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.

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.

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.

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.

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.