Vutrisiran hauv kev kho mob hATTR amyloidosis nrog polyneuropathy: txhim kho cov hlab ntsha puas tsuaj --- 2/2

-Sib piv nrog cov placebo, kev kho mob vutrisiran txhim kho Rasch Overall Disability Scale (R-ODS). R-ODS yog qhov suav nrog 24 tus neeg mob qib ntsuas, uas siv qhov ntsuas qhov hnyav ib leeg los ntsuas kev ua ub no thiab txwv kev koom nrog hauv zej zog. Kev ntsuas kev ua haujlwm pom tias muaj kev ua haujlwm ntau ntxiv, suav nrog kev muaj peev xwm ua haujlwm ntawm kev ua neej nyob niaj hnub thiab kev ua ub no hauv zej zog (qhov sib txawv hauv LS los ntawm cov placebo yog 4.3 [2.7,6.0], p=3.26x10-7).

—— Sib piv nrog cov placebo, cov neeg mob kho nrog vutrisiran tau nce qib ntawm kev hloov kho lub cev qhov hnyav (mBMI), qhia txog kev txhim kho kev noj zaub mov zoo nyob rau lub sijhawm 9-hlis (qhov sib txawv hauv LS piv nrog cov placebo yog 67.8 [43.0, 92.6 ], p=8.46 × 10−8).

—— Sib piv nrog cov placebo, cov neeg mob kho nrog vutrisiran kuj tau qhia pom QoL (EuroQol pom qhov sib piv, EQ-VAS, tus kheej ntsuas tus nqi kev noj qab haus huv) thiab kev puas siab puas ntsws (NIS) hauv kev txheeb xyuas cov leeg muaj zog, kev hnov ​​qab thiab kev xav rov qab. Kev txhim kho (qhov sib txawv nruab nrab ntawm EQ-VAS LS nrog cov placebo yog 9.8 [4.8,14.9], p=0.0001; qhov sib txawv nruab nrab ntawm NIS LS nrog cov placebo yog −13.7 [−17.3, −10.1], p=1.08 x 10−13 ).

—— Hauv cov pab pawg mob plawv ua ntej thiab hloov kho lub hom phiaj-kho-mob (mITT) cov neeg, piv nrog cov placebo, pab pawg kho mob vutrisiran tau pom kev txhim kho hauv kev tshawb fawb qhov kawg ntawm lub plawv biomarker NT-proBNP (ntsuas lub plawv siab) (pawg mob plawv) ). Pawg: kho cov duab sib txawv ntau qhov hloov pauv: 0.60 [0.43, 0.82], p=0.0016; mITT pab pawg: kho cov duab sib txawv ntau qhov hloov pauv: 0.63 [0.52,0.75], p=9.2 × 10−7).

Cov neeg mob uas yav dhau los tau txais TTR cov tshuaj tiv thaiv kab mob raug kho nrog vutrisian:

Qhov kev tshuaj xyuas zaum thib ob ntawm HELIOS-A txoj kev tshawb pom pom tias mNIS+7 thiab Norfolk QOL-DN ntawm cov neeg mob kho nrog vutrisiran tau muaj kev txhim kho zoo sib xws tsis hais txog kev siv TTR ruaj khov yav dhau los. Txawm hais tias TTR tsis tau tso cai thaum pib kawm, ob feem peb ntawm cov neeg mob hauv HELIOS-A txoj kev tshawb fawb yav dhau los tau siv TTR stabilizers. Qhov laj thawj feem ntau rau kev txiav txim siab tsis ruaj khov yog koom nrog HELIOS-A kev tshawb fawb thiab kev txhim kho kab mob. Rau kev txhim kho mNIS+7 txheeb ze rau cov placebo, rau cov neeg mob uas tsis tau siv yav dhau los ua kom ruaj khov, qhov nruab nrab LS yog -14.49 (-22.69, -6.29), thiab rau cov neeg mob uas yav dhau los siv cov tshuaj tiv thaiv kab mob, qhov nruab nrab LS yog -18.96 ( - 24.77, -13.16). Rau Norfolk QOL -DN, qhov sib txawv hauv LS los ntawm cov placebo yog -23.0 (−32.1, −14.0) thiab -14.9 (-22.1, -7.6), feem.

Hauv txoj kev tshawb no, nyob rau 9 lub hlis ntawm kev kho mob, vutrisiran tau qhia txog kev txhawb nqa kev nyab xeeb thiab kev tiv taus piv rau cov placebo, tsis hais seb TTR stabilizers tau siv ua ntej. Hauv txhua pab pawg, qhov hnyav ntawm feem ntau cov xwm txheej tsis zoo yog me me mus rau nruab nrab, thiab tsis muaj kev cuam tshuam txog kev siv tshuaj lossis kev tuag.

Vutrisiran yog kev kho mob subcutaneous RNAi hauv kev txhim kho rau kev kho mob ntawm ATTR amyloidosis, suav nrog cov muaj keeb (hATTR) thiab hom tsiaj qus (wtATTR) amyloidosis. Vutrisiran tuaj yeem tsom thiab ntsiag to tshwj xeeb tus xa xov RNA, thaiv nws ua ntej hom tsiaj qus thiab hloov pauv transthyretin (TTR) cov protein tsim. Vutrisiran tau txhaj tshuaj subcutaneously txhua lub hlis twg (3 lub hlis), uas tuaj yeem pab txo qis kev tso tawm ntawm TTR amyloid hauv cov nqaij, txhawb kev tshem tawm TTR amyloid tso rau hauv cov ntaub so ntswg, thiab muaj peev xwm rov ua haujlwm ntawm cov ntaub so ntswg. vutrisiran siv Alnylam' Kev Txhim Kho Kev Ruaj Ntseg Ruaj Ntseg (ESC) -GALNAc sib koom ua ke xa khoom platform, uas lub hom phiaj txhawm rau txhim kho lub zog thiab kev ua haujlwm ruaj khov hauv siab, tso cai rau txhaj tshuaj subcutaneous tsis tu ncua.

Hereditary transthyretin (hATTR) amyloidosis yog ib yam kab mob ua rau tuag taus thiab tuag taus los ntawm kev hloov pauv hauv TTR noob. TTR cov protein feem ntau yog tsim tawm hauv lub siab thiab ib txwm yog tus nqa cov vitamin A. Kev hloov pauv hauv TTR noob tuaj yeem ua rau muaj qhov txawv txav ntawm amyloid thiab ua rau lub cev puas tsuaj thiab cov ntaub so ntswg, xws li cov hlab ntsha hauv nruab nrab thiab lub plawv, ua rau lub cev muaj zog lub cev tsis muaj zog , autonomic neuropathy, thiab/lossis cardiomyopathy, thiab lwm yam kab mob tshwm sim uas nyuaj rau kho. hATTR amyloidosis sawv cev rau qhov tseem ceeb tsis xav tau kev kho mob, nrog rau mob hnyav thiab tuag taus, nrog kwv yees li 50,000 tus neeg mob thoob ntiaj teb. Lub sijhawm muaj sia nyob nruab nrab tom qab kuaj pom yog 4.7 xyoo, thiab cov neeg mob cardiomyopathy muaj lub sijhawm muaj sia nyob luv (nruab nrab 3.4 xyoo).

Alnylam tau tshaj tawm cov tshuaj, Onpattro (patisiran), rau kev kho mob ntawm hATTR-PN. Cov tshuaj tau pom zoo los ntawm Asmeskas FDA thaum Lub Yim Hli 2018 thiab dhau los ua thawj RNAi tshuaj pom zoo rau kev lag luam hauv 20 xyoo txij li RNAi tshwm sim tau pom. Nws yog qhov tsim nyog rau kev kho mob. hATTR-PN cov neeg laus.

Onpattro yog RNAi cov tshuaj uas tau txhaj tshuaj thiab txhaj txhua 3 lub lis piam. Cov tshuaj no tau tsim los txhawm rau phiaj thiab ua kom tsis meej cov lus tshwj xeeb RNA (mRNA) thiab thaiv kev tsim cov protein TTR, uas tuaj yeem pab txo qis thiab txhawb kev tshem tawm TTR amyloid hauv cov ntaub so ntswg thiab rov ua haujlwm ntawm cov ntaub so ntswg.