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

Blue­bird bio $BLUE has un­veiled its price for the new­ly ap­proved gene ther­a­py Zyn­te­glo (Lenti­Glo­bin), which came as a big sur­prise. And it wasn’t the on­ly un­ex­pect­ed twist in to­day’s sto­ry.

With some an­a­lysts bet­ting on a $900,000 price for the β-tha­lassemia treat­ment in Eu­rope, where reg­u­la­tors pro­vid­ed a con­di­tion­al ear­ly OK, blue­bird CEO Nick Leschly said Fri­day morn­ing that the pa­tients who are suc­cess­ful­ly treat­ed with their drug over 5 years will be charged twice that — $1.8 mil­lion — on the con­ti­nent. That makes this drug the sec­ond most ex­pen­sive ther­a­py on the plan­et, just be­hind No­var­tis’ new­ly ap­proved Zol­gens­ma at $2.1 mil­lion, with an­a­lysts still wait­ing to see what kind of pre­mi­um can be had in the US.

Re­gen­eron’s close­ly-watched bis­pe­cif­ic con­tin­ues to ring up high re­sponse rates

Re­gen­eron’s high-pro­file bis­pe­cif­ic REGN1979 is back in the spot­light at the Eu­ro­pean Hema­tol­ogy As­so­ci­a­tion sci­en­tif­ic con­fab. And while the stel­lar num­bers we saw at ASH have erod­ed some­what as more blood can­cer pa­tients are eval­u­at­ed, the re­sponse rates for this CD3/CD20 drug re­main high.

A to­tal of 13 out of 14 fol­lic­u­lar lym­phomas re­spond­ed to the drug, a 93% ORR, down from 100% at the last read­out. In 10 out of 14, there was a com­plete re­sponse. In dif­fuse large B-cell lym­phoma the re­sponse rate was 57% among pa­tients treat­ed at the 80 mg to 160 mg dose range. They were all com­plete re­spons­es. And 2 of these Cars were for pa­tients who had failed CAR-T ther­a­py.

In­vestors are in no mood to hear biotechs tout the suc­cess of a “key” sec­ondary end­point when the piv­otal Phase III flunks the pri­ma­ry goal. Just ask Savara. 

The Texas biotech $SVRA went look­ing for a sil­ver lin­ing as com­pa­ny ex­ecs blunt­ly con­ced­ed that Mol­gradex, an in­haled for­mu­la­tion of re­com­bi­nant hu­man gran­u­lo­cyte-macrophage colony-stim­u­lat­ing fac­tor (GM-CSF), failed to spur sig­nif­i­cant­ly im­proved treat­ment out­comes for pa­tients with a rare res­pi­ra­to­ry dis­ease called au­toim­mune pul­monary alve­o­lar pro­teinosis, or aPAP.

Late-stage da­ta pre­sent­ed at the Amer­i­can Di­a­betes As­so­ci­a­tion an­nu­al meet­ing in 2010 pushed Eli Lil­ly to put a crimp on teplizum­ab as the phar­ma gi­ant found it un­able to re­set the clock on new­ly di­ag­nosed type 1 di­a­betes. At the same con­fer­ence but in dif­fer­ent hands nine years lat­er, the drug is mak­ing a crit­i­cal come­back by scor­ing suc­cess in an­oth­er niche: de­lay­ing the on­set of the dis­ease.

In a Phase II tri­al with 76 high-risk in­di­vid­u­als — rel­a­tives of pa­tients with type 1 di­a­betes who have di­a­betes-re­lat­ed au­toan­ti­bod­ies in their bod­ies — teplizum­ab al­most dou­bled the me­di­an time of di­ag­no­sis com­pared to place­bo (48.4 months ver­sus 24.4 months). The haz­ard ra­tio for di­ag­no­sis was 0.41 (p=0.006).