Heart at­tack while on Repatha? Am­gen will give you your mon­ey back

Wash­ing­ton, DC —Am­gen has over­come one of the tough­est chal­lenges in car­dio re­search, out­lin­ing a clear health ben­e­fit for its PC­SK9 cho­les­terol drug Repatha. But be­fore pay­ers get a chance to gnaw at the num­bers be­ing put on dis­play to­day, look­ing for holes or find­ing fault with the lev­el of ben­e­fit, the phar­ma gi­ant wants to send them a sim­ple mes­sage: it’s ready to of­fer a ne­go­ti­at­ed truce to get them to drop their de­fens­es and pull out of the trench­es.

Af­ter find­ing ac­cess to Repatha blocked and locked by blan­ket pay­er re­jec­tions, cor­ralling this drug far from the main­stream, Am­gen $AMGN wants to par­lay.

If pay­ers will just con­sid­er the ben­e­fits Am­gen is demon­strat­ing to­day and take down their elab­o­rate bar­ri­ers, com­pa­ny ex­ecs say they are not on­ly will­ing to of­fer a re­fund when the drug fails, they’ll al­so ne­go­ti­ate an­nu­al pay­ment caps and risk shar­ing deals with in­sur­ers so pay­ers can be sure to keep con­trol of their bud­gets.

Sean Harp­er, EVP Re­search and De­vel­op­ment

Drug re­funds have be­gun to make their way in­to the sys­tem, but they’re still rare enough to make this a stand­out pro­pos­al for a man­u­fac­tur­er try­ing to es­tab­lish a big drug.

“We will work with pay­ers if they’re will­ing to just stop block­ing pa­tients from get­ting the drug,” Sean Harp­er, head of R&D at Am­gen, tells me.

Harp­er and his team showed up at Amer­i­can Col­lege of Car­di­ol­o­gy con­fer­ence in Wash­ing­ton DC on Fri­day to lay their case out with some pi­o­neer­ing da­ta. Study­ing this drug in 27,564 pa­tients over two years, re­searchers say, Repatha was able to low­er a com­pos­ite of car­dio risks by an av­er­age of 20%. And the im­prove­ment in­creased with time, grow­ing from a 16% risk ad­van­tage in year one to 25% af­ter 12 months.

That’s large enough to hit key end­points, but it’s al­so small enough to leave many an­a­lysts won­der­ing if this drug can ever make it to big block­buster sta­tus, which Am­gen is cer­tain it de­serves.

Break­ing down the da­ta, which every­one will do, re­searchers not­ed a 27% re­duc­tion in the risk of heart at­tacks, a 21% risk re­duc­tion for stroke and a 22% re­duc­tion on coro­nary revas­cu­lar­iza­tion. But sig­nif­i­cant­ly there was no im­pact on mor­tal­i­ty or un­sta­ble angi­na.

This was the first time that a tri­al has shown a clear car­dio ben­e­fit from PC­SK9 in­hi­bi­tion.

Sums up Harp­er: “This is huge that we can do this.”

In­vestors, though, were clear­ly not im­pressed. Am­gen’s shares were down 6% af­ter the head­lines hit. And this Tweet should give you a fla­vor for what’s dri­ving the skep­ti­cism:

Umer Raf­fat at Ever­cor­eISI not­ed that most of in­vestors were look­ing for a mor­tal­i­ty ben­e­fit and were clear­ly dis­ap­point­ed in not see­ing one. Am­gen’s bull­ish­ness on the da­ta ahead of the de­tails al­so in­flat­ed ex­pec­ta­tions. And the same bit­ter taste al­so ex­tend­ed to the rest of the play­ers in the field, in­clud­ing Re­gen­eron $REGN and Sanofi $SNY, which both got hit, as well as The Med­i­cines Com­pa­ny {$MD­CO -20%} which has a next-gen ther­a­py in the clin­ic it’s been see­ing suc­cess with.

Baird’s Bri­an Sko­r­ney called it a let down. He added:

The pri­ma­ry end­point just hit stat sig with a HR of 0.85 (be­low ex­pec­ta­tions), while the MACE sec­ondary end­point saw a 20% risk re­duc­tion (in-line). Even more dis­ap­point­ing, CV death failed to sep­a­rate from place­bo. Though we do think that to­day’s da­ta is ev­i­dence that PC­SK9 in­hi­bi­tion works, the ben­e­fit isn’t as pro­found as in­vestors were look­ing for and pay­ers are like­ly to lever­age this dis­ap­point­ment.

Am­gen has bet big on Repatha, bankrolling sev­er­al huge stud­ies to demon­strate the drug’s abil­i­ty to dra­mat­i­cal­ly slash LDL lev­els, which its in­ves­ti­ga­tors say is clear­ly a tox­in. Now it has a win on car­dio out­comes to make its point to physi­cians and a large po­ten­tial pa­tient pop­u­la­tion. But the tri­al suc­cess is not big enough by it­self to get pay­ers to stop re­ject­ing pre­scrip­tions “over and over and over again,” as Harp­er de­scribes the treat­ment to date.

Joshua J. Of­man, Am­gen

“The process on uti­liza­tion man­age­ment has been bro­ken,” says Am­gen val­ue man­age­ment chief Joshua J. Of­man. Ever since 2013’s in­tro­duc­tion of So­val­di pay­ers have been up­ping their game, fig­ur­ing out new ways to stop their mem­bers from get­ting ac­cess to new drugs like this. And in Repatha’s case, pay­ers are in over­drive, forc­ing physi­cians to go back and file over and over again.

The num­bers Am­gen is re­port­ing to­day are al­so be­ing pitched as far more con­ser­v­a­tive than what pa­tients see in the re­al world. All the pa­tients in the study got the best stan­dard of care, which is some­thing you won’t see in the re­al world. And Am­gen is hap­py to ne­go­ti­ate its next round of con­tracts based on re­al-world ex­pec­ta­tions.

So now Am­gen says they’ll guar­an­tee a low­er risk of heart at­tack and re­fund the cost of the drug for any pa­tient who has a heart at­tack. They’ll still come out well ahead if they can reach the at-risk pop­u­la­tion whose LDL lev­els can­not be con­trolled by cheap statins.

Am­gen’s full court press on Repatha has in­clud­ed a co­or­di­nat­ed at­tack on its big ri­val Pralu­ent from Re­gen­eron and Sanofi. At one point re­cent­ly a judge’s rul­ing threat­ened to push the com­pet­ing drug off the mar­ket as Am­gen — a ma­jor league lit­i­ga­tor — pressed its ar­gu­ment that Pralu­ent vi­o­lat­ed its PC­SK9 patents. But the part­ners man­aged to block that, for now.

Next up: Car­dio da­ta from Re­gen­eron and Sanofi. So far, these drugs have ap­peared very sim­i­lar, and it wouldn’t sur­prise many ob­servers if their com­peti­tor comes on around the same score. But every da­ta point will get care­ful scruti­ny as the gi­ants block and tack­le in search of every small ad­van­tage, while hop­ing to achieve a break­through on mar­ket­ing that can fi­nal­ly gen­er­ate some big num­bers.

So far, it’s not look­ing good.

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.

What lured Hal Bar­ron away?; Top FDA minds on ac­cel­er­at­ed ap­proval re­forms; ‘Dead wrong’ Aduhelm ad blitz; 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.

Nothing can really compete with Hal Barron’s departure from GlaxoSmithKline as the news of the week, but we do have plenty of original reporting and analysis from the Endpoints team in this edition. Enjoy and have a nice weekend.

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Mer­ck wins le­gal bat­tle over in­sur­ance cov­er­age af­ter ran­somware at­tack

Merck has emerged victorious from a years-long legal battle with insurers over the coverage of more than a billion dollars in losses from the malware NotPetya, with a New Jersey Superior Court judge concluding that the responsibility is on insurers to clarify their policies around cyber attacks.

The pharma giant was one of several victims of a global cyber attack back in 2017 that also hit Danish shipping company Maersk, American food company Mondelēz, French construction giant Saint-Gobain and even the systems monitoring the Chernobyl nuclear power stations, Bloomberg reported back in 2019.

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Crit­ics push back on Alzheimer’s As­so­ci­a­tion ad blitz to get Medicare to change its Aduhelm rul­ing: 'Dead wrong'

The latest Alzheimer’s Association advertising campaign encourages people to fight.

Not against the disease or for more research or treatments, but against the Centers for Medicare and Medicaid Services. More specifically, CMS’ recent reimbursement decision to only pay for Biogen and Eisai’s controversial Alzheimer’s drug Aduhelm for patients in clinical trials.

With CMS’ preliminary decision now in a 30-day comment period, patient advocates’ goal is to convince CMS to reverse its decision with a marketing blitz and public pressure.

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Dan O'Day, Gilead CEO (Jim Watson/AFP via Getty Images)

Fail­ing to con­firm clin­i­cal ben­e­fit, Gilead pulls 2 ac­cel­er­at­ed ap­proval in­di­ca­tions for can­cer drug

Gilead recently decided to pull two indications for its cancer drug Zydelig — in relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic leukemia (SLL) — after failing to complete the confirmatory trials required as part of the accelerated approvals from 2014.

“As the treatment landscape for FL and SLL has evolved, enrollment into the confirmatory study has been an ongoing challenge,” Gilead said in a statement, noting it formally notified the FDA of its decision to voluntarily withdraw these indications.

Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

NYU surgeon transplants an engineered pig kidney into the outside of a brain-dead patient (Joe Carrotta/NYU Langone Health)

An­oth­er day, an­oth­er xeno­trans­plant, as Unit­ed Ther­a­peu­tics looks to beat com­peti­tors to sci-fi-es­que break­through

Xenotransplantation is having a moment.

Last October, a team from NYU successfully transplanted a kidney from a pig into a brain-dead patient, although observers cast doubt on the importance of the experiment. Then, earlier this month, surgeons at the University of Maryland transplanted a pig heart into a dying human, who appears to still be stable.

Now, another group is planting a flag in the xenotransplantation field. Surgeons at the University of Alabama at Birmingham said Thursday they have achieved the first kidney transplant from a pig to a brain-dead patient, publishing their peer-reviewed findings online. The team, aiming to differentiate itself from the others through the genetic modifications used, is hoping there’s now enough research to soon begin clinical xenotransplantation studies.

Richard Pazdur (via AACR)

Time lim­its on ac­cel­er­at­ed ap­provals? FDA's on­col­o­gy chief Rick Paz­dur eyes po­ten­tial re­forms via in­ter­na­tion­al ap­proach­es

The spotlight on the accelerated approval pathway continues to shine bright, with the FDA’s top oncology official writing in an opinion that the pathway may be strengthened with bits and pieces of what other regulators in Europe and elsewhere have done with their expedited approval pathways, such as adding expiration dates for these faster approvals to ensure they confirm clinical benefit in a timely manner.

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