Takeda Maribavir Tau Txais Kev Ntsuam Xyuas Thib Kev Los Ntawm US FDA

Takeda Pharmaceuticals (Takeda) tsis ntev los no tshaj tawm tias Tsoom Fwv Asmeskas Khoom Noj thiab Tshuaj (FDA) tau lees txais daim ntawv thov tshuaj tshiab (NDA) rau cov tshuaj tua kab mob tshuaj tua kab mob maribavir (TAK-620) thiab tau tso cai kuaj xyuas qhov muaj feem thib, uas tau siv rau hauv cov khoom hloov pauv (SOT) )). Lossis hematopoietic cell hloov (HCT) cov neeg tau txais kev kho mob refractory, nrog lossis tsis muaj tshuaj tiv thaiv (R / R) cytomegalovirus (CMV) kev kis mob. Yog tias tau txais kev pom zoo, maribavir yuav yog thawj zaug thiab tsuas yog siv yeeb tshuaj hauv cov neeg hloov pauv kom kho R / R CMV tom qab hloov ntshav.

CMV yog tus kabmob DNA ntawm pes herpesvirus subfamily, muaj lub siab hom tsiaj tshwj xeeb. Tib neeg tsuas yog tus tswv tsev qub ntawm tib neeg cytomegalovirus (HCMV). CMV yog ib tus mob khaub thuas kis tau rau txhua tus neeg. Thaum muaj hnub nyoog 40, ntau dua ib nrab ntawm cov neeg laus tau kis tus mob CMV, thiab feem ntau tsis muaj tsos mob lossis tsis muaj tsos mob dab tsi. Txawm li cas los xij, hauv cov neeg uas muaj kev tiv thaiv kab mob tsis muaj zog (suav nrog cov hloov khoom hauv nruab nrog cev lossis qia neeg hauv hlwb), kev kis tus kab mob CMV yog ib qho kev mob hnyav heev uas yuav ua rau cov nqaij mos ua rau mob thiab thaum kawg ua rau tuag. Cov kev siv tshuaj tua kab mob uas twb muaj lawm tuaj yeem siv los kho CMV, tab sis cov tshuaj no yuav raug txwv nyob rau hauv lawv daim ntawv thov vim muaj kev phiv thiab / lossis tshuaj tiv thaiv.

Maribavir yog lub cev qhov ncauj tawm tsam tiv thaiv cytomegalovirus (CMV). Tam sim no nws tsuas yog ib qho nyob rau theem 3 kev kho mob txoj kev kho mob, siv hauv kev hloov khoom nruab nrog cev (SOT) lossis hematopoietic cell transplantation (HCT) rau kev kho mob tom qab hloov tshuaj Antiviral rau cov neeg mob uas muaj CMV / kab mob. Maribavir yog tib lub CMV tshuaj tua kabmob uas ua rau lub hom phiaj thiab inhibits UL97 protein kinase thiab nws lub cev ntuj. Kev tswj hwm CMV tam sim no muaj feem cuam tshuam rau kev lag luam nyuaj, suav nrog kev tswj tshuaj lom thiab tshem tawm viremia. Yog tias pom zoo, maribavir yuav muaj lub peev xwm rov qab kho qhov ua haujlwm ntawm refractory CMV tom qab hloov chaw, tsis hais qhov tawm tsam.

maribavir NDA yog ua raws cov piv rau Theem 3 TAK-620-303 (SOLSTICE, NCT02931539) cov kev sim, cov ntsiab lus tseem ceeb uas tau tshaj tawm ntawm Kev Hloov Chaw thiab Kev Kho Mob Cell (TCT) Lub Rooj Sib Tham 2021 thaum Lub Ob Hlis Ntuj xyoo no, thiab cov ntsiab lus tshuaj ntsuam xyuas tau luam tawm thaum Lub Peb Hlis Ntuj xyoo no hauv 2021. Tshaj tawm ntawm 47th Lub Rooj Sib Tham Txhua Xyoo ntawm European Society Kev Hloov Ntshav thiab Hloov Ntshav (EBMT). Cov txiaj ntsig tseem ceeb qhia tau hais tias maribavir muaj kev ua tau zoo dua piv nrog cov kev siv tshuaj tiv thaiv kev kho mob (IAT), kom mus txog lub hauv paus thiab qhov tseem ceeb kawg ntawm kev kawm. Tsis tas li ntawd, maribavir muaj kev kho mob qis dua-mob toxicity piv nrog cov tshuaj tua kab mob ua kom zoo. Cov txiaj ntsig ntawm pawg neeg tau soj ntsuam txhawb qhov ua tau zoo ntawm tag nrho cov tib neeg.

Obi Umeh, MD, tus lwm thawj coj ntawm Takeda thiab tus thawj coj ntawm maribavir txoj haujlwm thoob ntiaj teb, tau hais tias: "CMV yog ib qho kev muaj feem muaj cov kab mob kis rau cov neeg hloov ntshav. Tam sim no, cov kev xaiv ntawm kev siv tshuaj tua kab mob muaj tsawg. Cov kws kho mob yuav tsum ceev faj ntawm kev tshem tawm tus kab mob thiab kev tswj hwm thaum noj tshuaj. Tshuav nyiaj li cas, uas yuav cuam tshuam kev saib xyuas neeg mob thiab kev hloov chaw. Kev lees txais FDA ntawm NDA yog lub sijhawm tseem ceeb rau cov phiaj xwm maribavir txav mus rau tom ntej. Yog tias tau txais kev pom zoo, maribavir muaj peev xwm hloov qhov hloov kho tom qab CMV kev kho mob tom qab."

maribavir qauv tsim qauv

Txoj kev kawm TAK-620-303 yog nqa tawm hauv cov neeg hloov chaw ntawm refractory, nrog lossis tsis muaj tshuaj tiv thaiv (R / R) cytomegalovirus (CMV) kev kis mob / kab mob, thiab cov tshuaj tiv thaiv kev tiv thaiv tshuaj TAK-620 (maribavir) yuav raug soj ntsuam. ) Thiab cov tshuaj tiv thaiv kev siv tshuaj (cov kev kho mob tsim los ntawm tus neeg tshawb xyuas [IAT], ib qho sib xyaw ntawm ib lossis ntau ntawm cov tshuaj hauv qab no: ganciclovir [ganciclovir], valganciclovir [valganciclovir], foscarnet [foscarnet], thaj chaw sab hnub poob Dofovir [cidofovir]) tau muab coj los sib piv. Cov. Thawj qhov kawg ntawm txoj kev tshawb no yog CMV viremia clearance tus nqi paub tseeb thaum 8 lub lim tiam ntawm kev kho mob (kev kho lub sijhawm kawg), thiab qhov tseem ceeb kawg ntawm qhov kawg yog qhov CMV tshem tawm tus nqi thiab cov tsos mob tswj kom 16 lub lis piam.

Cov txiaj ntsig ntawm txoj kev tshawb fawb los ntawm tag nrho cov kev sim ntawm cov pej xeem pom tias maribavir zoo dua li cov tshuaj tiv thaiv kab mob siab tshaj plaws nyob rau hauv cov nqe lus ntawm CMV viremia tshem tawm tus nqi ntawm 8 lub lim tiam ntawm txoj kev tshawb no. Tshwj xeeb: hauv yim lub lim tiam ntawm txoj kev tshawb fawb, ntawm cov neeg hloov pauv uas tau txais kev kho mob los tiv thaiv, nrog lossis tsis muaj tshuaj tiv thaiv (R / R), CMV kab mob / mob kis, qhov feem ntawm cov neeg mob uas tau txais kev pom zoo tshem tawm ntawm CMV viremia, pawg kho mob maribavir (55.7%, n=131/235) yog ntau dua ob zaug kev pab pawg sib xyaw (23.9%, n=28/117) (kho qhov sib txawv [95% CI]: 32.8% [22.8-42.7]; p< 0.001="">

Cov ntaub ntawv ntawm kev hloov pawg tau qhia tias ntawm cov neeg tau txais kev hloov ntshav tau lees paub tias yog tus kabmob CMV-tiv thaiv cov kabmob ntawm qhov kev kuaj mob, qhov sib piv ntawm cov neeg mob uas tau ua tiav lees paub CMV viremia tshem tawm thaum lub lim tiam 8 ntawm txoj kev tshawb no (thaum kawg ntawm lub sijhawm kho ), kho nrog maribavir Cov pab pawg (62.8%, 76/121) tau ntau dua 3 zaug ntawm pawg pab pawg kho mob IAT (20.3%, 14/69) (kho sib txawv [95% CI]: 44.1% [31.3, 56.9]).

Hauv txoj kev tshawb fawb no, kev hloov pauv cov neeg tau txais kev kho nrog maribavir qhia pom muaj tsawg dua ntawm kev kho mob ntsig txog cov tshuaj lom neeg, uas yog cov muaj ntau hauv cov tshuaj tiv thaiv kab mob. Tshwj xeeb, kev hloov pauv cov neeg tau txais kev kho nrog maribavir muaj tsawg dua qhov kev kho mob ntsig txog neutropenia piv nrog kev hloov pauv cov neeg tau txais kev kho nrog valganciclovir / ganciclovir (1.7% [4/234] vs 25% [14/56]), piv nrog cov neeg tau txais kev hloov pauv foscarnet , qhov tshwm sim ntawm kev kho mob ntsig txog lub raum mob qis dua (1.7% [4/234] vs 19.1 [9/47]). Qhov tshwm sim ntawm qhov tshwm sim tsis zoo (TEAE) thaum txhua qib ntawm kev kho mob hauv cov pawg maribavir thiab pawg kho mob sib xws yog 97.4% (228/234) thiab 91.4% (106/116), feem. Cov feem ntau TEAEs nyob hauv pawg maribavir yog dysgeusia (35.9%, 84/234), xeev siab (8.5%, 20/234), thiab ntuav (7.7%). Qhov tshwm sim ntawm TEAEs hauv cov pab pawg maribavir thiab pawg kho mob sib txawv uas ua rau muaj kev cuam tshuam ntawm txoj kev tshawb nrhiav tshuaj muaj feem ntawm lawv yog 13.2% (31/234) thiab 31.9% (37/116). Muaj 2 tus neeg tuag vim kev kho mob ntsig txog TEAEs hnyav (1 hauv txhua pab pawg kho mob).

Cytomegalovirus (CMV) yog tus kab mob hu ua beta herpes uas feem ntau kis rau tib neeg; 40% -100% ntawm cov neeg laus muaj cov pov thawj ntawm kev kis tus kab mob yav dhau los. CMV feem ntau latent thiab asymptomatic hauv lub cev, tab sis tej zaum yuav rov qab ua haujlwm thaum txhaj tshuaj tiv thaiv kab mob. Cov tib neeg muaj lub cev tiv thaiv tsis haum yuav ua rau mob hnyav, nrog rau cov neeg mob uas tau txais cov tshuaj tiv thaiv kab mob ntsig txog hloov ntshav ntau yam mob xws li hematopoietic cell transplantation (HCT) lossis cov khoom hauv lub cev hloov chaw (SOT). Ntawm cov kwv yees li 200,000 tus neeg hloov ntshav hauv ib lub xyoos twg, CMV yog ib tus neeg kis tau tus mob tshaj plaws hauv kev hloov ntshav. Tus kwv yees tias muaj tshwm sim rau SOT hloov lwm tus neeg yog 16-56%, thiab qhov tshwm sim ntawm cov neeg txais HCT hloov pauv yog 30- 70%. Hauv cov neeg tau txais kev hloov ntshav, kev rov ua haujlwm ntawm CMV tuaj yeem ua rau muaj kev rau txim loj, nrog rau qhov ua kom ploj ntawm cov kabmob hloov, thiab hauv cov xwm txheej loj, nws tuaj yeem ua rau neeg tuag taus. Cov kev kho mob uas twb muaj lawm los kho CMV tom qab hloov tas yuav pom muaj kev phiv loj heev, yuav tsum tau txhaj tshuaj kho kom haum los yog tsis ua kom zoo txaus rau kev kis tus kab mob. Ib qho ntxiv, cov kev kho mob uas twb muaj lawm yuav xav tau lossis pw sijhawm ntev ntev vim yog kev tswj hwm.

Maribavir belongs rau ib chav kawm ntawm cov tshuaj hu ua benzimidazole nucleosides, uas tuaj yeem phiaj rau kev tiv thaiv UL97 protein kinase ntawm CMV, yog li muaj feem cuam tshuam rau ntau cov txheej txheem tseem ceeb ntawm CMV replication, suav nrog kev hloov kho DNA hloov pauv, kis kab mob ntawm lub cev, encapsidation, thiab txheej laus lub plhaub tawm. los ntawm cov nucleus ntawm lub cell mob.

Maribavir yog qhov ncauj kev siv tshuaj tua kab mob los tiv thaiv kab mob, tam sim no nyob rau theem III kev txhim kho kev kho mob, kev soj ntsuam rau hematopoietic qia cell hloov chaw (HSCT) lossis cov khoom nruab nrog cev uas muaj los ntawm CMV kev kis kab mob thiab muaj kev tawm tsam lossis tsis kam hloov rau cov qauv tam sim no CMV txoj kev kho tshuaj kho mob muaj peev xwm ntawm kev hloov pauv ( SOT) cov uas txais. Tam sim no, maribavir tsis tau pom zoo los ntawm ib lub tebchaws. Hauv Tebchaws Meskas thiab European Union, maribavir tau tso cai me nyuam ntsuag chaw tsim tshuaj (ODD) rau kev kho mob ntawm kab mob siab ntsws CMV viremia ntau nyob hauv pab pawg neeg mob siab thiab rau kev kho tus kab mob CMV hauv koob tshuaj tiv thaiv kab mob. Hauv Tebchaws Meskas, maribavir kuj tseem tau tso cai rau Kev Tsim Tshuaj Kho Mob (BTD) rau cov neeg tau txais kev hloov chaw tuaj kho cov kab mob CMV uas tiv taus lossis refractory rau cov kev kho mob dhau los. Hauv Suav teb, maribavir tau txais ntawv tso cai siv rau kev kuaj mob hauv lub Plaub Hlis 2020, thiab nws txoj kev loj hlob yog: rau kev kho mob ntawm tus mob CMV lossis kab mob.