Long-term in­clisir­an da­ta sug­gest The Med­i­cines Com­pa­ny/Al­ny­lam drug will flour­ish in piv­otal study, dis­rupt 'bad' cho­les­terol mar­ket

Ahead of the keen­ly an­tic­i­pat­ed piv­otal late-stage read­out for its Al­ny­lam $AL­NY-part­nered long-act­ing cho­les­terol fight­er in­clisir­an, The Med­i­cines Com­pa­ny on Sat­ur­day af­ter­noon un­veiled long-term Phase II da­ta that sug­gest­ed the bian­nu­al-dosed drug is as safe and ef­fec­tive as the ap­proved once-month­ly Repatha and Pralu­ent.

Un­like Repatha from Am­gen $AMGN, as well as Pralu­ent from Re­gen­eron $REGN and Sanofi $SNY — which work by in­hibit­ing the PC­SK9 pro­tein and there­by di­min­ish­ing LDL-C or “bad” cho­les­terol — in­clisir­an is a siR­NA ther­a­py de­signed to curb the pro­duc­tion of the PC­SK9 pro­tein at its source in the liv­er to oust LDL-C from the blood­stream.

De­spite the wide adop­tion of statins, such as Pfiz­er’s near­ly $13 bil­lion-at-peak Lip­i­tor, hy­per­c­ho­les­terolemia and as­so­ci­at­ed car­dio­vas­cu­lar dis­ease is en­dem­ic in the Unit­ed States, rep­re­sent­ing fer­tile ground for fresh, po­tent ther­a­pies to reap lu­cra­tive re­turns. Repatha and Pralu­ent were first ap­proved in 2015 in post-statin pa­tients amidst much fan­fare, but in­stead faced push­back from in­sur­ers for their high stick­er prices ($14,000) that led to low­er-than-ex­pect­ed adop­tion. How­ev­er, since then, tri­als have demon­strat­ed the PC­SK9 in­hibitors al­so sig­nif­i­cant­ly cut car­dio­vas­cu­lar risk — da­ta that are now re­flect­ed on their la­bels — and their man­u­fac­tur­ers have al­so slashed the prices of their re­spec­tive drugs by 60%, in a bid to boost tepid sales. So there is “nowhere for in­clisir­an to hide on ei­ther ef­fi­ca­cy or safe­ty (es­pe­cial­ly safe­ty),” Baird an­a­lysts wrote in a March ini­ti­a­tion note.

Da­ta on Sat­ur­day came from ORI­ON-3 — a fol­low-on tri­al from the Phase II ORI­ON-1 study. Pa­tients who com­plet­ed ORI­ON-1 were en­rolled in ORI­ON-3, and were di­vid­ed in­to two groups. In the first group, sub­jects (n=290) pre­vi­ous­ly treat­ed with any in­clisir­an dose in ORI­ON-1 re­ceived twice-a-year in­jec­tions of in­clisir­an sodi­um 300 mg. The main goal was the mean per­cent change in LDL-C from the ORI­ON-1 base­line val­ue, mea­sured at day 210.

An­a­lysts sug­gest­ed the da­ta bode well for the in­com­ing late-stage in­clisir­an read­out, ex­pect­ed in the third quar­ter. “These re­sults have in­creased our con­vic­tion in in­clisir­an as­cend­ing the Iron Throne of PC­SK9 drugs,” Baird an­a­lysts wrote in a note on Sun­day. The Med­i­cines Com­pa­ny’s shares were up near­ly 9% at $35.95 be­fore the bell on Mon­day.

In the ORI­ON stud­ies, pa­tients with ac­tive liv­er dis­ease were ex­clud­ed, which should al­low “in­clisir­an to avoid most of the ad­verse events seen pre­vi­ous­ly with some GalNAc siR­NA drug can­di­dates,” SVB Leerink an­a­lysts wrote in a note ear­li­er this month. That pre­dic­tion proved per­ti­nent. In terms of safe­ty, in­clisir­an was well tol­er­at­ed and no ma­te­r­i­al safe­ty is­sues were ob­served, The Med­i­cines Com­pa­ny $MD­CO said on Sat­ur­day.

How­ev­er, there was a sin­gle pa­tient with liv­er en­zyme el­e­va­tion, and one pa­tient death due to a stroke, which was deemed un­re­lat­ed to the drug.

“While MD­CO bears will cling to the sin­gle liv­er en­zyme el­e­va­tion event ob­served in ORI­ON-3, sev­er­al con­sid­er­a­tions make that ar­gu­ment un­ten­able,” ar­gued Baird an­a­lysts. For in­stance, the pa­tient that ex­pe­ri­enced the liv­er en­zyme el­e­va­tion was be­ing treat­ed with Arthrotec for a gout flare-up, they wrote. “In­vok­ing Oc­cam’s Ra­zor, the sim­plest ex­pla­na­tion for the liv­er en­zyme el­e­va­tion was the drug known for decades to cause liv­er en­zyme el­e­va­tions.”

Jef­feries an­a­lysts sug­gest­ed that over­all, the da­ta rep­re­sent­ed a “clean safe­ty pro­file…out to 3 years which was one of the key in­vestor ques­tions head­ing in­to the PI­II read­out.”

Da­ta al­so showed that in­clisir­an-treat­ed pa­tients ex­pe­ri­enced a 51% re­duc­tion in LDL-C lev­els through day 210, and time-av­er­aged ab­solute re­duc­tions of 59.4mg/dL for up to 3 years.

Am­gen’s Repatha re­port­ed LDL-C re­duc­tion of 56% at year 3, “in pa­tients with el­e­vat­ed LDL af­ter statin in­tol­er­ance or max-tol­er­at­ed statins (so a slight­ly dif­fer­ent group of pa­tients than ORI­ON-3),” Jef­feries an­a­lysts wrote in a note. “We be­lieve this dos­ing sched­ule is at­trac­tive to pa­tients and can im­prove ad­her­ence, since cur­rent­ly on­ly 55-60% pa­tients are com­pli­ant on PC­SK9 Ab ther­a­py.”

Apart from Pralu­ent and Repatha, in­clisir­an will like­ly al­so have to con­tend with Es­pe­ri­on’s $ES­PR LDL drug be­mpe­doic acid — which is un­der FDA re­view — al­though it has not shown to be as ef­fec­tive as the ap­proved PC­SK9 drugs.

Mean­while, pa­tients from ORI­ON-3’s group 2 (n=92) were pa­tients giv­en place­bo in ORI­ON-1. They have re­ceived one year of treat­ment with Repatha (140 mg in­jec­tions every two weeks) fol­lowed by three years of treat­ment with in­clisir­an sodi­um 300 mg giv­en on day 360 and 450 and every six months there­after. Da­ta on these pa­tients are ex­pect­ed some­time in 2022.


Im­age source: Shut­ter­stock

Martin Shkreli [via Getty]

Pris­on­er #87850-053 does not get to add drug de­vel­op­er to his list of cred­its

Just days after Retrophin shed its last ties to founder Martin Shkreli, the biotech is reporting that the lead drug he co-invented flopped in a pivotal trial. Fosmetpantotenate flunked both the primary and key secondary endpoints in a placebo-controlled trial for a rare disease called pantothenate kinase-associated neurodegeneration, or PKAN.

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We­bi­nar: Re­al World End­points — the brave new world com­ing in build­ing fran­chise ther­a­pies

Several biopharma companies have been working on expanding drug labels through the use of real world endpoints, combing through the data to find evidence of a drug’s efficacy for particular indications. But we’ve just begun. Real World Evidence is becoming an important part of every clinical development plan, in the soup-through-nuts approach used in building franchises.

I’ve recruited a panel of 3 top experts in the field — the first in a series of premium webinars — to look at the practical realities governing what can be done today, and where this is headed over the next few years, at the prodding of the FDA.

ZHEN SU — Merck Serono’s Senior Vice President and Global Head of Oncology
ELLIOTT LEVY — Amgen’s Senior Vice President of Global Development
CHRIS BOSHOFF — Pfizer Oncology’s Chief Development Officer

A premium subscription to Endpoints News is required to attend this webinar. Please upgrade to either an Insider or Enterprise plan for access. Already have Endpoints Premium? Please sign-in below. You can contact our Subscriptions team at help@endpointsnews.com with any issues.

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Hal Barron. GSK

GSK's Hal Bar­ron her­alds their sec­ond pos­i­tive piv­otal for cru­cial an­ti-BC­MA ther­a­py, point­ing to a push for quick OKs in a crowd­ed field

Hal Barron has his second positive round of Phase III data in hand for his anti-BCMA antibody drug conjugate belantamab mafodotin (GSK2857916). And GSK’s research chief says the data paves the way for their drive in search of an FDA approval for treating multiple myeloma.

It’s hard to overestimate the importance of this drug for GSK, a cornerstone of Barron’s campaign to make a dramatic impact on the oncology market and provide some long-lost excitement for the pharma giant’s pipeline. They’re putting this BCMA program at the front of that charge — looking to lead a host of rivals all aimed at the same target.

We don’t know what the data are yet, but DREAMM-2 falls on the heels of a promising set of data delivered 5 months ago for DREAMM-1. There investigators noted that complete responses among treatment-resistant patients rose to 15% in the extra year’s worth of data to look over, with a median progression-free survival rate of 12 months, up from 7.9 months reported earlier. The median duration of response was 14.3 months.

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UP­DAT­ED: An em­bold­ened As­traZeneca splurges $95M on a pri­or­i­ty re­view vouch­er. Where do they need the FDA to hus­tle up?

AstraZeneca is in a hurry.

We learned this morning that the pharma giant — not known as a big spender, until recently — forked over $95 million to get its hands on a priority review voucher from Sobi, otherwise known as Swedish Orphan Biovitrum.

That marks another step down on price for a PRV, which allows the holder to slash 4 months off of any FDA review time.

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Brian Kaspar. AveXis via Twitter

AveX­is sci­en­tif­ic founder fires back at No­var­tis CEO Vas Narasimhan, 'cat­e­gor­i­cal­ly de­nies any wrong­do­ing'

Brian Kaspar’s head was among the first to roll at Novartis after company execs became aware of the fact that manipulated data had been included in its application for Zolgensma, now the world’s most expensive therapy.

But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

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Why would Am­gen want to buy Alex­ion? An­a­lysts call hot­ly ru­mored takeover un­like­ly, but seize the mo­ment

A rumor that Amgen is closing in on buyout deal for Alexion has sparked a guessing game on just what kind of M&A strategy Amgen is pursuing and how much Alexion is worth.

Mizuho analyst Salim Syed first lent credence to the report out of the Spanish news outlet Intereconomía, which said Amgen is bidding as much as $200 per share. While the source may be questionable, “the concept of this happening doesn’t sound too crazy to me,” he wrote.

FDA asks why No­var­tis took two months to launch for­mal in­ter­nal probe, af­ter AveX­is flagged da­ta ma­nip­u­la­tion

And the plot thickens. Novartis $NVS officials are reportedly now scrambling to explain to the FDA why it took them two months to open an internal investigation into data discrepancies for their $2.1 million gene-therapy for spinal muscular dystrophy — the world’s most expensive drug.

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Build­ing on suc­cess­ful PD-1 pact, Eli Lil­ly li­cens­es di­a­betes drug to Chi­nese part­ners at In­novent

Eli Lilly is expanding its partnership with China’s Innovent in a deal involving a diabetes drug sitting in its Phase I reserves.

The two companies had jointly developed one of China’s first homegrown PD-1 agents, scoring an approval for Tyvyt (sintilimab) late last year for relapsed/refractory classical Hodgkin’s lymphoma. This time around, Lilly is out-licensing a piece of its diabetes pipeline, a leading franchise that has historically produced the top-selling Trulicity and Humalog.

Am­gen, Al­ler­gan biosim­i­lar of Roche's block­buster Rit­ux­an clears an­oth­er US piv­otal study 

Novartis $NVS may have given up, but Amgen $AMGN and Allergan $AGN are plowing ahead with their knockoff of Roche’s blockbuster biologic Rituxan in the United States.

Their copycat, ABP 798, was found to have a clinically equivalent impact as Rituxan — meeting the main goal of the study involving CD20-positive B-cell non-Hodgkin’s lymphoma patients. This is the second trial supporting the profile of the biosimilar. In January, it came through with positive PK results in patients with rheumatoid arthritis.