Seeing past the impossible

In an era when devel­op­ing a med­i­cine takes an aver­age £1.2 bil­lion over 12 years, tak­ing on inno­v­a­tive projects could seem a risky strat­e­gy. But chief sci­en­tif­ic offi­cer Dr David Alt­shuler explains how the Ver­tex strat­e­gy has allowed the com­pa­ny to forge a string of inno­v­a­tive suc­cess­es, includ­ing break­through treat­ments for cys­tic fibro­sis (CF). The lead­ing geneti­cist and pio­neer of human genome projects tells how the com­pa­ny, which has a research lab­o­ra­to­ry in Oxford, is tack­ling seri­ous dis­eases with unmet needs and seem­ing­ly intractable com­plex­i­ties.

What is Vertex’s approach to developing therapies?

We believe the great­est val­ue to soci­ety, patients and oth­er stake­hold­ers is to dis­cov­er and devel­op new med­i­cines that trans­form the lives of peo­ple with seri­ous dis­eases. That is our true north. We are not look­ing to make incre­men­tal advances or to treat down­stream symp­toms; we want to strike at the heart of dis­ease.

How does Vertex decide which disease conditions to research?

We start with a laser-like focus on seri­ous dis­eases for which there is no trans­for­ma­tive ther­a­py. Next, we look for a deep insight into the human causal dis­ease biol­o­gy, com­pelling evi­dence about the root cause in peo­ple, not just in the lab­o­ra­to­ry or in a fruit fly. We look for break­throughs in the sci­ence of ther­a­peu­tics. In many of the dis­eases we’re work­ing in, there may not have been exist­ing tools or approach­es to treat­ing the under­ly­ing cause of dis­ease, and our sci­en­tists have had to invent or part­ner to bring new process­es, tech­niques and ther­a­peu­tic strate­gies.

Isn’t that a risky starting point?

Actu­al­ly, we believe that a strat­e­gy focused on under­stand­ing the human causal biol­o­gy is more like­ly to result in break­throughs for patients. Take CF as an exam­ple. Thir­ty years ago, the cause of the dis­ease was iden­ti­fied as a muta­tion in a gene that is respon­si­ble for trans­port­ing chlo­ride, effec­tive­ly salt, across cell mem­branes. The need was clear, but there was no exist­ing tech­nol­o­gy to restore chlo­ride trans­port. So oth­ers focused on treat­ing infec­tions down­stream or to thin the mucus. These efforts helped patients and deserve praise but, cru­cial­ly, did not address the under­ly­ing cause. Ver­tex sci­en­tists said ‘well, we may be able to cre­ate a new type of med­i­cine that can restore the func­tion of the mutant pro­tein’. And, amaz­ing­ly, they were able to suc­ceed in that goal.

How did that work in CF?

As back­ground, the major­i­ty of oral med­i­cines act by block­ing the activ­i­ty of the tar­get. But with CF our sci­en­tists had the unprece­dent­ed idea to cre­ate a med­i­cine that acts on a mutant pro­tein to coax it to work more nor­mal­ly. It was unclear how to do this, but over 20 years of work that is exact­ly what they achieved.

How does that differ from other approaches?

Many com­pa­nies use what’s called a shots-on-goal approach. That is they try many dif­fer­ent approach­es based on lab­o­ra­to­ry mod­els, hop­ing one of them will help patients. Our view is to focus our resources and inno­va­tion on those rel­a­tive­ly few out­stand­ing sci­en­tif­ic oppor­tu­ni­ties where all the pieces line up: a seri­ous dis­ease with lim­it­ed treat­ment options, a deep insight into human biol­o­gy and the right bio­mark­ers, and a new ther­a­peu­tic approach.  We believe these oppor­tu­ni­ties deserve more atten­tion because that’s where we can make the great­est impact for patients right now.

Can you give a concrete example?

Because we select tar­gets that are well val­i­dat­ed, our clin­i­cal devel­op­ment strat­e­gy is to bring mul­ti­ple ther­a­peu­tic can­di­dates into the clin­ic and inves­ti­gate them in par­al­lel. By study­ing mul­ti­ple can­di­date med­i­cines at the same time, we can mit­i­gate risk of com­pound-spe­cif­ic fail­ures and this enables us to select the best pos­si­ble can­di­date based on patient data rather than lab­o­ra­to­ry data alone. In this way, the com­pound select­ed to advance into large, phase-III tri­als is intend­ed to have the best pro­file we can achieve. This approach requires con­vic­tion on the tar­get and greater upfront invest­ment, but enables more rapid progress and low­er risk of expen­sive late-stage fail­ure, all with the goal of bring­ing the best med­i­cines to patients as quick­ly and safe­ly as pos­si­ble.

What is in the Vertex pipeline?

We are pur­su­ing a num­ber of excit­ing projects that fit our strat­e­gy, includ­ing research for patients with sick­le cell dis­ease, beta tha­lassemia, type‑1 dia­betes and alpha 1 antit­rypsin defi­cien­cy dis­ease. We’ve assem­bled a robust toolk­it of tech­nolo­gies and capa­bil­i­ties, includ­ing cell and genet­ic ther­a­py plat­forms that will allow us to direct­ly address these dis­eases from mul­ti­ple angles. We are con­fi­dent our strat­e­gy has great promise for patients and, if we are able to help patients, every­thing else will fol­low.

What is the role of patient advocacy groups in your R&D strategy?

Appro­pri­ate engage­ment with patient organ­i­sa­tions is key to help us under­stand the lives and dai­ly expe­ri­ences of the peo­ple they rep­re­sent. Patient com­mu­ni­ties have insights that are cru­cial to inform the devel­op­ment of a med­i­cine, at all stages of the process. A good exam­ple of this is work­ing with patient groups to con­tin­u­al­ly improve the way we run clin­i­cal tri­als; patient-cen­tric clin­i­cal tri­als will ulti­mate­ly enhance the effec­tive­ness and speed of drug dis­cov­ery. In the case of CF, it has helped devel­op the first med­i­cine to treat the under­ly­ing cause of CF and we aim to fol­low this approach in all the dis­eases whether it is sick­le cell dis­ease, beta tha­lassemia, alpha 1 antit­rypsin defi­cien­cy dis­ease or oth­ers.

How important is R&D to Vertex successes?

Our strat­e­gy is to invest in sci­en­tif­ic inno­va­tions that break open or cre­ate new pos­si­bil­i­ties to treat seri­ous dis­eases. And we put our mon­ey where our mouth is: we spend more than 70 per cent of our oper­at­ing expens­es on research and devel­op­ment (R&D) and three out of five Ver­tex employ­ees are ded­i­cat­ed to R&D.

What does the pursuit of COVID-19 vaccines say about the biopharmaceutical industry?

The progress towards a vac­cine has been astound­ing and makes you very proud of every­one involved: com­pa­nies, aca­d­e­m­ic sci­en­tists and doc­tors, the reg­u­la­tors and gov­ern­ments. Because of advances in genomics and ther­a­peu­tics, the under­ly­ing cause of COVID was dis­cov­ered in weeks instead of years, and mul­ti­ple ther­a­peu­tics and vac­cines have been advanced all with­in 2020. This expe­ri­ence reminds us that when we tack­le seri­ous dis­eases with urgency, focus and col­lab­o­ra­tion, we can move for­ward in a man­ner that pre­vi­ous­ly would have been seen as impos­si­ble.

For more infor­ma­tion please vis­it vrtxpharma.co.uk

Date of Prep: Novem­ber 2020    UK-00–2000014

Pro­mot­ed by Ver­tex