Novartis STAMP Inhibitor Asciminib Theem III Txiaj Ntsig Zoo Pfizer Bosulif (bosutinib)!

Novartis tsis ntev los no tau tshaj tawm cov ncauj lus ntxaws ntxaws ntawm Phase III ASCEMBL txoj kev tshawb fawb txog cov tshuaj tiv thaiv tshuaj tua kab mob (ABL001) ntawm 62 ntawm Lub Rooj Sib Tham Txhua Xyoo ntawm Asmeskas Kev Noj Qab Haus Huv Hematology (ASH). Txoj kev tshawb nrhiav tau ua rau hauv Philadelphia chromosome-zoo mob myelogenous mob ntshav dawb (Ph + CML-CP) cov neeg mob uas tiv taus lossis tsis kam txais tsawg kawg yog ob lub tyrosine kinase inhibitors (TKI). Cov ntaub ntawv qhia tau hais tias txoj kev tshawb nrhiav tau mus txog qhov kawg: thaum 24 lub lim tiam ntawm kev kho mob, piv nrog Bosulif (bosutinib) kev kho mob pawg, qhov loj cov lus teb molecular (MMR) hauv pawg asciminib kho mob yuav luag ob npaug (25.5% vs 13.2% ; ob sab caj npab p=0.029). Raws li cov ntaub ntawv tshawb fawb, Novartis npaj yuav xa cov ntawv thov tshuaj tshiab rau asciminib hauv Tebchaws Meskas thiab European Union hauv thawj ib nrab xyoo 2021.

Txawm hais tias tau muaj kev txhim kho tseem ceeb hauv kev kho mob CML, ntau tus neeg mob uas tau txais ob lossis ntau dua TKI kev kho mob tsis lees paub. Piv txwv, hauv kev soj ntsuam tshawb xyuas ntawm cov neeg mob uas tsis ua tiav ob txoj kev kho mob TKI, pom tau tias nce txog 55% ntawm cov neeg mob tsis txaus siab rau kev kho mob. Tsis tas li ntawd, tus nqi tshuaj tiv thaiv kuj tseem nyob siab rau cov neeg mob kho nyob rau tom qab theem; Hauv kev kho ob-kab, tsawg kawg 60% ntawm cov neeg mob tsis tuaj yeem ua tiav MMR, thiab ntau li 56% ntawm cov neeg mob tsis ua tiav cov lus teb cytogenetic (CCyR) tsis pub dhau 2 xyoo tom qab ua raws. Vim tias muaj ob peb txoj kev kho mob sab laug, thiab tam sim no tsis muaj txoj cai kho thib peb uas tau tsim ua raws li cov txheej txheem kev kho mob, cov neeg mob ua tsis taus lossis tsis haum rau ob lossis ntau dua TKIs muaj qhov pheej hmoo ntawm kev nce qib.

Asciminib yog STAMP inhibitor, uas yav dhau los tau tso cai ceev ntawm Kev khiav ceev (FTD) los ntawm Asmeskas FDA. Cov tshuaj yog ib cov tshuaj uas tshwj xeeb lub hom phiaj myristoyl hnab tshos (STAMP) ntawm BCR-ABL1 protein, uas xauv BCR-ABL1 rau hauv kev tsis haum xeeb. Cov tshuaj sib tw uas tam sim no nyob rau hauv kev ua lag luam yog ua ke nrog ATP khi qhov chaw ntawm BCR-ABL1 protein. Asciminib ua los ntawm kev coj ntawm lwm tus kinase, ABL myristoyl hnab tshos.

Raws li STAMP inhibitor, asciminib tuaj yeem kov yeej kev hloov pauv hauv ATP qhov chaw khi ntawm BCR-ABL1, uas yuav pab daws TKI tsis kam rau kev kho tom qab CML thiab yuav daws cov phiaj xwm kev ua haujlwm, thiaj li txhim kho kev kwv yees ntawm cov neeg mob. Tam sim no, Novartis tab tom sim ua ntau qhov kev soj ntsuam los soj ntsuam asciminib rau cov neeg mob CML uas tau txais kev kho mob ntau yam, nrog rau lwm yam TKI rau kev kho cov neeg mob CML tshiab.

Dr. Michael J. Mauro, tus thawj coj ntawm Myeloproliferative Tumor Program ntawm Memorial Sloan-Kettering Cancer Center thiab tus xibfwb ntawm Weill Cornell Lub Tsev Kawm Ntawv ntawm Tshuaj, hais tias:" Cov ntaub ntawv tseem ceeb sib piv no yog qhov zoo, thiab lawv ntxiv dag zog rau asciminib' s muaj peev xwm los mus kov yeej cov kab mob mus ntev. CML tej zaum yuav ua lub luag haujlwm tseem ceeb hauv kev kho cov nyom uas tau ntsib thaum kho CML dhau los. Txawm hais tias qhov tshwm sim thiab nthuav dav ntawm TKI txoj kev kho tau ua rau muaj kev vam meej loj rau cov neeg mob CML nyob rau ob peb lub xyoo dhau los, ntau ntawm peb cov neeg mob uas tau txais kev kho mob siab tseem ntsib cov lus teb tsis muaj zog, mob mus ntxiv, thiab cov kev mob tshwm sim uas tsis tuaj yeem."

John Tsai, Tus Thawj Coj ntawm Kev Tsim Yeeb Tshuaj thiab Tus Thawj Saib Xyuas Kev Noj Qab Haus Huv ntawm Novartis Pharmaceuticals tau hais tias: "Tau ntau xyoo, Novartis tau yog qhov tseem ceeb ntawm kev tshawb fawb CML thiab tau hloov pauv qhov tseem ceeb ntawm cov neeg mob. Peb zoo siab heev uas tuaj yeem teb rau cov uas tsis tau teb sai sai rau TKIs tam sim no. Los yog intolerant cov neeg mob tau tsim cov tshuaj hloov pauv uas yuav hloov tau: ib hom tshuaj STAMP inhibitor tshiab. Muaj ntau qhov tsis xav tau kev kho mob uas yuav tsum tau ua nyob rau tom qab CML-temperament. Raws li cov txiaj ntsig no, peb ntseeg tias asciminib muaj qhov peev xwm dhau los ua tus neeg mob Ib qho tseem ceeb tshiab kev xaiv. Peb cia siab tias yuav tau faib cov ntaub ntawv nrog cov neeg tswj hwm kev cai thiab xa cov ntaub ntawv thoob ntiaj teb."

Asciminib tshuaj qauv (duab qhov chaw: medchemexpress.cn)

Xyoo tsis ntev los no, kev kho mob ntawm CML tau ua tiav. Thaum kho Ph + CML cov neeg mob, cov kws kho mob tuaj yeem xaiv nrog ob peb TKIs, suav nrog Novartis 'Gleevec (imatinib) thiab Tasigna (nilotinib). Feem ntau ntawm cov neeg mob tau txais kev kho mob tsis tseem ciaj sia tom qab 10 xyoo, tab sis lawv tseem muaj kev pheej hmoo ntawm kev mob tshwm sim.

Txawm hais tias cov neeg mob uas tiv taus thaum pib kho mob tuaj yeem hloov mus rau lwm tus TKI (piv txwv li, ua ntu zus TKI txoj kev kho), ntau cov kev kho mob tau pom zoo rau tib hom ATP los ua ke rau ntawm ABL1 kinase. Qhov sib thooj ntawm cov kev kho no txhais tau hais tias kev hloov pauv nyob hauv ib cheeb tsam ntawm kinase tuaj yeem hloov ntau yam tshuaj uas tsis muaj txiaj ntsig. Hauv lwm lo lus, kev kho mob TKI uas muaj tshwm sim tuaj yeem cuam tshuam nrog kev tiv thaiv yeeb tshuaj ntau ntxiv thiab kev nkag tsis tau.

Hauv qhov kev tshawb nrhiav ASCEMBL, 233 cov neeg mob tau txais kev qhaj ntawv kom tau txais asciminib (40 mg ob zaug ib hnub, n=157) lossis Bosulif (500 mg ib hnub ib zaug, n=76). Cov ntaub ntawv qhia tau hais tias nyob rau 24 lub lim tiam ntawm kev kho mob, pawg asciminib muaj cov lus teb siab dua ntawm cytogenetic ntau dua li pawg Bosulif (CCyR: 40.8% vs 24.2%), thiab ntau dua qhov sib sib zog nqus cov lus teb molecular (DMR): 10.8% hauv pawg asciminib 8.9% ntawm cov neeg mob ua tiav MR4 thiab MR4.5, piv nrog 5.3% thiab 1.3% hauv pab pawg Bosulif.

Qhov tshwm sim ntawm qib 3 qhov xwm txheej tsis zoo (AE) hauv pawg asciminib thiab pawg Bosulif yog 50.6% thiab 60.5%, ua ntu zus. Hauv pawg asciminib, qhov feem ntawm cov neeg mob uas tsis kho vim yog cov kev tshwm sim tsis zoo yog 5.8%, piv nrog 21.1% hauv pawg Bosulif. Ib yam li ntawd, qhov nquag tshwm sim ntawm qhov xwm txheej tsis zoo uas yuav tsum muaj kev cuam tshuam cov koob tshuaj thiab / lossis kev hloov kho koob tshuaj hauv pawg asciminib yog qis dua Bosulif (37.8% vs 60.5%). Thaum lub sij hawm ntawm cov ntaub ntawv txiav tawm, ib qho kev sib faib ntau dua ntawm cov neeg mob hauv pawg asciminib piv nrog Bosulif pawg tseem tseem tau txais kev kho mob (61.8% vs 30.3%).

Cov kev tshwm sim tsis zoo tshaj plaws ntawm qib ≥3 (tshwm sim> 10%) hauv pawg asciminib yog thrombocytopenia (17.3%) thiab neutropenia (14.7%), thaum pab pawg Bosulif raug nce alanine aminotransferase (ALT) (14.5%), neutropenia (11.8%) thiab zawv plab (10.5%). Ob tus neeg mob (1.3%) hauv cov pawg asciminib (ischemic stroke thiab arterial embolism) tuag; hauv pab pawg neeg Bosulif, ib (1.3%) tus neeg mob (hauv septic shock) tuag. Cov kev tshwm sim tsis zoo tshaj plaws (txhua qib; ≥20%): thrombocytopenia (28.8%) thiab neutropenia (21.8%) hauv pawg asciminib, raws plab (71.1%) thiab xeev siab (46.1%) hauv pab pawg Bosulif, Txhawb siab ALT (27.6) %), ntuav (26.3%), tawm pob ntawm daim tawv nqaij (23.7%), nce aspartate aminotransferase (21.1%), neutropenia (21.1%) thiab thrombocytopenia (18.4%).