CEO Ron Renaud (Translate Bio)

UP­DAT­ED: Lack of ear­ly ef­fi­ca­cy for Trans­late Bio's mR­NA-based cys­tic fi­bro­sis drug rais­es some big ques­tions

Look­ing to bring mR­NA ther­a­peu­tics to cys­tic fi­bro­sis, Trans­late Bio re­vealed its sec­ond in­ter­im analy­sis in a Phase I/II study show­ing their ex­per­i­men­tal drug to be large­ly safe and tol­er­a­ble. But ques­tions re­main whether or not the pro­gram, dubbed MRT5005, will prove ef­fi­ca­cious with a top an­a­lyst all but de­clar­ing an end to the pro­gram.

Trans­late said that da­ta from 12 pa­tients across three co­horts demon­strate that mul­ti­ple dos­es of their in­haled cys­tic fi­bro­sis treat­ment sug­gest the ther­a­py is safe. The mR­NA-cen­tric pro­gram al­so ap­peared safe in an ad­di­tion­al co­hort with 4 pa­tients in a sin­gle-dose co­hort.

How­ev­er, Trans­late did not ob­serve im­prove­ments in lung func­tion in any of the new­ly re­port­ed co­horts, see­ing no pat­tern of in­creas­es in ppFEV1 in the mul­ti­ple-dose co­horts and no in­crease in the sin­gle-dose co­hort.

CEO Ron Re­naud told End­points News he wasn’t con­cerned about the lack of ef­fi­ca­cy be­cause the study was geared to­ward safe­ty and too small to run a sta­tis­ti­cal analy­sis.

“When we set out to do this study, our pri­ma­ry ob­jec­tive here was to de­ter­mine safe­ty and tol­er­a­bil­i­ty. Could we get a mes­sen­ger RNA across that mu­cus lay­er of the lung? And I think we’ve been able to demon­strate that,” Re­naud told End­points.

Lung func­tion was in­clud­ed in the study as a sec­ondary safe­ty mea­sure, he added, not­ing that none of the pa­tients saw their lung func­tions de­crease.

In the im­me­di­ate wake of the news, Trans­late $TBIO shares sunk about 20% on Wednes­day af­ter­noon.

The da­ta read­out had been high­ly an­tic­i­pat­ed from SVB Leerink an­a­lyst Ge­of­frey Porges, who wrote in Jan­u­ary that he was cu­ri­ous about whether MRT5005 could set a prece­dent for mR­NA ther­a­pies in dis­eases where con­tin­u­ous treat­ment is re­quired. Porges set a bench­mark for lung func­tion im­prove­ment at a 5% in­crease in ppFEV1 to val­i­date the pro­gram’s ther­a­peu­tic po­ten­tial.

That didn’t hap­pen, though, and Porges ef­fec­tive­ly de­clared the drug dead ear­ly Thurs­day morn­ing. The best case sce­nario, he wrote, is a min­i­mum two-year de­lay to de­vel­op­ment should the com­pa­ny choose to re­for­mu­late the com­pound.

“To sum­ma­rize, the tri­al failed, at least in terms of of­fer­ing any ev­i­dence of ef­fi­ca­cy,” Porges wrote to in­vestors.

Re­naud is hop­ing to find more an­swers when the pro­gram moves for­ward with its next study. Re­naud said it’s too ear­ly to try to guess what an ef­fi­ca­cy study might look like, giv­en that the cur­rent tri­al is still on­go­ing.

“We do need to un­der­stand the ef­fi­ca­cy part of this; that is ab­solute­ly cor­rect. I would not say any­thing dif­fer­ent there,” Re­naud said. “Know­ing that we can do this, know­ing that we can de­liv­er this to the lung, is a ma­jor, ma­jor first step. Next part will be try­ing to fig­ure out how to get sys­tem­at­ic ef­fi­ca­cy with these pro­grams.”

The re­sults on­ly brought in more neg­a­tive re­ac­tions among an­a­lysts. Jef­fries’ Eun Yang said Wednes­day’s da­ta were “dis­ap­point­ing” and “con­fus­ing,” as pre­vi­ous­ly re­port­ed re­sults from the sin­gle-as­cend­ing dose co­hort showed a mean ppFEV1 in­crease of 15.7%. On top of that, Yang point­ed to five pa­tients who still had de­tectable lev­els of mR­NA or fat­ty par­ti­cles in their blood, in­di­cat­ing the ther­a­py is get­ting across the mu­cus lay­er and in­to lung tis­sue.

Over­all, though, Yang ex­pects most of Trans­late’s fu­ture suc­cess to come from its in­fec­tious dis­ease pro­grams, where it’s part­nered with Sanofi to de­vel­op an mR­NA-based Covid-19 vac­cine. Porges agreed with that sen­ti­ment, call­ing the vac­cine pro­gram un­proven but promis­ing.

“We are low­er­ing our prob­a­bil­i­ty of suc­cess from 40-50% to 20-25% for MRT5005 and de­lay­ing de­vel­op­ment time­line by ~1 year,” Yang wrote.

Trans­late’s study is ex­pect­ed to have one more in­ter­im analy­sis when all the da­ta are in, which should take place in the sec­ond half of this year.

As a whole, Trans­late is eval­u­at­ing the can­di­date in up to 40 pa­tients in the tri­al, in two por­tions ex­am­in­ing sin­gle and mul­ti­ple as­cend­ing dos­es. The sin­gle dose por­tion orig­i­nal­ly en­com­passed lev­els of 8, 16 and 24 mg, but Re­naud said they even­tu­al­ly added a 20 mg dose lev­el and scrapped the 24 mg co­hort.

Once Trans­late re­port­ed da­ta from those co­horts back in the sum­mer of 2019, they be­gan test­ing MRT5005 in the mul­ti­ple as­cend­ing dose co­horts at the 8, 16 and 20 mg lev­els. In these three co­horts, re­searchers saw a “gen­er­al­ly safe and well tol­er­at­ed” pro­file with no se­ri­ous ad­verse events, the com­pa­ny said.

All of the side ef­fects were mild to mod­er­ate, with three of 12 in­di­vid­u­als ex­pe­ri­enc­ing fever, chills or headache af­ter the first dose. The symp­toms did not re­cur af­ter the sec­ond dose, Trans­late said.

The fi­nal co­hort re­port­ed Wednes­day stems from the sin­gle as­cend­ing dose por­tion of the tri­al at the 20 mg lev­el. Safe­ty here was “gen­er­al­ly con­sis­tent” with the pre­vi­ous­ly re­port­ed co­horts from this por­tion, though Trans­late saw one se­ri­ous side ef­fect oc­cur as a pa­tient de­vel­oped a pul­monary ex­ac­er­ba­tion 22 days af­ter be­ing dosed.

There was al­so one in­stance of a pos­si­ble mild to mod­er­ate hy­per­sen­si­tiv­i­ty re­ac­tion, but that re­solved the next day af­ter the pa­tient re­ceived med­ical treat­ment.

Trans­late orig­i­nal­ly ac­quired MRT5005 back in late 2016 from Shire be­fore the phar­ma merged with Take­da. Shire had been work­ing on the mR­NA plat­form since 2008, and at the time Trans­late took over IND-en­abling stud­ies that were un­der­way. Trans­late first took the pro­gram in­to the clin­ic in the spring of 2018.

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In­no­v­a­tive MedTech De­mands Spe­cial­ist Clin­i­cal Tri­al Reg­u­la­to­ry Af­fairs and De­sign

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Mathai Mammen (Rob Tannenbaum, Endpoints News at BIO 2018)

Math­ai Mam­men makes an abrupt ex­it as head of the big R&D group at J&J

In an after-the-bell shocker, J&J announced Monday evening that Mathai Mammen has abruptly exited J&J as head of its top-10 R&D group.

Recruited from Merck five years ago, where the soft-spoken Mammen was being groomed as the successor to Roger Perlmutter, he had been one of the top-paid R&D chiefs in biopharma. His group spent $12 billion last year on drug development, putting it in the top 5 in the industry.

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Samantha Du, Zai Lab CEO

Any­one still look­ing for a CD47? Zai Lab shelves PhI pro­gram af­ter re­view­ing 'com­pet­i­tive land­scape'

Over the past few years, the promise of blocking CD47 — a “don’t eat me” signal co-opted by cancer cells — has sent drugmakers big and small into a frenzy. But one biotech is now bowing out.

Zai Lab is deprioritizing ZL-1201, its CD47 inhibitor, scrapping plans for a Phase II trial. It will now “pursue out-licensing opportunities,” the company said in its Q2 update. The decision was based on a review of the competitive landscape, it added, without going into further details.

Illustration: Kim Ryu for Endpoints News

Why non-opi­oid pain drugs keep fail­ing — and what's next for the field

In 1938, Rita Levi-Montalcini was forced to move her lab into her bedroom in Turin, as Mussolini’s facist government expelled Jewish people from studying or working in schools in Italy. Levi-Montalcini, then just a few years out of medical school and using sewing needles as scalpels in her makeshift lab, would soon discover nerve growth factor, or NGF, in chicken embryos.

Her discoveries formed the basis of our understanding of the peripheral nervous system and how cells talk to each other, and Levi-Montalcini went on to win the Nobel Prize in 1986. Much later, NGF was hailed as a promising target for new pain therapies, with some analysts quoting an $11 billion market. However, the latest anti-NGF candidate, Pfizer and Eli Lilly’s tanezumab, was rejected by the FDA last year because of a side effect that dissolved bone in some of its patients.

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Ted Love, Global Blood Therapeutics CEO

Up­dat­ed: Pfiz­er scoops up Glob­al Blood Ther­a­peu­tics and its sick­le cell ther­a­pies for $5.4B

Pfizer is dropping $5.4 billion to acquire Global Blood Therapeutics.

Just ahead of the weekend, word got out that Pfizer was close to clinching a $5 billion buyout — albeit with other potential buyers still at the table. The pharma giant, flush with cash from Covid-19 vaccine sales, apparently got out on top.

The deal immediately swells Pfizer’s previously tiny sickle cell disease portfolio from just a Phase I program to one with an approved drug, Oxbryta, plus a whole pipeline that, if all approved, the company believes could make for a $3 billion franchise at peak.

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Steve Paul, Karuna Therapeutics CEO (Third Rock)

Karuna's schiz­o­phre­nia drug pass­es a close­ly-watched PhI­II test, will head to FDA in mid-2023

An investigational pill that combines a former Eli Lilly CNS compound with an overactive bladder drug was better than placebo at reducing a scale of symptoms experienced by patients with schizophrenia in a Phase III trial.

Karuna Therapeutics’ drug passed the primary goal in EMERGENT-2, the Boston biotech said early Monday morning, alongside quarterly earnings. The study is the first of Karuna’s four Phase III clinical trials to read out in schizophrenia and will provide the backbone to the biotech’s first drug approval application, slated for mid-2023.

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HHS Secretary Xavier Becerra (Patrick Semansky/AP Images)

US weighs new route of ad­min­is­tra­tion for mon­key­pox vac­cine as cas­es climb — re­port

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'Messy at best': Is the US re­peat­ing the same Covid mis­steps with mon­key­pox mes­sag­ing?

When Kyle Planck first suspected he might have monkeypox in late June, he went to the CDC website and found six photos of different types of lesions. And that was about it for general public information.

Planck, who is a sixth-year PhD pharmacology researcher at Weill Cornell, kept looking though and found a separate part of the CDC website meant for healthcare professionals. There he found a medical slide deck with more pictures, professional journal articles and more details about symptoms and diagnosis.

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David Zaccardelli, Verona Pharma CEO

Verona’s COPD drug shines in PhI­II study, po­ten­tial­ly clear­ing path to FDA — shares jump

UK-based Verona Pharma’s COPD drug, ensifentrine, has succeeded in its Phase III trial, paving the way for a possible FDA approval.

In Verona’s Phase III ENHANCE-2 study, roughly 800 patients with moderate to severe COPD received ensifentrine or placebo through a nebulizer twice a day for 24 weeks. At 12 hours post-treatment on week 12, the placebo-corrected change in forced expiratory volume (FEV1) — a standard measure of lung function that tests how much breath one can forcefully exhale in one second — was 94 mL, leading the trial to meet its primary endpoint.