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.

Brian Kaspar. AveXis via Twitter

AveX­is sci­en­tif­ic founder fires back at No­var­tis CEO Vas Narasimhan, 'cat­e­gor­i­cal­ly de­nies any wrong­do­ing'

Brian Kaspar’s head was among the first to roll at Novartis after company execs became aware of the fact that manipulated data had been included in its application for Zolgensma, now the world’s most expensive therapy.

But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

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We­bi­nar: Re­al World End­points — the brave new world com­ing in build­ing fran­chise ther­a­pies

Several biopharma companies have been working on expanding drug labels through the use of real world endpoints, combing through the data to find evidence of a drug’s efficacy for particular indications. But we’ve just begun. Real World Evidence is becoming an important part of every clinical development plan, in the soup-through-nuts approach used in building franchises.

I’ve recruited a panel of 3 top experts in the field — the first in a series of premium webinars — to look at the practical realities governing what can be done today, and where this is headed over the next few years, at the prodding of the FDA.


ZHEN SU — Merck Serono’s Senior Vice President and Global Head of Oncology


ELLIOTT LEVY — Amgen’s Senior Vice President of Global Development


CHRIS BOSHOFF — Pfizer Oncology’s Chief Development Officer

A premium subscription to Endpoints News is required to attend this webinar. Please upgrade to either an Insider or Enterprise plan for access. Already have Endpoints Premium? Please sign-in below. You can contact our Subscriptions team at help@endpointsnews.com with any issues.

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Bob Smith, Pfizer

Pfiz­er is mak­ing a $500M state­ment to­day: Here’s how you be­come a lead play­er in the boom­ing gene ther­a­py sec­tor

Three years ago, Pfizer anted up $150 million in cash to buy Bamboo Therapeutics in Chapel Hill, NC as it cautiously stuck a toe in the small gene therapy pool of research and development.

Company execs followed up a year later with a $100 million expansion of the manufacturing operations they picked up in that deal for the UNC spinout, which came with $495 million in milestones.

And now they’re really going for it.

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Video: Putting the AI in R&D — with Badhri Srini­vasan, Tony Wood, Rosana Kapeller, Hugo Ceule­mans, Saurabh Sa­ha and Shoibal Dat­ta

During BIO this year, I had a chance to moderate a panel among some of the top tech experts in biopharma on their real-world use of artificial intelligence in R&D. There’s been a lot said about the potential of AI, but I wanted to explore more about what some of the larger players are actually doing with this technology today, and how they see it advancing in the future. It was a fascinating exchange, which you can see here. The transcript has been edited for brevity and clarity. — John Carroll

UP­DAT­ED: As­traZeneca’s Imfinzi/treme com­bo strikes out — again — in lung can­cer. Is it time for last rites?

AstraZeneca bet big on the future of their PD-L1 Imfinzi combined with the experimental CTLA-4 drug tremelimumab. But once again it’s gone down to defeat in a major Phase III study — while adding damage to the theory involving targeting cancer with a high tumor mutational burden.

Early Wednesday the pharma giant announced that their NEPTUNE study had failed, with the combination unable to beat standard chemo at overall survival in high TMB cases of advanced non-small cell lung cancer. We won’t get hard data until later in the year, but the drumbeat of failures will call into question what — if any — future this combination can have left.

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SEC calls out lit­tle Ther­a­peu­tic­sMD for its in­sid­er con­tacts with an­a­lysts to boost share price, then halt rout

Back in May 2017, following an FDA rejection, TherapeuticsMD saw its share price plummet to the lowest levels in two years. The little Florida biotech eventually found its way back to the good side of regulators, scoring a curious OK a year later for its therapy preventing vaginal pain during sex. But the SEC is now accusing it of selectively disclosing nonpublic information in attempts to manipulate its stock.

In two instances in June and July of 2017, TherapeuticsMD allegedly violated the Regulation Fair Disclosure rule by sharing material information with certain sell-side analysts and not the public, resulting in a more favorable stock move than otherwise would be expected.

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Therapists Marcela Ot'alora and Bruce Poulter are trained to conduct MDMA-assisted psychotherapy. In this reenactment, they demonstrate how they help guide and watch over a patient who is revisiting traumatic memories while under the influence of MDMA. (Photo: Multidisciplinary Association for Psychedelic Studies)

MD­MA, now in Phase III, shows promise as a PTSD treat­ment

The first time Lori Tipton tried MDMA, she was skeptical it would make a difference.

“I really was, at the beginning, very nervous,” Tipton said.

MDMA is the main ingredient in the club drug known as ecstasy or molly. But Tipton wasn’t taking pills sold on the street to get high. She was trying to treat her post-traumatic stress disorder by participating in a clinical trial.

After taking a dose of pure MDMA, Tipton lay in a quiet room with two specially trained psychotherapists. They sat next to her as she recalled some of her deepest traumas, such as discovering her mother’s body after Tipton’s mother killed two people and then herself in a murder-suicide.

Ted Ashburn. Oncorus

Cowen, Per­cep­tive lead $79.5M Se­ries B for 's­tand­out' biotech shep­herd­ing on­colyt­ic virus to clin­ic

As several Big Pharma players secure biotech partners in the oncolytic virus space for new immuno-oncology combos, Cowen and Perceptive Advisors have come out with their own bet on a startup that promises to shine.

The marquee investors are joining MPM, Deerfield, Celgene, Astellas, Arkin Bio Ventures and UBS Oncology Impact Fund in backing the drug developer, Oncorus, which will now deploy the $79.5 million in Series B cash toward clinical development of its lead program. Other new investors include Surveyor Capital, Sphera Funds, IMM Investment, QUAD Investment Management, UTC Investment, SV Investment Corp and Shinhan Investment-Private Equity, the last five of which are Korean-based funds.

Fu­til­i­ty analy­sis au­gurs de­feat in piv­otal tri­al test­ing of Nu­Cana's lead drug in metasta­t­ic pan­cre­at­ic can­cer

Nearly two years after making its public debut, UK-based NuCana’s mission to make chemotherapies more potent and safer was dealt a blow, after a pivotal study testing its lead experimental drug halted enrollment in a hard-to-treat advanced form of cancer, following a futility analysis.

The drug, Acelarin, is being evaluated for use in metastatic pancreatic cancer patients who were not considered suitable for combination chemotherapy. In the late-stage ACELARATE study — which compared the experimental drug against the chemotherapy gemcitabine — 200 patients had been enrolled by the sponsor, Clatterbridge Cancer Centre, before an analysis from an independent safety and data monitoring panel suggested the study’s main goal would not be met.