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.”

 

De­vel­op­ment of the Next Gen­er­a­tion NKG2D CAR T-cell Man­u­fac­tur­ing Process

Celyad’s view on developing and delivering a CAR T-cell therapy with multi-tumor specificity combined with cell manufacturing success
Overview
Transitioning potential therapeutic assets from academia into the commercial environment is an exercise that is largely underappreciated by stakeholders, except for drug developers themselves. The promise of preclinical or early clinical results drives enthusiasm, but the pragmatic delivery of a therapy outside of small, local testing is most often a major challenge for drug developers especially, including among other things, the manufacturing challenges that surround the production of just-in-time and personalized autologous cell therapy products.

Paul Hudson, Getty Images

UP­DAT­ED: Sanofi CEO Hud­son lays out new R&D fo­cus — chop­ping di­a­betes, car­dio and slash­ing $2B-plus costs in sur­gi­cal dis­sec­tion

Earlier on Monday, new Sanofi CEO Paul Hudson baited the hook on his upcoming strategy presentation Tuesday with a tell-tale deal to buy Synthorx for $2.5 billion. That fits squarely with hints that he’s pointing the company to a bigger future in oncology, which also squares with a major industry tilt.

In a big reveal later in the day, though, Hudson offered a slate of stunners on his plans to surgically dissect and reassemble the portfoloio, saying that the company is dropping cardio and diabetes research — which covers two of its biggest franchise arenas. Sanofi missed the boat on developing new diabetes drugs, and now it’s pulling out entirely. As part of the pullback, it’s dropping efpeglenatide, their once-weekly GLP-1 injection for diabetes.

“To be out of cardiovascular and diabetes is not easy for a company like ours with an incredibly proud history,” Hudson said on a call with reporters, according to the Wall Street Journal. “As tough a choice as that is, we’re making that choice.”

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What does $6.9B buy these days in on­col­o­gy R&D? As­traZeneca has a land­mark an­swer

Given the way the FDA has been whisking through new drug approvals months ahead of their PDUFA date, AstraZeneca and their partners Daiichi Sankyo may not have to wait until Q2 of next year to get a green light on trastuzumab deruxtecan (DS-8201).

The pharma giant this morning played their ace in the hole, showing off why they were willing to commit to a $6.9 billion deal — with $1.35 billion in a cash upfront — to partner on the drug.

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Paul Hudson, Sanofi

Paul Hud­son promis­es a bright new fu­ture at Sanofi, kick­ing loose me-too drugs and fo­cus­ing on land­mark ad­vances. But can he de­liv­er?

Paul Hudson was on a mission Tuesday morning as he stood up to address Sanofi’s new R&D and business strategy.

Still fresh into the job, the new CEO set out to convince his audience — including the legions of nervous staffers inevitably devoting much of their day to listening in — that the pharma giant is shedding the layers of bureaucracy that had held them back from making progress in the past, dropping the duds in the pipeline and reprioritizing a more narrow set of experimental drugs that were promised as first-in-class or best-in-class.  The company, he added, is now positioned to “go after other opportunities” that could offer a transformational approach to treating its core diseases.

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Large advertisements for the drug Vivitrol decorate the walls of Grand Central Station on June 15, 2017 in New York City. (Photo: Andrew Lichtenstein via Getty)

FDA slaps down Alk­er­mes for mis­lead­ing Viv­it­rol ads — don't for­get vul­ner­a­bil­i­ty to opi­oid over­dose

The ads piqued interest as soon as they started appearing in 2016: at Grand Central Station, on the Red Line in Cambridge, and on a billboard off the New Jersey Turnpike. All showed a young person, generally with his or her arms crossed, and the question, “what is Vivitrol?”

Vivitrol’s maker, Alkermes, was in the midst of a marketing and lobbying campaign to promote the anti-opioid addiction drug — a campaign that would face significant backlash for tarnishing competitors despite little evidence for Vivitrol’s superiority.

FDA in-house re­view spot­lights an is­sue with one of Hori­zon's end­points but notes ef­fi­ca­cy for lead drug

The FDA in-house review highlights a disagreement of investigators’ use of a key endpoint by Horizon Pharma in the late-stage trial for the top drug in its pipeline, but largely agreed that the antibody was effective.

Horizon submitted a BLA for thyroid eye disease (TED) drug teprotumumab in March, less than two years after they bought the drug (and the rest of a division) from Narrow River for $145 million upfront. With breakthrough status, priority review, orphan designation and in-house sales projections of up to $750 million, the one-time Roche reject became the marquee pipeline asset for a company that’s developed some of the world’s most expensive drugs.

Seat­tle Ge­net­ics de­tails pos­i­tive OS and PFS da­ta for tu­ca­tinib in breast can­cer

Seattle Genetics $SGEN is showing off more positive data around tucatinib, its pivotal-stage drug for HER2 positive breast cancer.

A month after hearing about solidly upbeat hazard ratios, we learned today that the estimated progression-free survival rate at one year was 33% in the tucatinib arm compared to 12% for patients taking trastuzumab and capecitabine alone.

Median PFS was 7.8 months (95% CI: 7.5, 9.6) in the tucatinib arm, compared to 5.6 months (95% CI: 4.2, 7.1) in the control arm.

Bat­tered, cash hun­gry In­tec feels the burn of No­var­tis re­jec­tion

It’s a case of some bad timing for Intec.

Just when a key trial testing the company’s Accordion drug delivery tech imploded in Parkinson’s disease, they handed Novartis data from a successful PK study of a custom Accordion pill engineered to deliver a Novartis compound to entice the Swiss drugmaker into signing a licensing agreement.

Novartis said thanks, but no thanks.

For the cash-strapped Israeli drug developer, the failure to clinch the deal marks a big blow. As of the third quarter, the company has $15.7 million in cash and equivalents, which HC Wainwright analysts estimate will keep the lights on into mid-2020.

Bris­tol-My­ers shows off a low-pro­file AML con­tender it gained from Cel­gene buy­out — and they’re tak­ing it straight to the FDA

Bristol-Myers Squibb reaped an enormous pipeline with its much-criticized $64 billion megadeal to buy Celgene. And it got a few hidden gems in the deal.

One of those gems was brought out for display on Tuesday, with a late-breaker at ASH on CC-486, which is now being prepped for regulatory filings at the FDA and elsewhere.

Celgene top-lined the positive results in a maintenance setting for acute myeloid leukemia a few months ago, but at ASH investigators pulled back the curtains on the all-important data they believe will give them an advantage in the commercial wars to come.

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