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.

Forge Bi­o­log­ics’ cGMP Com­pli­ant and Com­mer­cial­ly Vi­able Be­spoke Affin­i­ty Chro­matog­ra­phy Plat­form

Forge Biologics has developed a bespoke affinity chromatography platform approach that factors in unique vector combinations to streamline development timelines and assist our clients in efficiently entering the clinic. By leveraging our experience with natural and novel serotypes and transgene conformations, we are able to accelerate affinity chromatography development by nearly 3-fold. Many downstream purification models are serotype-dependent, demanding unique and time-consuming development strategies for each AAV gene therapy product1. With the increasing demand to propel AAV gene therapies to market, platform purification methods that support commercial-scale manufacturing of high-quality vectors with excellent safety and efficacy profiles are essential.

Mathai Mammen, FogPharma's next CEO

Math­ai Mam­men hands in J&J's R&D keys to lead Greg Ver­dine’s Fog­Phar­ma 

In the early 1990s, Mathai Mammen was a teaching assistant in Greg Verdine’s Science B46 course at Harvard. In June, the former R&D head at Johnson & Johnson will succeed Verdine as CEO, president and chair of FogPharma, the same month the seven-year-old biotech kickstarts its first clinical trial.

After leading R&D at one of the largest drugmakers in the world, taking the company through more than half a dozen drug approvals in the past few years, not to mention a Covid-19 vaccine race, Mammen departed J&J last month and will take the helm of a Cambridge, MA biotech attempting to go after what Verdine calls the “true emperor of all oncogenes” — beta-catenin.

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Jeff Bluestone (R), Sonoma Biotherapeutics CEO

Jef­frey Blue­stone brings his start­up haul to $400M+, join­ing forces with Re­gen­eron on cell ther­a­pies

These days, when Jeffrey Bluestone gets together with his contemporaries in science, the conversation often turns to retirement plans.

But a little more than three years ago, Bluestone reached a momentous turning point in his career, exiting a prestigious post at UCSF, where he had spent decades in the scientific pursuit of new therapies. And it had nothing to do with retirement anytime in the near future.

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FDA ap­proves Nar­can opi­oid over­dose re­ver­sal spray for over-the-counter sale

The FDA today approved Emergent BioSolutions’ Narcan brand naloxone nasal spray for over-the-counter sales. The nod was expected and comes on the heels of a unanimous 19-0 advisory committee vote in favor of approval last month.

The move to OTC means the opioid overdose reversal agent will now be available on grocery, convenience and gas stations shelves, as well as potentially for purchase online.

CSL CEO Paul McKenzie (L) and CMO Bill Mezzanotte

Q&A: New­ly-mint­ed CSL chief ex­ec­u­tive Paul McKen­zie and chief med­ical of­fi­cer Bill Mez­zan­otte

Paul McKenzie took over as CEO of Australian pharma giant CSL this month, following in the footsteps of long-time CSL vet Paul Perreault.

With an eye on mRNA, and quickly commercializing its new, $3.5 million-per-shot gene therapy for hemophilia B, McKenzie and chief medical officer Bill Mezzanotte answered some questions from Endpoints News this afternoon about where McKenzie is going to take the company and what advances may be coming to market from CSL’s pipeline. Below is a lightly edited transcript.

Boehringer re­ports ro­bust sales led by type 2 di­a­betes and pul­monary drugs, promis­es more to come high­light­ing obe­si­ty

Boehringer Ingelheim reported human pharma sales of €18.5 billion on Wednesday, led by type 2 diabetes and heart failure drug Jardiance and pulmonary fibrosis med Ofev. Jardiance sales reached €5.8 billion, growing 39% year over year, while Ofev took in €3.2 billion, notching its own 20.6% annual jump.

However, Boehringer is also looking ahead with its pipeline, estimating “In the next seven years the company expects about 20 regulatory approvals in human pharma.”

Feng Zhang (Susan Walsh/AP Images)

In search of new way to de­liv­er gene ed­i­tors, CRISPR pi­o­neer turns to mol­e­c­u­lar sy­ringes

Bug bacteria are ruthless.

Some soil bacteria have evolved tiny, but deadly injection systems that attach to insect cells, perforate them and release toxins inside — killing a bug in just a few days’ time. Scientists, on the other hand, want to leverage that system to deliver medicines.

In a paper published Wednesday in Nature, MIT CRISPR researcher Feng Zhang and his lab describe how they engineered these syringes made by bacteria to deliver potential therapies like toxins that kill cancer cells and gene editors. With the help of an AI program, they developed syringes that can load proteins of their choice and selectively target human cells.

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Blue­bird to miss Q1 dead­line for lo­vo-cel fil­ing, shares sliced

Bluebird bio had expected to submit a BLA for its sickle cell disease gene therapy lovotibeglogene autotemcel, or lovo-cel, by Friday. Now, that deadline is getting punted for at least a couple of weeks.

CEO Andrew Obenshain detailed the update during the company’s full-year earnings call Wednesday morning after the gene therapy specialist reported the development in its Q4 and 2022 report.

“We will likely miss the Q1 2023 submission goal,” Obenshain said, noting the application is fully written and ready to go. But bluebird is still waiting on FDA feedback for the company’s CMC module submitted in early March.

J&J bows out of RSV vac­cine race, end­ing PhI­II study and ced­ing to Pfiz­er, GSK

Johnson & Johnson announced Wednesday morning it is ending development of its adult RSV vaccine that was in the middle of a 27,200-patient trial, giving up a big slice of what’s expected to be the next multibillion-dollar pharma market.

The decision came down to the shifting RSV “competitive landscape,” a company spokesperson tells Endpoints News, adding the “breadth of options” was much different than when J&J first started its pivotal study. The spokesperson declined to comment on the Phase III data, saying only the shot is undergoing an “ongoing assessment.”

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