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

Hal Barron, GSK via YouTube

What does $29B buy you in Big Phar­ma? In Glax­o­SmithK­line’s case, a whole lot of un­com­fort­able ques­tions about the pipeline

Talk about your bad timing.

A little over a week ago, GSK R&D chief Hal Barron marked his third anniversary at the research helm by taking a turn at the virtual podium during JP Morgan to make the case that he and his team had built a valuable late-stage pipeline capable of churning out more than 10 blockbusters in the next 5 years.

And then, just days later, one of the cancer drugs he bet big on as a top prospect — bintrafusp, partnered with Merck KGaA — failed its first pivotal test in non-small cell lung cancer.

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5AM Ven­tures: Fu­el­ing the Next Gen­er­a­tion of In­no­va­tors

By RBC Capital Markets
With Andy Schwab, Co-Founder and Managing Partner at 5AM Ventures

Key Points

Prescription Digital Therapeutics, cell therapy technologies, and in silico medicines will be a vital part of future treatment modalities.
Unlocking the potential of the microbiome could be the missing link to better disease diagnosis.
Growing links between academia, industry, and venture capital are spinning out more innovative biotech companies.
Biotech is now seen by investors as a growth space as well as a safe haven, fuelling the recent IPO boom.

Janet Woodcock (AP Images)

End­points poll: Janet Wood­cock takes the (in­ter­im) helm at the FDA. And a large ma­jor­i­ty of our read­ers want her to stay there

It’s official: Janet Woodcock is now the acting chief of the FDA.

And — according to an Endpoints poll — most industry readers would like her to stay there, although a significant minority is strongly opposed.

To recap: Joe Biden is reportedly choosing between Woodcock and former deputy FDA commissioner Joshua Sharfstein as his nominee for the permanent position. Given their respective track records, the decision is set to determine the agency’s lodestar for years to come.

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An Endpoints Zoom meeting; and the email header employees will see if your company is a Premium subscriber

What’s next for End­points — and how to sup­port our in­de­pen­dent bio­phar­ma news mis­sion

The firehose of biopharma news is gushing these days.

That’s why broader and deeper is the theme for 2021 at Endpoints. You can expect new coverage outside our core R&D focus, with deeper reporting in some key areas. When John Carroll and I launched Endpoints nearly five years ago, we were wading in waist-high waters. Now we’re a team of 25 full-time staffers (and growing) with plans to cover the flood of biopharma news, Endpoints-style.

Fast on Glax­o­SmithK­line's heels, Au­rinia wins OK to steer a sec­ond lu­pus nephri­tis drug straight to the mar­ket

GlaxoSmithKline’s Benlysta isn’t alone in the small circle of approved lupus nephritis drugs anymore.

Little Aurinia Pharmaceuticals has gotten the green light from the FDA to start marketing its first and only program, voclosporin, under the brand name Lupkynis — something CEO Peter Greenleaf says it’s been ready to do since December.

Regulators went right down to the wire on the decision, keeping the company and the entire salesforce it’s already assembled on its toes.

Eli Lil­ly's an­ti­body cuts risk of Covid-19 by up to 80% among the most vul­ner­a­ble — but will it have a place next to vac­cines?

Eli Lilly says bamlanivimab lowered the risk of contracting symptomatic Covid-19 in a first-of-its-kind trial involving nursing home residents and staff, paving the way for a new option to protect against the virus.

But how big of an impact it might have, and what role it will play, at a time vaccines are being rolled out to the exact population it is targeting still remains unclear.

Among 965 participants in the study — all of whom tested negative for the coronavirus at baseline — the number of symptomatic cases reported in the bamlanivimab arm was 57% lower than that in the placebo arm (odds ratio 0.43, p=0.00021). In addition to that primary endpoint, all secondary endpoints reached statistical significance.

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Charlie Fuchs, Roche and Genentech global head of product development for oncology and hematology (Yale Cancer Center)

Yale can­cer spe­cial­ist Char­lie Fuchs tapped as new glob­al de­vel­op­ment chief for Roche/Genen­tech

Roche and their big sub Genentech have just recruited a top cancer specialist at Yale to head up global product development in oncology and hematology.

I just got word that the pharma giant, which leads one of the most active cancer research operations in the world, recruited Charlie Fuchs, director of the Yale Cancer Center and physician-in-chief of Smilow Cancer Hospital. He’ll join the global operation March 1 and will be based in South San Francisco, where Genentech is based.

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Jonathan Weissman (MIT)

Can a new CRISPR tech­nique un­lock the se­crets of how can­cer spreads?

Jonathan Weissman’s team watched the cancer cells spread across the doomed mouse. Engineered with a bioluminescent enzyme, they appeared in scans first as a small navy blue diamond lodged near the heart; a week later, as a triangle splayed across the mouse’s upper body, with streaks of green and two distinct bright red hubs of activity. By day 54, the mouse resembled a lava lamp.

The images would have been familiar to any cancer biologist, but they didn’t actually tell you much about what was going on: why the cancer was metastasizing or which cells were responsible. For that, Weissman’s team had designed a new tool. Inside the original navy blue diamond, they had engineered the microbiological equivalent of an airplane’s black box — a “molecular recorder” that, after the mouse’s death, could allow them to extract the cells and wind back intimate footage of a single cancer’s ascent.

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Glax­o­SmithK­line scraps a LAG3 study, mark­ing an­oth­er fail­ure for the pipeline af­ter a crit­i­cal set­back

Another gap has appeared in GlaxoSmithKline’s pipeline.

Friday morning the Australian biotech Immutep put out word that Hal Barron’s R&D group at GSK had decided to scrap a Phase II proof-of-concept study in ulcerative colitis for their anti-LAG3 therapy GSK2831781. According to the biotech, the program didn’t survive an interim review.

The trial was stopped by GSK based on the assessment of clinical data as part of a planned interim analysis conducted in consultation with the trial’s Data Review Committee. GSK is conducting further reporting, assessment and analyses of the efficacy and safety data and evaluating the biology to determine next steps for the GSK2831781 development program.

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