Hopes for non-viral gene therapy take a blow as Generation Bio announces significant setback

Geoff McDonough, Generation Bio CEO

Last year, dur­ing the height of the biotech IPO boom, Gen­er­a­tion Bio raised $230 mil­lion on a swing-for-the-fences ap­proach to gene ther­a­py.

Launched out of UMass Med­ical School, the com­pa­ny promised to de­vel­op the world’s first non-vi­ral gene ther­a­py. Such an ap­proach, if proven, could elim­i­nate many of the key hur­dles that have hin­dered the field over the last decade: It would al­low doc­tors to dose pa­tients who have pre-ex­ist­ing im­mu­ni­ty to the virus­es com­mon­ly used to­day, to re­dose a pa­tient if the ther­a­py ever wore off, and to avoid many of the im­mune-re­lat­ed safe­ty con­cerns that have come to the fore over the last 18 months.

But the promise al­so raised skep­ti­cism from many in the gene ther­a­py field. Re­searchers have been try­ing to make non-vi­ral de­liv­ery work since the 1990s. No one ever has.

And so far, nei­ther has Gen­er­a­tion Bio. The com­pa­ny an­nounced new an­i­mal da­ta for its lead pro­gram Tues­day morn­ing. And as in pre­vi­ous re­ports, the ther­a­py was high­ly ef­fec­tive in mice. But it failed to do much in mon­keys, set­ting back a pro­gram they had hoped to have au­tho­rized for clin­i­cal tri­als in 2022.

Gen­er­a­tion Bio’s stock $GBIO fell 42% on the news, from $13.90 to $8.06.

The com­pa­ny’s ini­tial fo­cus has been on he­mo­phil­ia A, where a re­dos­able gene ther­a­py could be par­tic­u­lar­ly ad­van­ta­geous. The lead­ing he­mo­phil­ia A pro­gram from Bio­Marin has been racked by con­cerns that the one-and-done ther­a­py might be­gin to wear off a few years af­ter ad­min­is­tra­tion.

It was al­so a nat­ur­al tar­get for Gen­er­a­tion Bio’s plat­form, be­cause he­mo­phil­ia gene ther­a­pies in­volve get­ting fac­tor VI­II — the clot­ting pro­tein he­mo­phil­ia pa­tients are miss­ing — to be ex­pressed in the liv­er. Gen­er­a­tion’s de­liv­ery tech, an ad­vanced form of the lipid-nanopar­ti­cles used in mR­NA vac­cines, traf­fics most di­rect­ly to that or­gan.

In mice, Gen­er­a­tion Bio was able to in­duce 205% of nor­mal hu­man fac­tor VI­II ex­pres­sion. But in mon­keys, the true test for both pre­dict­ing hu­man ef­fi­ca­cy and per­suad­ing the FDA to OK clin­i­cal tri­als, ex­pres­sion on­ly reached ‘up to 2%’ — a far cry from the rough­ly 60% ex­pres­sion that Bio­Marin saw in the first year af­ter ad­min­is­ter­ing their ther­a­py in pa­tients. And sub­stan­tial­ly less than the 8.3% pa­tients were at af­ter five years.

Gen­er­a­tion in­di­cat­ed, though, that the lev­el of ex­pres­sion was less a prob­lem than the fact they kept see­ing dif­fer­ent re­sults in dif­fer­ent mon­keys, both on safe­ty and ef­fi­ca­cy.

There was ‘high­er-than-ex­pect­ed vari­abil­i­ty in both fac­tor VI­II ex­pres­sion and tol­er­a­bil­i­ty with­in and across stud­ies,’ the com­pa­ny said in a re­lease.

That will send in­ves­ti­ga­tors back to the lab and de­lay clin­i­cal tri­als, al­though Gen­er­a­tion wouldn’t say by how much or when the com­pa­ny would have a time­line.

‘Ad­di­tion­al op­ti­miza­tion is need­ed to trans­late the im­prove­ment in po­ten­cy and re­duc­tion in vari­abil­i­ty ob­served in mice to NHP, and to sup­port nom­i­na­tion of a de­vel­op­ment can­di­date for the com­pa­ny’s he­mo­phil­ia A pro­gram,’ they said.

The set­back won’t kill Gen­er­a­tion’s he­mo­phil­ia pro­gram. LNPs, though, are eas­i­est to de­liv­er to the liv­er and if the com­pa­ny can’t get re­peat­able re­sults there, it doesn’t bode well for their plans in the eye and mus­cle.

Any com­pa­ny that fig­ures out non-vi­ral gene ther­a­py, or a dif­fer­ent im­prove­ment on the cur­rent ade­no-as­so­ci­at­ed virus­es that dom­i­nate the field, will be sit­ting on a gold mine. But there’s not much ev­i­dence yet to say re­searchers are close.

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