Biotech Voices is a collection of exclusive opinion editorials from some of the leading voices in biopharma on the biggest industry questions today. Think you have a voice that should be heard? Reach out to Amber Tong.

A team of genome en­gi­neers at a start­up biotech has been work­ing for years to cre­ate a cell ther­a­py with the hope that it will cure an ag­gres­sive form of can­cer. Af­ter much gru­el­ing tri­al and er­ror at the edit­ing bench, they are ready to eval­u­ate their drug can­di­date in clin­i­cal tri­als. Things are go­ing well, and they’re ec­sta­t­ic to see that tu­mors are shrink­ing, T cell counts are ris­ing, and the dis­ease is re­treat­ing. But there’s a cloud on this bright hori­zon. A side ef­fect is show­ing up with some of the pa­tients in the tri­al, one which might have long-term con­se­quences for their well-be­ing. The sci­en­tists have an idea: What if they can flip what they call an “off-switch” on one pair of genes they’ve iden­ti­fied that could turn off this side ef­fect of the drug while re­tain­ing the new drug’s cu­ra­tive pow­ers? It sounds like an easy fix but its im­ple­men­ta­tion is go­ing to take a long time.

In the cur­rent reg­u­la­to­ry en­vi­ron­ment, af­ter an im­por­tant dis­cov­ery is made, a tri­al al­ter­ation is re­quired, which is a cost­ly and lengthy process that lim­its the abil­i­ty to bring nov­el unique ther­a­pies quick­ly to pa­tients with high un­met needs. If those genome en­gi­neers at the start­up want to make even the slight­est im­prove­ment to their drug can­di­date, which may at­ten­u­ate the pre­vi­ous­ly men­tioned se­ri­ous side ef­fect, they’ll be re­quired to start all over again with a 2.0 ver­sion. This kind of ver­sion­ing is cus­tom­ary in the biotech in­dus­try and can of­ten be a race against time.

An era of in­ter-dis­ci­pli­nary ad­vances

In our cur­rent cli­mate of drug in­no­va­tion, phar­ma­ceu­ti­cals are be­ing de­vel­oped through hy­per-pre­cise ge­net­ic edit­ing. No longer rel­e­gat­ed to a siloed dis­ci­pline, block­buster drugs are be­ing de­vel­oped by the team ef­forts of gene ther­a­py, cell ther­a­py, gene edit­ing, pro­tein en­gi­neer­ing, syn­thet­ic bi­ol­o­gy and ar­ti­fi­cial in­tel­li­gence. These com­bined dis­ci­plines pro­vide lim­it­less ca­pa­bil­i­ties to de­vel­op new ther­a­pies. This ag­ile ca­pac­i­ty could make in-tri­al drugs in­cre­men­tal­ly safer and more ef­fec­tive.

An ex­am­ple of what can emerge from this mul­ti­dis­ci­pli­nary world, that is mak­ing it rel­e­vant, is the in­ven­tion of al­lo­gene­ic CAR-T cell ther­a­pies. An ar­ti­fi­cial gene cod­ing for a de­signed Chimeric Anti­gen Re­cep­tor (the CAR part of the word) is de­liv­ered by a syn­thet­ic ves­sel called lentivirus in­to T cells, white cells which are our bod­ies’ im­mune re­sponse fight­ers. Then, through syn­thet­ic bi­ol­o­gy, T cells are edit­ed out (or in) to gain or lose spe­cif­ic func­tions. This process is made pos­si­ble by us­ing a gene edit­ing tool called TAL­EN, which are en­zymes that can be en­gi­neered to cut spe­cif­ic se­quences of DNA. The en­gi­neer­ing of TAL­EN is pow­ered by deep learn­ing al­go­rithms. We may re­fer to the treat­ments that arise from this work as “cell ther­a­py” or “gene ther­a­py,” but it’s high con­cen­tra­tion of so­phis­ti­cat­ed tech­nolo­gies work­ing to­geth­er.

A new ther­a­peu­tic mod­el

In 2015, dur­ing the an­nu­al meet­ing of the Amer­i­can So­ci­ety of Hema­tol­ogy (ASH), the com­plete re­mis­sion of the first pa­tient treat­ed with off-the-shelf CAR-T cells was an­nounced. It took near­ly 20 years of tri­al and er­ror at the edit­ing bench to go from con­cept to the first pa­tient treat­ment. Now, five years lat­er, the num­ber of on­go­ing tri­als in the sec­tor of cell and gene ther­a­py is rapid­ly in­creas­ing. A re­port re­leased in March 2020 by the Phar­ma­ceu­ti­cal Re­search and Man­u­fac­tur­ers of Amer­i­ca (PhRMA) iden­ti­fied 362 in­ves­ti­ga­tion­al cell and gene ther­a­pies cur­rent­ly in clin­i­cal de­vel­op­ment, a 20% in­crease since 2018.

Though the in­crease in tri­al num­bers and the mul­ti­tude of ad­vances in the way we uti­lize gene and cell ther­a­pies seem pos­i­tive, there is not a di­rect cor­re­la­tion be­tween the ad­vance in re­search we see in the lab and the way pa­tients are treat­ed in the clin­ic. Fur­ther­more, the drugs that these pa­tients re­ceive were in­vent­ed many years ago. To prove this point: Ap­proved cel­lu­lar ther­a­pies pro­vid­ing rev­o­lu­tion­iz­ing cures, like the first two au­tol­o­gous CAR-T prod­ucts Yescar­ta and Kym­ri­ah, were in­vent­ed over 15 years ago, and have side ef­fects, due to the CAR-T per­sis­tence re­sult­ing in B cell apla­sia (dis­ap­pear­ance of B cells). Im­prove­ments have yet to be im­ple­ment­ed in the com­pound and will need to be eval­u­at­ed in a clin­i­cal set­ting.

The cur­rent par­a­digm in phar­ma­ceu­ti­cal de­vel­op­ment is that pa­tients will get the “Old­er Gen” drugs with the af­fer­ent side ef­fects rather than the “Next Gen” ther­a­pies that could solve the is­sue, be­cause of the length, cost and com­plex­i­ty of the cur­rent reg­u­la­to­ry frame­work not al­low­ing for the im­ple­men­ta­tion of im­prove­ments in the drug de­vel­op­ment phase.

Bet­ter treat­ments, ready soon­er

While rapid, re­spon­sive ver­sion­ing is the norm in oth­er in­dus­tries, like soft­ware, com­put­er or rock­et sci­ence de­vel­op­ment, the ob­vi­ous dif­fer­ence in the phar­ma­ceu­ti­cal sec­tor is that there are dis­tinct eth­i­cal and safe­ty con­cerns in con­duct­ing re­spon­sive ver­sion­ing in tri­als on hu­man be­ings; the safe­ty of pa­tients in clin­i­cal tri­als is para­mount. That be­ing said, what if we could ex­pe­dite the process and bring in­no­va­tion to pa­tients faster with­in a fit­ted reg­u­la­to­ry frame­work?

In re­cent years, sev­er­al new clin­i­cal process­es were cre­at­ed, in­tend­ed to stream­line and ex­pe­dite drug de­vel­op­ment and clin­i­cal tri­al eval­u­a­tion. To name a few: the cre­ation of Phase 0, bas­ket, and um­brel­la clin­i­cal tri­als. Though Phase 0 tri­als seem to ad­dress the ex­pe­di­tion of the tri­als them­selves, if any changes are made with­in this phase, a full IND ap­pli­ca­tion with the usu­al three pre-ap­proval phas­es is still re­quired to “re-ver­sion” your Phase 0 tri­al. Es­sen­tial­ly, with sim­ple pro­posed mod­i­fi­ca­tions, you are be­ing asked to start from scratch, from a reg­u­la­to­ry stand­point.

When the chance for fail­ure in clin­i­cal tri­als (specif­i­cal­ly in an­ti-can­cer drug clin­i­cal tri­als) is so high (fail­ure rate is more than 90%) and when more than half of these new drug can­di­dates in on­col­o­gy fail dur­ing lat­er stages of clin­i­cal de­vel­op­ment, the path to ex­pe­dit­ing the im­ple­men­ta­tion of ver­sion­ing and re­vi­sion dur­ing ear­ly-stage tri­als is fun­da­men­tal to ad­dress pa­tients’ needs, in a time­ly man­ner.

If a mech­a­nism ex­ist­ed, by which se­ries of ver­sions of a prod­uct line could be test­ed, then adapt it or tune it up, ac­cord­ing to the re­sponse ob­served in clin­i­cal tri­als, pa­tients would have ac­cess to in­no­va­tion faster and the mod­ern med­i­cine will progress fur­ther at a quick pace. Of course, pre­clin­i­cal proof of con­cept re­quire­ments and CMC must be part of the reg­u­la­to­ry equa­tion, but the abil­i­ty to stream­line test­ing of var­i­ous ver­sions of a ther­a­peu­tic con­cept in the clin­ic could trig­ger a huge de­vel­op­men­tal ac­cel­er­a­tion to the ben­e­fit of pa­tients.

The pro­pos­al would be to open a new era in drug de­vel­op­ment and adapt the reg­u­la­to­ry en­vi­ron­ment to the speed of in­no­va­tion and its op­por­tu­ni­ties in the in­ter­est of pa­tients. The cur­rent reg­u­la­to­ry frame­work and IND process (In­ves­ti­ga­tion­al New Drug) seems set in stone for a sin­gle prod­uct de­vel­op­ment.

What if dif­fer­ent ver­sions of a prod­uct can­di­date could en­ter in clin­i­cal de­vel­op­ment phase un­der the same In­ves­ti­ga­tion­al New Ther­a­py (INT) num­ber? In this INT, and un­der an ini­tial um­brel­la Core Pro­to­col (with­out mak­ing any short­cuts on prod­uct can­di­dates man­u­fac­tur­ing, qual­i­ty and con­trol or pre­clin­i­cal as­sess­ment of any of the ver­sions of the ther­a­py), in­cre­men­tal ver­sions of the prod­uct can­di­date could en­ter in small clin­i­cal co­horts. Once there is a sign of mean­ing­ful ef­fi­ca­cy and good safe­ty pro­file on one of the ver­sions, then this ver­sion of prod­uct can­di­date would be pushed in­to ex­pan­sion and piv­otal tri­al tar­get­ing a reg­is­tra­tion. In ju­ris­dic­tion with­out the IND con­cept, the pro­posed Core Pro­to­col will be as­so­ci­at­ed with a Core Prod­uct Dossier hold­ing the re­quired in­for­ma­tion for each of the prod­uct can­di­date ver­sions.

The goal of this process would be to get away from the track to get on­to a larg­er road, with bound­aries, where nim­ble­ness is al­lowed to adapt the right ver­sion be­fore mov­ing to com­mer­cial­iza­tion. This would be in the best in­ter­est of pa­tients to get the lat­est ther­a­py faster in a safe set­ting.

An­dré Chouli­ka is a vi­rol­o­gist and a biotech­nol­o­gist. He is the founder & CEO of Cel­lec­tis, a biotech­nol­o­gy com­pa­ny. He is al­so one of the in­ven­tors of nu­cle­ase-based genome edit­ing in the 90s.

Biotech Voic­es is a con­tributed col­umn from se­lect End­points News read­ers. Read pre­vi­ous pieces here. To in­quire about sub­mis­sions, con­tact Kyle Blanken­ship at kyle@end­pointsnews.com.

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