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.

In his­toric Covid-19 ad­comm, vac­cine ex­perts de­bate a sea of ques­tions — but of­fer no clear an­swers

The most widely anticipated and perhaps most widely watched meeting in the FDA’s 113-year history ended late Thursday night with a score of questions and very few answers.

For nearly 9 hours, 18 different outside experts listened to public health agencies and foundations present how the United States’ Covid-19 vaccine program developed through October, and they debated where it should go from there: Were companies testing the right metrics in their massive trials? How long should they track patients before declaring a vaccine safe or effective? Should a vaccine, once authorized, be given to the volunteers in the placebo arm of a trial?

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Michel Vounatsos, Biogen CEO (via YouTube)

UP­DAT­ED: Bio­gen spot­lights a pair of painful pipeline set­backs as ad­u­canum­ab show­down looms at the FDA

Biogen has flagged a pair of setbacks in the pipeline, spotlighting the final failure for a one-time top MS prospect while scrapping a gene therapy for SMA after the IND was put on hold due to toxicity.

Both failures will raise the stakes even higher on aducanumab, the Alzheimer’s drug that Biogen is betting the ranch on, determined to pursue an FDA OK despite significant skepticism they can make it with mixed results and a reliance on post hoc data mining. And the failures are being reported as Biogen was forced to cut its profit forecast for 2020 as a generic rival started to erode their big franchise drug.

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Pascal Soriot, AstraZeneca CEO (Zach Gibson/Bloomberg via Getty Images)

UP­DAT­ED: FDA gives As­traZeneca the thumbs-up to restart PhI­II Covid-19 vac­cine tri­als, and J&J is prepar­ing to re­sume its study

Several countries had restarted their portions of AstraZeneca’s global Phase III Covid-19 vaccine trial after the study was paused worldwide in early September, but the US notably stayed on the sidelines — until now. Friday afternoon the pharma giant announced the all clear from US regulators. And on top of that, J&J announced Friday evening that it’s preparing to resume its own Phase III vaccine trial.

Stephen Hahn, FDA commissioner (AP Images)

As FDA sets the stage for the first Covid-19 vac­cine EUAs, some big play­ers are ask­ing for a tweak of the guide­lines

Setting the stage for an extraordinary one-day meeting of the Vaccines and Related Biological Products Advisory Committee this Thursday, the FDA has cleared 2 experts of financial conflicts to help beef up the committee. And regulators went on to specify the safety, efficacy and CMC input they’re looking for on EUAs, before they move on to the full BLA approval process.

All of this has already been spelled out to the developers. But the devil is in the details, and it’s clear from the first round of posted responses that some of the top players — including J&J and Pfizer — would like some adjustments and added feedback. And on Thursday, the experts can offer their own thoughts on shaping the first OKs.

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Ul­tragenyx in­jects $40M to grab Solid's mi­crody­s­trophin trans­gene — while side­step­ping the AAV9 vec­tor that stirred up safe­ty fears

Since before Ilan Ganot started Solid Bio to develop a gene therapy for kids like his son, who has Duchenne muscular dystrophy, Ultragenyx CEO Emil Kakkis has been watching and advising the former investment banker as he navigated the deep waters of drug development.

Just as Solid is getting back up on its feet after a yearlong clinical hold, Kakkis has decided to jump in for a formal alliance.

With a $40 million upfront, Ultragenyx is grabbing 14.45% of Solid’s shares $SLDB and the rights to its microdystrophin construct for use in combination with AAV8 vectors. Solid’s lead program, which utilizes AAV9, remains unaffected. The company also retains rights to other applications of its transgene.

Dan O'Day, Gilead CEO (Andrew Harnik, AP Images)

UP­DAT­ED: FDA anoints Gilead­'s remde­sivir as the Covid-19 treat­ment win­ner, hand­ing down full ap­proval — de­spite some deep skep­ti­cism

Seven months into the Covid-19 pandemic, the race to develop a treatment for the disease that’s proved to be the biggest health crisis in a century has an officially designated winner: Gilead. And they’re picking up the prize — worth billions in peak sales — despite a major study that concluded the drug was no help in reducing the number of people who die from the virus.

The FDA handed down a thumbs-up for remdesivir, the company announced Thursday afternoon, as the drug becomes the first fully approved treatment for Covid-19 in the US. Remdesivir, to be marketed as Veklury, will come with a label for treatment in adults and children older than 12 in Covid-19 cases that require hospitalization.

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Stephen Hoge, Moderna president (Moderna)

On morn­ing of FDA Covid-19 ad­comm, Mod­er­na com­pletes PhI­II en­roll­ment, putting them neck-and-neck with Pfiz­er

Weeks away from a potential EUA application, Moderna announced they have completed enrollment in their 30,000-person Phase III Covid-19 vaccine trial, with over a third of volunteers non-white and a quarter over the age of 65.

The announcement caps what has been the most closely-watched recruitment race in the history of drug development, as Pfizer and Moderna rushed to get enough volunteers to prove whether or not experimental vaccines could actually protect people from contracting Covid-19. Pfizer reached that mark on Sept. 15. Moderna said around the same time that they would slow down enrollment to ensure they enrolled enough participants from minority and at-risk groups.

A top drug pro­gram at Bay­er clears a high bar for CKD — open­ing the door to an FDA pitch

Over the past 4 years, Bayer has been steering a major trial through a pivotal program to see if their drug finerenone could slow down the pace of chronic kidney disease in patients suffering from both CKD as well as Type 2 diabetes.

Today, their team jumped on a virtual meeting hosted by the American Society of Nephrology to offer a solid set of pivotal data to demonstrate that the drug can delay dialysis or a kidney replacement as well as cardio disease, while also adding some worrying signs of hyperkalemia among the patients taking the drug. And they’re hustling it straight to regulators in search of an approval for kidney disease and cardio patients — one of the toughest challenges in the book, as demonstrated by repeated past failures.

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Adam Koppel and Jeffrey Schwartz, Bain

Bain ex­ecs Adam Kop­pel and Jef­frey Schwartz line up $125M for their first blank check deal as Wall Street con­tin­ues to em­brace biotech

Adam Koppel and Jeffrey Schwartz have jumped into the blank check game, raising $125 million for a stock listing in search of a company.

Their SPAC, BCLS Acquisition Corp, raised $125 million this week, with a line on $25 million more as it scouts for a biotech in search of money and a place on Wall Street.

The two principals at Bain Life Sciences have been on a romp since they set up the Bain operation 4 years ago. Their S-1 spells out a track record of 22 deals totaling $650 million for the life sciences group, which led to 9 IPOs.