Christophe Weber, Takeda CEO (Miho Takahashi/The Yomiuri Shimbun via AP Images)

FDA of­fers sup­port for Takeda's po­ten­tial cy­tomegalovirus drug ahead of ad­comm

Af­ter al­most two decades of dis­cus­sions with FDA re­gard­ing the de­vel­op­ment of Take­da’s po­ten­tial drug for post-trans­plant cy­tomegalovirus (CMV), which it bought in its ac­qui­si­tion of Shire in 2019, the agency seems to be of­fer­ing pos­i­tive marks for the drug’s safe­ty and ef­fi­ca­cy pro­file ahead of Thurs­day’s ad­comm.

Ac­cord­ing to FDA’s brief­ing doc­u­ments re­leased ahead of the meet­ing, marib­avir proved safe across mul­ti­ple stud­ies and sta­tis­ti­cal­ly su­pe­ri­or to in­ves­ti­ga­tor-as­signed treat­ment (IAT) in a Phase III tri­al, which Take­da an­nounced ear­li­er this year.

FDA’s con­cerns about dis­con­tin­u­a­tions in the IAT arm of the tri­al al­so did not over­shad­ow that sta­tis­ti­cal suc­cess.

While FDA not­ed the Phase III re­sults “ap­peared to be dri­ven by treat­ment dis­con­tin­u­a­tion in the IAT group (dis­con­tin­u­a­tion was con­sid­ered treat­ment fail­ure in the pri­ma­ry analy­sis),” sev­er­al sen­si­tiv­i­ty analy­ses of the pri­ma­ry end­point “showed that marib­avir re­mained sta­tis­ti­cal­ly su­pe­ri­or to IAT for the pri­ma­ry end­point, and thus the treat­ment ef­fect re­mains ro­bust.”

In ad­di­tion­al im­por­tant sub­group analy­ses, FDA said marib­avir re­mained su­pe­ri­or to IAT for the pri­ma­ry end­point with the ex­cep­tion of the “re­frac­to­ry” sub­group and for the sub­group of pa­tients with CMV dis­ease.

But FDA not­ed that one of its “ma­jor con­cerns” in the tri­al “was the po­ten­tial for bias due to the open-la­bel de­sign of the tri­al. Al­though bias is sug­gest­ed by the demon­stra­tion of more dis­con­tin­u­a­tions in the IAT arm than in the marib­avir arm, bias can­not be de­fin­i­tive­ly demon­strat­ed or ruled out, par­tic­u­lar­ly be­cause of the known safe­ty pro­file of the drugs in the IAT arm.”

And over­all, the agency said marib­avir “pro­vides some ad­van­tages over cur­rent­ly avail­able ther­a­pies, i.e., it ap­pears to have a bet­ter safe­ty pro­file, with taste dis­tur­bance be­ing the most com­mon ad­verse re­ac­tion as­so­ci­at­ed with its use. In these tri­als, most sub­jects did not dis­con­tin­ue marib­avir due to taste dis­tur­bance or oth­er ad­verse re­ac­tions. Ad­di­tion­al­ly, marib­avir is avail­able as an oral tablet (as is val­gan­ci­clovir), pro­vid­ing ease of ad­min­is­tra­tion.”

Ad­comm mem­bers will vote on two ques­tions on whether the over­all ben­e­fit-risk as­sess­ment is fa­vor­able for marib­avir to treat trans­plant re­cip­i­ents with CMV in­fec­tion and dis­ease, with one ques­tion ask­ing if that risk-ben­e­fit pro­file is still fa­vor­able with or with­out those with geno­typ­ic re­sis­tance to oth­er an­tivi­rals, in­clud­ing gan­ci­clovir, val­gan­ci­clovir, fos­car­net or cid­o­fovir.

If ap­proved, Take­da’s marib­avir could be the first drug specif­i­cal­ly ap­proved for treat­ment of post-trans­plant CMV in­fec­tion, which FDA says is one of the most com­mon in­fec­tious com­pli­ca­tions in post-trans­plant re­cip­i­ents. FDA al­so not­ed that the avail­able CMV an­tivi­ral drugs, in­clud­ing gan­ci­clovir, val­gan­ci­clovir, fos­car­net and cid­o­fovir, all have sig­nif­i­cant tox­i­c­i­ties.

An ap­proval would al­so cap a long and rocky his­to­ry for the drug, which has changed hands sev­er­al times over the last two decades through pos­i­tive and neg­a­tive tri­als.

Glax­o­SmithK­line first syn­the­sized the drug 20 years ago and did some ear­ly clin­i­cal work, be­fore li­cens­ing it to the rare dis­ease and in­fec­tious dis­ease-fo­cused biotech Vi­roPhar­ma.

Vi­roPhar­ma then took it through Phase II, then missed the pri­ma­ry end­point in a Phase III study in 2009. Marib­avir failed to pre­vent CMV in­fec­tions bet­ter than place­bo in pa­tients re­ceiv­ing bone mar­row trans­plants. Vi­roPhar­ma sug­gest­ed a high­er dose might lead to a bet­ter re­sponse, but end­ed up pass­ing the can­di­date to Shire dur­ing a $4.2 bil­lion buy­out in 2013.

Shire ran with Vi­roPhar­ma’s idea, in­creas­ing the dose in var­i­ous phar­ma­co­ki­net­ic and ef­fi­ca­cy stud­ies, and in 2016, a Phase II study showed that it helped clear in­fec­tions. The FDA com­mend­ed the re­sults with a break­through des­ig­na­tion in 2018. And the fol­low­ing year, Take­da com­plet­ed its ac­qui­si­tion of Shire for $62 bil­lion.

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.

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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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.

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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