Dan Menichella (AP Photo/Andrew Harnik)

UP­DAT­ED: Food or drug? FDA blasts Flag­ship-backed mi­cro­bio­me play­er’s ‘non-IND’ Covid-19 tri­al

When Kalei­do Bio­sciences un­veiled re­sults from a mul­ti-cen­ter, open la­bel, con­trolled clin­i­cal study test­ing its mi­cro­bio­me prod­uct in Covid-19 pa­tients back in March, the biotech tout­ed it as a “non-IND” tri­al that yield­ed pos­i­tive re­sults and paved the way for an IND.

But it turned out that the FDA was not im­pressed with that tac­tic.

The agency has is­sued a warn­ing let­ter to Kalei­do blast­ing its “fail­ure to sub­mit INDs for the con­duct of clin­i­cal in­ves­ti­ga­tions with an in­ves­ti­ga­tion­al new drug” that falls un­der sec­tion 505 of the fed­er­al Food, Drug, and Cos­met­ic Act. Kalei­do now has 15 days to ex­plain it­self or re­port the ac­tions it’s tak­en to pre­vent sim­i­lar vi­o­la­tions — or else face reg­u­la­to­ry ac­tion.

“We are re­view­ing the let­ter cur­rent­ly and look for­ward to pro­vid­ing a re­sponse with­in the giv­en time­frame and con­tin­u­ing our dis­cus­sions with the FDA,” CEO Dan Menichel­la, to whom the let­ter was di­rect­ly ad­dressed, said in an emailed state­ment.

Kalei­do was well aware of the FDA’s ob­jec­tions, ac­cord­ing to the let­ter, which stat­ed that in­spec­tor Kent Con­for­ti had pre­sent­ed a Form 483 and dis­cussed it with staff in ear­ly March.

Reg­u­la­tors re­ceived a re­sponse on March 23, the eve of Kalei­do’s study re­sult an­nounce­ment, in which Kalei­do ar­gued that KB109, the syn­thet­ic gly­can be­ing test­ed in the study, was in fact “a food rather than a drug.”

Specif­i­cal­ly, Kalei­do ar­gued that the in­ves­ti­ga­tions were con­duct­ed “to eval­u­ate the ef­fect of KB109 on the mi­cro­bio­me[,] as well as to de­ter­mine the safe­ty and tol­er­a­bil­i­ty of KB109 in the dis­eased pop­u­la­tion[,]” that is, hu­man sub­jects with mild to mod­er­ate COVID-19, and thus it in­ves­ti­gat­ed KB109 for use as a food rather than a drug.

To sup­port this ar­gu­ment, Kalei­do as­sert­ed that it did not in­tend for these “food stud­ies” to eval­u­ate whether KB109 would be an ef­fec­tive treat­ment or mit­i­ga­tion for COVID-19; rather, Kalei­do ar­gued that the sec­ondary end­points in these stud­ies were de­ter­mi­na­tive of safe­ty and tol­er­a­bil­i­ty. For this rea­son, Kalei­do stat­ed that KB109 was a food in­ter­ven­tion, and con­sis­tent with Agency guid­ance, it was ap­pro­pri­ate to con­duct these stud­ies with­out an IND in a pop­u­la­tion with COVID-19.

The pro­to­col, dubbed Pro­to­col K031-120 and Pro­to­col K032-120, and Kalei­do’s press re­leas­es sug­gest­ed oth­er­wise, the FDA said. Not on­ly was Kalei­do’s ob­jec­tive to com­pare the safe­ty and ef­fi­ca­cy of KB109 in com­bi­na­tion with sup­port­ive self-care un­der quar­an­tine against sup­port­ive self-care alone, the biotech al­so mea­sured par­tic­i­pants’ symp­toms and health­care uti­liza­tion among oth­er things like bio­mark­ers and their gut mi­cro­bio­me struc­ture.

To the FDA, that sounds a lot like the ef­fi­ca­cy end­points it has rec­om­mend­ed in its guid­ances to help spon­sors nav­i­gate de­vel­op­ing Covid-19 treat­ments.

For Pro­to­col K032-120, while some end­points could be con­sid­ered safe­ty out­comes that might be eval­u­at­ed on­ly to en­sure that treat­ment with KB109 was not wors­en­ing the course of COVID-19, oth­er end­points (for ex­am­ple, pro­por­tion of sub­jects ex­pe­ri­enc­ing hos­pi­tal ad­mis­sion dur­ing the fol­low-up pe­ri­od, mea­sures of health­care uti­liza­tion, and pro­por­tion of sub­jects with oxy­gen sat­u­ra­tion be­low nor­mal) clear­ly as­sessed the use of KB109 in com­bi­na­tion with SCC for the treat­ment or mit­i­ga­tion of COVID-19.

The ar­gu­ment for de­scrib­ing KB109 as a med­ical food fails be­cause no dis­tinc­tive nu­tri­tion­al re­quire­ments have been es­tab­lished for Covid-19, which is a pre­req­ui­site for defin­ing med­ical food, the FDA wrote. Be­sides, the stud­ies went be­yond “di­etary man­age­ment” and eval­u­at­ed a host of oth­er ef­fects on Covid-19 in­fec­tion.

“As Kalei­do not­ed in its re­sponse to the Form FDA 483, whether an in­ves­ti­ga­tion­al ar­ti­cle is a drug or a food de­pends on the in­tent of the in­ves­ti­ga­tion,” its let­ter read. And KB109 was used in these clin­i­cal in­ves­ti­ga­tions as a drug be­cause it was “stud­ied for use in the mit­i­ga­tion and treat­ment of COVID-19.”

The FDA asked Kalei­do to get in line, ad­dress the de­fi­cien­cies and set up pro­ce­dures to en­sure com­pli­ance with reg­u­la­tions in the fu­ture.

Ed­i­tor’s Note: This sto­ry has been up­dat­ed to in­cor­po­rate a com­ment from Kalei­do.

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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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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Hal Barron, Endpoints UKBIO20 (Jeff Rumans)

'Al­tos was re­al­ly a once-in-a-life­time op­por­tu­ni­ty': Hal Bar­ron re­flects on his big move

By all accounts, Hal Barron had one of the best jobs in Big Pharma R&D. He made more than $11 million in 2020, once again reaping more than his boss, Emma Walmsley, who always championed him at every opportunity. And he oversaw a global R&D effort that struck a variety of big-dollar deals for oncology, neurodegeneration and more.

Sure, the critics never let up about what they saw as a rather uninspiring late-stage pipeline, where the rubber hits the road in the Big Pharma world’s hunt for the next big near-term blockbuster, but the in-house reviews were stellar. And Barron was firmly focused on bringing up the success rate in clinical trials, holding out for the big rewards of moving the dial from an average 10% success rate to 20%.

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Troy Wilson, Kura CEO

FDA lifts par­tial hold on Ku­ra's Phase Ib AML pro­gram as biotech re­dou­bles mit­i­ga­tion ef­forts

Kura Oncology is clear to resume studies for its early-stage leukemia program after the FDA lifted a clinical hold Thursday afternoon.

Regulators had placed the hold on a Phase Ib study of KO-539, an experimental oral treatment for some genetic subsets of acute myeloid leukemia last November after a patient died while taking the drug. Kura expects to begin enrolling patients again imminently, CEO Troy Wilson told Endpoints News.

Robert Califf, FDA commissioner nominee (Graeme Sloan/Sipa USA/Sipa via AP Images)

Califf on ac­cel­er­at­ed ap­provals: Com­pa­nies need to do more work be­fore FDA says OK

As he awaits a tight Senate vote, Rob Califf, President Joe Biden’s nominee to be the next FDA commissioner, is signaling where the agency may move on accelerated approvals if he takes over at FDA.

Building off comments from his Senate confirmation hearing, in which Califf said that he’s “a fan of accelerated approval” but the US needs a better system to evaluate these drugs once they’re on the market, the nominee raised questions about how well the current structure serves patients.

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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