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

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