Au­rinia eye drug falls short in im­prov­ing tol­er­a­bil­i­ty ver­sus Resta­sis, but beats on ef­fi­ca­cy

Al­ler­gan’s best-sell­ing dry eye drug Resta­sis was de­vel­oped af­ter the im­muno­sup­pres­sant was orig­i­nal­ly shown to en­hance tear pro­duc­tion in dogs. Sim­i­lar­ly, Cana­da’s Au­rinia Phar­ma $AUPH found its ex­per­i­men­tal treat­ment was do­ing well in ca­nine stud­ies, prompt­ing their eval­u­a­tion of the drug — vo­closporin opthalmic so­lu­tion (VOS) — in hu­mans. And now in a Phase II study com­par­ing VOS to Resta­sis, VOS failed the pri­ma­ry end­point of beat­ing the block­buster drug’s tol­er­a­bil­i­ty score, but did demon­strate a sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment on sec­ondary end­points eval­u­at­ing ef­fi­ca­cy.

Richard Glick­man

Resta­sis is a pre­scrip­tion eye drop that con­tains cy­closporine, which tar­gets a ubiq­ui­tous en­zyme called cal­cineurin found in cell cy­to­plasm. It takes about 3-6 months for the drug to work, and about 17% of pa­tients dis­con­tin­ue us­ing the drug due to both­er­some side-ef­fects such as burn­ing and itch­ing. Still, large­ly due to a per­sis­tent mar­ket­ing ef­fort the drug has gen­er­at­ed bil­lions of dol­lars in rev­enue for Al­ler­gan since its 2003 ap­proval. The com­pa­ny has used a cre­ative so­lu­tion to en­hance the patent life of its sec­ond-biggest sell­er, by trans­fer­ring the drug’s patents to a Na­tive Amer­i­can tribe to stave off com­pe­ti­tion, but that strat­e­gy has run in­to le­gal and PR trou­ble. Al­ler­gan and their Mo­hawk al­lies are now tak­ing the case to the Supreme Court — pro­vid­ed the jus­tices agree to hear it.

Au­rinia’s VOS has a long way to go be­fore it can win ap­proval. But if it does, it will com­pete with cheap Resta­sis gener­ics — rais­ing the bar sub­stan­tial­ly on any mar­ket show­down.

VOS is a “next-gen” cy­closporine in­hibitor sus­pend­ed in a na­nomi­cel­lar so­lu­tion, de­signed to be four times as po­tent as cy­closporine.

“VOS is a de­riv­a­tive of cy­closporin…it binds dif­fer­ent­ly, and is more po­tent, there­fore we ac­tu­al­ly need less drug. In this case, we de­cid­ed to use more of the drug,” Au­rinia CEO Richard Glick­man ex­plained in an in­ter­view pre­ced­ing the re­sults. “When you treat pa­tients with an eye drop, they blink. When they blink they ac­tu­al­ly wipe off a great deal of that drug — so ba­si­cal­ly we are de­liv­er­ing more drug, so even if they blink and wipe it off — the idea is that more drug pen­e­trates the eye.”

VOS was test­ed against Resta­sis in a 100-pa­tient 28-day study. The main goal of the study, to im­prove tol­er­a­bil­i­ty as mea­sured by “drop dis­com­fort” one minute fol­low­ing drug ad­min­is­tra­tion, was not met, with both arms re­port­ing sim­i­lar rates.

“We didn’t see a sig­nif­i­cant dif­fer­ence cause there was very lit­tle dis­com­fort at all on the ad­min­is­tra­tion of drops…and we can’t re­al­ly be sure why,” Au­rinia chief med­ical of­fi­cer Neil Solomons told End­points News. The com­pa­ny’s shares were down about 5% in morn­ing trad­ing.

Neil Solomons

Al­ler­gan orig­i­nal­ly sought US ap­proval for Resta­sis in 1999, but that ap­pli­ca­tion failed on the ba­sis of in­con­sis­tent da­ta from two late-stage tri­als, fol­low­ing which the drug­mak­er re­an­a­lyzed its da­ta and amend­ed its ap­pli­ca­tion four times. The FDA ul­ti­mate­ly sanc­tioned the drug’s ap­proval in 2003, based on a sur­ro­gate sign — the Schirmer re­sponse — a test used to mea­sure tear pro­duc­tion. Since then oth­er drugs for dry eye have been ap­proved by the FDA, in­clud­ing Sun Phar­ma’s Ce­qua and Shire’s Xi­idra, which both take up to 12 weeks to take ef­fect.

Dry eye, which typ­i­cal­ly oc­curs with age, is char­ac­ter­ized by the di­min­ished quan­ti­ty and/or qual­i­ty of tears, which fail to keep the sur­face of the eye ad­e­quate­ly lu­bri­cat­ed. It is es­ti­mat­ed to im­pact more than 16 mil­lion in the Unit­ed States.

In Au­rinia’s head-to-head tri­al, VOS eclipsed Resta­sis on two mea­sures of ef­fi­ca­cy: The Schirmer test (STT) and Flu­o­res­cein Corneal Stain­ing/FCS (a test used mea­sure struc­tur­al dam­age to the cornea). At week four, VOS showed rapid and sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ments (STT: p=.0051; FCS: p=.0003) over Resta­sis. Da­ta showed that VOS be­gan to con­fer a sta­tis­ti­cal­ly sig­nif­i­cant re­duc­tion in FCS ver­sus Resta­sis by week 2, the com­pa­ny added.

“The ef­fi­ca­cy end­points clear­ly sig­nal that VOS has the po­ten­tial to have a more rapid on­set than Resta­sis,” Can­tor Fitzger­ald’s El­e­mer Piros wrote in a note.

“If you ac­tu­al­ly look at the da­ta across the board, it’s quite con­sis­tent and re­mark­able — we didn’t need to slice and dice the da­ta, or cre­ate a sub­set of pa­tients — we just picked the wrong pri­ma­ry end­point,” Glick­man said. “We’re ac­tu­al­ly a lot sur­prised by the mag­ni­tude of the re­sponse ac­tu­al­ly, be­cause when we pow­ered the study we thought it would be eas­i­er to pick the low hang­ing fruit, which was…drop dis­com­fort. Drop dis­com­fort turns out to be tougher than we thought in the sense that both drugs in our study ac­tu­al­ly didn’t both­er pa­tients a whole lot.”

Leerink’s Joseph Schwartz sug­gest­ed that the sur­pris­ing ef­fi­ca­cy da­ta over­shad­owed the miss on tol­er­a­bil­i­ty.

“We think the on par tol­er­a­bil­i­ty of VOS de­spite a ~16x high­er con­cen­tra­tion of drug de­liv­ered il­lus­trates that there could be room for im­prove­ment via eval­u­at­ing low­er dos­es in fu­ture tri­als, a con­cept man­age­ment dis­closed as a po­ten­tial strat­e­gy in their next study. Sur­pris­ing­ly, giv­en the study’s pow­er­ing as­sump­tions, treat­ment with VOS sig­nif­i­cant­ly im­proved key ef­fi­ca­cy out­comes, which we think are more rel­e­vant for reg­is­tra­tional stud­ies and mar­ket up­take,” Schwartz wrote in a note.

Au­rinia is con­vinced the dataset is com­pelling enough to plan a larg­er Phase II/III tri­al.

If all goes well go­ing for­ward, the British Co­lum­bia-based com­pa­ny is hop­ing a drug­mak­er with deep­er pock­ets comes along to help out on the com­mer­cial side. Mean­while, the com­pa­ny’s main fo­cus is its lu­pus pro­gram, for which late-stage da­ta are ex­pect­ed by the end of 2019.

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