FDA+ roundup: More than 2 years af­ter a CRL, Lex­i­con is still bat­tling the de­ci­sion; UK phar­ma in­dus­try weighs di­rec­tion of MHRA

Back in March 2019, the FDA made clear to Sanofi and its part­ner Lex­i­con Phar­ma­ceu­ti­cals that it couldn’t ap­prove the ap­pli­ca­tion for their di­a­betes drug be­cause the da­ta sub­mit­ted do not show that the drug is safe.

“The da­ta demon­strat­ed that the ad­di­tion of so­tagliflozin to in­sulin is as­so­ci­at­ed with an in­creased risk of di­a­bet­ic ke­toaci­do­sis (DKA), a se­ri­ous and of­ten life-threat­en­ing con­se­quence of in­sulin in­suf­fi­cien­cy,” the agency said in a rare ex­pla­na­tion of the com­plete re­sponse let­ter. “Time-to-event analy­ses of the clin­i­cal tri­al da­ta showed ear­li­er de­vel­op­ment of DKA in so­tagliflozin-treat­ed pa­tients than in pa­tients as­signed to place­bo, with­out ev­i­dence that the risk stopped in­creas­ing over time.”

While FDA said the clin­i­cal tri­al da­ta showed that so­tagliflozin, which is ap­proved in the EU, re­duced HbA1c, a val­i­dat­ed sur­ro­gate end­point due to im­proved glycemic con­trol, the agency al­so said the ef­fect “was mod­est.” The FDA’s En­docrino­log­ic and Meta­bol­ic Drugs Ad­vi­so­ry Com­mit­tee split 8-8 on whether the over­all ben­e­fits out­weighed the risks.

“Di­a­bet­ic ke­toaci­do­sis is an in­her­ent risk of type 1 di­a­betes and an in­crease was seen with so­tagliflozin com­pared to in­sulin alone,” Lex­i­con CMO Pablo La­puer­ta said in a state­ment af­ter the ad­comm vote. “We be­lieve this can po­ten­tial­ly be ad­dressed with prop­er ed­u­ca­tion and mon­i­tor­ing.”

Typ­i­cal­ly, com­pa­nies that re­ceive CRLs try to work with FDA, ad­dress the de­fi­cien­cies out­lined, and re­sub­mit their ap­pli­ca­tion as quick­ly as pos­si­ble for ap­proval.

But Lex­i­con, af­ter Sanofi hand­ed over con­trol of so­tagliflozin and sent its stock shares in­to a tail­spin, ap­pealed the CRL twice, and is now seek­ing a hear­ing to fur­ther dis­cuss the ap­pli­ca­tion. FDA, mean­while, has to con­tin­ue to go through the process that’s af­ford­ed to drug­mak­ers, de­spite re­ject­ing both ap­peals in Nov. 2019 and March 2020 and stand­ing by its de­ter­mi­na­tion that the drug’s DKA risk out­weighed its ben­e­fits.

Most re­cent­ly, in a let­ter dat­ed this year, CDER has agreed to post­pone its pro­pos­al to refuse to ap­prove the NDA un­til Nov. 26.

New, FDA-fund­ed book on phar­ma man­u­fac­tur­ing lays bare the risks of try­ing to get in­no­v­a­tive

The Na­tion­al Acad­e­mies of Sci­ences, En­gi­neer­ing, and Med­i­cine re­cent­ly pub­lished a new FDA-fund­ed book on in­no­va­tions in phar­ma­ceu­ti­cal man­u­fac­tur­ing, mak­ing clear that it can be “a risky propo­si­tion.”

The re­al­i­ty con­strain­ing the pace of in­no­va­tion around phar­ma man­u­fac­tur­ing, ac­cord­ing to the book, “is the re­al­i­ty that for­mal reg­u­la­to­ry re­view of tech­nol­o­gy oc­curs specif­i­cal­ly in the con­text of in­di­vid­ual prod­ucts.”

What that means is that the FDA doesn’t ap­prove new tech­nolo­gies that can be used for dif­fer­ent drugs, but it eval­u­ates the tech­nol­o­gy with re­spect to its suit­abil­i­ty to de­liv­er a high-qual­i­ty prod­uct con­sis­tent­ly. The au­thors add:

Al­though that par­a­digm might be ap­pro­pri­ate for the phar­ma­ceu­ti­cal reg­u­la­to­ry regime, it places a large bur­den on any man­u­fac­tur­er that seeks to bring for­ward a nov­el tech­nol­o­gy in sup­port of prod­uct ap­proval for the first time. Even if reg­u­la­tors have had ex­po­sure to and gen­er­al­ly sup­port a par­tic­u­lar man­u­fac­tur­ing in­no­va­tion, on­ly when a prod­uct that us­es it has been ful­ly sub­ject­ed to de­tailed re­view and ap­proval can an ini­tial un­der­stand­ing of its gen­uine reg­u­la­to­ry sta­tus be achieved. It is en­tire­ly in­cum­bent on the man­u­fac­tur­er to sat­is­fy all re­quire­ments that reg­u­la­tors need to ap­prove the prod­uct, which might in­clude unan­tic­i­pat­ed ac­tiv­i­ties, costs, and time that could af­fect the fi­nan­cial vi­a­bil­i­ty of the prod­uct.

The book al­so calls for much more reg­u­la­to­ry har­mo­niza­tion to al­low for more glob­al in­no­va­tion, ex­plain­ing, “Any progress that can be made to en­hance or ac­cel­er­ate reg­u­la­to­ry har­mo­niza­tion and con­sis­ten­cy will clear­ly re­duce cur­rent dis­in­cen­tives for glob­al im­ple­men­ta­tion of in­no­v­a­tive man­u­fac­tur­ing tech­nol­o­gy.”

Phar­ma in­dus­try group to MHRA: Don’t make the UK ir­rel­e­vant

Fresh off the UK drug reg­u­la­tor’s de­ci­sion to au­tho­rize Mer­ck’s new Covid-19 ear­ly treat­ment pill, which was the first au­tho­riza­tion in the world, the UK phar­ma in­dus­try’s as­so­ci­a­tion is call­ing on the MHRA to con­tin­ue to be a strong leader or else com­pa­nies might skip out on launch­ing new prod­ucts on the is­land en­tire­ly.

Thanks to Brex­it, and the cut­ting of ties be­tween the UK and the Eu­ro­pean Med­i­cines Agency, once head­quar­tered in Lon­don, the UK’s MHRA now has to find a hap­py medi­um be­tween stick­ing with the in­ter­na­tion­al sci­ence and shin­ing bright enough as a leader to con­tin­ue to at­tract new med­i­cines.

“The UK now can shape its in­de­pen­dent reg­u­la­to­ry pol­i­cy strat­e­gy in a way that places the MHRA at the fore­front of de­vel­op­ing ‘gold stan­dard’ reg­u­la­to­ry frame­works and in­no­v­a­tive prac­tices for new tech­nolo­gies,” the As­so­ci­a­tion of the British Phar­ma­ceu­ti­cal In­dus­try said in a re­cent re­port. “How­ev­er, this should be done in a way that en­sures the UK re­mains in­ter­na­tion­al­ly com­pet­i­tive. Dras­ti­cal­ly di­verg­ing from the di­rec­tion of trav­el of oth­er world-lead­ing reg­u­la­tors could have neg­a­tive con­se­quences, such as the UK be­com­ing a late launch mar­ket – or no launch mar­ket at all – for new treat­ments.”

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.

Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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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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CBO: Medicare ne­go­ti­a­tions will ham­per drug de­vel­op­ment more than pre­vi­ous­ly thought

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.

Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

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Chamath Palihapitiya and Pablo Legorreta

Bil­lion­aires Chamath Pal­i­hapi­tiya and Pablo Legor­re­ta hatch an $825M SPAC for cell ther­a­py biotech

Three years after Royalty Pharma chief Pablo Legorreta led a group of investors to buy up a pair of biotechs and create a new startup called ProKidney, the biotech is jumping straight into an $825 million public shell created by SPAC king and tech billionaire Chamath Palihapitiya.

ProKidney was founded 6 years ago but really got going at the beginning of 2019 with the $62 million acquisition of inRegen, which was working on an autologous — from the patient — cell therapy for kidney disease. After extracting kidney cells from patients, researchers expand the cells in the lab and then inject them back into patients, aiming to restore the kidneys of patients suffering from CKD.

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Joshua Brumm, Dyne Therapeutics CEO

FDA or­ders DMD tri­al halt, rais­ing ques­tions about a whole class of promis­ing drugs

Dyne Therapeutics’ stock took a nasty hit this morning after the biotech put out word that the FDA had slapped a clinical hold on their top program for Duchenne muscular dystrophy. And now speculation is bouncing around Biotwitter that there could be a class effect at work here that would implicate other drug developers in the freeze.

Dyne execs didn’t have a whole lot to say about why the FDA sidelined their IND for DYNE-251 in DMD while “requesting additional clinical and non-clinical information for” the drug.

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Gilead says a net­work of sup­pli­ers and dis­trib­u­tors sold tens of thou­sands of fake ver­sions of its HIV meds

Gilead has accused a network of unauthorized drug suppliers and distributors of selling counterfeit versions of its HIV meds, some of which ended up in US pharmacies, according to court documents unsealed Tuesday.

Over the last two years, Gilead says the distributor defendants sold 85,246 bottles of Gilead meds (including its HIV meds Biktarvy and Descovy) with counterfeit documentation — some of which had tampered bottles, or contained an entirely different drug.