Their lead drug failed both main goals in key study, but Or­p­hazyme plans to pitch sub­group analy­ses to reg­u­la­tors

Or­p­hazyme at­tempt­ed on Wednes­day to en­thuse in­vestors about the re­sults of a Phase II/III study test­ing their lead drug, ari­mo­clo­mol, in pa­tients with a rare ge­net­ic dis­or­der, un­der­scor­ing some pos­i­tive sub­group analy­ses — even though the ex­per­i­men­tal treat­ment missed its pri­ma­ry end­points. The com­pa­ny is now prepar­ing mar­ket­ing fil­ings and plan­ning to en­gage with reg­u­la­tors to get ari­mo­clo­mol on the mar­ket at the ear­li­est.

The com­pa­ny’s shares (CPH: $OR­PHA) shot up about 40% in re­sponse on Wednes­day, but climbed down about 5% on Thurs­day af­ter­noon GMT.

The drug is be­ing eval­u­at­ed for use in Nie­mann-Pick dis­ease Type C (NPC), an in­her­it­ed neu­rode­gen­er­a­tive dis­ease char­ac­ter­ized by the body’s in­abil­i­ty to trans­port cho­les­terol and oth­er lipids in­side of cells that caus­es an ab­nor­mal ac­cu­mu­la­tion with­in var­i­ous tis­sues in­clud­ing the brain. In the 12-month study, 50 pa­tients be­tween the age of 2 and 18 were giv­en ei­ther ari­mo­clo­mol or place­bo on top of stan­dard of care.

The com­pa­ny high­light­ed sub­group analy­ses that sug­gest the drug has a sig­nif­i­cant im­pact on the dis­ease. But that comes af­ter the com­pa­ny ac­knowl­edged months ago that the drug failed the pri­ma­ry end­point.

An­ders Hins­by

“With this high­ly com­pelling da­ta set, we are look­ing for­ward to work­ing with reg­u­la­to­ry au­thor­i­ties to make ari­mo­clo­mol avail­able to pa­tients as fast as pos­si­ble,” Or­p­hazyme chief An­ders Hins­by said in a state­ment.

The tri­al had two pri­ma­ry end­points track­ing dis­ease pro­gres­sion: the 5-do­main NPC Clin­i­cal Sever­i­ty Scale (NPC-CSS), a dis­ease-spe­cif­ic out­come mea­sure, as well as Clin­i­cal Glob­al Im­pres­sion of Im­prove­ment scale (CGI-I), a self-rat­ing tool, at the be­hest of the FDA.

In terms of NPC-CSS, the com­pa­ny said treat­ment with ari­mo­clo­mol ad­junct to rou­tine clin­i­cal care re­sult­ed in a 74% re­duc­tion in dis­ease pro­gres­sion, but the p-val­ue at 0.0506 in­di­cat­ed the ef­fect was not sta­tis­ti­cal­ly sig­nif­i­cant. But re­searchers claimed that two sub­group analy­ses of­fered stronger con­vic­tion of the drug’s po­ten­tial ben­e­fit. When look­ing at pa­tients 4 years or old­er (44/50), treat­ment pro­gres­sion slowed in pa­tients on ari­mo­clo­mol ver­sus place­bo, with a p-val­ue of 0.0219. An­oth­er sub­group analy­sis, re­quest­ed by the EMA, showed that ari­mo­clo­mol had a sig­nif­i­cant im­pact com­pared to a place­bo in pa­tients who got miglu­s­tat — orig­i­nal­ly sold by Acte­lion un­der the brand name Za­vesca — as part of stan­dard care, with a p-val­ue of 0.0071.

On the CGI-I end­point, an in­flat­ed place­bo re­sponse de­terred the drug from demon­strat­ing an im­pact on the main goal, the com­pa­ny said, adding that when con­sid­er­ing pa­tients who se­vere­ly pro­gressed dur­ing the tri­al, on­ly 10.7% of ari­mo­clo­mol-treat­ed pa­tients got “much worse” or “very much worse” com­pared to 26.7% in the place­bo con­trol group.

Oth­er sub­group analy­ses al­so sug­gest­ed a lack of sta­tis­ti­cal sig­nif­i­cant im­prove­ment with the drug, al­though some ex­plorato­ry bio­mark­er da­ta were fa­vor­able to ari­mo­clo­mol.

Safe­ty da­ta were al­so pos­i­tive, with se­ri­ous side-ef­fects oc­cur­ring less fre­quent­ly in the ari­mo­clo­mol group (14.7%) com­pared to place­bo con­trol (37.5%).

The ball is now in the reg­u­la­to­ry court, but con­sid­er­ing NPC is a rare dis­ease af­fect­ing an es­ti­mat­ed in 1/120 000 live births, it could go ei­ther way.

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.