Next-gen ther­a­pies are evolv­ing fast. The drug de­vel­op­ment mod­el needs to keep up

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 senior editors Kyle Blankenship and 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.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

Covid-19 vac­cine boost­ers earn big thumbs up, but Mod­er­na draws ire over world sup­ply; What's next for Mer­ck’s Covid pill?; The C-suite view on biotech; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

You may remember that at the beginning of this year, Endpoints News set a goal to go broader and deeper. We are still working towards that, and are excited to share that Beth Snyder Bulik will be joining us on Monday to cover all things pharma marketing. You can sign up for her weekly Endpoints MarketingRx newsletter in your reader profile.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 119,700+ biopharma pros reading Endpoints daily — and it's free.

No­var­tis de­vel­op­ment chief John Tsai: 'We go deep in the new plat­form­s'

During our recent European Biopharma Summit, I talked with Novartis development chief John Tsai about his experiences over the 3-plus years he’s been at the pharma giant. You can read the transcript below or listen to the exchange in the link above.

John Carroll: I followed your career for quite some time. You’ve had more than 20 years in big pharma R&D and you’ve obviously seen quite a lot. I really was curious about what it was like for you three and a half years ago when you took over as R&D chief at Novartis. Obviously a big move, a lot of changes. You went to work for the former R&D chief of Novartis, Vas Narasimhan, who had his own track record there. So what was the biggest adjustment when you went into this position?

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Roche's Tecen­triq cross­es the fin­ish line first in ad­ju­vant lung can­cer, po­ten­tial­ly kick­ing off gold rush

While falling behind the biggest PD-(L)1 drugs in terms of sales, Roche has looked to carve out a space for its Tecentriq with a growing expertise in lung cancer. The drug will now take an early lead in the sought-after adjuvant setting — but competitors are on the way.

The FDA on Friday approved Tecentriq as an adjuvant therapy for patients with Stage II-IIIA non small cell lung cancer with PD-(L)1 scores greater than or equal to 1, making it the first drug of its kind approved in an early setting that covers around 40% of all NSCLC patients.

Amit Etkin, Alto Neuroscience CEO (Alto via Vimeo)

A star Stan­ford pro­fes­sor leaves his lab for a start­up out to re­make psy­chi­a­try

About five years ago, Amit Etkin had a breakthrough.

The Stanford neurologist, a soft-spoken demi-prodigy who became a professor while still a resident, had been obsessed for a decade with how to better define psychiatric disorders. Drugs for depression or bipolar disorder didn’t work for many patients with the conditions, and he suspected the reason was how traditional diagnoses didn’t actually get at the heart of what was going on in a patient’s brain.

Susan Galbraith, Executive VP, Oncology R&D, AstraZeneca

As­traZeneca on­col­o­gy R&D chief Su­san Gal­braith: 'Y­ou're go­ing to need or­thog­o­nal com­bi­na­tion­s'

 

Earlier in the week we broadcast our 4th annual European Biopharma Summit with a great lineup of top execs. One of the one-on-one conversations I set up was with Susan Galbraith, the oncology research chief at AstraZeneca. In a wide-ranging discussion, Galbraith reviewed the cancer drug pipeline and key trends influencing development work at the pharma giant. You can watch the video, above, or stick with the script below. — JC

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Tillman Gerngross, Adagio CEO

Q&A: Till­man Gern­gross ex­plains why his Covid mAb will have an edge over an al­ready crowd­ed field

If anyone knows about monoclonal antibodies, it’s serial entrepreneur, Adimab CEO, and Dartmouth professor of bioengineering Tillman Gerngross.

Even the name of Gerngross’ new antibody startup Adagio Therapeutics is meant to reflect his vision behind the development of his Covid-19 mAb: slowly, he said, explaining that “everyone else, whether it’s Regeneron, Lilly, or AstraZeneca, Vir, they all valued speed over everything.”

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Susan Galbraith speaking at Endpoints News' virtual EUBIO21 summit

Imfinzi/treme­li­mum­ab com­bo scores As­traZeneca an­oth­er OS win — this time in liv­er can­cer

Is the tide turning on AstraZeneca’s battered PD-L1/CTLA4 combo?

A single priming dose of the experimental tremelimumab, followed by Imfinzi every four weeks, beat Nexavar (sorafenib) in helping a group of liver cancer patients live longer in a Phase III study, the company reported, meeting the primary endpoint.

Specifically, the two drugs extended overall survival for patients with unresectable hepatocellular carcinoma who had not received prior systemic therapy and were not eligible for localized treatment.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 119,700+ biopharma pros reading Endpoints daily — and it's free.

FDA's vac­cine ad­comm unan­i­mous­ly sup­ports Mod­er­na's boost­er in same pop­u­la­tions as Pfiz­er's boost­er

The FDA’s vaccine advisory committee on Thursday voted 19-0 in support of expanding Moderna’s Covid-19 vaccine EUA for booster doses for certain high-risk individuals. FDA is expected to authorize the Moderna booster shortly.

Similarly to the Pfizer booster shot, Moderna’s will likely be authorized for those older than 65, adults at high risk of severe Covid-19, and adults whose frequent institutional or occupational exposure to SARS-CoV-2 puts them at high risk of serious complications of Covid-19. But unlike the Pfizer adcomm, where FDA had to scramble to get the committee to vote in favor of a booster, this committee was unanimous with the Moderna shot.