FDA shoots down Mallinck­rodt's re­demp­tion at­tempt, spurns rare kid­ney dis­ease drug for a sec­ond time

What­ev­er hope Mallinck­rodt had fol­low­ing a nar­row rec­om­men­da­tion by the FDA ad­vi­so­ry com­mit­tee to ap­prove ter­li­pressin has been dashed by a firm re­jec­tion.

The com­plete re­sponse let­ter stabbed right through the UK drug­mak­er’s case for the drug, as reg­u­la­tors are ask­ing for “more in­for­ma­tion to sup­port a pos­i­tive risk-ben­e­fit pro­file for ter­li­pressin” as a treat­ment of the rare kid­ney dis­ease known as he­pa­tore­nal syn­drome type 1, or HRS-1.

This is the sec­ond time reg­u­la­tors are spurn­ing the drug, which got a fast track des­ig­na­tion in 2005 on­ly to be re­ject­ed in 2009. Soon af­ter­wards its orig­i­nal de­vel­op­er, Or­phan Ther­a­peu­tics, out-li­censed North Amer­i­can rights to Ikaria Ther­a­peu­tics, which Mallinck­rodt ac­quired in 2015.

Dis­ap­point­ed, Mallinck­rodt CSO Steven Ro­mano said his team stands by the da­ta from the Phase III CON­FIRM study, “the largest clin­i­cal tri­al ever con­duct­ed in this rare con­di­tion” in­volv­ing 300 pa­tients.

Steven Ro­mano

“HRS-1 is a com­plex dis­ease that af­fects a crit­i­cal­ly ill pa­tient pop­u­la­tion with no ap­proved treat­ment in the U.S. at present,” he added in a state­ment. “We are sur­prised by and dis­agree with the FDA’s de­ci­sion and re­main com­mit­ted to pur­su­ing all avail­able op­tions as we con­tin­ue work­ing with the FDA to­ward ap­proval of ter­li­pressin in or­der to help ad­dress this dif­fi­cult and life-threat­en­ing syn­drome.”

Just a year ago, Cowen an­a­lysts hailed the pos­i­tive da­ta as a “key suc­cess” for em­bat­tled Mallinck­rodt, which was fac­ing a litany of fail­ures for its ac­quired pipeline while un­der a cloud of opi­oid lit­i­ga­tion and law­suits tar­get­ing “ill-got­ten gains” from Ac­thar, its cash cow.

To­day the CRL counts as “yet an­oth­er set­back” in SVB Leerink an­a­lyst Ami Fa­dia’s eyes.

“We note that de­spite the over­all pos­i­tive vote, in our view the tone of the Ad­Com dis­cus­sion was de­cid­ed­ly cau­tious, strug­gling to bal­ance the high-un­met need with no cur­rent­ly avail­able treat­ment op­tions with con­cerns about lack of clin­i­cal ben­e­fit and an un­cer­tain risk mit­i­ga­tion plan,” she wrote.

On the ef­fi­ca­cy front, the FDA’s (and some of the out­side ex­perts’) chief con­cern was that the pri­ma­ry end­point — which ter­li­pressin met — was a sur­ro­gate end­point that mea­sures cre­a­ti­nine lev­els in blood. But it was un­clear whether that led to clin­i­cal im­prove­ments for HRS-1 pa­tients, who were char­ac­ter­ized by cir­rho­sis and could de­vel­op life-threat­en­ing kid­ney fail­ure with­in days.

More im­por­tant­ly, more pa­tients died in the drug arm than in the place­bo arm. And the FDA wasn’t sat­is­fied with the risk mit­i­ga­tion strat­e­gy that Mallinck­rodt of­fered. There was, how­ev­er, “no clear out­line on what would be con­sid­ered suf­fi­cient for ap­proval,” Fa­dia point­ed out.

Af­ter much de­lib­er­a­tion in Ju­ly, the Car­dio­vas­cu­lar and Re­nal Drugs Ad­vi­so­ry Com­mit­tee vot­ed 8-7 for ap­proval. Paul Rid­ker, a car­di­ol­o­gist at Brigham and Women’s Hos­pi­tal and one of the pan­elists, said he vot­ed yes but al­so wrote in “but bare­ly.”

Ap­proved in Eu­rope un­der the brand name Gly­pressin, ter­li­pressin now faces an un­cer­tain fu­ture in the US.

Mallinck­rodt, which has hint­ed at a po­ten­tial bank­rupt­cy fil­ing, didn’t spec­i­fy what the next steps will be. In­vestors sent the stock $MNK down 11.62%, edg­ing close to pen­ny-stock ter­ri­to­ry at $1.06.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

So — that pig-to-hu­man trans­plant; Po­ten­tial di­a­betes cure reach­es pa­tient; Ac­cused MIT sci­en­tist lash­es back; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

We’re incredibly excited to welcome Beth Bulik, seasoned pharma marketing reporter, to the team. You can find much of her work in our new Marketing channel — and in her weekly newsletter, Endpoints PharmaRx, which will launch in early November. Add it to your subscriptions here.

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UP­DAT­ED: Agenus calls out FDA for play­ing fa­vorites with Mer­ck, pulls cer­vi­cal can­cer BLA at agen­cy's re­quest

While criticizing the FDA for what may be some favoritism towards Merck, Agenus on Friday officially pulled its accelerated BLA for its anti-PD-1 inhibitor balstilimab as a potential second-line treatment for cervical cancer because of the recent full approval for Merck’s Keytruda in the same indication.

The company said the BLA, which was due for an FDA decision by Dec. 16, was withdrawn “when the window for accelerated approval of balstilimab closed,” thanks to the conversion of Keytruda’s accelerated approval to a full approval four months prior to its PDUFA date.

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How to col­lect and sub­mit RWD to win ap­proval for a new drug in­di­ca­tion: FDA spells it out in a long-await­ed guid­ance

Real-world data are messy. There can be differences in the standards used to collect different types of data, differences in terminologies and curation strategies, and even in the way data are exchanged.

While acknowledging this somewhat controlled chaos, the FDA is now explaining how biopharma companies can submit study data derived from real-world data (RWD) sources in applicable regulatory submissions, including new drug indications.

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NYU surgeon transplants an engineered pig kidney into the outside of a brain-dead patient (Joe Carrotta/NYU Langone Health)

No, sci­en­tists are not any clos­er to pig-to-hu­man trans­plants than they were last week

Steve Holtzman was awoken by a 1 a.m. call from a doctor at Duke University asking if he could put some pigs on a plane and fly them from Ohio to North Carolina that day. A motorcyclist had gotten into a horrific crash, the doctor explained. He believed the pigs’ livers, sutured onto the patient’s skin like an external filter, might be able to tide the young man over until a donor liver became available.

David Livingston (Credit: Michael Sazel for CeMM)

Renowned Dana-Far­ber sci­en­tist, men­tor and bio­phar­ma ad­vi­sor David Liv­ingston has died

David Livingston, the Dana-Farber/Harvard Med scientist who helped shine a light on some of the key molecular drivers of breast and ovarian cancer, died unexpectedly last Sunday.

One of the senior leaders at Dana-Farber during his nearly half century of work there, Livingston was credited with shedding light on the genes that regulate cell growth, with insights into inherited BRCA1 and BRCA2 mutations that helped lay the scientific foundation for targeted therapies and earlier detection that have transformed the field.

Marty Duvall, Oncopeptides CEO

On­copep­tides stock craters as it pulls can­cer drug Pepax­to from the mar­ket

Shares of Oncopeptides crashed more than 70% in early Friday trading after the company said it’s pulling its multiple myeloma drug Pepaxto (melphalan flufenamide) from the US market after failing a confirmatory trial. The move will force the company to close its US and EU business units and enact significant layoffs.

The FDA had scheduled an adcomm meeting next Thursday to discuss Pepaxto, which first won accelerated approval in February and costs about $19,000 per course of treatment. The committee was to weigh in on whether the confirmatory trial demonstrated a worse overall survival in the treatment arm compared to the control arm.

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Pfiz­er pitch­es its Covid-19 vac­cine for younger chil­dren ahead of ad­comm next week

Pfizer will present its case to the FDA’s vaccine adcomm next week, seeking authorization for a lower-dose version of its Covid-19 vaccine for kids ages 5 through 12, which the Biden administration said will likely begin rolling out early next month.

Two primary doses of the 10 µg vaccine (the dose for those ages 12 and up is 30 μg) given 3 weeks apart in this group of children “have shown a favorable safety and tolerability profile, robust immune responses against all variants of concern including Delta, and vaccine efficacy of 90.7% against laboratory-confirmed symptomatic COVID-19,” the company said in briefing documents ahead of next Tuesday’s meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee.

No­vo CEO Lars Fruer­gaard Jør­gensen on R&D risk, the deal strat­e­gy and tar­gets for gen­der di­ver­si­ty


I kicked off our European R&D summit last week with a conversation involving Novo Nordisk CEO Lars Fruergaard Jørgensen. Novo is aiming to launch a new era of obesity management with a new approval for semaglutide. And Jørgensen had a lot to say about what comes next in R&D, how they manage risk and gender diversity targets at the trendsetting European pharma giant.

John Carroll: I’m here with Lars Jørgensen, the CEO of Novo Nordisk. Lars, it’s been a really interesting year so far with Novo Nordisk, right? You’ve projected a new era of growing sales. You’ve been able to expand on the GLP-1 franchise that was already well established in diabetes now going into obesity. And I think a tremendous number of people are really interested in how that’s working out. You have forecast a growing amount of sales. We don’t know specifically how that might play out. I know a lot of the analysts have different ideas, how those numbers might play out, but that we are in fact embarking on a new era for Novo Nordisk in terms of what the company’s capable of doing and what it’s able to do and what it wants to do. And I wanted to start off by asking you about obesity in particular. Semaglutide has been approved in the United States for obesity. It’s an area of R&D that’s been very troubled for decades. There have been weight loss drugs that have come along. They’ve attracted a lot of attention, but they haven’t actually ever gained traction in the market. My first question is what’s different this time about obesity? What is different about this drug and why do you expect it to work now whereas previous drugs haven’t?

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