Bernhardt Zeiher, outgoing Astellas CMO (Astellas)

Q&A: Astel­las' re­tir­ing head of de­vel­op­ment re­flects on gene ther­a­py deaths

For any­one who’s been fol­low­ing dis­cus­sions about the safe­ty alarms sur­round­ing the ade­no-as­so­ci­at­ed virus­es (AAV) com­mon­ly used to de­liv­er gene ther­a­py, Astel­las should be a fa­mil­iar name.

The Japan­ese phar­ma — which bought out Au­dentes Ther­a­peu­tics near the end of 2019 and lat­er built a gene ther­a­py unit around the ac­qui­si­tion — rocked the field when it re­port­ed three pa­tient deaths in a tri­al test­ing AT132, the lead pro­gram from Au­dentes de­signed to treat a rare mus­cle dis­ease called X-linked my­otubu­lar my­opa­thy (XLMTM).

When the com­pa­ny restart­ed the tri­al, it ad­just­ed the dose and in­sti­tut­ed a bat­tery of oth­er mea­sures to try to pre­vent the same thing from hap­pen­ing again. But trag­i­cal­ly, the first pa­tient to re­ceive the new reg­i­men died just weeks af­ter ad­min­is­tra­tion. The ther­a­py re­mains un­der clin­i­cal hold, and just weeks ago, Astel­las flagged an­oth­er safe­ty-re­lat­ed hold for a sep­a­rate gene ther­a­py can­di­date. In the process of in­ves­ti­gat­ing the deaths, the com­pa­ny has al­so tak­en flak about the way it dis­closed in­for­ma­tion.

Big ques­tions re­main — ques­tions that can have big im­pli­ca­tions about the fu­ture of AAV gene ther­a­pies.

Bern­hardt Zei­her did not imag­ine any of it when he first joined Astel­las as the ther­a­peu­tic area leader in in­flam­ma­tion, im­munol­o­gy and in­fec­tious dis­eases. But his as­cent to chief med­ical of­fi­cer and head of de­vel­op­ment co­in­cid­ed al­most ex­act­ly with Astel­las’ big move in­to gene ther­a­py, putting him of­ten in the dri­ver’s seat to grap­ple with the set­backs.

As Zei­her pre­pares to re­tire next month af­ter a 12-year tenure — leav­ing the un­fin­ished tasks to his suc­ces­sor, a sea­soned can­cer drug de­vel­op­er — he chat­ted with End­points News, in part, to dis­cuss the ef­fort to un­der­stand what hap­pened, lessons learned and the crit­i­cism along the way.

The tran­script has been light­ly edit­ed for length and clar­i­ty.

End­points: I want to al­so ask you a bit about the gene ther­a­py ef­forts you’ve been work­ing on. Astel­las has re­al­ly been at the fore­front of dis­cov­er­ing the safe­ty con­cerns as­so­ci­at­ed with AAV gene ther­a­py. What’s that been like for you?

Zei­her: Well, I have to ad­mit, it’s been a bit of a roller coast­er. We ac­quired Au­dentes. Huge amount of en­thu­si­asm. What we saw with AT132 — that was the lead pro­gram in XLMTM — was just re­mark­able ef­fi­ca­cy. I mean, kids who went from be­ing on ven­ti­la­tors, not able to eat for them­selves, sit up, do things like that, to off ven­ti­la­tors, walk­ing, you know, re­al­ly — one in­ves­ti­ga­tor called it this Lazarus-like ef­fect. It was just re­al­ly dra­mat­ic ef­fi­ca­cy. And then to have the safe­ty events that oc­curred. So they ac­tu­al­ly oc­curred with­in that first year of the ac­qui­si­tion. So we had the three pa­tient deaths. Me and my or­ga­ni­za­tion be­came very, very much in­volved. In fact, Ed Con­ner, who had been the chief med­ical of­fi­cer, he left af­ter some of the deaths, but I stepped in as the kind of act­ing chief med­ical of­fi­cer, we had an­oth­er chief med­ical of­fi­cer who was in­volved, and then we had a fourth death, and I be­came act­ing again for a pe­ri­od of time.

Endpoints News

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