Al­ny­lam shares crater af­ter tri­al deaths force in­ves­ti­ga­tors to scrap PhI­II RNAi drug

Late Wednes­day Al­ny­lam shocked its in­vestors with news that it has de­cid­ed to scrap re­vusir­an, its sec­ond most ad­vanced RNAi ther­a­py in the pipeline, due to a spike in the num­ber of deaths among pa­tients tak­ing the drug in a late-stage tri­al. All dos­ing has been stopped and won’t be re­sumed.

Shares in Al­ny­lam plunged 48% by late Thurs­day morn­ing, wip­ing out close to $3 bil­lion in mar­ket cap. Re­newed fears about the fate and fu­ture of RNAi al­so clawed back oth­er stocks, in­clud­ing ri­val Io­n­is $IONS, down 7%. The re­ac­tion dragged the Nas­daq biotech stock in­dex down 2%.

The drug was be­ing de­vel­oped for hered­i­tary AT­TR amy­loi­do­sis with car­diomy­opa­thy. But the biotech says that prob­lems with pe­riph­er­al neu­ropa­thy in an­oth­er study spurred the Cam­bridge, MA-based biotech to take a clos­er look at the Phase III da­ta it had been gath­er­ing.

Al­ny­lam in­ves­ti­ga­tors say that they did not find sol­id ev­i­dence of a drug-re­lat­ed neu­ropa­thy sig­nal. What they did find, af­ter un­blind­ing da­ta, was “an im­bal­ance of mor­tal­i­ty in the re­vusir­an arm as com­pared to place­bo.” And they don’t know why.

“This is drug de­vel­op­ment and these things do hap­pen,” not­ed CEO John Maraganore in a call with an­a­lysts, de­clin­ing to break down how many pa­tients died in each arm. A to­tal of 18 pa­tients died in the study — which en­rolled 206 pa­tients — and there was an im­bal­ance, he added, which elim­i­nat­ed any chance of demon­strat­ing a ben­e­fit over risk for the drug. This is a par­tic­u­lar­ly sick, old­er pop­u­la­tion of pa­tients, he said. And none of the deaths have been de­ter­mined to be drug re­lat­ed.

This news comes just days af­ter Al­ny­lam took a nasty hit on its stock price af­ter a much ear­li­er-stage drug, the RNAi liv­er dis­ease drug ALN-AAT, was scrapped af­ter three pa­tients ex­pe­ri­enced spik­ing liv­er en­zymes in a Phase I/II. That’s a clas­sic sign of pro­gram-killing tox­i­c­i­ty.

An­a­lysts didn’t like the sound of any of this, and a few start­ed draw­ing lines be­tween the Phase III set­back and oth­er projects in the works at Al­ny­lam — ex­act­ly the kind of seep­age the biotech was try­ing hard to pre­vent.

“Re­vusir­an dis­con­tin­u­a­tion may have lim­it­ed read-through to the Patisir­an in FAP,” not­ed Jef­feries’ Gena Wang Thurs­day morn­ing, “how­ev­er, we see po­ten­tial­ly high risk to TTRsc02 pro­gram be­cause 1) same siR­NA se­quence as re­vusir­an; 2) in­crease in neu­ropa­thy in Ph2OLE and im­bal­ance of mor­tal­i­ty in Ph3 sug­gest lack of drug ac­tiv­i­ty for re­vusir­an even though the caus­es could be un­der­ly­ing dis­ease; 3) giv­en re­vusir­an’s mor­tal­i­ty im­bal­ance and mor­tal­i­ty as pri­ma­ry end­point in tafadamis (PFE) Ph3 tri­al for FAC/SSA, the va­lid­i­ty of 6MWT as pri­ma­ry end­point re­mains to be seen.”

Al­ny­lam has been one of the pi­o­neers of RNAi drug de­vel­op­ment, go­ing through plen­ty of ups and downs along the way. The com­pa­ny was once a dar­ling of Big Phar­ma, lost a lot of at­ten­tion when de­vel­op­ment times seemed too long and risky, then re­gained a lot of its verve with a big buy-in from Sanofi. Its two late-stage stud­ies have sparked high hopes among long­time in­vestors, who have been wait­ing years for the big pay­off.

Al­ny­lam al­so isn’t the on­ly RNAi com­pa­ny to face safe­ty is­sues. Io­n­is CEO Stan­ley Crooke sparked a pan­ic ear­li­er in the year, ex­plain­ing dur­ing a call with an­a­lysts in May that their drug for TTR amy­loid car­diomy­opa­thy – at high dos­es — had been linked to per­plex­ing low platelet counts in pa­tients. That caused the FDA to trig­ger a clin­i­cal hold on a pro­gram, spurring Glax­o­SmithK­line to put a planned Phase III on a back burn­er.

Wednes­day evening, the com­pa­ny was try­ing to sound re­as­sur­ing. And in­ves­ti­ga­tors hit heav­i­ly on the dif­fer­ent tech­nolo­gies that dis­tin­guish this drug from the rest of Al­ny­lam’s clin­i­cal-stage drugs. But that’s go­ing to be a tough act to pull off.

“Pa­tient safe­ty comes first. We have stopped all dos­ing and are ac­tive­ly mon­i­tor­ing pa­tients across re­vusir­an stud­ies to en­sure their safe­ty. We will al­so con­tin­ue to eval­u­ate EN­DEAV­OUR da­ta to un­der­stand the po­ten­tial cause of these find­ings,” said Maraganore in a state­ment. “While this out­come is dis­ap­point­ing giv­en the lack of avail­able treat­ment op­tions for pa­tients suf­fer­ing from this dev­as­tat­ing dis­ease, we re­main com­mit­ted to serv­ing the needs of the AT­TR amy­loi­do­sis com­mu­ni­ty. We would like to thank pa­tients, care­givers, in­ves­ti­ga­tors, and study staff who have been so sup­port­ive of the re­vusir­an pro­gram.”

 

Novotech CEO Dr. John Moller

Novotech CRO Award­ed Frost & Sul­li­van Best Biotech CRO Asia-Pa­cif­ic 2019

Known in the in­dus­try as the Asia-Pa­cif­ic CRO, Novotech is now lead CRO ser­vices provider for the grow­ing num­ber of in­ter­na­tion­al biotechs se­lect­ing the re­gion for their stud­ies.

Re­flect­ing this Asia-Pa­cif­ic growth, Novotech staff num­bers are up 20% since De­cem­ber 2018 to 600 in-house clin­i­cal re­search peo­ple across a full range of ser­vices, across the re­gion.

Novotech’s ca­pa­bil­i­ties have been rec­og­nized by an­a­lysts like Frost & Sul­li­van, most re­cent­ly with the pres­ti­gious Asia-Pa­cif­ic CRO Biotech of the year award for best prac­tices in clin­i­cal re­search for biotechs for the fifth year. See oth­er awards here.

Bet­ter than Am­bi­en? Min­er­va soars on PhI­Ib up­date on sel­torex­ant for in­som­nia

A month af­ter roil­ing in­vestors with what skep­tics dis­missed as cher­ry pick­ing of its de­pres­sion da­ta, Min­er­va is back with a clean slate of da­ta from its Phase IIb in­som­nia tri­al.

In a de­tailed up­date, the Waltham, MA-based biotech said sel­torex­ant (MIN-202) hit both the pri­ma­ry and sev­er­al sec­ondary end­points, ef­fec­tive­ly im­prov­ing sleep in­duc­tion and pro­long­ing sleep du­ra­tion. In­ves­ti­ga­tors made a point to note that the ef­fects were con­sis­tent across the adult and el­der­ly pop­u­la­tions, with the lat­ter more prone to the sleep dis­or­der.

Gene ther­a­py biotech sees its stock rock­et high­er on promis­ing re­sults for rare cas­es of but­ter­fly dis­ease

Shares of Krys­tal Biotech took off this morn­ing $KRYS af­ter the lit­tle biotech re­port­ed promis­ing re­sults from its gene ther­a­py to treat a rare skin dis­ease called epi­der­mol­y­sis bul­losa.

Fo­cus­ing on an up­date with 4 new pa­tients, re­searchers spot­light­ed the suc­cess of KB103 in clos­ing some stub­born wounds. Krys­tal says that of 4 re­cur­ring and 2 chron­ic skin wounds treat­ed with the gene ther­a­py, the KB103 group saw the clo­sure of 5. The 6th — a chron­ic wound, de­fined as a wound that had re­mained open for more than 12 weeks — was par­tial­ly closed. That brings the to­tal so far to 8 treat­ed wounds, with 7 clo­sures.

Ab­b­Vie gets a green light to re­sume re­cruit­ing pa­tients for one myelo­ma study — but Ven­clex­ta re­mains un­der a cloud

Three months af­ter reg­u­la­tors at the FDA forced Ab­b­Vie to halt en­rolling pa­tients in its tri­als of a com­bi­na­tion us­ing Ven­clex­ta (vene­to­clax) to treat drug-re­sis­tant cas­es of mul­ti­ple myelo­ma, the agency has green-light­ed the re­sump­tion of one of those stud­ies, while keep­ing the rest on the side­lines.

The CANO­VA (M13-494) study can now get back in busi­ness re­cruit­ing pa­tients to test the drug for a pop­u­la­tion that shares a par­tic­u­lar ge­net­ic bio­mark­er. To get that per­mis­sion, Ab­b­Vie — which is part­nered with Roche on this pro­gram — was forced to re­vise the pro­to­col, mak­ing un­spec­i­fied changes in­volv­ing risk mit­i­ga­tion mea­sures, pro­to­col-spec­i­fied guide­lines and an up­dat­ed fu­til­i­ty cri­te­ria.

Alex­ion wins pri­or­i­ty re­view for Ul­tomiris' aHUS in­di­ca­tion; FDA ex­pands ap­proval of Ver­tex's Symdeko

→ Alex­ion $ALXN has scored a speedy re­view for Ul­tomiris for pa­tients with atyp­i­cal he­molyt­ic ure­mic syn­drome (aHUS) af­ter post­ing pos­i­tive da­ta from a piv­otal study in Jan­u­ary. The drug is the rare dis­ease com­pa­ny’s shot at pro­tect­ing its block­buster blood dis­or­der fran­chise that is cur­rent­ly cen­tered around its flag­ship drug, Soliris, which is a com­ple­ment in­hibitor typ­i­cal­ly ad­min­is­tered every two weeks. Ul­tomiris has a sim­i­lar mech­a­nism of ac­tion but re­quires less-fre­quent dos­ing — every eight weeks. The de­ci­sion date has been set to Oc­to­ber 19. Late last year, Ul­tomiris se­cured ap­proval for noc­tur­nal he­mo­glo­bin­uria (PNH) pa­tients.

UP­DAT­ED: In sur­prise switch, Bris­tol-My­ers is sell­ing off block­buster Ote­zla, promis­ing to com­plete Cel­gene ac­qui­si­tion — just lat­er

Apart from revealing its checkpoint inhibitor Opdivo blew a big liver cancer study on Monday, Bristol-Myers Squibb said its plans to swallow Celgene will require the sale of blockbuster psoriasis treatment Otezla to keep the Federal Trade Commission (FTC) at bay.

The announcement — which has potentially delayed the completion of the takeover to early 2020 — irked investors, triggering the New York-based drugmaker’s shares to tumble Monday morning in premarket trading.

Celgene’s Otezla, approved in 2014 for psoriasis and psoriatic arthritis, is a rising star. It generated global sales of $1.6 billion last year, up from the nearly $1.3 billion in 2017. Apart from the partial overlap of Bristol-Myers injectable Orencia, the company’s rival oral TYK2 psoriasis drug is in late-stage development, after the firm posted encouraging mid-stage data on the drug, BMS-986165, last fall. With Monday’s decision, it appears Bristol-Myers is favoring its experimental drug, and discounting Otezla’s future.

The move blindsided some analysts. Credit Suisse’s Vamil Divan noted just days ago:

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Bris­tol-My­ers star Op­di­vo fails sur­vival test in a matchup with Nex­avar aimed at shak­ing up the big HCC mar­ket

Bris­tol-My­ers Squibb has suf­fered an­oth­er painful set­back in its years-long quest to ex­pand the reach of Op­di­vo. The phar­ma gi­ant this morn­ing not­ed that their Check­mate-459 study com­par­ing Op­di­vo with Bay­er’s Nex­avar in front­line cas­es of he­pa­to­cel­lu­lar car­ci­no­ma — the most com­mon form of liv­er can­cer — failed to hit the pri­ma­ry end­point on over­all sur­vival.

This was a sig­nif­i­cant mile­stone in Bris­tol-My­ers’ tal­ly of PD-1 cat­a­lysts this year. Nex­avar (so­rafenib) has been the stan­dard of care in front­line HCC for the past decade, though Op­di­vo has been mak­ing head­way in sec­ond-line HCC cas­es, where it’s go­ing toe-to-toe with Bay­er’s Sti­var­ga (re­go­rafenib) af­ter re­cent ap­provals shook up the mar­ket.

Fol­low­ing news of job cuts in Eu­ro­pean R&D ops, Sanofi con­firms it’s of­fer­ing US work­ers an 'ear­ly ex­it'

Ear­li­er in the week we learned that Sanofi was bring­ing out the bud­get ax to trim 466 R&D jobs in Eu­rope, re­tool­ing its ap­proach to car­dio as re­search chief John Reed beefed up their work in can­cer and gene ther­a­pies. And we’re end­ing the week with news that the phar­ma gi­ant has al­so been qui­et­ly re­duc­ing staff in the US, tar­get­ing hun­dreds of jobs as the com­pa­ny push­es vol­un­tary buy­outs with a fo­cus on R&D sup­port ser­vices.

Why would the FDA ap­prove an­oth­er con­tro­ver­sial drug to spur a woman’s li­bido with these da­ta? And why no ex­pert pan­el re­view?

AMAG Pharmaceuticals’ newly approved drug for spurring women’s sexual desire may never make much money, but it’s a big hit at sparking media attention.

The therapy — Vyleesi (bremelanotide) — got the green light from regulators on Friday evening, swiftly lighting up a range of stories around the world, from The New York Times to The Guardian. Several headlines inevitably referred to it as the “female Viagra,” invoking Pfizer’s old erectile dysfunction blockbuster.

But the two drugs have little in common.

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