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.

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

What lured Hal Bar­ron away?; Top FDA minds on ac­cel­er­at­ed ap­proval re­forms; ‘Dead wrong’ Aduhelm ad blitz; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Nothing can really compete with Hal Barron’s departure from GlaxoSmithKline as the news of the week, but we do have plenty of original reporting and analysis from the Endpoints team in this edition. Enjoy and have a nice weekend.

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Dan O'Day, Gilead CEO (Jim Watson/AFP via Getty Images)

Fail­ing to con­firm clin­i­cal ben­e­fit, Gilead pulls 2 ac­cel­er­at­ed ap­proval in­di­ca­tions for can­cer drug

Gilead recently decided to pull two indications for its cancer drug Zydelig — in relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic leukemia (SLL) — after failing to complete the confirmatory trials required as part of the accelerated approvals from 2014.

“As the treatment landscape for FL and SLL has evolved, enrollment into the confirmatory study has been an ongoing challenge,” Gilead said in a statement, noting it formally notified the FDA of its decision to voluntarily withdraw these indications.

Richard Pazdur (via AACR)

Time lim­its on ac­cel­er­at­ed ap­provals? FDA's on­col­o­gy chief Rick Paz­dur eyes po­ten­tial re­forms via in­ter­na­tion­al ap­proach­es

The spotlight on the accelerated approval pathway continues to shine bright, with the FDA’s top oncology official writing in an opinion that the pathway may be strengthened with bits and pieces of what other regulators in Europe and elsewhere have done with their expedited approval pathways, such as adding expiration dates for these faster approvals to ensure they confirm clinical benefit in a timely manner.

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Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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Covid-19 roundup: HHS may strug­gle to ab­sorb Op­er­a­tion Warp Speed; Eu­rope has no plans for a fourth vac­cine dose

Operation Warp Speed, perhaps the greatest achievement of the former Trump administration, promptly delivered Covid-19 vaccine supplies nationwide when they became available, thanks to collaborations between HHS and the Department of Defense, while helping to fund and aid the manufacture of billions of doses.

But since the Biden administration took over a year ago, acting FDA commissioner Janet Woodcock transitioned out of her role as the therapeutics lead in Warp Speed, which has been converted into a new operation without the fancy name (now known as the “HHS-DOD COVID-19 Countermeasures Acceleration Group”), and as of the start of 2022, the Department of Defense is no longer helping HHS on the program.

Mer­ck wins le­gal bat­tle over in­sur­ance cov­er­age af­ter ran­somware at­tack

Merck has emerged victorious from a years-long legal battle with insurers over the coverage of more than a billion dollars in losses from the malware NotPetya, with a New Jersey Superior Court judge concluding that the responsibility is on insurers to clarify their policies around cyber attacks.

The pharma giant was one of several victims of a global cyber attack back in 2017 that also hit Danish shipping company Maersk, American food company Mondelēz, French construction giant Saint-Gobain and even the systems monitoring the Chernobyl nuclear power stations, Bloomberg reported back in 2019.

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Flori­da man con­vict­ed of fal­si­fy­ing clin­i­cal tri­al re­sults sen­tenced to over 2 years in prison

A Florida man who falsified medical records in connection to clinical trials was sentenced to 30 months in prison in federal court Thursday.

Daniel Tejeda, 35, of Clewiston, was also ordered to pay $2.1 million in restitution. Tejeda was a project manager and study manager for the CRO Tellus Clinical Research, and made it appear that subjects were participating in trials when they weren’t. Two other research workers from Florida were sentenced in the same case in August for 46 and 30 months, respectively.