FDA rais­es ques­tions about Mallinck­rodt's HRS-1 drug be­fore ad­vi­so­ry hear­ing

Last Au­gust, UK drug­mak­er Mallinck­rodt pre­sent­ed pos­i­tive topline find­ings for its em­bat­tled ter­li­pressin, il­lus­trat­ing the can­di­date met its pri­ma­ry end­point in treat­ing a life-threat­en­ing form of liv­er dis­ease that caus­es kid­ney fail­ure.

But the FDA con­tin­ues to have ques­tions about ter­li­pressin’s safe­ty and ef­fi­ca­cy. Af­ter de­ter­min­ing from the out­set of the tri­al that the pri­ma­ry end­point would on­ly clas­si­fy as a sur­ro­gate end­point, the agency is ques­tion­ing whether or not pa­tients “trend­ed to­ward clin­i­cal im­prove­ments” while on ter­li­pressin. Reg­u­la­tors will con­vene in a hear­ing to­day and have re­leased a doc­u­ment out­lin­ing their think­ing ahead of the meet­ing.

In par­tic­u­lar, the FDA high­light­ed “a sig­nif­i­cant safe­ty con­cern” re­gard­ing a high­er num­ber of pa­tients in the ter­li­pressin arm who suf­fered res­pi­ra­to­ry fail­ure than in the place­bo arm. More than half of these events oc­curred with­in five days of ad­min­is­ter­ing treat­ment and 61 per­cent re­sult­ed in death, com­pared to 20 per­cent in the con­trol.

The FDA did note that be­cause of the med­ical com­plex­i­ties in most of the pa­tients stud­ied, it is dif­fi­cult to de­ter­mine to what ex­tent, if any, the role ter­li­pressin played in each of the in­di­vid­ual cas­es. The agency is al­so con­cerned about an in­creased rate of sep­sis and sep­tic shock in the treat­ment arm.

Ter­li­pressin has faced sev­er­al chal­lenges in its quest to win ap­proval to treat he­pa­tore­nal syn­drome type 1 in the US ever since it re­ceived a com­plete re­sponse let­ter all the way back in 2009. At the time, the FDA re­quired Mallinck­rodt to con­duct an ad­di­tion­al study to prove the ef­fi­ca­cy and safe­ty of ter­li­pressin, but the fol­low-up again failed to reach sta­tis­ti­cal sig­nif­i­cance.

The third tri­al for ter­li­pressin, which the FDA is eval­u­at­ing in to­day’s hear­ing, did show a sta­tis­ti­cal­ly sig­nif­i­cant re­ver­sal in HRS-1 com­pared to the place­bo. Ad­di­tion­al­ly, due to high mor­tal­i­ty rates of HRS-1, pa­tients may some­times re­quire re­nal re­place­ment ther­a­py, and those in the ter­li­pressin arm showed high­er rates of RRT-free sur­vival de­spite ter­li­pressin treat­ment in com­bi­na­tion with RRT not show­ing an as­so­ci­a­tion with im­proved sur­vival.

But be­cause the pri­ma­ry end­point of the study cap­tured treat­ment ef­fects on a lab­o­ra­to­ry pa­ra­me­ter (serum cre­a­ti­nine), the agency con­sid­ered it a sur­ro­gate end­point. Whether or not the FDA ap­proves ter­li­pressin for use to treat HRS-1, in light of the tri­al meet­ing for that end­point, is up for de­bate. It’s worth not­ing that ter­li­pressin is ap­proved for use in Eu­rope un­der the brand name Gly­pressin.

HRS-1 is a life-threat­en­ing con­di­tion in­volv­ing a rapid de­cline in kid­ney func­tion in peo­ple with ad­vanced liv­er dis­ease. The ail­ment is most com­mon in in­di­vid­u­als with ad­vanced cir­rho­sis and as­cites, but can al­so oc­cur in some with acute liv­er fail­ure and oth­er liv­er dis­eases. Half of those with HRS-1 die with­in two weeks of di­ag­no­sis and 80 per­cent with­in three months.

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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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.

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 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.

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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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.

Covid-19 roundup: An mR­NA play­er gets a boost out of the lat­est round of an­i­mal da­ta; Phase­Bio pulls the plug on treat­ment tri­al

The big tell for CureVac $CVAC is coming up with a looming early-stage readout on their mRNA Covid-19 vaccine in the clinic. But for now they’ll make do with an upbeat assessment on the preclinical animal data they used to get into the clinic.

Researchers for the German biotech say they got the high antibody titers and T cell activation they were looking for, lining up a hamster challenge to demonstrate — in a simple model — that the vaccine could protect the furry creatures. Like the other mRNA vaccines, the drug sends instructions to spur cells to decorate themselves with the distinctive spike on the virus to elicit an immune response.