With two can­cer drugs on the mar­ket, the spot­light is on Agios’ rare meta­bol­ic dis­ease fran­chise led by mi­tapi­vat, its ex­per­i­men­tal drug un­der de­vel­op­ment for a range of con­di­tions in­clud­ing pyru­vate ki­nase de­fi­cien­cy, tha­lassemia, and sick­le cell dis­ease.

At the Eu­ro­pean Hema­tol­ogy As­so­ci­a­tion An­nu­al Con­gress (EHA), the com­pa­ny is­sued two up­dates on the ef­fect of mi­tapi­vat — a drug de­signed to tar­get pyru­vate ki­nase-R (PKR), an en­zyme in­volved in the con­ver­sion of sug­ar, or glu­cose, in­to en­er­gy that is crit­i­cal for the sur­vival of red blood cells.

The first up­date came from an on­go­ing mid-stage study test­ing the drug in two forms of tha­lassemia, an in­her­it­ed blood dis­or­der. In the study, 12 out of 13 pa­tients saw sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ments in he­mo­glo­bin con­cen­tra­tion, set­ting the stage for a piv­otal tri­al next year.

The tri­al, which has so far en­rolled 20 pa­tients, is eval­u­at­ing the ef­fect of the drug in more mod­er­ate forms of the dis­ease, in pa­tients that are not de­pen­dent on blood trans­fu­sions. Pa­tients start­ed on a low­er 50 gm dose and then were grad­u­al­ly giv­en the high­er 100 mg dose.

Tha­lassemia, caused by mu­ta­tions al­pha or be­ta glo­bin genes, is char­ac­ter­ized by ei­ther no or too lit­tle he­mo­glo­bin — the pro­tein that trans­ports oxy­gen in red blood cells. Pa­tients can ex­pe­ri­ence a range of symp­toms such as ane­mia, weak­ness, frag­ile bones and di­min­ished fer­til­i­ty.

The main goal of  ≥ 1.0 g/dL in­crease in Hb con­cen­tra­tion was met by about 92% of the 13 pa­tients ready for eval­u­a­tion fol­low­ing 12 weeks of treat­ment — the mean change from base­line for the evalu­able pa­tients was 1.34 g/dL over weeks 4-12. Oth­er mark­ers of red blood cell func­tion and per­for­mance al­so fa­vored the drug.

Ac­celeron’s Re­blozyl, which is en­gi­neered to work by tar­get­ing a pro­tein nec­es­sary to en­hance the pro­duc­tion and mat­u­ra­tion of red blood cells, was ap­proved last year for more se­vere be­ta-tha­lassemia pa­tients who are trans­fu­sion-de­pen­dent. Mean­while, blue­bird bio, has an eye-pop­ping­ly ex­pen­sive gene ther­a­py to com­bat the dis­ease ap­proved in Eu­rope, and is aim­ing for a US nod.

Jack­ie Fouse

Akin to blue­bird, whose gene ther­a­py is al­so primed for use in sick­le cell dis­ease, Jack­ie Fouse-led Agios is al­so test­ing mi­tapi­vat in the blood dis­or­der that is char­ac­ter­ized by atyp­i­cal he­mo­glo­bin mol­e­cules, which can dis­tort red blood cells in­to a sick­le, or cres­cent, shape.

Ear­ly da­ta from an on­go­ing phase I SCD tri­al test­ing mul­ti­ple mi­tapi­vat dos­es (5 mg, 20 mg, 50 mg) showed the com­pa­ny had en­rolled 9 pa­tients till date — each got the drug for two weeks, be­fore be­ing ta­pered off. One pa­tient dis­con­tin­ued the tri­al due to a pre-ex­ist­ing con­di­tion, but the re­main­ing 8 were eval­u­at­ed.

Five out of 8 pa­tients achieved the main goal of en­hanc­ing he­mo­glo­bin lev­els by  ≥1.0 g/dL from base­line. Da­ta showed the use of the drug was as­so­ci­at­ed with de­creas­es in he­molyt­ic mark­ers.

Un­til re­cent­ly, the treat­ment land­scape for the dis­ease was bar­ren, but the last few years have seen a tri­fec­ta of ap­provals. Most re­cent­ly, last No­vem­ber saw two ap­provals: No­var­tis’ ther­a­py, Adakveo, de­signed to pre­vent pe­ri­od­ic episodes of sear­ing pain called va­so-oc­clu­sive crises (VOCs) that de­prive the body of oxy­gen-rich blood and Glob­al Blood Ther­a­peu­tics’ Oxbry­ta, which works by in­creas­ing he­mo­glo­bin’s affin­i­ty for oxy­gen. Mi­tapi­vat is ex­pect­ed to work in SCD by de­creas­ing a salt in red blood cells that plays a role in lib­er­at­ing oxy­gen from he­mo­glo­bin in pe­riph­er­al cir­cu­la­tion and en­hanc­ing lev­els of a cen­tral metabo­lite called adeno­sine triphos­phate (ATP).

Agios al­so has two piv­otal stud­ies test­ing mi­tapi­vat in pyru­vate ki­nase de­fi­cien­cy, a rare in­her­it­ed dis­ease that is char­ac­ter­ized by the ac­cel­er­at­ed de­struc­tion of red blood cells. Da­ta from these tri­als are ex­pect­ed lat­er this year or ear­ly 2021.

Sep­a­rate­ly on Fri­day, Agios said it was re­lin­quish­ing its roy­al­ty rights on glob­al net sales of Bris­tol My­ers Squibb’s Id­hi­fa, as as its rights to re­ceive up to $55 mil­lion in out­stand­ing reg­u­la­to­ry mile­stone pay­ments from Bris­tol My­ers Squibb, to Roy­al­ty Phar­ma for $255 mil­lion.

The drug, al­lied with Cel­gene (now a Bris­tol My­ers com­pa­ny), was ap­proved in 2017 for use in acute myeloid leukemia.

Following a promise last year to go “big and fast in breast cancer,” Gilead has secured a win for Trodelvy in the most common form.

The drug was approved to treat HR-positive, HER2-negative breast cancer patients who’ve already received endocrine-based therapy and at least two other systemic therapies for metastatic cancer, Gilead announced on Friday.

Trodelvy won its first indication in metastatic triple-negative breast cancer back in 2020, and has since added urothelial cancer to the list. HR-positive HER2-negative breast cancer accounts for roughly 70% of new breast cancer cases worldwide per year, according to senior VP of oncology clinical development Bill Grossman, and many patients develop resistance to endocrine-based therapies or worsen on chemotherapy.