Turn­ing the cor­ner on treat­ing the root cause of sick­le cell dis­ease

Ear­ly in my ca­reer, as a med­ical res­i­dent, I saw first-hand the enor­mous chal­lenges faced by chil­dren and adults with sick­le cell dis­ease (SCD), a ge­net­ic blood dis­or­der that his­tor­i­cal­ly has lacked ad­e­quate treat­ment op­tions. Peo­ple liv­ing with this life-long dis­ease are main­ly those with an­ces­tors from sub-Sa­ha­ran Africa, as well as peo­ple of His­pan­ic, South Asian, South­ern Eu­ro­pean and Mid­dle East­ern de­scent. These pa­tients suf­fer from dev­as­tat­ing phys­i­cal symp­toms, in­clud­ing pro­gres­sive, even­tu­al­ly fa­tal, or­gan dam­age and ex­cru­ci­at­ing pain. In ad­di­tion, they en­counter emo­tion­al, men­tal and so­cial bur­dens – non-phys­i­cal as­pects of liv­ing with SCD that al­so take a se­ri­ous toll on pa­tients and their care­givers.

As a young clin­i­cian, I was of­ten dis­ap­point­ed, an­gry and even ashamed at how these pa­tients were treat­ed. In­deed, for a long time, SCD has been a se­vere­ly ne­glect­ed dis­ease, but re­cent­ly we have turned a cor­ner in the form of im­por­tant in­no­va­tions that are chang­ing how peo­ple with SCD are cared for, giv­ing the SCD com­mu­ni­ty hope for the fu­ture.

In the more than 100 years since physi­cians be­gan rec­og­niz­ing SCD as a dis­tinct dis­ease, the care of those af­fect­ed pro­gressed at a snail’s pace. For most of this time, physi­cians were lim­it­ed to man­ag­ing pain and try­ing to make their pa­tients as com­fort­able as pos­si­ble. In the 1950s and 1960s, a num­ber of dis­cov­er­ies deep­ened our un­der­stand­ing of this in­her­it­ed dis­or­der. Most no­tably, sci­en­tists dis­cov­ered that the root cause of SCD is the poly­mer­iza­tion of he­mo­glo­bin, the pro­tein in red blood cells that trans­ports oxy­gen to cells and or­gans. This mol­e­c­u­lar process caus­es red cells to be­come de­formed and take on the sick­le shape that is char­ac­ter­is­tic of the dis­ease. Poly­mer­iza­tion ul­ti­mate­ly re­sults in he­mol­y­sis (the de­struc­tion of red blood cells) and ane­mia, which in turn sets off a cas­cade of events that can lead to long-term and dev­as­tat­ing con­se­quences, in­clud­ing mul­ti-or­gan fail­ure, stroke and ear­ly death.

De­spite this fun­da­men­tal in­sight about the mol­e­c­u­lar dri­ver of SCD, there was a glar­ing lack of in­no­va­tion and ini­tia­tive by the bio­phar­ma­ceu­ti­cal in­dus­try and acad­e­mia to ap­ply this dis­cov­ery to the de­vel­op­ment of new treat­ments, as il­lus­trat­ed by the very few med­i­cines for SCD ap­proved by the FDA over the past few decades. Much of the fo­cus con­tin­ued to be on treat­ing the symp­toms and com­pli­ca­tions of the dis­ease – sim­i­lar to what we saw in the ear­ly days of HIV/AIDS. How­ev­er, in the last decade, we be­gan to see a re­newed in­ter­est in SCD. A shift oc­curred to­ward de­vel­op­ing treat­ments that are tru­ly dis­ease-mod­i­fy­ing. The FDA has kept pace with this trend by chang­ing how it eval­u­ates clin­i­cal tri­al re­sults and ap­proves in­no­v­a­tive med­i­cines, so com­pa­nies can get them to pa­tients in need faster.

At Glob­al Blood Ther­a­peu­tics (GBT), our fo­cus from the start has been on sick­le he­mo­glo­bin poly­mer­iza­tion, the root cause of the dis­ease. Low he­mo­glo­bin is a key mark­er and risk pre­dic­tor that has been es­tab­lished in the lit­er­a­ture as play­ing a crit­i­cal role in clin­i­cal out­comes for in­di­vid­u­als with SCDᶦ, much like how vi­ral load is a key mark­er used to eval­u­ate how well peo­ple with HIV are re­spond­ing to an­ti-vi­ral treat­ment. Con­cen­trat­ing on this oxy­gen-car­ry­ing mol­e­cule, GBT re­searchers looked be­yond symp­toms to the un­der­ly­ing bi­ol­o­gy of SCD. We specif­i­cal­ly en­gi­neered a mol­e­cule to ad­dress the sci­en­tif­ic chal­lenges posed by SCD.

To­day, peo­ple with SCD are fi­nal­ly ben­e­fit­ing from the in­no­va­tion of dis­ease-mod­i­fy­ing treat­ments. Re­cent­ly, the FDA ap­proved our med­i­cine, Oxbry­ta™ (vox­elo­tor) tablets, for the treat­ment of SCD in adults and chil­dren 12 years of age and old­er. Oxbry­ta is the first FDA-ap­proved med­i­cine that specif­i­cal­ly tar­gets the root cause of SCD by di­rect­ly in­hibit­ing the poly­mer­iza­tion of he­mo­glo­bin. It works by se­lec­tive­ly en­ter­ing red blood cells and bind­ing to he­mo­glo­bin, re­sult­ing in an in­crease in the affin­i­ty of he­mo­glo­bin for oxy­gen. This sta­bi­lizes the red blood cells in an oxy­genat­ed state, pre­vent­ing poly­mer­iza­tion and the re­sul­tant sick­ling and de­struc­tion of red blood cells. The reg­u­la­to­ry ap­proval of Oxbry­ta would not have been pos­si­ble with­out the stead­fast ded­i­ca­tion and com­mit­ment to col­lab­o­ra­tion from the med­ical, sci­en­tif­ic and SCD com­mu­ni­ties, as well as the FDA.

Oxbry­ta marks a new phase in the evo­lu­tion of care for peo­ple with SCD. While pain is of­ten as­sumed to be the most com­mon symp­tom of SCD, the man­i­fes­ta­tions of this dis­ease vary great­ly from per­son to per­son. In fact, about half of all peo­ple with SCD do not ex­pe­ri­ence pain crises at all.ᶦᶦ The uni­ver­sal com­mon­al­i­ty among in­di­vid­u­als with SCD is that they suf­fer from he­mo­glo­bin poly­mer­iza­tion. By stop­ping this mol­e­c­u­lar process where it starts, we have the po­ten­tial to mean­ing­ful­ly mod­i­fy the course of this se­ri­ous dis­ease rather than just ad­dress the symp­toms.

The re­cent trans­for­ma­tion in how we ap­proach SCD treat­ment – with two re­cent FDA ap­provals of SCD med­i­cines and on­go­ing re­search pro­grams by GBT and oth­er com­pa­nies – rep­re­sents a true par­a­digm shift and makes me more op­ti­mistic than ever about the fu­ture for the SCD com­mu­ni­ty.

Full Pre­scrib­ing In­for­ma­tion for Oxbry­ta is avail­able here.

ᶦ Ata­ga KI, et al. Blood. 2018;132:12.
ᶦᶦ Shah N., et al. Sick­le Cell Dis­ease Com­pli­ca­tions: Preva­lence and Re­source Uti­liza­tion. Plos One. 2019. Jul 5;14(7):e0214355.