As­traZeneca's vac­cine hit its first road­block with In­di­an reg­u­la­tors. Will lin­ger­ing doubts de­rail its plans else­where?

British drug­mak­er As­traZeneca is al­ready run­ning be­hind ear­ly com­peti­tors in the hunt for a Covid-19 vac­cine with in­ter­im da­ta that have re­ceived less-than-stel­lar feed­back. With those da­ta in hand, In­dia has said “no thanks” to an ear­ly ap­proval for the shot, po­ten­tial­ly set­ting the stage for even more set­backs.

On Tues­day, In­di­an reg­u­la­tors re­fused to grant As­traZeneca’s ade­n­ovirus-based Covid-19 vac­cine an emer­gency use au­tho­riza­tion based on a dearth of ad­e­quate safe­ty and ef­fi­ca­cy da­ta, Reuters re­port­ed, cit­ing lo­cal broad­cast­er NDTV.

In­dia’s ear­ly no comes just hours af­ter As­traZeneca’s in­ter­im da­ta were pub­lished in The Lancet un­veil­ing ex­pand­ed safe­ty da­ta and fur­ther break­ing down the 70% av­er­age ef­fi­ca­cy fig­ure that has con­found­ed an­a­lysts and cast doubts on whether the vac­cine will ever com­pete with more ef­fec­tive com­peti­tors from Pfiz­er and Mod­er­na — and maybe oth­ers yet to read out.

In a note to clients Wednes­day break­ing down the da­ta, SVB Leerink an­a­lyst An­drew Berens was less than kind to the ear­ly read­out, de­spite one of the dos­ing reg­i­mens in three Phase III tri­als — a half-dose first shot fol­lowed by a full-dose primer — hit­ting 90% ef­fi­ca­cy.

“The pub­li­ca­tion high­lights a num­ber of vari­ances in the dos­ing reg­i­mens uti­lized in these tri­als that could make it dif­fi­cult for the reg­u­la­to­ry agen­cies to have con­fi­dence in the op­ti­mum dos­ing pro­to­col for full ap­proval with­out ad­di­tion­al stud­ies,” Berens wrote.

For one, the big vari­abil­i­ty be­tween the low-dose/high-dose com­bo and the high-dose/high-dose reg­i­men—which on­ly post­ed 62% ef­fi­ca­cy across three pooled tri­als did lit­tle to in­spire con­fi­dence. The more ef­fec­tive reg­i­men could be enough to spur reg­u­la­tors’ in­ter­est, but there are prob­lems with that da­ta as well, Berens said; sig­nif­i­cant­ly few­er pa­tients re­ceived that reg­i­men and those who did typ­i­cal­ly skewed younger.

Mene Pan­ga­los

Mean­while lo­cal tri­al pro­to­cols var­ied wide­ly, Berens not­ed, with pa­tients re­ceiv­ing boost­er shots at dif­fer­ent in­ter­vals across study sites. On a call with me­dia Tues­day, As­traZeneca’s ex­ec­u­tive VP of bio­phar­ma R&D Mene Pan­ga­los said that vari­abil­i­ty in boost­er tim­ing wasn’t nec­es­sar­i­ly a bad thing: With glob­al de­mand and lim­it­ed sup­plies, pa­tients could be forced to wait on a sec­ond shot in the fu­ture.

Mean­while, Berens al­so cast doubt on the shot’s man­u­fac­tur­ing, which ap­peared to show vari­able strengths across dif­fer­ent pro­duc­tion sites. As­traZeneca ar­gued those dif­fer­ences were with­in a com­fort­able range giv­en the ge­o­graph­i­cal­ly dis­parate sup­ply chain, but Berens begged to dif­fer.

“We be­lieve this could be a detri­ment when at­tempt­ing to gain reg­u­la­to­ry ap­proval as the man­u­fac­tur­ing process may not be uni­form and tighter re­lease spec­i­fi­ca­tions for vac­cines are gen­er­al­ly pre­ferred,” he wrote.

Man­u­fac­tur­ing had been a boon for As­traZeneca in com­par­i­son to its ear­ly mR­NA-based vac­cine com­peti­tors from Pfiz­er and Mod­er­na. For one, As­traZeneca’s shot can be stored and dis­trib­uted in­def­i­nite­ly at room tem­per­a­ture while Pfiz­er’s shot, in par­tic­u­lar, re­quires stren­u­ous cold-chain lo­gis­tics that could make it hard to dis­trib­ute in de­vel­op­ing coun­tries.

With those ques­tions in mind, In­dia’s big no is both an im­me­di­ate sur­prise — the coun­try and its vac­cine gi­ant, the Serum In­sti­tute of In­dia, have been churn­ing out mil­lions of dos­es of the shot for lo­cal and in­ter­na­tion­al use — but could be a sign of things to come as As­traZeneca faces rolling re­view in the EU, UK and else­where.

The drug­mak­er on Tues­day said it was still await­ing US da­ta and would with­hold an FDA fil­ing in the mean­time.

As­traZeneca can al­so lean on its rel­a­tive­ly clean safe­ty pro­file — one of the high­lights from its Lancet pub­li­ca­tion. Across four pooled stud­ies en­com­pass­ing 20,000 pa­tients, As­traZeneca’s vac­cine saw 79 se­vere events com­pared with 89 events in the con­trol arms. As­traZeneca re­port­ed three cas­es of trans­verse myelitis, which caus­es swelling in the spinal cord, two of which were deemed un­re­lat­ed to the vac­cine.

The third case, which caused As­traZeneca’s vac­cine to go on clin­i­cal hold ear­li­er this year, was de­ter­mined to be “pos­si­bly re­lat­ed” to the shot, Berens wrote. That black mark aside, the vac­cine re­sult­ed in no hos­pi­tal­iza­tions or deaths in the three tri­als pooled for ef­fi­ca­cy while there were 10 hos­pi­tal­iza­tions and one death in the con­trol arms.

For a look at all End­points News coro­n­avirus sto­ries, check out our spe­cial news chan­nel.

UP­DAT­ED: Mer­ck pulls Keytru­da in SCLC af­ter ac­cel­er­at­ed nod. Is the FDA get­ting tough on drug­mak­ers that don't hit their marks?

In what could be an early shot in the battle against drugmakers that whiff on confirmatory studies to support accelerated approvals, the FDA ordered Bristol Myers Squibb late last year to give up Opdivo’s approval in SCLC. Now, Merck is next on the firing line — are we seeing the FDA buckling down on post-marketing offenders?

Merck has withdrawn its marketing approval for PD-(L)1 inhibitor Keytruda in metastatic small cell lung cancer as part of what it describes as an “industry-wide evaluation” by the FDA of drugs that do not meet the post-marketing checkpoints on which their accelerated nods were based, the company said Monday.

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Hal Barron, Endpoints UKBIO19

GSK, Vir's hopes for a Covid-19 an­ti­body fall flat in NIH 'mas­ter pro­to­col' with no ben­e­fit in hos­pi­tal­ized pa­tients

GlaxoSmithKline and Vir Biotechnology were hopeful that one of their partnered antibodies would carve out a win after getting the invite to a major NIH study in hospitalized Covid-19 patients. But just like Eli Lilly, the pair’s drug couldn’t hit the mark, and now they’ll be left to take a hard look at the game plan.

The NIH has shut down enrollment for GSK and Vir’s antibody VIR-7831 in its late-stage ACTIV-3 trial after the drug showed negligible effect in achieving sustained recovery in hospitalized Covid-19 patients, the partners said Wednesday.

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The 2021 top 100 bio­phar­ma in­vestors: As the pan­dem­ic hit and IPOs boomed, VCs swung in­to ac­tion like nev­er be­fore

The global pandemic may have roiled economies, killed hundreds of thousands and throttled entire industries, but the only effect it had on biopharma venture investing was to help turbocharge the field to giddy new heights.

Below you’ll find the new top 100 venture investors in the industry, ranked by the number of deals they were publicly involved in, as tracked by DealForma chief Chris Dokomajilar. The numbers master then calculated the estimated amount of money they put into each deal — divvying up the cash by the number of players — to indicate how they managed their syndicates.

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As Brain­Storm con­tin­ues to tout ‘clear sig­nal’ on ALS drug, the FDA of­fers a rare pub­lic slap­down on the da­ta

A little more than a week after BrainStorm acknowledged that regulators at the FDA had informed them that the biotech needed more data before it could expect to gain an approval for its ALS treatment NurOwn — while still touting a “clear signal” of efficacy and not ruling out an application — the agency has decided to clarify the record in a most unusual statement.

The FDA statement amounts to a straight slap own, offering a different set of efficacy numbers from the company’s public presentation last November and ruling out any chance of statistical significance.

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Martine Rothblatt, United CEO (Jack Plunkett, AP Images)

Unit­ed ax­es PAH pro­gram Trevyent, once bought for cheap in ac­qui­si­tion of a ri­val, af­ter FDA feed­back

About three years after acquiring SteadyMed and its experimental pulmonary arterial hypertension drug Trevyent, United Therapeutics has decided to kick the program to the curb.

In an 8-K form filed with the SEC on Tuesday, United revealed that they are shutting down development of Trevyent after receiving feedback from the FDA last week. The move marks the end of a long and bumpy road for the program, which had previously earned an RTF in 2017 and a CRL last April, as United moves forward with new Tyvaso formulations.

In­tro­duc­ing End­points FDA+, our new pre­mi­um week­ly reg­u­la­to­ry news re­port led by Zachary Bren­nan

CRLs. 483s. CBER, CDER and RWE. For biopharma professionals, these acronyms command attention because of the fundamental role FDA plays in drug development. Now Endpoints is doubling down on regulatory coverage, and launching a weekly report focusing on developments out of White Oak, with analysis and insight into what it all means.

Coverage will be led by our new senior editor, Zachary Brennan. He joins Endpoints from POLITICO, where he covered pharma. Prior to that he was the managing editor for Regulatory Focus, a news publication from the Regulatory Affairs Professionals Society.

UP­DAT­ED: Feds clear the road for J&J to start de­liv­er­ing mil­lions of dos­es of their Covid-19 vac­cine — but frets linger about run­ner-up sta­tus

All the pieces needed to trigger a third wave of Covid-19 vaccine supply to start washing over the US fell neatly into place over the weekend.

After providing for a brief mime of regulatory judiciousness, the FDA stamped their emergency approval on J&J’s Covid-19 vaccine Saturday, adding to the Biden administration’s plan aimed at ending the pandemic in the near term — at least in the US. The CDC came through on Sunday with its stamp of approval and J&J is reportedly expected to start delivering vaccine sometime in the next few days.

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Antoine Papiernik, Sofinnova managing director (Business Wire)

Sofinno­va Part­ners stays fo­cused on late-stage deals with a new, $540M crossover fund

One of Europe’s most high-profile biopharma investors is getting $540 million to invest in new crossover deals for late-stage companies.

The Paris-based VC says the fresh Sofinnova Crossover Fund raise positions them as the “largest crossover investor in Europe dedicated to late-stage biopharma and medtech investments.”

They got a leg up in France after winning a special “Tibi” designation from the French government, giving them access to a pool of €6 billion that helped them gain an edge with institutional investors. Since they were founded close to 50 years ago, the venture group has backed more than 500 companies and currently has more than €2 billion under management.

Presage teams with Mer­ck on its Phase 0 test­ing; Kem­Pharm AD­HD drug wins ap­proval in chil­dren aged 6 and up

Seattle-based Presage Biosciences, which approaches drug development through its microdosing platform, has some new partnerships and cash to come with them.

Presage closed a $13 million financing round Tuesday, aiming to expand its network of clinical trial sites and advance development of its microdosing injection devices. They also closed partnership deals with Merck and Maverick Therapeutics.

The financing included $7 million from new investors, including the LabCorp Venture Fund, Bristol Myers Squibb, and InHarv Partners. An additional $6 million convertible note from Takeda Ventures will convert to equity.