Zotsatira Zatsopano Zayeso za Gene Therapy for Severe Hemophilia A

BioMarin Pharmaceutical Inc. lero yalengeza kufalitsidwa kwa zotsatira za kafukufuku wa Phase 3 GENEr8-1 wa valoctocogene roxaparvovec, kafukufuku wa majini ochizira anthu akuluakulu omwe ali ndi hemophilia A kwambiri, mu New England Journal of Medicine (NEJM). Nkhani yomwe ili ndi mutu, "Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A," inanena chaka chimodzi kapena kuposerapo za zomwe zatsatiridwa kuchokera mu kafukufukuyu ndipo zikufotokozedwa m'nkhani yomwe idasindikizidwa m'magazini yomweyo ya Journal kuvomereza phindu lomwe lingakhalepo chifukwa cha kukhetsa magazi kwa zero ndikupewa. kugwiritsa ntchito prophylactic therapy.  

Nkhani yoyambirira yofufuza inanena kuti kutsatira kulowetsedwa kumodzi kwa valoctocogene roxaparvovec otenga nawo gawo adakumana ndi kuchepa kwachulukidwe kwa magazi pachaka, kuchepetsedwa kwa kugwiritsa ntchito factor VIII, komanso kuchuluka kwa factor VIII, kuposa momwe adachitira chaka chisanafike kulembetsa. Pachiwerengero chodziwika bwino cha rollover chomwe chili ndi anthu 112 omwe adalembetsa nawo kafukufuku wosagwirizana, amatanthauza kuti chinthu cha VIII chimagwiritsidwa ntchito mokhazikika komanso kuti chiwopsezo cha kukhetsa magazi pambuyo pa sabata 4 chinachepa pambuyo pa kulowetsedwa ndi 99% ndi 84%, motsatira (onse P <0.001) . Ponseponse, otenga nawo gawo 121/134 (90%) analibe magazi ochiritsira kapena magazi ochepa omwe adachiritsidwa pambuyo pa kulowetsedwa, poyerekeza ndi factor VIII prophylaxis monga momwe zalembedwera mu kafukufuku wosagwirizana. Pamasabata 49-52, 88% ya omwe adatenga nawo gawo anali ndi ntchito yapakati pa VIII ya 5 IU / dL kapena kupitilira apo, monga momwe amayezera pogwiritsa ntchito kuyesa kwa chromogenic substrate (CS). 

"Kutaya magazi kumayimira kulemedwa kwakukulu kwa kasamalidwe ka matenda komanso kufunikira kwachipatala kosakwanira kwa anthu ambiri. Ndikulimbikitsidwa kuti m'chaka choyamba cha chithandizo, 90% ya omwe adachita nawo phunziroli anali ndi magazi a zero kapena ochepa omwe adalandira chithandizo pambuyo pa kulowetsedwa kusiyana ndi factor VIII prophylaxis, "anatero Margareth C. Ozelo, MD, PhD, Mtsogoleri, Hemocentro UNICAMP. Yunivesite ya Campinas ndi Wofufuza Wamkulu Wotsogolera pa Phunziro la GENEr8-1. "Zotsatirazi zikuwonetsa kuthekera kopitilira kutulutsa magazi kwa hemostatic ndi chithandizo cha jini cha hemophilia A."

"Ndife onyadira kukhala apainiya pophunzira za mankhwala a jini owopsa kwambiri a hemophilia A komanso kugawana zomwe wodwala aliyense payekhapayekha zomwe zimathandizira kumvetsetsa kwathunthu zamankhwala omwe atha kusintha," adatero Hank Fuchs, MD, Purezidenti wa Worldwide. Research and Development ku BioMarin. "Valoctocogene roxaparvovec adaphunziridwa kwa nthawi yayitali kuposa njira ina iliyonse yochizira haemophilia A, ndipo chaka ndi chaka, tikupitiliza kudziwa momwe chithandizo chofufuzirachi chingapindulire miyoyo ya anthu omwe ali ndi haemophilia A. Ndife othokoza kwa omwe adachita nawo kafukufukuyu ndi ofufuza za gawo lawo lofunikira mu pulogalamu yachitukukoyi, yomwe ikuphatikiza GENEr8-1, kafukufuku wamkulu kwambiri wa gene therapy mu hemophilia A.

Chitetezo cha Valoctocogene Roxaparvovec

Ichi ndiye chidziwitso chaposachedwa kwambiri chachitetezo chochokera pakuwunika kwazaka ziwiri kwa Gawo 3 GENEr8-1 ndipo chimakhudza chitetezo chonse cha valoctocogene roxaparvovec. Chitetezo chophatikizidwa muzofalitsa za NEJM zimachokera ku kusanthula kwa chaka chimodzi. Onse omwe adachita nawo phunziro la Phase 3 adalandira mlingo umodzi wa 6e13 vg / kg. Palibe otenga nawo mbali omwe adapanga zoletsa ku Factor VIII, malignancy, kapena thromboembolic zochitika. M'chaka chachiwiri, palibe zizindikiro zatsopano zachitetezo zomwe zinatuluka, ndipo palibe zochitika zazikulu zokhudzana ndi chithandizo (SAE) zomwe zinanenedwa. Odwala ambiri adasiya kugwiritsa ntchito corticosteroid (CS) m'chaka choyamba, ndipo panalibe ma SAE okhudzana ndi CS mwa odwala otsala omwe amachotsedwa CS m'chaka chachiwiri. Ponseponse, zowopsa zodziwika bwino (AE) zolumikizidwa ndi valoctocogene roxaparvovec zidachitika koyambirira ndikuphatikiza kulowetsedwa kwakanthawi kogwirizana ndi kukwera pang'ono kapena pang'ono kwa michere yachiwindi popanda zotsatira zachipatala zokhalitsa. Kukwera kwa Alanine aminotransferase (ALT) (otenga nawo mbali 119, 89%), kuyesa kwa labotale kwa chiwindi, kunakhalabe AE yofala kwambiri. Zochitika zina zodziwika bwino zinali mutu (omwe atenga nawo gawo 55, 41%), arthralgia (otenga nawo gawo 53, 40%), nseru (otenga nawo gawo 51, 38%), kukwera kwa aspartate aminotransferase (AST) (otenga nawo gawo 47, 35%), ndi kutopa (40). otenga nawo mbali, 30%). Mu phunziro la Phase 1/2, SAE ya salivary gland mass inadziwika mwa wophunzira wina, yemwe adachiritsidwa zaka zoposa zisanu zapitazo, ndipo adanenedwa kuti sakugwirizana ndi valoctocogene roxaparvovec ndi wofufuzayo. Akuluakulu azaumoyo adadziwitsidwa kumapeto kwa 2021, ndipo maphunziro onse akupitilirabe popanda kusinthidwa. Komiti yodziyimira payokha yowunika za data (DMC) idawunikiranso nkhaniyi. Kuwunika kwa genomic kukuchitika monga momwe zafotokozedwera mu protocol yachipatala. 

GENER8-1 Kufotokozera Kwaphunziro

Kafukufuku wapadziko lonse wa Phase 3 GENEr8-1 ndi kafukufuku wa mkono umodzi, wotseguka wowunika mphamvu ndi chitetezo cha valoctocogene roxaparvovec mwa anthu omwe ali ndi hemophilia A (FVIII ≤ 1 IU/dL) omwe amathandizidwa mosalekeza ndi prophylactic exogenous factor VIII. kwa osachepera chaka chimodzi asanalembetse. Mapeto amphamvu kwambiri anali kusintha kuchokera ku chiyambi cha chinthu VIII (CS assay) pa masabata 49-52 pambuyo pa kulowetsedwa. Mapeto achiwiri ogwira ntchito amaphatikizapo kusintha kuchokera ku chiyambi pa ntchito ya pachaka ya factor VIII yokhazikika komanso chiwerengero cha pachaka cha zigawo za magazi pambuyo pa sabata 4. Chitetezo chinayesedwa mwa kujambula zochitika zovuta, kuyesa ma laboratory, ndi kufufuza thupi. Ponseponse, anthu onse a 134 adalandira kulowetsedwa kwa valoctocogene roxaparvovec pa mlingo wa 6e13 vg / kg, ndipo onse omwe anali nawo anali ndi miyezi yochepa ya 12 yotsatiridwa panthawi yodula deta. Oyamba 22 adalembetsa mwachindunji mu kafukufuku wa Gawo 3, 17 mwa iwo analibe kachilombo ka HIV ndipo adamwa mankhwala osachepera zaka 2 tsiku lodulidwa lisanafike. Otsala a 112 (chiwerengero cha anthu) adamaliza osachepera miyezi isanu ndi umodzi mu kafukufuku wosiyana wosalowererapo kuti awone momwe magazi amakhalira, kugwiritsa ntchito factor VIII, komanso moyo wokhudzana ndi thanzi pomwe akulandira factor VIII prophylaxis isanagubuduze ndikulandila kamodzi. kulowetsedwa kwa valoctocogene roxaparvovec mu kafukufuku wa GENEr8-1.