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Cachexia chirwere chesystemic chinoratidzwa nekuderera kwehuremu, tsandanyama uye adipose tishu atrophy, uye systemic kuzvimba. Cachexia ndeimwe yematambudziko makuru uye zvikonzero zvekufa kwevarwere vegomarara. Zvinofungidzirwa kuti chiitiko checachexia muvarwere vekenza chinogona kusvika 25% kusvika 70%, uye vanhu vangangosvika mamirioni mapfumbamwe pasi rose vanotambura necachexia gore rega rega, 80% yavo inotarisirwa kufa mukati megore rimwe chete rekuongororwa. Pamusoro pezvo, cachexia inokanganisa zvakanyanya hupenyu hwemurwere (QOL) uye inowedzera huturu hune chekuita nekurapa.

Kupindira kunobudirira kwecachexia kwakakosha zvikuru pakuvandudza hupenyu uye kufungidzira kwevarwere vegomarara. Zvisinei, pasinei nekufambira mberi mukudzidza kwepathophysiological mechanisms ye cachexia, mishonga yakawanda yakagadzirwa zvichienderana nemaitiro anogoneka inongoshanda zvishoma kana kuti isingabatsiri. Parizvino hapana kurapwa kunoshanda kwakabvumidzwa neUS Food and Drug Administration (FDA).

Cachexia (wasting syndrome) inowanzoitika kune varwere vane marudzi akawanda ekenza, kazhinji zvichiita kuti uremu huremerwe, kupera kwemhasuru, kuderedzwa kwehupenyu, kusashanda zvakanaka, uye kupfupika kwekurarama. Maererano nezviyero zvakabvumiranwa pasi rose, iyi multifactorial syndrome inotsanangurwa se body mass index (BMI, uremu [kg] yakakamurwa nehupamhi [m] squared) isingasviki makumi maviri kana, muvarwere vane sarcopenia, kurasikirwa kwehuremu kupfuura 5% mumwedzi mitanhatu, kana kurasikirwa kwehuremu hunopfuura 2%. Parizvino, hapana mishonga yakabvumidzwa muUnited States neEurope kunyanya kurapwa kwegomarara cachexia, zvichikonzera kushomeka kwekurapa.
Mitemo ichangoburwa inorumbidza yakaderera-dose olanzapine yekuvandudza kudya uye uremu kune varwere vane kenza yepamusoro zvakanyanya kubva pamhedzisiro yeimwe-center kudzidza. Pamusoro peizvi, kushandiswa kwenguva pfupi kweprogesterone analogues kana glucocorticoids kunogona kupa zvikomborero zvishoma, asi kune ngozi yemigumisiro yakaipa (yakadai sekushandiswa kweprogesterone inobatanidza nezviitiko zvethromboembolic). Miedzo yemakiriniki yemamwe madhiragi yatadza kuratidza kushanda kwayo zvakakwana kuhwina mvumo yekutonga. Kunyange zvazvo anamorine (shanduro yemuromo yekukura kwehomoni inobudisa peptides) yakagamuchirwa muJapan kurapwa kwekenza cachexia, mushonga wacho wakawedzera kuumbwa kwemuviri kune imwe nhanho, hauna kuvandudza simba rekubata, uye pakupedzisira hauna kubvumirwa neU.S. Food and Drug Administration (FDA). Pane kudiwa kwekukurumidzira kweakachengeteka, anoshanda uye anonangwa marapirwo ecancer cachexia.
Growth differentiation factor 15 (GDF-15) is stress-induced cytokine inosunga kune glia-derived neurotrophic factor family receptor alpha-like protein (GFRAL) muuropi hwemashure. Iyo GDF-15-GFRAL nzira yakaonekwa seyakakura regulator yeanorexia uye uremu regulation, uye inoita basa mupathogenesis yecachexia. Mune mhando dzemhuka, GDF-15 inogona kukonzera cachexia, uye inhibition yeGDF-15 inogona kuderedza chiratidzo ichi. Mukuwedzera, mazinga akakwirira eGDF-15 muvarwere vekenza anobatanidzwa nekuderera kwehuremu hwemuviri uye skeletal muscle mass, kuderera kwesimba, uye kupfupika kupona, kusimbisa kukosha kweGDF-15 sechinhu chinogona kurapa chinangwa.
ponsegromab (PF-06946860) inosarudzika yakasarudzika yemunhu monoclonal antibody inokwanisa kusunga kutenderera GDF-15, nekudaro ichivharira kudyidzana kwayo neGFRAL receptor. Muchikamu chiduku chakazaruka-label 1b kuedza, varwere ve10 vane kenza cachexia uye yakakwirira kutenderera GDF-15 mazinga akabatwa neponsegromab uye akaratidza kuvandudzwa kwehuremu, chido, uye basa remuviri, nepo serum GDF-15 mazinga akadziviswa uye zviitiko zvakashata zvakanga zvakaderera. Kubva pane izvi, takaita Phase 2 kliniki yekuedza kuongorora kuchengetedzwa uye kushanda kweponsegromab kune varwere vane kenza cachexia ine yakakwirira kutenderera GDF-15 mazinga, zvichienzaniswa ne placebo, kuedza kufungidzira kuti GDF-15 ndiyo yekutanga pathogenesis yechirwere.
Chidzidzo ichi chaisanganisira varwere vakuru vane cachexia yakabatana nekenza (isiri diki kenza yemapapu, kenza yepancreatic, kana colorectal cancer) ine serum GDF-15 level inosvika 1500 pg/ml, Eastern Tumor Consortium (ECOG) fitness chimiro che ≤3, uye tarisiro yehupenyu ingangoita mwedzi mina.
Varwere vakanyoreswa vakagoverwa kuti vagamuchire 3 doses yeponsegromab 100 mg, 200 mg, kana 400 mg, kana placebo, pasi pemasvondo e4 muchiyero che1: 1: 1. Mhedziso yekutanga yaive shanduko yehuremu hwemuviri maererano nekutanga pamavhiki e12. Mhedziso yakakosha yechipiri yaive shanduko kubva kune yekutanga mune anorexia cachexia Sub-Scale (FAACT-ACS) mamakisi, kuongororwa kwekurapa basa reanorexia cachexia. Mamwe magumo ekupedzisira aisanganisira cancer-inosanganisirwa cachexia chiratidzo diary zvibodzwa, yekutanga shanduko mukuita kwemuviri uye gait endpoints kuyerwa uchishandisa inopfekwa yedhijitari yehutano michina. Minimum shoma nguva yekupfeka zvinodiwa inotsanangurwa pachine nguva. Kuongororwa kwekuchengetedza kwaisanganisira nhamba yezviitiko zvakashata panguva yekurapa, laboratory test results, zvakakosha zviratidzo, uye electrocardiograms. Mhedziso yekuongorora yaisanganisira shanduko yekutanga mu lumbar skeletal muscle index (skeletal muscle area yakakamurwa nehupamhi squared) inobatanidza ne systemic skeletal muscle.

Huwandu hwevarwere ve187 vakapihwa zvisina tsarukano kuti vagamuchire ponsegromab 100 mg (46 varwere), 200 mg (46 varwere), 400 mg (50 varwere), kana placebo (45 varwere). Makumi manomwe nevana (40 muzana) vaive nekenza isiri diki yemapapu, 59 (32 muzana) vaive nekenza yepancreatic, uye makumi mashanu neina (29 muzana) vaive negomarara remukati.
Misiyano pakati pe100 mg, 200 mg, uye 400 mg mapoka uye placebo yaive 1.22 kg, 1.92 kg, uye 2.81 kg, zvichiteerana.

Nhamba yacho inoratidza magumo ekutanga (kuchinja kwehuremu hwemuviri kubva pakutanga kusvika kumavhiki gumi nemaviri) kune varwere vane cancer cachexia muponsegromab uye mapoka e placebo. Mushure mekugadzirisa kukwikwidza kwenjodzi yekufa uye zvimwe zviitiko zvakafanana, sekuvhiringidzwa kwekurapa, iyo yekutanga yekupedzisira yakaongororwa neyakaomeswa Emax modhi uchishandisa vhiki 12 mhinduro kubva kuBayesian joint longitudinal analysis (kuruboshwe). Mhedzisiro dzekutanga dzakaongororwawo nenzira yakafanana, vachishandisa zvinofungidzirwa zvinangwa zvekurapa chaiko, uko kucherechedzwa mushure mezviitiko zvese zvakafanana kwakaderedzwa (nhamba yekurudyi). Nguva dzekuvimba (inoratidzwa muchinyorwa

Mhedzisiro ye400 mg ponsegromab pahuremu hwemuviri yaienderana mumapoka makuru ekutanga, anosanganisira cancer mhando, serum GDF-15 level quartile, platinum-based chemotherapy exposure, BMI, uye baseline systemic kuzvimba. Kuchinja kwehuremu kwaienderana neGDF-15 inhibition pamasvondo gumi nemaviri.

Kusarudzwa kwezvikamu zvakakosha zvakabva pane post-hoc Bayesian joint longitudinal analysis, iyo yakaitwa mushure mekugadzirisa kukwikwidzana kwekufa kwekufa zvichienderana nechinangwa chinofungidzirwa chechirongwa chekurapa. Nguva dzekuvimba hadzifanirwe kushandiswa sechinotsiva kuongororwa kwekufungidzira pasina kugadziridzwa kwakawanda. BMI inomiririra body mass index, CRP inomiririra C-reactive protein, uye GDF-15 inomiririra kukura kusiyanisa factor 15.
Pakutanga, chikamu chepamusoro chevarwere mu ponsegromab 200 mg boka rakashuma kuti hapana kuderera kwechido; Kuenzaniswa ne placebo, varwere vari mu ponsegromab 100 mg uye 400 mg mapoka vakarondedzera kuvandudzwa kwechido kubva pakutanga kwemavhiki e12, nekuwedzera kweFAACT-ACS scores ye4.12 uye 4.5077, maererano. Pakanga pasina misiyano yakakosha muzvikamu zveFAACT-ACS pakati peboka re200 mg neboka re placebo.
Nekuda kwezvakafanotaurwa zvinodiwa nguva yekupfeka uye nyaya dzemidziyo, varwere makumi mashanu nepfumbamwe ne68, zvichiteerana, vakapa data pamusoro pekuchinja kwekuita kwemuviri uye mafambiro ekufamba ane chekuita nekutanga. Pakati pevarwere ava, vachienzaniswa neboka re placebo, varwere vari muboka re 400 mg vakave nekuwedzera kwekuita basa rose pamasvondo e12, nekuwedzera kwe72 maminitsi ekusagadzikana kwekuita muviri pazuva. Mukuwedzera, boka re400 mg rakave nekuwedzera kwe lumbar skeletal muscle index pavhiki 12.
Chiitiko chezviitiko zvakashata chaiva 70% muboka reponsegromab, zvichienzaniswa ne80% muboka re placebo, uye zvakaitika mu90% yevarwere vanowana systemic anticancer therapy panguva imwe chete. Chiitiko chekusvotwa uye kurutsa kwaive kwakadzikira muboka reponsegromab.