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.”

 

Mi­no­ryx and Sper­o­genix ink an ex­clu­sive li­cense agree­ment to de­vel­op and com­mer­cial­ize lerigli­ta­zone in Chi­na

September 23, 2020 – Hong Kong, Beijing, Shanghai (China) and Mataró, Barcelona (Spain)  

Minoryx will receive an upfront and milestone payments of up to $78 million, as well as double digit royalties on annual net sales 

Sperogenix will receive exclusive rights to develop and commercialize leriglitazone for the treatment of X-linked adrenoleukodystrophy (X-ALD), a rare life-threatening neurological condition

President Trump walks past HHS secretary Alex Azar (Getty Images)

Azar falls in line un­der Trump again. Ex­perts say he's re­in­forc­ing a dark sig­nal sent to the FDA

In the latest incident where Alex Azar has steadfastly taken the side of President Donald Trump over that of the FDA, the HHS secretary was noncommittal this morning when asked if he supports the attempt by his subordinates at the FDA to strengthen guidelines for a vaccine EUA.

Appearing on NBC’s Today Show, the HHS secretary muddied the waters, stating that the guidance that matters is the one that is “actually already out there.”

CDC’s Robert Redfield, NIAID’s Anthony Fauci, Admiral Brett Giroir at HHS, and FDA’s Stephen Hahn prepare to testify at a House hearing on June 23 (Getty)

'Ex­treme­ly po­lit­i­cal' — Trump neuters FDA's at­tempt to strength­en vac­cine EUA

Stephen Hahn went before a Senate committee Wednesday and declared he’s fighting. “Every one of the decisions we have reached has been made by career FDA scientists based on science and data, not politics,” he exclaimed, adding that “FDA will not permit any pressure from anyone to change that. I will fight for science.”

A few hours later, he was undermined by President Donald Trump when a reporter asked if he was okay with stricter vaccine guidelines that the FDA was said to be cooking up. “That has to be approved by the White House. We may or may not approve it. That sounds like a political move,” he decided.

New York governor Andrew Cuomo (AP Images)

An­drew Cuo­mo says New York will un­der­take its own vac­cine re­view process, and wouldn’t rec­om­mend trust­ing the fed­er­al gov­ern­ment

The concerns keep mounting over President Donald Trump’s politicization of the FDA and other federal agencies guiding the development of a safe and effective vaccine. And today, the telegenic New York governor Andrew Cuomo appeared to introduce even more politics into the matter — latest in an ongoing series of incidents that have cast the proudly independent FDA in starkly political terms.

During his daily press conference Cuomo said that the state will review any coronavirus vaccines approved by the federal government, citing a lack of trust of the Trump administration. The announcement comes one day after Trump accused the FDA of making an “extremely political” move in proposing stricter vaccine guidance.

PhII Alzheimer's fail­ure deals new blow to Roche, AC Im­mune — but the tau hy­poth­e­sis is far from dead

The leading anti-tau antibody has failed its first Phase II testing, casting a shadow on a popular target (just trailing amyloid beta) for Alzheimer’s disease.

Roche and AC Immune are quick to acknowledge disappointment in the topline readout, which suggested that semorinemab did not reduce cognitive decline among patients with early Alzheimer’s disease, who are either just starting to have symptoms or have mild manifestations.

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Laura Shawver (Silverback Therapeutics)

Fol­low­ing a hefty Se­ries B, Sil­ver­back Ther­a­peu­tics quick­ly pulls in $85M for 'an im­por­tant growth phase'

Months after reeling in a $78 million Series B round, Silverback Therapeutics has hooked an even larger Series C.

The Seattle-based company announced Wednesday that it netted $85 million from a slate of new and previous investors. The quick boost could be a sign that an IPO is on the way.

In an email, Silverback CEO Laura Shawver told me she was “not able to provide any additional comments about Silverback” beyond what was shared in the company’s news release. In the prepared statement, she said the company is at “an important growth phase.”

Covid-19 roundup: Op­er­a­tion Warp Speed's 7th vac­cine is live at­ten­u­at­ed; Small biotech touts big suc­cess where gi­ants have failed

Operation Warp Speed is stacking its vaccine portfolio with a “TBD” new candidate: a live attenuated vaccine that can be administered in a single dose, potentially as an oral formulation rather than an injection.

Sound familiar?

That could be because the unannounced candidate appears to match the profile of an inoculation being developed by Merck, according to Bloomberg, which first reported the development based on a presentation by Moncef Slaoui.

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On­ly five months af­ter a Se­ries A launch, Taysha goes pub­lic with $157M IPO

As has been the trend in 2020, Taysha Gene Therapies has become the latest biotech to make a quick ascent from a small, privately-funded company to enjoying its very own Nasdaq ticker.

The Dallas-based biotech raised $157 million for its IPO after pricing shares at $20 apiece Thursday, the high-point of its expected range. Initially pegging $100 million in financing, Taysha offered a little less than 8 million shares and will trade under the $TSHA symbol.

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CEO Markus Warmuth (Monte Rosa)

Monte Rosa rakes in $96M Se­ries B as it pre­pares 'mol­e­c­u­lar glue' plat­form for IND-en­abling stud­ies

About four months after completing an extension to its Series A, Monte Rosa Therapeutics is putting its next foot forward with another heap of cash.

The Boston-based biotech is back with $96 million in Series B financing with a goal to get its lead program ready for IND-enabling studies by the end of the year. Though Monte Rosa is keeping its specific target a secret for now, the company has been researching how to utilize its protein degradation technology in breast cancer and non-small cell lung cancer, among other areas.