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

Health­care Dis­par­i­ties and Sick­le Cell Dis­ease

In the complicated U.S. healthcare system, navigating a serious illness such as cancer or heart disease can be remarkably challenging for patients and caregivers. When that illness is classified as a rare disease, those challenges can become even more acute. And when that rare disease occurs in a population that experiences health disparities, such as people with sickle cell disease (SCD) who are primarily Black and Latino, challenges can become almost insurmountable.

Jacob Van Naarden (Eli Lilly)

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David Meek, new Mirati CEO (Marlene Awaad/Bloomberg via Getty Images)

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