Tus PI3Kδ Tshiab Tshaj Lij Choj / Tus Kab Mob Tshiab CD20 Monoclonal Antibody Combination (umbralisib + Ublituximab) Theem III Saib Xyuas Zoo!

TG Kev Kho Mob yog lub tuam txhab biopharmaceutical ua kom muaj kev tsim kho tshiab rau cov neeg mob uas muaj kabmob B cell-mediated. Tsis ntev los no, lub tuam txhab tshaj tawm cov txiaj ntsig zoo saum toj ntawm kab thoob ntiaj teb Theem III UNITY-CLL xeem. Qhov kev sim no tau sim rau cov neeg mob uas tsis tau txais kev kho mob (kev kho mob thawj zaug) thiab rov mob / rov huam dua (kho mob) mob lymphocytic rau cov leeg (CLL), thiab tau tshuaj xyuas kev ua tau zoo thiab kev nyab xeeb ntawm kev sib koom ua ke ntawm umbralisib thiab ublituximab (U2), thiab sib piv nrog rau obinutuzumab + chlorambucil tov.

Qhov kev sim siab tau ua raws li Cov Kev Ntsuas Xyuas Tshwj Xeeb Tshwj Xeeb (SPA) pom zoo nrog FDA. Cov txiaj ntsig tau pom tias qhov kev sim tau mus txog thawj qhov kev ntsuas hauv kev soj ntsuam ua ntej: Raws li kev ntsuam xyuas kev ywj pheej (IRC) kev soj ntsuam, piv nrog obinutuzumab + chlorambucil kho pawg, pawg kho mob U2 tsis muaj kev vam meej ntawm kev muaj sia nyob (PFS) Ib qho kev txhim kho sib piv (p< 0.0001)="" tau="" ua="" tiav,="" thiab="" cov="" txiaj="" ntsig="" kho="" tau="" pom="" nyob="" rau="" ob="" qho="" tag="" nrho="" tsis="" muaj="" kev="" kho="" mob="" (kev="" kho="" mob="" thaum="" xub="" thawj)="" thiab="" rov="" mob="" rov="" huam="" dua="" (kho)="" cll="" cov="" neeg="">

Vim tias nws ua tau zoo tshaj, kev sim siab yuav raug txiav kom ntxov ua ntej kev pom zoo ntawm Lub Tswv Yim Yuam Xyuas Cov Ntaub Ntawv Kev Nyab Xeeb (DSMB). Raws li cov ntaub ntawv los ntawm kev sim, TG npaj yuav xa U2 kev tswj hwm rau kev thov siv rau cov neeg mob CLL uas yav tas los tsis tau txais kev kho mob (kev kho mob thaum xub thawj) thiab rov mob / tso tawm (kho) cov neeg mob CLL txog xyoo 2020.

Umbralisib yog qhov ncauj, ib zaug-txhua hnub, tiam tshiab PI3Kδ inhibitor uas tshwj xeeb inhibits CK1-ε, uas tej zaum yuav ua rau nws kov yeej qee qhov teeb meem thev taus cuam tshuam nrog thawj PI3Kδ inhibitor. ublituximab yog qhov tshiab glycoengineered anti-CD20 monoclonal antibody uas tsom lub cim tshwj xeeb epitope ntawm CD20 antigen ntawm cov laus B lymphocytes.

Yog tias tau txais kev pom zoo, U2 yuav muab cov tshuaj tshiab uas tsis siv tshuaj kho rau cov neeg mob CLL uas yav tas los tsis tau txais kev kho mob (kev kho mob thaum pib) thiab cov neeg mob CLL uas tsis tau ua tiav lossis rov kho dua cov kev kho mob yav dhau los.

Mob ntsws lymphocytic mob ntsws (CLL) yog cov feem ntau muaj cov ntshav liab neeg laus. Nws kwv yees tias xyoo 2020, ntau dua 20,000 tus mob tshiab ntawm CLL yuav raug kuaj hauv Tebchaws Meskas. Txawm hais tias cov tsos mob ntawm CLL yuav ploj mus rau qee lub sijhawm tom qab pib kho, tus kab mob no suav tias yog kev kho tsis tau, thiab ntau tus neeg yuav xav tau kev kho ntxiv vim tias kev rov mob ntxiv ntawm cov hlwb malignant.

John Gribben, MD, xibfwb ntawm Medical Oncology, Barts Cancer Institute, London, UK tau hais tias: "Peb zoo siab pom tias qhov kev sim tseem ceeb no yog thawj-kab thiab rov tso tawm / rov ua rau cov neeg mob CLL sib xyaw ua ke ntawm umbralisib thiab ublituximab tau ua tiav cov txiaj ntsig tau zoo. Hnub no cov txiaj ntsig tau cim rau thawj qib kev ua tiav kev soj ntsuam raws li PI3Kδ kev kho mob hauv pawg neeg mob CLL, suav nrog cov neeg mob uas tsis tau txais kev kho mob yav tas los. Tam sim no, CLL tseem tsis tau muaj txoj kev kho tau thiab tseem muaj kev kho mob sai sai, tshwj xeeb tshaj yog cov uas muab cov txheej txheem sib txawv thiab cov kev xaiv muaj kev nyab xeeb kho."

ublituximab yog ib yam tshiab ntawm glycoengineered anti-CD20 monoclonal antibody uas tsom lub cim tshwj xeeb epitope ntawm CD20 antigen ntawm cov laus B lymphocytes. Qhov epitope no txawv ntawm ntau cov CD20 monoclonal tshuaj tiv thaiv tam sim no rau ntawm kev ua lag luam, suav nrog ofatumumab, ocrelizumab / rituximab, obinutuzumab (GA101).

Tam sim no, ublituximab tab tom nyob rau theem III kev kho mob hauv kev kho mob rau ntau yam mob sclerosis (MS) thiab mob ntsws lymphocytic ntev li ntshav (CLL).

Umbralisib yog qhov ua ob txoj kev tiv thaiv ntawm phosphoinositide-3-kinase δ (PI3Kδ) thiab casein kinase 1ε (CK-1ε), uas tuaj yeem ua rau nws kov yeej qee qhov teeb meem zam kev cuam tshuam nrog cov thawj PI3Kδ inhibitors. Phosphatidylinositol-3 kinase (PI3K) yog chav kawm ntawm cov enzymes koom rau hauv ntau yam haujlwm ntawm cev xws li kev loj hlob ntawm tes thiab kev ciaj sia, kev hloov ntawm tes, kev thauj mus los, thiab kev tiv thaiv kab mob. PI3K muaj plaub lub subtypes (α, β, δ, thiab γ), ntawm uas δ subtype yog qhia tau pom nyob rau hauv cov hlwb hematopoietic keeb kwm, feem ntau cuam tshuam nrog B-cell-txuam lymphoma.

Umbrasib muaj nanomolar potency tiv thaiv ty subtype ntawm PI3K, thiab muaj qhov siab xaiv rau γ, β, thiab ty subtypes. Umbralisib kuj tseem tshwj xeeb ua rau casein kinase 1-ε (CK1-ε), uas tej zaum yuav muaj qhov cuam tshuam los tiv thaiv tus mob qog nqaij hlav, thiab kuj tseem tuaj yeem hloov kho T cell ua si cuam tshuam nrog kev tiv thaiv kab mob tsis zoo uas tau pom yav dhau los hauv PI3K inhibitors.

Cov PI3Kδ pom zoo tam sim no cuam tshuam nrog autoimmunity-mediated toxicity, xws li hepatotoxicity, pulmonary toxicity, thiab colitis. Piv nrog kev pom zoo PI3K inhibitors, tus kab mob hloov pauv ntawm umbralisib' s tshwj xeeb sib txawv, nws qhov tshwj xeeb cuam tshuam rau CK1-ε, thiab nws cov cim tshwj xeeb thiab cov ntawv pov thawj tshuaj lom neeg tuaj yeem muaj cov yam ntxwv sib txawv hauv PI3K inhibitor chav kawm.

Lub Ib Hlis xyoo no, TG pib xa cov ntawv thov siv tshuaj tshiab (NDA) rau Asmeskas FDA, nrhiav kev pom zoo sai ntawm cov kab mob hlab hlwb rau cov neeg mob uas tau kho tus mob qog ua ntej lawm cov kab mob lymphoma (MZL) thiab follicular lymphoma (FL).

Yav dhau los, FDA tau tso cai rau plaub qhov chaw tsim nyog rau cov tshuaj rau me nyuam (ODD) rau kev hloov pauv, suav nrog FL thiab tag nrho peb MZLs (cov qog ntshav, ntxiv ntshav, thiab spleen MZL). Ib qho ntxiv, FDA tau tso cai rau umbralisib dhau los ua kev tsim tshuaj rau tshuaj (BTD) rau kev kho mob ntawm cov neeg mob laus uas muaj mob rov qab los yog refractory MZL uas yav tas los tau txais tsawg kawg ib qho kev tiv thaiv CD20 kho.