Near­ly a year af­ter Au­den­tes' gene ther­a­py deaths, the tri­al con­tin­ues. What hap­pened re­mains a mys­tery

Na­tal­ie Holles was five months in­to her tenure as Au­dentes CEO and work­ing to smooth out a $3 bil­lion merg­er when the world crashed in.

Holles and her team re­ceived word on the morn­ing of May 5 that, hours be­fore, a pa­tient died in a tri­al for their lead gene ther­a­py. They went in­to triage mode, alert­ing the FDA, call­ing tri­al in­ves­ti­ga­tors to be­gin to un­der­stand what hap­pened, and, the next day, writ­ing a let­ter to alert the pa­tient com­mu­ni­ty so they would be the first to know. “We want­ed to be as forth­right and trans­par­ent as pos­si­ble,” Holles told me late last month.

The brief let­ter not­ed two oth­er pa­tients al­so suf­fered se­vere re­ac­tions af­ter re­ceiv­ing a high dose of the ther­a­py and were un­der­go­ing treat­ment. One died a month and a half lat­er, at which point news of the deaths be­came pub­lic, jolt­ing an emer­gent gene ther­a­py field and rais­ing ques­tions about the safe­ty of the high dos­es Au­dentes and oth­ers were now us­ing. The third pa­tient died in Au­gust.

“It was deeply sad­den­ing,” Holles said. “But I was — we were — res­olute and de­ter­mined to un­der­stand what hap­pened and learn from it and get back on track.”

Eleven months have now passed since the first death and the ther­a­py, a po­ten­tial cure for a rare and fa­tal mus­cle-wast­ing dis­ease called X-linked my­otubu­lar my­opa­thy, is back on track, the FDA hav­ing cleared the com­pa­ny to re­sume dos­ing at a low­er lev­el. Au­dentes it­self is no more; last month, Japan­ese phar­ma gi­ant Astel­las an­nounced it had com­plet­ed work­ing out the kinks of the $3 bil­lion merg­er and had re­struc­tured and re­brand­ed the sub­sidiary as Astel­las Gene Ther­a­pies. Holles, hav­ing suc­cess­ful­ly steered both ef­forts, de­part­ed.

Still, ques­tions about pre­cise­ly what led to the deaths of the 3 boys still linger. Tri­al in­ves­ti­ga­tors re­leased key de­tails about the case last Au­gust and De­cem­ber, point­ing to a bi­o­log­i­cal land­mine that Au­dentes could not have seen com­ing — a mo­ment of pro­found med­ical mis­for­tune. In an emerg­ing field that’s promised cures for dev­as­tat­ing dis­eases but al­so seen its share of safe­ty set­backs, the cas­es pro­vid­ed a cau­tion­ary tale.

Au­dentes “con­tributed in a pos­i­tive way by giv­ing a painful but im­por­tant ex­am­ple for oth­ers to look at and learn from,” Ter­ry Flotte, dean of the UMass School of Med­i­cine and ed­i­tor of the jour­nal Hu­man Gene Ther­a­py, told me. “I can’t see any­thing they did wrong.”

Yet some re­searchers say they’re still wait­ing on Astel­las to re­lease more da­ta. The com­pa­ny has yet to pub­lish a full pa­per de­tail­ing what hap­pened, nor have they in­di­cat­ed that they will. In the mean­time, it re­mains un­clear what trig­gered the events and how to pre­vent them in the fu­ture.

“Since Au­dentes was the first one and we don’t have ad­di­tion­al in­for­ma­tion, we’re kind of in a hold­ing pat­tern, fly­ing around, wait­ing to fig­ure out how to land our ve­hi­cles,” said Jude Samul­s­ki, pro­fes­sor of phar­ma­col­o­gy at UNC’s Gene Ther­a­py Cen­ter and CSO of the gene ther­a­py biotech AskBio, now a sub­sidiary of Bay­er.

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