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.

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Susan Galbraith, AstraZeneca EVP, Oncology R&D

Can­cer pow­er­house As­traZeneca rolls the dice on a $75M cash bet on a buzzy up­start in the on­col­o­gy field

After establishing itself in the front ranks of cancer drug developers and marketers, AstraZeneca is putting its scientific shoulder — and a significant amount of cash — behind the wheel of a brash new upstart in the biotech world.

The pharma giant trumpeted news this morning that it is handing over $75 million upfront to ally itself with Scorpion Therapeutics, one of those biotechs that was newly birthed by some top scientific, venture and executive talent and bequeathed with a fortune by way of a bankroll to advance an only hazily explained drug platform. And they are still very much in the discovery and preclinical phase.

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Lat­est news on Pfiz­er's $3B+ JAK1 win; Pacts over M&A at #JPM22; 2021 by the num­bers; Bio­gen's Aduhelm reck­on­ing; The sto­ry of sotro­vimab; 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.

For those of you who attended #JPM22 in any shape or form, we hope you had a fruitful time. Regardless of how you spent the past hectic week, may your weekend be just what you need it to be.

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A $3B+ peak sales win? Pfiz­er thinks so, as FDA of­fers a tardy green light to its JAK1 drug abroc­i­tinib

Back in the fall of 2020, newly crowned Pfizer chief Albert Bourla confidently put their JAK1 inhibitor abrocitinib at the top of the list of blockbuster drugs in the late-stage pipeline with a $3 billion-plus peak sales estimate.

Since then it’s been subjected to serious criticism for the safety warnings associated with the class, held back by a cautious FDA and questioned when researchers rolled out a top-line boast that their heavyweight contender had beaten the champ in the field of atopic dermatitis — Dupixent — in a head-to-head study.

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Robert Califf, FDA commissioner nominee (Graeme Sloan/Sipa USA/Sipa via AP Images)

Rob Califf ad­vances as Biden's FDA nom­i­nee, with a close com­mit­tee vote

Rob Califf’s second confirmation process as FDA commissioner is already much more difficult than his near unanimous confirmation under the Obama administration.

The Senate Health Committee on Thursday voted 13-8 in favor of advancing Califf’s nomination to a full Senate vote. Several Democrats voted against Califf, including Sen. Bernie Sanders and Sen. Maggie Hassan. Several other Democrats who aren’t on the committee, like West Virginia’s Joe Manchin and Ed Markey of Massachusetts, also said Thursday that they would not vote for Califf. Markey, Hassan and Manchin all previously expressed reservations about the prospect of Janet Woodcock as an FDA commissioner nominee too.

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Michel Vounatsos, Biogen CEO (World Economic Forum/Ciaran McCrickard)

Bio­gen vows to fight CM­S' draft cov­er­age de­ci­sion for Aduhelm be­fore April fi­nal­iza­tion

Biogen executives made clear in an investor call Thursday they are not preparing to run a new CMS-approved clinical trial for their controversial Alzheimer’s drug anytime soon.

As requested in a draft national coverage decision from CMS earlier this week, Biogen and other anti-amyloid drugs will need to show “a meaningful improvement in health outcomes” for Alzheimer’s patients in a randomized, placebo-controlled trial to get paid for their drugs, rather than just the reduction in amyloid plaques that won Aduhelm its accelerated approval in June.

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CRO own­er pleads guilty to ob­struct­ing FDA in­ves­ti­ga­tion in­to fal­si­fied clin­i­cal tri­al da­ta

The co-owner of a Florida-based clinical research site pleaded guilty to lying to an FDA investigator during a 2017 inspection, revealing that she falsely portrayed part of a GlaxoSmithKline pediatric asthma study as legitimate, when in fact she knew that certain data had been falsified, the Department of Justice said Wednesday.

Three other employees — Yvelice Villaman Bencosme, Lisett Raventos and Maytee Lledo — previously pleaded guilty and were sentenced in connection with falsifying data associated with the trial at the CRO Unlimited Medical Research.

‘Skin­ny la­bels’ on gener­ics can save pa­tients mon­ey, re­search shows, but re­cent court de­ci­sions cloud fu­ture

New research shows how generic drug companies can successfully market a limited number of approved indications for a brand name drug, prior to coming to market for all of the indications. But several recent court decisions have created a layer of uncertainty around these so-called “skinny” labels.

While courts have generally allowed generic manufacturers to use their statutorily permitted skinny-label approvals, last summer, a federal circuit court found that Teva Pharmaceuticals was liable for inducing prescribers and patients to infringe GlaxoSmithKline’s patents through advertising and marketing practices that suggested Teva’s generic, with its skinny label, could be employed for the patented uses.

A patient in Alaska receiving an antibody infusion to prevent Covid hospitalizations in September. All but one of these treatments has been rendered useless by Omicron (Rick Bowmer/AP Images)

How a tiny Swiss lab and two old blood sam­ples cre­at­ed one of the on­ly ef­fec­tive drugs against Omi­cron (and why we have so lit­tle of it)

Exactly a decade before a novel coronavirus broke out in Wuhan, Davide Corti — a newly-minted immunologist with frameless glasses and a quick laugh — walked into a cramped lab on the top floor of an office building two hours outside Zurich. He had only enough money for two technicians and the ceiling was so low in parts that short stature was a job requirement, but Corti believed it’d be enough to test an idea he thought could change medicine.

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