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

Image courtesy of The Janssen Pharmaceutical Companies of Johnson & Johnson.

Pro­tect­ing the glob­al phar­ma­ceu­ti­cal in­no­va­tion ecosys­tem – what’s at stake?

We are living in a new era of healthcare that is rapidly advancing progress impacting patient outcomes and experiences. We’ve seen a remarkable pace of transformational innovation, applied research, and advanced clinical development over the last decade.

Despite this tremendous progress, there is much more work to be done, and patients are counting on us – now more than ever – to continue that momentum. At the heart of our industry is a focus on developing and delivering medicines for some of the world’s most challenging diseases, including those that have few or no effective treatments today.

Roger Perlmutter, Eikon Therapeutics CEO

Roger Perl­mut­ter builds Eikon's pipeline with deal-mak­ing flur­ry, rais­ing $106M more

Eikon Therapeutics announced three business development deals on Thursday, effectively dropping in a pipeline of cancer drugs alongside more than $100 million in fresh funding.

The Hayward, CA-based company has become one of biotech’s richest startups since its 2019 founding, having raised nearly $775 million. It’s developing a massive, automated research approach built around Nobel Prize-winning microscope science to peer inside cells and watch proteins in action. After its Series B last year, PitchBook reported a $3.02 billion valuation. And while CEO Roger Perlmutter declined to comment on that figure, he said its first tranche of nearly $106 million in Series C funding is a “meaningful step-up to our Series B valuation.”

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Who's con­fi­dent­ly in­vest­ing in biotech star­tups dur­ing these tense days? We've got some an­swers

We’ve got a changeup to our event schedule in Boston next week, where we’ll be doing a mix of live/streaming events at our base at The Seaport Hotel as part of a two-day lineup of webinars, virtual firesides and a cocktail hour Q&A with a veteran of the biotech financing scene.

The 9:30-10:30 am ET live slot on Tuesday, June 6, will now feature a panel conversation on the current state of affairs for VC investing in biotech, focusing on what startups are getting cash — and how. Alaa Halawa, head of US ventures at Mubadala, is confirmed, along with Brian Goodman at MPM and Geoff von Maltzahn, a general partner at Moderna-buoyed Flagship. I have a couple of other invites out and will let you know how that plays out.

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Eu­ro­pean Par­lia­ment calls mem­ber states to ac­tion on an­timi­cro­bial re­sis­tance

Members of the European Parliament have called on EU countries to develop national action plans against antimicrobial resistance (AMR), calling it a top-three priority health threat.

Parliament on Thursday announced recommendations for the fight against AMR, including national action plans that must be updated at least every two years, an EU-level database tracking AMR and antimicrobial use and increased partnership between the pharma industry, patient groups and academia.

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Andrey Zarur, GreenLight Biosciences CEO

Green­Light Bio­sciences se­cures merg­er as it looks to go pri­vate

GreenLight Bioscience, the developer and manufacturer of RNA vaccines and therapeutics, is set to be acquired.

The company announced earlier this week that it would be acquired by a group of buyers led by Fall Line Capital in a cash deal valuing GreenLight at around $45.5 million. According to a release, Fall Line and the group agreed to acquire all of the shares of the company for $0.30 per share. The deal is expected to close sometime in the third quarter of this year.

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Roche plans to di­vest from lega­cy Genen­tech man­u­fac­tur­ing fa­cil­i­ty in Cal­i­for­nia

Roche is planning to make some changes to its subsidiary’s manufacturing network in California.

The Swiss pharma announced Wednesday that it plans to divest from Genentech’s manufacturing facility in Vacaville, CA, around 58 miles northeast of San Francisco. According to a statement from Roche, the move is part of a “broader strategy” to bring its manufacturing capabilities in line with its future pipeline. Roche is starting the process of finding a buyer for the site but has not named any candidates yet.

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FDA lifts hold on Mol­e­c­u­lar Tem­plates’ mul­ti­ple myelo­ma tri­al af­ter less than two months

The FDA has lifted a partial clinical hold on Molecular Templates’ early-stage trial for a multiple myeloma drug, the biotech company announced Thursday morning.

Regulators had put the trial on partial hold in early April, pausing patient enrollment, following two adverse heart-related events in patients who received the highest dose of Molecular Templates’ treatment MT-0169 last year. One patient had asymptomatic grade 2 myocarditis, or heart muscle inflammation, while the other had a grade 3 cardiomyopathy. Both recovered within two months.

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Peter van de Sande, Synaffix CEO

Lon­za shells out $107M cash to snap up Synaf­fix and its ADC plat­form

After lining up a string of partnerships over the years, Dutch antibody-drug conjugate specialist Synaffix has found a new home: Lonza, the contract development and manufacturing giant.

Lonza is paying about $107 million (€100 million) in cash to acquire Synaffix, with up to $64 million (€60 million) in “additional performance-based consideration” on the table. Synaffix’s ADC tech platform will now become part of Lonza’s offering for biopharma clients, lending its bioconjugate technologies to not just ADCs but also targeted gene therapy, immune cell engagers and other applications.

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As­traZeneca gives up on late-stage IL-23 drug due to tri­al de­lays, com­pet­i­tive land­scape

AstraZeneca is shelving an IL-23 antibody that’s been through a winding journey around pharma — including stops at Amgen and Allergan — and putting an end to Phase II and III trials testing the drug for inflammatory bowel disease.

“The decision to discontinue brazikumab’s IBD development follows a recent review of brazikumab’s development timeline and the context of a competitive landscape that has continued to evolve,” a press release reads.

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