An­oth­er failed tri­al for Or­p­hazyme's 'pipeline-in-a-pro­duc­t' leaves shad­ow on drug's fu­ture

The tu­mul­tuous ride for Or­p­hazyme con­tin­ued on Fri­day as the com­pa­ny an­nounced that a piv­otal tri­al for its lead drug ari­mo­clo­mol failed yet again, this time in the treat­ment of ALS, seed­ing doubt in a drug that had re­cent­ly been cleared by the FDA for pri­or­i­ty re­view. The lat­est fail­ure casts a dark­er shad­ow on the up­com­ing de­ci­sion de­spite Or­p­hazyme’s up­beat out­look.

In a state­ment, the Dan­ish biotech an­nounced that the drug did not meet its pri­ma­ry or sec­ondary end­points eval­u­at­ing func­tion and sur­vival. But the com­pa­ny has not an­nounced any da­ta sur­round­ing the fail­ure, in­stead say­ing that it will pub­lish the com­plete re­sults lat­er this year.

In­vestors re­act­ed ac­cord­ing­ly to the news, as the $ORPH stock dropped 24.16% pre­mar­ket to $6.41.

Or­p­hazyme is a 1-drug com­pa­ny and has ex­pec­ta­tions that ari­mo­clo­mol — dubbed its “pipeline-in-a-prod­uct” — has the abil­i­ty to treat sev­er­al dif­fer­ent dis­eases. The com­pa­ny pur­chased the drug from CytRx in 2011 for $150,000 up­front, and the po­ten­tial to make $120 mil­lion. But with that chal­lenge has come re­peat­ed frus­tra­tion as this is not the first time that the drug has flopped.

In March, the com­pa­ny an­nounced that ari­mo­clo­mol failed to hit its end­points in Phase II/III tri­als for pa­tients with in­clu­sion body myosi­tis, a de­bil­i­tat­ing mus­cle-wast­ing dis­ease. The com­pa­ny al­so in­tends to ad­vance ari­mo­clo­mol in­to clin­i­cal de­vel­op­ment in Gauch­er dis­ease, the in­her­it­ed dis­or­der that caus­es sug­ar-con­tain­ing fats to ac­cu­mu­late in the lyso­somes of cells and af­fect the brain, bone mar­row, spleen and liv­er. That pro­gram is cur­rent­ly in Phase II.

Thomas Blaet­tler

The drug just bare­ly missed both pri­ma­ry end­points in its Phase III Nie­mann-Pick dis­ease type C study rough­ly 2.5 years ago. But the FDA ac­cept­ed its ap­pli­ca­tion in Sep­tem­ber 2020 for the rare neu­rode­gen­er­a­tive con­di­tion and gave it pri­or­i­ty re­view, re­in­forc­ing Or­p­hazyme’s nar­ra­tive that the FDA viewed the ap­pli­ca­tion fa­vor­ably.  There is no ap­proved med­i­cine for NPC, a rare dis­ease that is es­ti­mat­ed to im­pact 1 in 100,000 lives.

“We are dis­heart­ened by these re­sults, as we had hoped ari­mo­clo­mol might rep­re­sent a vi­able new ap­proach against the for­mi­da­ble chal­lenge of this dev­as­tat­ing dis­ease,” CMO Thomas Blaet­tler said. “With over 18 months of eval­u­a­tion, this tri­al rep­re­sents one of the longest run­ning clin­i­cal stud­ies in this cat­e­go­ry. While un­suc­cess­ful, the da­ta gen­er­at­ed will con­tribute mean­ing­ful­ly to the sci­en­tif­ic di­a­logue on this chal­leng­ing dis­ease.”

The PDU­FA date for Nie­mann-Pick is June 17.

The com­pa­ny is in the midst of a tough stretch. In De­cem­ber 2020, then-CEO Kim Strat­ton re­signed abrupt­ly, and Or­p­hazyme of­fered no ex­pla­na­tion for the move oth­er than that the choice was Strat­ton’s de­ci­sion “fol­low­ing a di­a­logue ini­ti­at­ed by the board of di­rec­tors.”

The drug just nar­row­ly missed its first pri­ma­ry end­point on its 50-per­son Phase II/III NPC study back in Jan­u­ary 2019. Sci­en­tists saw both a 74% re­duc­tion in dis­ease sever­i­ty and a p-val­ue of 0.0506. Two pre-spec­i­fied sub­group analy­ses reached sig­nif­i­cance, with dis­ease pro­gres­sion slow­ing in pa­tients over the age of 4 and in pa­tients who had been tak­ing an Acte­lion drug some­times pre­scribed for the dis­ease. But for this round of tri­als in ALS, the com­pa­ny did not re­lease any da­ta, leav­ing the pub­lic in the dark as to how it per­formed in the tri­al.

Topline da­ta will be pre­sent­ed at the vir­tu­al Eu­ro­pean Net­work to Cure ALS meet­ing from May 12-14, the com­pa­ny said in a state­ment, while com­plete da­ta will be pub­lished lat­er in the year.

The ran­dom­ized, place­bo-con­trolled tri­al for ALS fea­tured 245 at 29 sites across 12 coun­tries in North Amer­i­ca and Eu­rope, the com­pa­ny said in its re­lease. Pa­tients ei­ther re­ceived 3 dai­ly 248mg dos­es of ari­mo­clo­mol or the place­bo for up to 76 weeks.

The pri­ma­ry end­point was to de­ter­mine the ef­fi­ca­cy through the com­bined as­sess­ment of func­tion and sur­vival, and the sec­ondary end­points in­clud­ed sur­vival, ALS Func­tion­al Rat­ing Scale-Re­vised and slow vi­tal ca­pac­i­ty.

Christophe Bour­don, Or­p­hazyme CEO

Un­pack­ing the Aduhelm de­ci­sion, Ver­tex's half full glass, a $525M J&J breakup, and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

By now you have surely read about the FDA’s controversial approval of Biogen’s Alzheimer’s drug and all its reverberations. But I’d still recommend checking out the meaty recap below to make sure you didn’t miss all the angles that the Endpoints team has covered. If you’d rather look ahead, look no further than our three-day virtual panels next week at BIO, where we will discuss what the new normal means for every part of the industry.

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What does a clear ma­jor­i­ty of the bio­phar­ma in­dus­try think of the FDA ap­proval of ad­u­canum­ab? 'Hor­ri­fy­ing' 'Dan­ger­ous' 'Con­fus­ing' 'Dis­as­ter'

Over the years, we’ve become used to seeing a consensus emerge early in our industry polls at Endpoints News. And when we took the pulse of drug hunters on the heels of a controversial FDA approval for aducanumab this week, it became immediately apparent that the vast majority of our readers — heavily concentrated among biopharma staffers and execs — were incensed by what they had just witnessed.

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Aaron Kesselheim (Scott Eisen/AP Images for AIDS Healthcare Foundation)

Har­vard’s Aaron Kessel­heim re­signs from ex­pert pan­el in wake of ad­u­canum­ab OK, blast­ing FDA for ‘worst drug ap­proval de­ci­sion in re­cent U.S. his­to­ry'

A third member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee has resigned in the wake of Biogen’s controversial Aduhelm approval, slamming the agency as he left and further deepening the controversy surrounding the decision.

Harvard University professor Aaron Kesselheim quit in protest Thursday afternoon, calling the Aduhelm OK “probably the worst drug approval decision in recent U.S. history.” Kesselheim follows both Joel Perlmutter, a neurologist from Washington University in St. Louis, and David Knopman, a neurologist from the Mayo Clinic, out the door.

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David Knopman (Mayo Clinic via YouTube)

A sec­ond ad­comm mem­ber aban­dons his post in af­ter­math of con­tro­ver­sial ad­u­canum­ab de­ci­sion

As the fallout from the FDA’s approval of Alzheimer’s med aducanumab grows, a second member of the adcomm overseeing that drug’s review has walked away. But even with two experts now having resigned from that committee in protest, is there enough broad-level outrage to prevent another aducanumab from getting approved?

The FDA on Wednesday lost another member of its Peripheral and Central Nervous System Drugs Advisory Committee as Mayo Clinic neurologist David Knopman hit the exit over the agency’s decision to approve Biogen’s Alzheimer’s drug Aduhelm despite the committee’s near-unanimous vote against it.

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Reshma Kewalramani, Vertex CEO (BIO via YouTube)

UP­DAT­ED: Ver­tex strikes out on its lat­est big shot at a rare ge­net­ic dis­ease. But they're go­ing to keep on swing­ing

It’s been several months since Vertex culled one of its small molecules for alpha-1 antitrypsin deficiency (AATD), taking a big hit after evidence of liver damage surfaced in a key Phase II trial. Now we learned that the company has whiffed on its second shot, and there’s nothing left in the clinic to treat the rare genetic disease — but that won’t stop it from trying.

Despite avoiding the safety issues that plagued the last candidate, Vertex $VRTX is taking the axe to VX-864 after Phase II results revealed the magnitude of the drug’s response is “unlikely to translate into substantial clinical benefit.” As a result of the news, the company’s stock fell 12.5% after hours.

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FDA au­tho­rizes about 10M J&J vac­cine dos­es, trash­es 60M more from trou­bled Emer­gent plant

The FDA on Friday released about 10 million doses of J&J’s vaccine for use, and disposed of another 60 million doses that were manufactured at the now-shuttered Emergent BioSolutions facility in Baltimore where cross-contamination occurred.

The agency said it’s not yet ready to allow the Emergent plant to be included in the J&J EUA, but that may occur soon. FDA came to the decision to authorize some of the doses after reviewing facility records and quality testing results.

Paul Hudson, Sanofi CEO (Eric Piermont/AFP via Getty Images)

Months af­ter FDA re­jec­tion, Sanofi touts piv­otal win for rare dis­ease drug su­tim­limab as it preps to re­file

One of the pillar drugs of Sanofi’s $11.6 billion pickup of Bioverativ hit a big setback late last year when the FDA sent its application for approval back. Now, as Sanofi gears up to resubmit the drug for review, the drugmaker is touting pivotal data it hopes will help take it over the finish line.

Sanofi’s sutimlimab nailed all three of its primary endpoints in its Phase III CADENZA study for patients with cold agglutinin disease, a rare disorder that can cause severe anemia, without a recent history of blood transfusion, the French drugmaker said Friday. The topline results will be presented at this weekend’s virtual EHA meeting.

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Ver­tex and CRISPR Ther­a­peu­tics un­veil more pos­i­tive gene ther­a­py da­ta, but busul­fan again casts a shad­ow over the field

Less than 12 hours after revealing a flop on its second shot for alpha-1 antitrypsin deficiency, Vertex plowed ahead with another data drop from its partnership with CRISPR Therapeutics. And though the topline proved positive, concerns over conditioning agents continue to linger over the collaboration, as well as the entire gene therapy space.

Presenting data from two trials at the European Hematology Association annual meeting, the pair announced that follow-up data of at least three months for 22 patients with genetic blood disorders indicated a “consistent and sustained” response to the experimental drug CTX001. All 15 patients with transfusion-dependent beta thalassemia did not need further blood transfusions and all seven with severe sickle cell disease were pain free, the biotechs announced.

Janet Woodcock, acting FDA commissioner, at Thursday's Senate Appropriations hearing (Bill Clark/CQ Roll Call via AP Images)

Sen­a­tors lam­bast new Alzheimer’s drug’s price but give Janet Wood­cock a free pass on the ap­proval de­ci­sion

Senate Finance Democrats took aim at Biogen’s pricey new Alzheimer’s drug on Thursday, but members on both sides of the aisle at a separate appropriations hearing didn’t question acting FDA commissioner Janet Woodcock on the approval.

“I was appalled that Biogen priced their Alzheimer’s drug approved by the FDA at $56,000 per year — I’m not going to debate whether this is effective or not, but it’s double the household median income for Michiganders over the age of 65,” Sen. Debbie Stabenow (D-MI) said at the finance hearing.