Safe­ty con­cerns lead to a split FDA pan­el vote on Sanofi/Lex­i­con di­a­betes drug

The first po­ten­tial pill for pa­tients with the less com­mon type 1 di­a­betes, who pro­duce no in­sulin, was the sub­ject of an atyp­i­cal hung ju­ry vote at an FDA pan­el on Thurs­day, in which ex­perts were di­vid­ed even­ly over whether the life-threat­en­ing risk of di­a­bet­ic ke­toaci­do­sis as­so­ci­at­ed with the drug off­set its ben­e­fit.

The drug, so­tagliflozin, from Lex­i­con Phar­ma and Sanofi is be­ing de­vel­oped for both type I and type II di­a­betes. It is de­signed to in­hib­it two pro­teins in­volved in glu­cose reg­u­la­tion: SGLT1, which is re­spon­si­ble for glu­cose re­ab­sorp­tion in the GI tract and SGLT2, which is re­spon­si­ble for glu­cose re­ab­sorp­tion by the kid­ney.  Many ex­ist­ing di­a­betes drugs on­ly tar­get SGLT2. Al­though the mol­e­cule is cur­rent­ly be­ing test­ed in a pletho­ra of tri­als in pa­tients with type II di­a­betes, the oral drug is cur­rent­ly un­der FDA re­view for type 1 di­a­bet­ics, who face mul­ti­ple dai­ly in­jec­tions of in­sulin, or use an in­sulin pump, to achieve glycemic con­trol.

The ap­pli­ca­tion for type 1 di­a­bet­ics was on the ba­sis of three late-stage tri­als. How­ev­er, an in­crease in the risk of di­a­bet­ic ke­toaci­do­sis (DKA) was ob­served with so­tagliflozin treat­ment — and it was this is­sue that was cen­tral to the split 8-8 vote on Thurs­day. Al­though the FDA is not ob­lig­at­ed to fol­low the rec­om­men­da­tions of the pan­el, it usu­al­ly does. In this case, the reg­u­la­tor has re­ceived a de­cid­ed­ly mixed mes­sage, and is set to make its de­ci­sion by March 22. The drug is al­so un­der EMA re­view.

In a re­port pub­lished on Tues­day, FDA re­view­ers ac­knowl­edged that the risk of DKA has been ob­served with SGLT2 in­hibitor use in type II di­a­bet­ics, and ex­ist­ing ap­proved drugs in the class car­ry warn­ings to high­light the risk. “While all pa­tients with type 1 di­a­betes may to some de­gree be at risk for DKA, so­tagliflozin ther­a­py clear­ly in­creas­es that risk, and the risk may be un­pre­dictable,” reg­u­la­to­ry staff wrote.

In the meet­ing of in­de­pen­dent ex­perts on Thurs­day, near­ly all pan­elists, re­gard­less of their fi­nal vote, agreed the drug — to be sold as Zyn­quista — would on­ly be ap­pro­pri­ate for a small sub­set of par­tic­u­lar­ly at­ten­tive type I di­a­betes pa­tients, in con­text of the DKA risk.

Stifel’s Stephen Wil­ley said he was sur­prised at the emer­gence of a more-neg­a­tive tone from the agency’s pre­sen­ta­tion rel­a­tive to what was in­clud­ed with­in the FDA staff re­port post­ed two days pri­or, de­spite valid points made about the com­pa­ny’s risk mit­i­ga­tion plan.

Wil­ley wrote: “…the agency’s at­tempt to frame so­tagliflozin-me­di­at­ed DKA risk rel­a­tive to post-mar­ket­ing DKA events as­so­ci­at­ed with off-la­bel SGLT2i uti­liza­tion was in­her­ent­ly flawed. We’re not triv­i­al­iz­ing the risk here…How­ev­er, we do be­lieve the as­sump­tion of risk – par­tic­u­lar­ly for a drug which has sur­passed the re­quired ef­fi­ca­cy thresh­old in a dis­ease which has been ab­sent of in­no­va­tion since the ad­vent of in­sulin it­self – should be an in­di­vid­u­al­ized de­ci­sion made be­tween pa­tient/physi­cian…this same sto­ry has al­ready played out in the world of in­sulin pumps – where­by tran­si­tion­ing a type I di­a­betes pa­tient from in­jectable to pump-de­liv­ered in­sulin sig­nif­i­cant­ly in­creased DKA rates. Yet with suf­fi­cient pa­tient aware­ness/ed­u­ca­tion, these rates be­came man­age­able over time.”

Most an­a­lysts trimmed their ex­pec­ta­tions of the drug’s ap­proval for type I di­a­bet­ics.

Wil­ley said his mod­el still as­sumed a com­mer­cial launch in the US and EU in 2019, ac­knowl­edg­ing that the tim­ing was un­clear giv­en the re­sult of FDA pan­el meet­ing. He cut his 2021 US sales es­ti­mate to $245 mil­lion from $385 mil­lion. “If ap­proved, we still be­lieve this could prove to be a >$750M prod­uct in both the U.S. and EU with <12% mar­ket share amongst a grow­ing num­ber of type I di­a­bet­ic adults,” he not­ed.

Oth­er an­a­lysts were some­what more pes­simistic. Need­ham’s Alan Carr said he now be­lieves an FDA ap­proval in type I di­a­betes is pos­si­ble, but not prob­a­ble, and that he had elim­i­nat­ed the rev­enue stream from his mod­el. Cowen an­a­lysts, mean­while, were ready to throw in the tow­el, say­ing they now ex­pect an FDA re­jec­tion in March.

Lex­i­con’s shares $LXRX tum­bled about 25%, while Sanofi’s stock $SNY slipped about 1% in ear­ly trad­ing on Fri­day.

Donald and Melania Trump watch the smoke of fireworks from the South Lawn of the White House on July 4, 2020 (via Getty)

Which drug de­vel­op­ers of­fer Trump a quick, game-chang­ing ‘so­lu­tion’ as the pan­dem­ic roars back? Eli Lil­ly and Ab­Cellera look to break out of the pack

We are unleashing our nation’s scientific brilliance and will likely have a therapeutic and/or vaccine solution long before the end of the year.

— Donald Trump, July 4

Next week administration officials plan to promote a new study they say shows promising results on therapeutics, the officials said. They wouldn’t describe the study in any further detail because, they said, its disclosure would be “market-moving.”

— NBC News, July 3

Something’s cooking. And it’s not just July 4 leftovers involving stale buns and uneaten hot dogs.

Over the long weekend observers picked up signs that the focus in the Trump administration may swiftly shift from the bright spotlight on vaccines being promised this fall, around the time of the election, to include drugs that could possibly keep patients out of the hospital and take the political sting out of the soaring Covid-19 numbers causing embarrassment in states that swiftly reopened — as Trump cheered along.

So far, Gilead has been the chief beneficiary of the drive on drugs, swiftly offering enough early data to get remdesivir an emergency authorization and into the hands of the US government. But their drug, while helpful in cutting stays, is known for a limited, modest effect. And that won’t tamp down on the hurricane of criticism that’s been tearing at the White House, and buffeting the president’s most stalwart core defenders as the economy suffers.

We’ve had positive early-stage vaccine data, most recently from Pfizer and BioNTech, playing catchup on an mRNA race led by Moderna — where every little sign of potential trouble is magnified into a lethal threat, just as every advance excites a frenzy of support. But that race still has months to play out, with more Phase I data due ahead of the mid-stage numbers looming ahead. A vaccine may not be available in large enough quantities until well into 2021, which is still wildly ambitious.

So what about a drug solution?

Trump’s initial support for a panacea focused on hydroxychloroquine. But that fizzled in the face of data underscoring its ineffectiveness — killing trials that aren’t likely to be restarted because of a recent population-based study offering some support. And there are a number of existing drugs being repurposed to see how they help hospitalized patients.

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Covid-19 roundup: Left out no longer, No­vavax se­cures largest Warp Speed deal yet: $1.6B

It looks like Novavax won’t be left out of Operation Warp Speed after all.

A month after the Gaithersburg, MD biotech saw its shares tumble when it was left off the first reported list of finalists for the White House’s Covid-19 vaccine accelerator, HHS and the Department of Defense have announced a $1.6 billion deal to scale up their Covid-19 candidate. It is the largest deal HHS has announced yet, eclipsing the $1.2 billion deal the administration reached with AstraZeneca in May.

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Shoshanna Shendelman, Applied Therapeutics CEO (Applied Therapeutics)

A lit­tle biotech slaps back at a 'crim­i­nal' short at­tack, vow­ing to pur­sue a pros­e­cu­tion of their case

As short attacks go, Biotech Research Partners’ assault on Applied Therapeutics’ “cherry picked” data and a variety of so-called red flags didn’t cause a whole lot of damage. Ahead of the July 4 holiday, its shares $APLT were dinged and showed signs of quick recovery.

But that didn’t stop an incendiary response, as the biotech swung into action bright and early Monday morning.

Applied Therapeutics accused the authors of the short report of manipulating graphs and figures, misrepresenting data and included factual misrepresentations — all of which added up, in their view, to fraud.

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UP­DAT­ED: Im­munomedics spells out PFS ben­e­fit of Trodelvy in mTNBC, hunt­ing a full OK just weeks af­ter ac­cel­er­at­ed ap­proval

By the time the FDA finally granted an accelerated OK for Immunomedics’ Trodelvy, we already got a very strong hint that their confirmatory Phase III study in metastatic triple-negative breast cancer was a success.

That’s because the independent data safety monitoring committee recommended that the trial be stopped early. But just what pointed them to the conclusion was still unclear.

“We do not know the totality of their decision other than it’s pretty evident that the primary endpoint was met; otherwise they could not request to halt the study,” Behzad Aghazadeh, the executive chairman, told Endpoints News at the time.

Cel­lec­tis slammed af­ter pa­tient dies and FDA slaps a hold on their tri­al for an off-the-shelf CAR-T for mul­ti­ple myelo­ma

Cellectis was slammed after the market close on Monday as the biotech reported that the FDA demanded it hit the brakes on their MELANI-01 trial for their off-the-shelf cell therapy UCARTCS1A after one of the patients in the study died of treatment-related cardiac arrest.

The multiple myeloma patient had previously been treated unsuccessfully with various therapies, noted the biotech, and had been given dose level two (DL2) of their allogeneic CAR-T.

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Jean-Paul Clozel, Idorsia CEO (Patrick Straub/Keystone via AP Images)

Sec­ond PhI­II study for Idor­si­a's sleep drug re­turns pos­i­tive re­sults, but al­so rais­es new ques­tions

Following a successful Phase III study in April showcasing the safety and potential of its new sleep drug, Idorsia posted some mixed news in the second Phase III study, but that won’t stop a planned filing aimed at regulatory approval.

The drug, a dual orexin receptor antagonist (DORA) called daridorexant, was found to significantly improve sleep maintenance and subjective total sleep time in 25 mg doses, replicating results from the first Phase III study. However, improvements in sleep onset and daytime functioning narrowly missed statistical significance, despite numerical consistency with the April study.

Bill Haney, Dragonfly CEO (Dave Pedley/Getty Images for SXSW)

A boom­ing Drag­on­fly is tak­ing its TriN­KETs to Copen­hagen as the lat­est Bris­tol My­ers pact spurs ex­pan­sion plans — out­side the US

Bristol Myers Squibb is making a habit out of collaborating with the crew at Dragonfly, adding their 3rd deal in a series that now will take them into newly charted R&D territory. And the fast-growing team at the Cambridge-based biotech is adding a facility in Copenhagen for its next growth spurt, where the government is making it easy to recruit scientists internationally as the U.S. throttles back.

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Ernest Loumaye, ObsEva CEO (ObsEva)

UP­DAT­ED: Ob­sE­va’s sec­ond uter­ine fi­broids PhI­II comes through, send­ing some in­vestors to the hills

In the three-company race to develop a new uterine fibroid treatment, ObsEva long lagged behind AbbVie and Myovant. Still, they hoped that better efficacy — including a 93.9% response rate in one Phase III trial — could ultimately deliver better sales.

Now, though, the second of those Phase III studies is out, and it has brought the Swedish biotech back to earth.

In the second of their Phase III trials, 75.5% of patients who took ObsEva’s experimental tablet linzagolix plus a hormone saw their bleeding reduced by at least 50% and at least 80 ml after 24 weeks. Pooling those results with new data from their first Phase III trial — which showed a 93.9% response rate at 24 weeks and a 91.6% response rate at 52 weeks — ObsEva calculated a collective 84.7% responder rate for patients taking their therapy and said the data “confirm potential best-in-class” status.

Covid-19 roundup: Teamed up with NIH, Re­gen­eron launch­es PhI­II pre­ven­tion tri­al for an­ti­body cock­tail

As Regeneron moves its antibody cocktail into Phase II/III trials testing REGN-COV2 as a treatment for both hospitalized and non-hospitalized patients with Covid-19, the biotech is also starting a Phase III in the prevention setting.

The National Institute of Allergy and Infectious Diseases — which orchestrated the large, randomized study for remdesivir that produced positive results — will jointly run the study.

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