De­spite safe­ty, ef­fi­ca­cy con­cerns, FDA Ad­Com nar­row­ly rec­om­mends Mallinck­rodt drug

A day af­ter the FDA de­tailed sig­nif­i­cant con­cerns about just how ef­fec­tive or safe an ex­per­i­men­tal Mallinck­rodt liv­er drug was, an ad­vi­so­ry com­mit­tee de­cid­ed by a sin­gle vote to rec­om­mend it for ap­proval.

“I vot­ed yes to ap­prove, but I al­so wrote in, ‘but bare­ly,’” Paul Rid­ker, a car­di­ol­o­gist at Brigham and Women’s Hos­pi­tal and one of the pan­elists, said at the meet­ing, ac­cord­ing to Fierce­Biotech. The vote was 8-7.

The FDA does not have to fol­low the com­mit­tee’s rec­om­men­da­tion, but gen­er­al­ly does.

The de­bate cen­tered in part on what Mallinck­rodt’s pri­ma­ry end­point meant. The drug, known as ter­li­pressin, had been test­ed for he­pa­tore­nal syn­drome type 1 (HRS-1), a rapid­ly pro­gress­ing dis­ease where pa­tients with cir­rho­sis can de­vel­op life-threat­en­ing kid­ney fail­ure with­in days. The on­ly cur­rent treat­ment is liv­er trans­plant. Be­tween 40% and 70% of pa­tients who don’t re­ceive a trans­plant will die with­in a month.

Ter­li­pressin, through, did not im­prove over­all sur­vival; more pa­tients, in fact, died in the drug arm than in the treat­ment arm. Rather, Mallinck­rodt mea­sured “ver­i­fied HRS re­ver­sal” — a mea­sure that looks at whether a bi­o­log­i­cal mark­er of kid­ney func­tion, serum cre­a­ti­nine lev­els, de­clined to less than 1.5 mg/dl by day 14. For 29% of pa­tients on the drug-arm it did, com­pared to 16% on the place­bo arm.

The FDA agreed to that pri­ma­ry end­point, ac­knowl­edg­ing that it was dif­fi­cult to de­sign tri­als for HRS and that some ev­i­dence sug­gest­ed cre­a­tine re­ver­sal leads to bet­ter out­comes post-trans­plant. But they said Mallinck­rodt would al­so need to show that pa­tients al­so saw their clin­i­cal out­comes trend­ed in the right di­rec­tion. The agency asked the pan­el to de­ter­mine if Mallinck­rodt showed that.

On top of the ef­fi­ca­cy de­bates, there were al­so sig­nif­i­cant ques­tions about safe­ty. In the Phase III tri­al, the FDA not­ed, 9% of drug-arm pa­tients died of res­pi­ra­to­ry fail­ure, com­pared with 1% of place­bo. More drug-arm pa­tients al­so died of sep­sis and sep­tic shock than in the con­trol group.

The three main clin­i­cal out­comes Mallinck­rodt mea­sured were length of ICU vis­it, post-trans­plant sur­vival and length of time with­out re­sort­ing to re­nal re­place­ment ther­a­py. The ad­vi­sors agreed that the com­pa­ny didn’t show im­prove­ment on the first two, but did on the lat­ter. For 8 of the 15 mem­bers, that was enough to war­rant ap­proval in a dis­ease that leaves pa­tients with few oth­er op­tions.

Watch­ing the meet­ing, though, SVB Leerink’s Ami Fa­dia saw at least one hur­dle be­fore ap­proval. A ma­jor­i­ty said the drug was worth it, but like the FDA, they still had ques­tions on how Mallinck­rodt would man­age the safe­ty con­cerns, in­clud­ing that in­creased risk of death.

“It ap­pears that for Mallinck­rodt to ob­tain reg­u­la­to­ry and/or com­mer­cial suc­cess with ter­li­pressin this will re­quire a much more thor­ough risk mit­i­ga­tion plan, sig­nif­i­cant pa­tient and physi­cian ed­u­ca­tion and po­ten­tial­ly some sort of post-ap­proval re­quire­ment,” Fa­dia wrote in a note to in­vestors.

The PDU­FA date is Sep­tem­ber 12. The drug was al­ready re­ject­ed once, in 2009.

Jan Hatzius (Photographer: Christopher Goodney/Bloomberg via Getty Images)

When will it end? Gold­man econ­o­mist gives late-stage vac­cines a good shot at tar­get­ing 'large shares' of the US by mid-2021 — but the down­side is daunt­ing

It took decades for hepatitis B research to deliver a slate of late-stage candidates capable of reining the disease in.

With Covid-19, the same timeline has devoured all of 5 months. And the outcome will influence the lives of billions of people and a multitrillion-dollar world economy.

Count the economists at Goldman Sachs as optimistic that at least one of these leading vaccines will stay on this furiously accelerated pace and get over the regulatory goal line before the end of this year, with a shot at several more near-term OKs. That in turn should lead to the production of billions of doses of vaccines that can create herd immunity in the US by the middle of next year, with Europe following a few months later.

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Lund­beck sounds taps on an­oth­er CNS drug, re­treat­ing from a mine field still oc­cu­pied by a Mer­ck team

Lundbeck has snipped another clinical-stage branch of its CNS research, dumping a schizophrenia program after determining that their therapy would have no positive influence on the disease.

Designed originally as a 240-patient study, researchers set out in early 2019 to see if a homegrown drug dubbed Lu AF11167 could make it through a proof-of-concept study. The drug is a PDE10Ai inhibitor, targeting an enzyme which it said at the time offered a new pathway to retuning the body’s neurotransmitter dopamine. The big idea was that by hitting their target, the drug would modulate “dopamine D1 and D2 receptor-mediated intraneuronal signaling without binding to these receptors,” influencing negative symptoms of schizophrenia.

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UP­DAT­ED: No­vavax her­alds the lat­est pos­i­tive snap­shot of ear­ly-stage Covid-19 vac­cine — so why did its stock briefly crater?

High-flying Novavax $NVAX became the latest of the Covid-19 vaccine players to stake out a positive set of biomarker data from its early-stage look at its vaccine in humans.

Their adjuvanted Covid-19 vaccine was “well-tolerated and elicited robust antibody responses numerically superior to that seen in human convalescent sera,” the company noted. According to the biotech:

All subjects developed anti-spike IgG antibodies after a single dose of vaccine, many of them also developing wild-type virus neutralizing antibody responses, and after Dose 2, 100% of participants developed wild-type virus neutralizing antibody responses. Both anti-spike IgG and viral neutralization responses compared favorably to responses from patients with clinically significant COVID‑19 disease. Importantly, the IgG antibody response was highly correlated with neutralization titers, demonstrating that a significant proportion of antibodies were functional.

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J&J gets a fresh OK for es­ke­t­a­mine, but is it re­al­ly the game-chang­er for de­pres­sion Trump keeps tweet­ing about?

Backed by an enthusiastic set of tweets from President Trump and a landmark OK for depression, J&J scooped up a new approval from the FDA for Spravato today. But this latest advance will likely bring fresh scrutiny to a drug that’s spurred some serious questions about the data, as well as the price.

First, the approval.

Regulators stamped their OK on the use of Spravato — developed as esketamine, a nasal spray version of the party drug Special K or ketamine — for patients suffering from major depressive disorder with acute suicidal ideation or behavior.

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Sean Nolan and RA Session II

Less than 3 months af­ter launch, the AveX­is crew’s Taysha rais­es $95M Se­ries B. Is an IPO next?

The old AveXis team is moving quickly in Dallas.

Three months ago, they launched Taysha with $30 million in Series A funding and a pipeline of gene therapies out of UT Southwestern. Now, they’ve announced an oversubscribed $95 million Series B. And the biotech is declining all interview requests on the news, the kind of broad silence that can indicate an IPO is in the pipeline.

Biotechs, including those relatively fresh off launch, have been going public at a frenzy since the pandemic began. Investors have showed a willingness to put upwards of $200 million to companies that have yet to bring a drug into the clinic. Still, if Taysha were to go public in the near future, it would be perhaps the shortest path from launch to IPO in recent biotech memory.

Stéphane Bancel, Moderna CEO (Steven Ferdman/Getty Images)

Mod­er­na CEO Stéphane Ban­cel out­lines a prospec­tive moth­er­lode of Covid-19 vac­cine rev­enue — will a back­lash fol­low?

Moderna shows no sign of slowing down, or turning charitable when it comes to pricing supplies of its Covid-19 vaccine.

One of the leaders in the Phase III race to get a Covid-19 vaccine across the finish line in record time, Moderna says it’s on track to complete enrollment in one of the most avidly watched studies in the world next month. And the biotech has already banked some $400 million in deposits for vaccine supply as it works through negotiations with countries around the world — as CEO Stéphane Bancel sets out to hire a commercial team.

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Covid-19 roundup: J&J and BAR­DA agree to $1 bil­lion for 100 mil­lion dos­es; Plas­ma re­duces mor­tal­i­ty by 50% — re­ports

J&J has become the latest vaccine developer to agree to supply BARDA with doses of their Covid-19 vaccine, signing an agreement that will give the government 100 million doses in exchange for $1 billion in funding.

The agreement, similar to those signed by Novavax, Sanofi and AstraZeneca-Oxford, provides funding not only for individual doses but to help J&J ramp up manufacturing. Pfizer, by contrast, received $1.95 billion for the doses alone. Still, if one looked at each agreement as purchase amounts, J&J’s deal would be $10 per dose, slotting in between Novavax’s $16 per dose and AstraZeneca’s $4 per dose.

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RA, No­var­tis back Gen­tiBio's seed round, plans to launch de­vel­op­ment of En­gTreg ther­a­pies

Boston, MA-based startup GentiBio landed a $20 million seed fund from three investors to dive into engineered regulatory T cell (EngTreg) development.

Marquee investors OrbiMed, Novartis Venture Fund and RA Capital Management have backed GentiBio’s mission to develop EngTregs for the treatment of autoimmune, alloimmune, autoinflammatory, and allergic diseases. Unlike other companies studying treatments using a patient’s own Tregs, GentiBio plans to make use of CD4+ immune cells, found in the blood.

Paul Laikind, ViaCyte CEO

Stem cell play­er Vi­a­Cyte ex­pands col­lab­o­ra­tion with Gore to de­vel­op sub­cu­ta­neous di­a­betes treat­ment

Longtime stem cell player ViaCyte has teamed up with a materials science company in an effort to solve immunosuppression challenges and advance its type 1 diabetes treatments.

Expanding on an existing collaboration, ViaCyte and W.L. Gore have agreed to combine the biotech’s PEC-Encap candidate with a Gore-produced membrane in what they hope will eliminate the need for immunosuppressive drugs. Such treatments have created foreign body responses in the past, and stamping these reactions out is the main goal, ViaCyte CEO Paul Laikind said.