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.”

Dupixent, the blockbuster anti-inflammatory drug from Sanofi and Regeneron, has cleared a high-stakes Phase III study in chronic obstructive pulmonary disease, the companies announced Thursday morning.

If they hold up in a second, identical trial, the data pave the way for Dupixent to become the first biologic to treat patients whose COPD remains uncontrolled despite being on maximal standard-of-care inhaled therapy — the patient population studied in the pivotal program. The companies had spotlighted this as a key readout as they look to expand the Dupixent franchise and explore its full potential.

Novartis is calling off a UK-based trial for Leqvio in the primary prevention of cardiovascular events in patients with high cholesterol, the company confirmed on Wednesday.

The Swiss pharma giant made the decision after “careful evaluation,” a spokesperson told Endpoints News via email. The trial, dubbed ORION-17, was planned in partnership with England’s National Health Service (NHS) and was part of the company’s strategy to establish Leqvio as a standard of care in cardiovascular disease management.

89bio said its drug was better than placebo at lessening fibrosis without worsening nonalcoholic steatohepatitis, or NASH, in two of three dose groups.

The San Francisco biotech said it thinks the Phase IIb data pave the way for a potential Phase III, following in the footsteps of another biotech in its drug class, Akero Therapeutics. To fund a late-stage study, CEO Rohan Palekar told Endpoints News 89bio “would need to raise additional capital,” with the company having about $188 million at the end of last year.