How No­var­tis as­sess­es a drug's prob­a­bil­i­ty of suc­cess pri­or to the piv­otal tri­al

Tran­si­tion­ing a de­vel­op­ing com­pound from ear­ly phase clin­i­cal tri­als to a piv­otal tri­al(s) can be a make-or-break de­ci­sion for a small- or medi­um-sized phar­ma. And some­times com­pa­nies aren’t very good at mak­ing the right de­ci­sion.

While many com­pa­nies of­ten re­ly on out­dat­ed ways to as­sess the prob­a­bil­i­ty of any giv­en com­pound’s suc­cess in mak­ing that tran­si­tion, and clear­ly some are bet­ter than oth­ers — an ac­com­pa­ny­ing ed­i­to­r­i­al ex­plains how Pfiz­er’s “end to end” suc­cess is “al­most twofold high­er than the in­dus­try bench­mark” — No­var­tis sci­en­tists re­cent­ly pub­lished in the May is­sue of Clin­i­cal Phar­ma­col­o­gy & Ther­a­peu­tics its frame­work for as­sess­ing the prob­a­bil­i­ty of suc­cess at the end of a small­er Phase II tri­al, or pri­or to that piv­otal tri­al.

“The prob­a­bil­i­ty of suc­cess (PoS) of a pro­gram, a sin­gle num­ber ex­pressed as a per­cent­age re­flect­ing the mul­ti­tude of risks that may in­flu­ence the fi­nal pro­gram out­come, is a key de­ci­sion-mak­ing tool,” No­var­tis’ Lisa Hamp­son and col­leagues wrote. “De­spite its im­por­tance, com­pa­nies of­ten re­ly on crude in­dus­try bench­marks that may be ‘ad­just­ed’ by ex­perts based on un­doc­u­ment­ed cri­te­ria and which are typ­i­cal­ly mis­aligned with the de­f­i­n­i­tion of suc­cess used to dri­ve com­mer­cial fore­casts, lead­ing to over­ly op­ti­mistic ex­pect­ed net present val­ue cal­cu­la­tions.”

In­stead, Hamp­son of­fers an ap­proach or­ga­nized in four steps that us­es “an in­no­v­a­tive Bayesian ap­proach to syn­the­size all rel­e­vant ev­i­dence,” in­clud­ing:

  1. Ob­tain tai­lored in­dus­try bench­marks that are up­dat­ed every 6-12 months, which is par­tic­u­lar­ly im­por­tant for cell and gene ther­a­pies, the au­thors note, on the prob­a­bil­i­ty of ef­fi­ca­cy suc­cess for a Phase IIb pro­gram and a Phase III, the prob­a­bil­i­ty of ap­proval for an NDA sub­mis­sion, and the prob­a­bil­i­ty of no so-called “Safe­ty Show­stop­per Event” in Phase III.
  2. Es­ti­mate the prob­a­bil­i­ty of over­all suc­cess in Phase III based on in­dus­try bench­marks and Phase IIb da­ta.
  3. Es­ti­mate the prob­a­bil­i­ty of reg­u­la­to­ry ap­proval and meet­ing re­main­ing to­tal prod­uct pro­file (TPP) thresh­olds (i.e. out­comes and thresh­olds nec­es­sary for mar­ket ac­cess) with a score­card on as­sess­ing spon­sor align­ment with the reg­u­la­tor, un­ac­count­ed safe­ty risks, and qual­i­ty and com­pli­ance risks, among oth­ers.
  4. In­cor­po­rate and ad­just­ment fac­tor to re­flect ex­cep­tion­al un­ac­count­ed events (i.e. un­known un­knowns).

The pa­per al­so walks through a hy­po­thet­i­cal ex­am­ple (an in­ter­leukin re­cep­tor an­tag­o­nist al­ready ap­proved for asth­ma that’s un­der de­vel­op­ment for COPD) for the No­var­tis step-by-step process, find­ing that while the prob­a­bil­i­ty of a Phase III end­ing up with sta­tis­ti­cal­ly sig­nif­i­cant out­come was es­ti­mat­ed at 58%, ac­tu­al­ly hit­ting that mark and meet­ing the TPP tar­gets with­out an SSE was es­ti­mat­ed at 25%. With the score­card fac­tored in, the fi­nal PoS for the hy­po­thet­i­cal drug was es­ti­mat­ed at 24%.

“In this ex­am­ple, the PoS was quite low and no­tably low­er than the prob­a­bil­i­ty of achiev­ing sta­tis­ti­cal sig­nif­i­cance in phase III, even though ex­perts be­lieved the drug to be ef­fi­ca­cious. This was due to am­bi­tious thresh­olds set in the TPP for the key ef­fi­ca­cy out­comes,” the au­thors not­ed.

The pa­per then walks through a re­al-world ex­am­ple, us­ing Am­gen and As­traZeneca’s teze­pelum­ab for asth­ma. While the spon­sors ini­ti­at­ed a Phase III study for the drug in the re­al world (and it was ap­proved in this in­di­ca­tion late last year), the as­sess­ment in this pa­per was done with on­ly pub­lic in­for­ma­tion and car­ried out pri­or to the Phase III.

The No­var­tis mod­el found that teze­pelum­ab’s Phase III suc­cess with sta­tis­ti­cal­ly sig­nif­i­cant re­sults was 99%, al­though fac­tor­ing in all the steps brought the fi­nal PoS to 82%.

“An im­por­tant con­sid­er­a­tion when im­ple­ment­ing the new PoS frame­work in a com­plex or­ga­ni­za­tion is change man­age­ment,” the au­thors added. And while some project teams at No­var­tis raised con­cerns about whether cer­tain pro­grams might be au­to­mat­i­cal­ly ter­mi­nat­ed based on a PoS thresh­old, the au­thors not­ed that “even high-risk pro­grams may be sup­port­ed, if the med­ical need is high or the mar­ket op­por­tu­ni­ty is large.”

In the ac­com­pa­ny­ing com­men­tary, au­thors from the Uni­ver­si­ty of Flori­da and the Uni­ver­si­ty of Cal­i­for­nia San Fran­cis­co un­der­score the im­por­tance of mak­ing an in­formed and ob­jec­tive de­ci­sion be­fore pro­ceed­ing to lat­er-stage tri­als, par­tic­u­lar­ly as about 90% of all drug can­di­dates fail dur­ing clin­i­cal de­vel­op­ment.

Vas Narasimhan (Photographer: Jason Alden/Bloomberg via Getty Images)

No­var­tis de­tails plans to axe 8,000 staffers as Narasimhan be­gins sec­ond phase of a glob­al re­org

We now know the number of jobs coming under the axe at Novartis, and it isn’t small.

The pharma giant is confirming a report from Swiss newspaper Tages-Anzeiger that it is chopping 8,000 jobs out of its 108,000 global staffers. A large segment will hit right at company headquarters in Basel, as CEO Vas Narasimhan axes some 1,400 of a little more than 11,000  jobs in Switzerland.

The first phase of the work is almost done, the company says in a statement to Endpoints News. Now it’s on to phase two. In the statement, Novartis says:

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Bob Nelsen (Lyell)

As bear mar­ket con­tin­ues to beat down biotech, ARCH clos­es a $3B ear­ly-stage fund

One of the biggest names in biotech investing has a whole lot of new money to spend.

ARCH Venture Partners closed its 12th venture fund early Wednesday morning, the firm said, bringing in almost $3 billion to invest in early-stage biotechs. The move comes about a year and a half after ARCH announced its previous fund, for almost $2 billion back in January 2021.

In a statement, ARCH managing director and co-founder Bob Nelsen appeared to brush off concerns about the broader market troubles, alluding to the downturn that’s seen several biotechs downsize and the XBI fall back to almost pre-pandemic levels.

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Hank Safferstein, Generian CEO

Astel­las sub­sidiary to part­ner with Pitts­burgh up­start in search for 'un­drug­gable' pro­teins

As Astellas continues its drive to build out its gene therapy portfolio and capabilities, a subsidiary of the Japanese pharma company has entered into a collaboration with a little-known Pittsburgh biotech.

Astellas-owned Mitobridge and Generian Pharmaceuticals announced on Wednesday that they will work together in a new deal for “undruggable” protein targets. Generian will net an undisclosed upfront payment and could get up to $180 million in milestones, should anything from its platform prove successful, as well as single-digit royalties on global net sales.

Adam Simpson, Icosavax CEO

Reel­ing from Covid flop, Icosavax says its RSV can­di­date passed ear­ly test. But in­vestors need some more con­vinc­ing

Three months separated from a disappointing readout of its Covid-19 vaccine, Icosavax is back with what it calls positive topline data for a different VLP vaccine candidate — although investors aren’t impressed.

IVX-121, a vaccine candidate for respiratory syncytial virus (RSV), appeared to generate “robust” immune responses among both young and older adults, as measured by neutralizing antibodies, and appeared generally well-tolerated, Icosavax reported.

Sanofi to cut in­sulin prices for unin­sured from $99 to $35, match­ing the in­sulin cap com­ing through Con­gress

As the House-passed bill to cap the monthly price of insulin at $35 nationwide makes its way for a Senate vote soon, Sanofi announced Wednesday morning that beginning next month it will cut the monthly price of its insulins for uninsured Americans to $35, down from $99 previously.

The announcement from Sanofi, which allows the uninsured to buy one or multiple Sanofi insulins (Lantus, Insulin Glargine U-100, Toujeo, Admelog, and Apidra) at $35 for a 30-day supply effective July 1, follows House passage (232-193) of the monthly cap in March, with just 12 Republicans voting in favor of the measure.

Lina Gugucheva, NewAmsterdam Pharma CBO

Phar­ma group bets up to $1B-plus on the PhI­II res­ur­rec­tion of a once dead-and-buried LDL drug

Close to 5 years after then-Amgen R&D chief Sean Harper tamped the last spade of dirt on the last broadly focused CETP cholesterol drug — burying their $300 million upfront and the few remaining hopes for the class with it — the therapy has been fully resurrected. And today, the NewAmsterdam Pharma crew that did the Lazarus treatment on obicetrapib is taking another big step on the comeback trail with a €1 billion-plus regional licensing deal, complete with close to $150 million in upfront cash.

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How pre­pared is bio­phar­ma for the cy­ber dooms­day?

One of the largest cyberattacks in history happened on a Friday, Eric Perakslis distinctly remembers.

Perakslis, who was head of Takeda’s R&D Data Sciences Institute and visiting faculty at Harvard Medical School at the time, had spent that morning completing a review on cybersecurity for the British Medical Journal. Moments after he turned it in, he heard back from the editor: “Have you heard what’s going on right now?”

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Scoop: Roche scraps one of two schiz­o­phre­nia PhII tri­als af­ter fail­ing the pri­ma­ry end­point

Roche has terminated one of two Phase II trials testing its drug ralmitaront in patients with schizophrenia, the Big Pharma confirmed to Endpoints News.

The study was terminated last month, according to a June 22 update to the registry on Begun in September 2020, the trial was looking at ralmitaront in patients with acute schizophrenia. The trial enrolled 286 patients out of an originally planned 308.

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Scoop: Boehringer qui­et­ly shut­ters a PhII for one of its top drugs — now un­der re­view

Boehringer Ingelheim has quietly shut down a small Phase II study for one of its lead drugs.

The private pharma player confirmed to Endpoints News that it had shuttered a study testing spesolimab as a therapy for Crohn’s patients suffering from bowel obstructions.

A spokesperson for the company tells Endpoints:

Taking into consideration the current therapeutic landscape and ongoing clinical development programs, Boehringer Ingelheim decided to discontinue our program in Crohn’s disease. It is important to note that this decision is not based on any safety findings in the clinical trials.

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