No­var­tis ad­mits to ‘mis­take’ af­ter par­tial clin­i­cal hold placed on Zol­gens­ma tri­al

No­var­tis on Wednes­day said that the FDA placed a par­tial hold on in­trathe­cal clin­i­cal tri­als of its gene ther­a­py Zol­gens­ma (onasemno­gene abepar­vovec-xioi) for spinal mus­cu­lar at­ro­phy (SMA) pa­tients based on find­ings in a small pre­clin­i­cal an­i­mal study.

On Thurs­day, a No­var­tis spokesper­son told Fo­cus that a draft re­port of the pre­clin­i­cal safe­ty find­ings was pre­sent­ed to the AveX­is safe­ty man­age­ment team last March and the com­pa­ny “de­ter­mined at that time that the safe­ty find­ing should be in­clud­ed in the an­nu­al up­date of the in­ves­ti­ga­tor brochure planned for Sep­tem­ber 2019. Un­for­tu­nate­ly, a mis­take was made, and this up­date was not im­ple­ment­ed.”

The omis­sion was lat­er iden­ti­fied as part of a No­var­tis re­view re­lat­ed to the Form 483 re­sponse from Au­gust, and the spokesper­son told Fo­cus, “This omis­sion was iden­ti­fied and the is­sue quick­ly as­sessed and man­aged pur­suant to ex­ist­ing No­var­tis safe­ty process­es and we no­ti­fied health au­thor­i­ties and clin­i­cal tri­al in­ves­ti­ga­tors.”

But the spokesper­son al­so said that No­var­tis no­ti­fied in­ves­ti­ga­tors and the FDA at the end of last week on the find­ings and was no­ti­fied about the par­tial clin­i­cal hold ear­li­er this week.

The com­pa­ny al­so stressed that the par­tial hold does not im­pact the mar­ket­ing of Zol­gens­ma or some oth­er clin­i­cal tri­als.

“This was a small, AveX­is-ini­ti­at­ed pre-clin­i­cal study in which an­i­mal find­ings showed dor­sal root gan­glia (DRG) mononu­clear cell in­flam­ma­tion, some­times ac­com­pa­nied by neu­ronal cell body de­gen­er­a­tion or loss. The tri­al in­volved 12 non-hu­man pri­mates,” the No­var­tis spokesper­son said.

The clin­i­cal sig­nif­i­cance of the DRG in­flam­ma­tion ob­served in this pre-clin­i­cal an­i­mal study is not known and was not seen in pri­or an­i­mal stud­ies, the com­pa­ny added. “We will con­tin­ue to close­ly mon­i­tor for any re­ports of re­lat­ed safe­ty events in pa­tients,” No­var­tis said. “We will work dili­gent­ly with FDA to iden­ti­fy any ad­di­tion­al ac­tions nec­es­sary to re­sume dos­ing in the AVXS-101 in­trathe­cal clin­i­cal tri­als.”

In Au­gust, No­var­tis ran in­to trou­ble with the FDA when da­ta ma­nip­u­la­tion was un­cov­ered in the Zol­gens­ma ap­pli­ca­tion, al­though the ma­nip­u­la­tion did not af­fect the FDA’s as­sess­ment of the gene ther­a­py’s safe­ty or ef­fi­ca­cy. Ques­tions re­lat­ed to the time­line of the un­cov­er­ing of the ma­nip­u­la­tion were al­so raised.

RAPS: First pub­lished in Reg­u­la­to­ry Fo­cus™ by the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety, the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care prod­ucts. Click here for more in­for­ma­tion.


Zachary Brennan

managing editor, RAPS

Com­mu­ni­cat­ing the val­ue of pre­ci­sion med­i­cine

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Ed­i­tas and Cel­gene sub Juno are tack­ling hottest im­munother­a­py cells

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Reata's bar­dox­olone of­fers promise in pa­tients with rare kid­ney dis­or­der

After surprising Wall Street with positive data on its drug, omaveloxolone, in patients suffering from a notoriously hard-to-treat degenerative neuromuscular disorder last month, Reata Pharma on Monday unveiled pivotal results from a trial testing another drug, bardoxolone, in patients with a rare, genetic form of chronic kidney disease for which there exist no approved therapies.

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