­search, sin­gled out the eteplirsen case as a new text­book ex­am­ple of what oth­er com­pa­nies should avoid.

“Path tak­en by Sarep­ta NOT a good mod­el for oth­er de­vel­op­ment pro­grams,” de­clared one of Jenk­ins’ talk­ing points un­der a fi­nal sec­tion marked “lessons learned” from eteplirsen and oth­er cas­es.

What fol­lowed was a litany of sins that FDA in­sid­ers have laid at the door of Sarep­ta, which gained the FDA’s stamp of ap­proval to sell Ex­ondys 51 for $300,000 a year, de­spite the heat­ed ob­jec­tions raised by se­nior of­fi­cials over the lack of safe­ty and ef­fi­ca­cy da­ta laced with barb ob­jec­tions over what was pre­sent­ed. In the end, Sarep­ta was able to gain an ap­proval af­ter pa­tient ad­vo­cates and in­flu­en­tial play­ers in Wash­ing­ton DC de­mand­ed it, with lit­tle more than da­ta from a tiny study that was re­peat­ed­ly chal­lenged by re­view­ers but en­dorsed by Janet Wood­cock and per­mit­ted by Com­mis­sion­er Robert Califf.

Jenk­ins had quite a few points to make, and they re­flect­ed the laun­dry list of is­sues that the agency had spot­light­ed to crit­i­cize Sarep­ta re­peat­ed­ly over the course of its re­view and a de­fense of its po­si­tion in light of the biotech’s chal­lenge, plus a few new ones. The FDA, he said, want­ed to make clear that bad­ly planned pro­grams could on­ly de­lay a re­view and OK; as­says, par­tic­u­lar­ly ones that re­ly on in­va­sive pro­ce­dures with chil­dren, need to be well val­i­dat­ed; stud­ies need to be care­ful­ly blind­ed and ran­dom­ized; ev­i­dence of an im­pact on bio­mark­ers has to be care­ful­ly eval­u­at­ed, ex­clud­ing ‘any’ ef­fect that might reg­is­ter, re­view­ers should not be sub­ject­ed to at­tacks, and so on.

Since Sarep­ta won an ap­proval for eteplirsen, there have been some se­ri­ous con­cerns that the FDA has low­ered its stan­dards to the point that more com­pa­nies were like­ly to fol­low suit, wag­ing a lob­by­ing cam­paign to back in­ad­e­quate tri­al re­sults. NYU bioethi­cist Art Ca­plan told End­points re­cent­ly that more de­vel­op­ers are bound to use Sarep­ta as a role mod­el, not­ing that the in­dus­try and reg­u­la­tors need to come up with a new set of rules that could make some sense when it comes to more such pitch­es on the rare dis­ease front.

Jenk­ins, though, wants to hold the line with a more tra­di­tion­al ap­proach, leav­ing Sarep­ta as the ex­cep­tion that could help prove the rule.

Here’s the full man­i­festo:

• A poor­ly planned and ex­e­cut­ed de­vel­op­ment pro­gram for a rare dis­ease mis­us­es valu­able pa­tient re­sources and serves to de­lay ob­tain­ing the knowl­edge re­quired to un­der­stand the ben­e­fits and risks of a drug to sup­port reg­u­la­to­ry re­view and ap­proval

• FDA pro­vides valu­able ad­vice and guid­ance to spon­sors, we can­not re­quire spon­sors to fol­low our ad­vice

Path tak­en by Sarep­ta NOT a good mod­el for oth­er de­vel­op­ment pro­grams

• As­says for bio­mark­ers should be well val­i­dat­ed be­fore use to avoid ob­tain­ing mis­lead­ing in­for­ma­tion and wast­ing clin­i­cal spec­i­mens

• Par­tic­u­lar­ly true when in­va­sive pro­ce­dure re­quired to col­lect tis­sue in chil­dren

• Rig­or­ous blind­ing and con­trol pro­ce­dures should be in place to min­i­mize bias in as­say in­ter­pre­ta­tion

• Pro­to­col should spec­i­fy blind­ing pro­ce­dures, ad­ju­di­ca­tion meth­ods, in­de­pen­dence of read­ers, etc.

• In many cas­es, ran­dom­ized con­trolled clin­i­cal tri­als rep­re­sent the fastest way to de­ter­mine if a drug is ef­fec­tive

• Ran­dom­ize as ear­ly as pos­si­ble in de­vel­op­ment to avoid po­ten­tial­ly mis­lead­ing and un­in­ter­pretable find­ings from open-la­bel tri­als

• Em­ploy meth­ods to lim­it time on place­bo (e.g., dose-re­sponse, de­layed start, ran­dom­ized with­draw­al, in­ter­im analy­sis)

• Re­port ear­ly tri­al re­sults ac­cu­rate­ly, post hoc analy­ses of failed tri­als are gen­er­al­ly hy­poth­e­sis gen­er­at­ing for next tri­al, not ev­i­dence to sup­port ap­proval

• Knowl­edge of nat­ur­al his­to­ry of dis­ease crit­i­cal to in­tel­li­gent de­sign of clin­i­cal tri­als

• Con­duct nat­ur­al his­to­ry tri­als be­fore clin­i­cal tri­als be­gin

• If a nat­ur­al his­to­ry ex­ter­nal con­trol group is pro­posed, it should be iden­ti­fied prospec­tive­ly to en­sure com­pa­ra­bil­i­ty to treat­ment group

• Nat­ur­al his­to­ry ex­ter­nal con­trol group cre­at­ed post hoc is very dif­fi­cult to in­ter­pret, un­less ef­fect of test drug is very large, due to known and un­known con­found­ing

• Use of ac­cel­er­at­ed ap­proval path­way should be prospec­tive­ly planned, NOT as a “res­cue” for a failed pro­gram

• Spon­sor and FDA should agree on the sur­ro­gate and drug ef­fect con­sid­ered “rea­son­ably like­ly” to pre­dict clin­i­cal ben­e­fit be­fore un­blind­ing da­ta

• “Any” ef­fect of a drug on a bio­mark­er is not a ba­sis for AA

• Ide­al­ly, the con­fir­ma­to­ry tri­al to fur­ther de­fine clin­i­cal ben­e­fit should be start­ed be­fore AA is grant­ed to en­sure the tri­al will be com­plet­ed in a time­ly man­ner

• FDA wel­comes the en­gage­ment of pa­tients and care­givers in help­ing to de­sign de­vel­op­ment pro­grams that will re­sult in drugs that pro­vide mean­ing­ful clin­i­cal ben­e­fit to those with dis­ease

• Ap­proval de­ci­sions must be based on da­ta from ad­e­quate and well-con­trolled clin­i­cal tri­als, which may in­clude PROs and oth­er pa­tient-de­rived mea­sures

• Ex­pe­ri­ence of pa­tients en­rolled in tri­als can be very help­ful; dis­cor­dant re­sults be­tween tri­al da­ta and pa­tient anec­dotes are very hard to rec­on­cile

• FDA re­view­ers are com­mit­ted to fa­cil­i­tat­ing de­vel­op­ment of ef­fec­tive and safe drugs for rare dis­eases

• Up­hold­ing statu­to­ry stan­dards for ap­proval in face of hopes and de­sires of pa­tients, fam­i­lies, spon­sors, and in­vestors is a very dif­fi­cult job

• Per­son­al at­tacks on FDA re­view­ers cre­ates an at­mos­phere of dis­trust and iso­la­tion rather than col­lab­o­ra­tion

• Re­cruit­ment and re­ten­tion of qual­i­fied re­view staff is very chal­leng­ing in such an en­vi­ron­ment

Nick Leschly via Getty

UP­DAT­ED: Blue­bird shares sink as an­a­lysts puz­zle out $1.8M stick­er shock and an un­ex­pect­ed de­lay

Blue­bird bio $BLUE has un­veiled its price for the new­ly ap­proved gene ther­a­py Zyn­te­glo (Lenti­Glo­bin), which came as a big sur­prise. And it wasn’t the on­ly un­ex­pect­ed twist in to­day’s sto­ry.

With some an­a­lysts bet­ting on a $900,000 price for the β-tha­lassemia treat­ment in Eu­rope, where reg­u­la­tors pro­vid­ed a con­di­tion­al ear­ly OK, blue­bird CEO Nick Leschly said Fri­day morn­ing that the pa­tients who are suc­cess­ful­ly treat­ed with their drug over 5 years will be charged twice that — $1.8 mil­lion — on the con­ti­nent. That makes this drug the sec­ond most ex­pen­sive ther­a­py on the plan­et, just be­hind No­var­tis’ new­ly ap­proved Zol­gens­ma at $2.1 mil­lion, with an­a­lysts still wait­ing to see what kind of pre­mi­um can be had in the US.

News­mak­ers at #EHA19: Re­gen­eron, Ar­Qule track progress on re­sponse rates

Re­gen­eron’s close­ly-watched bis­pe­cif­ic con­tin­ues to ring up high re­sponse rates

Re­gen­eron’s high-pro­file bis­pe­cif­ic REGN1979 is back in the spot­light at the Eu­ro­pean Hema­tol­ogy As­so­ci­a­tion sci­en­tif­ic con­fab. And while the stel­lar num­bers we saw at ASH have erod­ed some­what as more blood can­cer pa­tients are eval­u­at­ed, the re­sponse rates for this CD3/CD20 drug re­main high.

A to­tal of 13 out of 14 fol­lic­u­lar lym­phomas re­spond­ed to the drug, a 93% ORR, down from 100% at the last read­out. In 10 out of 14, there was a com­plete re­sponse. In dif­fuse large B-cell lym­phoma the re­sponse rate was 57% among pa­tients treat­ed at the 80 mg to 160 mg dose range. They were all com­plete re­spons­es. And 2 of these Cars were for pa­tients who had failed CAR-T ther­a­py.

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.

Endpoints News

Basic subscription required

Unlock this story instantly and join 53,000+ biopharma pros reading Endpoints daily — and it's free.

Neil Woodford, Woodford Investment Management via YouTube

Un­der siege, in­vest­ment man­ag­er Wood­ford faces an­oth­er in­vest­ment shock

Em­bat­tled UK fund man­ag­er Neil Wood­ford — who has con­tro­ver­sial­ly blocked in­vestors from pulling out from his flag­ship fund to stem the blood­let­ting, af­ter a slew of dis­ap­point­ed in­vestors fled fol­low­ing a se­ries of sour bets — is now pay­ing the price for his ac­tions via an in­vestor ex­o­dus on an­oth­er fund.

Har­g­reaves Lans­down, which has in the past sold and pro­mot­ed the Wood­ford funds via its re­tail in­vest­ment plat­form, has re­port­ed­ly with­drawn £45 mil­lion — its en­tire po­si­tion — from the in­vest­ment man­ag­er’s In­come Fo­cus Fund.

Search­ing for the next block­buster to fol­low Darza­lex, J&J finds a $150M an­ti-CD38 drug from part­ner Gen­mab

Now that J&J and Genmab have thrust Darzalex onto the regulatory orbit for first-line use in multiple myeloma, the partners are lining up a deal for a next-gen follow-on to the leading CD38 drug.


Janssen — J&J’s biotech unit — has its eyes on HexaBody-CD38, a preclinical compound generated on Genmab’s tech platform designed to make drugs more potent via hexamerization.


Genmab is footing the bill on studies in multiple myeloma and diffuse large B-cell lymphoma; once it completes clinical proof of concept, Janssen has the option to license the drug for a $150 million exercise fee. There’s also $125 million worth of milestones in play.

Endpoints News

Basic subscription required

Unlock this story instantly and join 53,000+ biopharma pros reading Endpoints daily — and it's free.

Turns out, Rudy Tanzi did­n't see much of a sto­ry about a hid­den link be­tween En­brel and Alzheimer's ei­ther

The Wash­ing­ton Post man­aged to whip up the quick­est in­dus­try con­sen­sus I’ve ever seen that one of its re­porters was pur­vey­ing overblown non­sense with a sto­ry that Pfiz­er was sit­ting on da­ta sug­gest­ing that En­brel could be an ef­fec­tive treat­ment for Alzheimer’s. 

In cov­er­ing that bit of an­ti-Big Phar­ma fan­ta­sy — there are lots of rea­sons to go af­ter phar­ma, but this piece was lu­di­crous — I not­ed com­ments in the sto­ry from some promi­nent peo­ple in the field crit­i­ciz­ing Pfiz­er for not pub­lish­ing the da­ta. I sin­gled out Rudy Tanzi at Har­vard and then ap­plied some added crit­i­cism for the things he’s done to hype — in my opin­ion — high­ly ques­tion­able as­sump­tions. You can see it in the link. 

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.

Endpoints News

Basic subscription required

Unlock this story instantly and join 53,000+ biopharma pros reading Endpoints daily — and it's free.

Savara shares are crushed as PhI­II tri­al flunks pri­ma­ry, key sec­on­daries — but they can’t stop be­liev­ing

In­vestors are in no mood to hear biotechs tout the suc­cess of a “key” sec­ondary end­point when the piv­otal Phase III flunks the pri­ma­ry goal. Just ask Savara. 

The Texas biotech $SVRA went look­ing for a sil­ver lin­ing as com­pa­ny ex­ecs blunt­ly con­ced­ed that Mol­gradex, an in­haled for­mu­la­tion of re­com­bi­nant hu­man gran­u­lo­cyte-macrophage colony-stim­u­lat­ing fac­tor (GM-CSF), failed to spur sig­nif­i­cant­ly im­proved treat­ment out­comes for pa­tients with a rare res­pi­ra­to­ry dis­ease called au­toim­mune pul­monary alve­o­lar pro­teinosis, or aPAP.

As an­oth­er an­tibi­otics biotech sinks in­to a cri­sis, warn­ings of a sec­tor ‘col­lapse’

Another antibiotics company is scrambling to survive today, forcing the company’s founding CEO to exit in a reorganization that eliminates its research capabilities as the survivors look to improve on minuscule sales of their newly approved treatment. And the news — on top of an alarming series of failures — spurred at least one figure in the field to warn of a looming collapse of the antimicrobial resistance research field.

Endpoints News

Basic subscription required

Unlock this story instantly and join 53,000+ biopharma pros reading Endpoints daily — and it's free.