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.”

 

Is a pow­er­house Mer­ck team prepar­ing to leap past Roche — and leave Gilead and Bris­tol My­ers be­hind — in the race to TIG­IT dom­i­na­tion?

Roche caused quite a stir at ASCO with its first look at some positive — but not so impressive — data for their combination of Tecentriq with their anti-TIGIT drug tiragolumab. But some analysts believe that Merck is positioned to make a bid — soon — for the lead in the race to a second-wave combo immuno-oncology approach with its own ambitious early-stage program tied to a dominant Keytruda.

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Fangliang Zhang, AP Images

UP­DAT­ED: Leg­end fetch­es $424 mil­lion, emerges as biggest win­ner yet in pan­dem­ic IPO boom as shares soar

Amid a flurry of splashy pandemic IPOs, a J&J-partnered Chinese biotech has emerged with one of the largest public raises in biotech history.

Legend Biotech, the Nanjing-based CAR-T developer, has raised $424 million on NASDAQ. The biotech had originally filed for a still-hefty $350 million, based on a range of $18-$20, but managed to fetch $23 per share, allowing them to well-eclipse the massive raises from companies like Allogene, Juno, Galapagos, though they’ll still fall a few dollars short of Moderna’s record-setting $600 million raise from 2018.

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As it hap­pened: A bid­ding war for an an­tibi­ot­ic mak­er in a mar­ket that has rav­aged its peers

In a bewildering twist to the long-suffering market for antibiotics — there has actually been a bidding war for an antibiotic company: Tetraphase.

It all started back in March, when the maker of Xerava (an FDA approved therapy for complicated intra-abdominal infections) said it had received an offer from AcelRx for an all-stock deal valued at $14.4 million.

The offer was well-timed. Xerava was approved in 2018, four years after Tetraphase posted its first batch of pivotal trial data, and sales were nowhere near where they needed to be in order for the company to keep its head above water.

Drug man­u­fac­tur­ing gi­ant Lon­za taps Roche/phar­ma ‘rein­ven­tion’ vet as its new CEO

Lonza chairman Albert Baehny took his time headhunting a new CEO for the company, making it absolutely clear he wanted a Big Pharma or biotech CEO with a good long track record in the business for the top spot. In the end, he went with the gold standard, turning to Roche’s ranks to recruit Pierre-Alain Ruffieux for the job.

Ruffieux, a member of the pharma leadership team at Roche, spent close to 5 years at the company. But like a small army of manufacturing execs, he gained much of his experience at the other Big Pharma in Basel, remaining at Novartis for 12 years before expanding his horizons.

Covid-19 roundup: Ab­b­Vie jumps in­to Covid-19 an­ti­body hunt; As­traZeneca shoots for 2B dos­es of Ox­ford vac­cine — with $750M from CEPI, Gavi

Another Big Pharma is entering the Covid-19 antibody hunt.

AbbVie has announced a collaboration with the Netherlands’ Utrecht University and Erasmus Medical Center and the Chinese-Dutch biotech Harbour Biomed to develop a neutralizing antibody that can treat Covid-19. The antibody, called 47D11, was discovered by AbbVie’s three partners, and AbbVie will support early preclinical work, while preparing for later preclinical and clinical development. Researchers described the antibody in Nature Communications last month.

Pfiz­er’s Doug Gior­dano has $500M — and some ad­vice — to of­fer a cer­tain breed of 'break­through' biotech

So let’s say you’re running a cutting-edge, clinical-stage biotech, probably public, but not necessarily so, which could see some big advantages teaming up with some marquee researchers, picking up say $50 million to $75 million dollars in a non-threatening minority equity investment that could take you to the next level.

Doug Giordano might have some thoughts on how that could work out.

The SVP of business development at the pharma giant has helped forge a new fund called the Pfizer Breakthrough Growth Initiative. And he has $500 million of Pfizer’s money to put behind 7 to 10 — or so — biotech stocks that fit that general description.

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Bris­tol My­ers is clean­ing up the post-Cel­gene merg­er pipeline, and they’re sweep­ing out an ex­per­i­men­tal check­point in the process

Back during the lead up to the $74 billion buyout of Celgene, the big biotech’s leadership did a little housecleaning with a major pact it had forged with Jounce. Out went the $2.6 billion deal and a collaboration on ICOS and PD-1.

Celgene, though, also added a $530 million deal — $50 million up front — to get the worldwide rights to JTX-8064, a drug that targets the LILRB2 receptor on macrophages.

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Leen Kawas, Athira CEO (Athira)

Can a small biotech suc­cess­ful­ly tack­le an Ever­est climb like Alzheimer’s? Athi­ra has $85M and some in­flu­en­tial back­ers ready to give it a shot

There haven’t been a lot of big venture rounds for biotech companies looking to run a Phase II study in Alzheimer’s.

The field has been a disaster over the past decade. Amyloid didn’t pan out as a target — going down in a litany of Phase III failures — and is now making its last stand at Biogen. Tau is a comer, but when you look around and all you see is destruction, the idea of backing a startup trying to find complex cocktails to swing the course of this devilishly complicated memory-wasting disease would daunt the pluckiest investors.

GSK presents case to ex­pand use of its lu­pus drug in pa­tients with kid­ney dis­ease, but the field is evolv­ing. How long will the mo­nop­oly last?

In 2011, GlaxoSmithKline’s Benlysta became the first biologic to win approval for lupus patients. Nine years on, the British drugmaker has unveiled detailed positive results from a study testing the drug in lupus patients with associated kidney disease — a post-marketing requirement from the initial FDA approval.

Lupus is a drug developer’s nightmare. In the last six decades, there has been just one FDA approval (Benlysta), with the field resembling a graveyard in recent years with a string of failures including UCB and Biogen’s late-stage flop, as well as defeats in Xencor and Sanofi’s programs. One of the main reasons the success has eluded researchers is because lupus, akin to cancer, is not just one disease — it really is a disease of many diseases, noted Al Roy, executive director of Lupus Clinical Investigators Network, an initiative of New York-based Lupus Research Alliance that claims it is the world’s leading private funder of lupus research, in an interview.