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ʻO ka Cachexia kahi maʻi ʻōnaehana i hōʻike ʻia e ka pohō kaumaha, ka ʻiʻo a me ka adipose tissue atrophy, a me ka mumū ʻōnaehana. ʻO Cachexia kekahi o nā pilikia nui a me nā kumu o ka make i nā maʻi maʻi kanesa. Ua manaʻo ʻia ʻo ka nui o ka cachexia i nā maʻi maʻi maʻi hiki ke piʻi i ka 25% a 70%, a ma kahi o 9 miliona mau kānaka ma ka honua holoʻokoʻa e loaʻa ana i ka cachexia i kēlā me kēia makahiki, 80% o lākou e manaʻo ʻia e make i loko o hoʻokahi makahiki o ka maʻi. Eia kekahi, pili nui ka cachexia i ka maikaʻi o ke ola o ka maʻi (QOL) a hoʻonui i ka ʻona pili i ka lāʻau.

He mea koʻikoʻi ka hana kūpono o cachexia no ka hoʻomaikaʻi ʻana i ka maikaʻi o ke ola a me ka wānana o nā maʻi maʻi maʻi. Eia nō naʻe, ʻoiai ka holomua o ke aʻo ʻana i nā ʻano pathophysiological o cachexia, ʻoi aku ka nui o nā lāʻau lapaʻau i kūkulu ʻia e pili ana i nā mīkini hiki ke hana wale ʻia a ʻaʻole pono. ʻAʻohe lāʻau lapaʻau maikaʻi i ʻae ʻia e ka US Food and Drug Administration (FDA).

ʻO ka Cachexia (wasting syndrome) ka mea maʻamau i nā poʻe maʻi me nā ʻano maʻi maʻi he nui, e hopena pinepine ai i ke kaumaha o ke kaumaha, ka pau ʻana o ka ʻiʻo, ka emi ʻana o ka maikaʻi o ke ola, ka hana ʻino, a me ke ola pōkole. Wahi a nā kūlana i ʻae ʻia ma waena o ka honua, ua wehewehe ʻia kēia maʻi multifactorial ma ke ʻano he helu helu kino (BMI, ke kaumaha [kg] i puʻunaue ʻia e ke kiʻekiʻe [m] squared) ma lalo o 20 a i ʻole, i nā mea maʻi me ka sarcopenia, he pohō kaumaha o ʻoi aku ma mua o 5% i loko o ʻeono mahina, a i ʻole ke kaumaha o ke kaumaha ma mua o 2%. I kēia manawa, ʻaʻohe lāʻau lapaʻau i ʻae ʻia ma ʻAmelika Hui Pū ʻIa a me ʻEulopa kūikawā no ka mālama ʻana i ka cachexia maʻi kanesa, ka hopena i nā koho lapaʻau liʻiliʻi.
ʻO nā alakaʻi hou e paipai ana i ka olanzapine haʻahaʻa no ka hoʻomaikaʻi ʻana i ka ʻai a me ke kaumaha o nā poʻe maʻi me ka maʻi maʻi maʻi maʻi maʻi ma muli o nā hopena o kahi noiʻi kikowaena hoʻokahi. Ma waho aʻe o kēia, ʻo ka hoʻohana pōkole ʻana i nā analogues progesterone a i ʻole glucocorticoids hiki ke hāʻawi i nā pōmaikaʻi liʻiliʻi, akā aia ka pilikia o nā hopena ʻino (e like me ka hoʻohana ʻana i ka progesterone e pili ana i nā hanana thromboembolic). ʻAʻole i hōʻike ʻia nā hoʻokolohua lapaʻau o nā lāʻau lapaʻau ʻē aʻe i ka pono kūpono e lanakila ai i ka ʻae kānāwai. ʻOiai ua ʻae ʻia ka anamorine (he ʻano waha o ka hormone ulu e hoʻokuʻu ana i nā peptides) ma Iapana no ka mālama ʻana i ka cachexia maʻi kanesa, ua hoʻonui wale ka lāʻau i ke kino i kekahi ʻano, ʻaʻole i hoʻomaikaʻi i ka ikaika, a ʻaʻole i ʻae ʻia e ka US Food and Drug Administration (FDA). Loaʻa ka makemake wikiwiki no ka mālama palekana, kūpono a i kuhikuhi ʻia no ka cachexia maʻi kanesa.
ʻO ka helu hoʻokaʻawale ulu 15 (GDF-15) he cytokine i hoʻoulu ʻia i ke koʻikoʻi e hoʻopaʻa ana i ka glia-derived neurotrophic factor family receptor alpha-like protein (GFRAL) ma ka lolo hope. Uaʻikeʻia ke ala GDF-15-GFRAL ma keʻano he mea hoʻoponopono nui o ka anorexia a me ka hoʻoponopono kaumaha, a he hana i ka pathogenesis o cachexia. Ma nā ʻano holoholona, ​​hiki i ka GDF-15 ke hoʻoulu i ka cachexia, a hiki i ka inhibition o GDF-15 ke hoʻohaʻahaʻa i kēia hōʻailona. Eia kekahi, pili nā kiʻekiʻe kiʻekiʻe o GDF-15 i nā maʻi maʻi maʻi me ka emi ʻana o ke kaumaha o ke kino a me ka nui o ka ʻiʻo iwi, ka emi ʻana o ka ikaika, a me ka pōkole o ke ola ʻana, e hōʻike ana i ka waiwai o GDF-15 ma ke ʻano he hopena lapaʻau.
ʻO ka ponsegromab (PF-06946860) he antibody monoclonal kanaka i koho nui ʻia e hiki ke hoʻopaʻa i ke kaʻe ʻana i ka GDF-15, no laila ke kāohi nei i kāna pilina me ka GFRAL receptor. Ma kahi hoʻāʻo liʻiliʻi o ka wehe ʻana i ka papa inoa 1b, ua mālama ʻia nā maʻi he 10 me ka cachexia maʻi kanesa a me ka pae kiʻekiʻe o ka pae GDF-15 me ka ponsegromab a hōʻike i ka hoʻomaikaʻi ʻana i ke kaumaha, makemake, a me ka hana kino, ʻoiai ua kāohi ʻia nā pae serum GDF-15 a ua haʻahaʻa nā hopena ʻino. Ma muli o kēia, ua alakaʻi mākou i kahi hoʻokolohua lapaʻau Phase 2 e loiloi i ka palekana a me ka pono o ka ponsegromab i nā poʻe maʻi me ka cachexia maʻi maʻi me ka kiʻekiʻe o ka pae GDF-15 kiʻekiʻe, i hoʻohālikelike ʻia me kahi placebo, e hoʻāʻo ai i ka hypothesis ʻo GDF-15 ka pathogenesis mua o ka maʻi.
Ua komo ka haʻawina i nā poʻe maʻi me ka cachexia e pili ana i ka maʻi maʻi (non-liʻiliʻi liʻiliʻi maʻi maʻi ʻāʻī, pancreatic cancer, a i ʻole colorectal cancer) me kahi serum GDF-15 pae o ka liʻiliʻi loa 1500 pg/ml, kahi helu kūlana kūpono o ka Eastern Tumor Consortium (ECOG) o ≤3, a me ka manaʻolana ola o ka liʻiliʻi 4 mahina.
Ua hoʻokaʻawale ʻia nā poʻe maʻi i hoʻopaʻa inoa ʻia e loaʻa i 3 mau ʻano o ka ponsegromab 100 mg, 200 mg, a i ʻole 400 mg, a i ʻole placebo, subcutaneously i kēlā me kēia 4 pule i ka ratio o 1:1:1. ʻO ka hopena mua ka hoʻololi ʻana i ke kaumaha o ke kino e pili ana i ka baseline ma 12 mau pule. ʻO ka hopena hope kiʻekiʻe ka hoʻololi ʻana mai ka baseline i ka helu anorexia cachexia Sub-Scale (FAACT-ACS), kahi loiloi o ka hana therapeutic no ka anorexia cachexia. ʻO nā helu hope ʻē aʻe e pili ana i ka maʻi kanesa pili i ka cachexia symptom diary scores, nā hoʻololi baseline i ka hoʻoikaika kino a me nā hopena gait i ana ʻia me ka hoʻohana ʻana i nā polokalamu olakino kikohoʻe. Hōʻike mua ʻia nā koi manawa hoʻohana liʻiliʻi. ʻO ka loiloi palekana e pili ana i ka helu o nā hanana ʻino i ka wā o ka mālama ʻana, nā hopena hōʻike hoʻokolohua, nā hōʻailona koʻikoʻi, a me nā electrocardiograms. Loaʻa nā hoʻololi ʻana i nā hoʻololi kumu o ka ʻiʻo ʻiʻo lumbar skeletal (wahi puʻupuʻu iwi i puʻunaue ʻia e ke kiʻekiʻe squared) pili me ka ʻiʻo iwi iwi.

ʻO ka huina o 187 mau maʻi i hoʻokaʻawale ʻia e loaʻa i ka ponsegromab 100 mg (46 mau maʻi), 200 mg (46 mau maʻi), 400 mg (50 mau maʻi), a i ʻole placebo (45 mau maʻi). He kanahikukūmāhā (40 pākēneka) i loaʻa i ka maʻi maʻi maʻi maʻi ʻaʻole liʻiliʻi, 59 (32 pākēneka) i loaʻa i ka maʻi maʻi pancreatic, a he 54 (29 pākēneka) i loaʻa i ka maʻi maʻi colorectal.
ʻO nā ʻokoʻa ma waena o nā hui 100 mg, 200 mg, a me 400 mg a me kahi placebo he 1.22 kg, 1.92 kg, a me 2.81 kg.

Hōʻike ke kiʻi i ka helu hope mua (hoʻololi i ke kaumaha o ke kino mai ka papa kuhikuhi a hiki i 12 mau pule) no nā poʻe maʻi me ka cachexia maʻi maʻi ma nā hui ponsegromab a me placebo. Ma hope o ka hoʻoponopono ʻana no ka hoʻokūkū hoʻokūkū o ka make a me nā hanana like ʻole, e like me ka hoʻopau ʻana i ka mālama ʻana, ua nānā ʻia ka hopena mua e kahi kumu hoʻohālike Emax me ka hoʻohana ʻana i nā hopena pule 12 mai kahi loiloi longitudinal hui Bayesian (hema). Ua kālailai ʻia nā helu hope mua ma ke ʻano like, me ka hoʻohana ʻana i nā pahuhopu i manaʻo ʻia no ka mālama maoli ʻana, kahi i ʻoki ʻia ai nā ʻike ma hope o nā hanana like ʻole (kiʻi pololei). Nā wā hilinaʻi (i hōʻike ʻia ma ka ʻatikala

ʻO ka hopena o 400 mg ponsegromab ma ke kaumaha o ke kino i kūlike ma waena o nā pūʻulu preset nui, me ke ʻano maʻi kanesa, serum GDF-15 level quartile, platinum-based chemotherapy exposure, BMI, a me ka ʻōnaehana ʻōnaehana baseline. Ua kūlike ka hoʻololi kaumaha me GDF-15 inhibition ma 12 pule.

Ua hoʻokumu ʻia ke koho ʻana o nā pūʻulu koʻikoʻi ma luna o kahi loiloi lōʻihi post-hoc Bayesian, i mālama ʻia ma hope o ka hoʻoponopono ʻana no ka pilikia hoʻokūkū o ka make ma muli o ka pahuhopu i manaʻo ʻia o ka hoʻolālā lapaʻau. ʻAʻole pono e hoʻohana ʻia nā wā hilinaʻi ma ke ʻano he pani no ka hoʻāʻo ʻana i ke kuhiakau me ka ʻole o nā hoʻololi he nui. Hōʻike ka BMI i ka helu helu kino kino, ʻo CRP e hōʻike ana i ka protein C-reactive, a ʻo GDF-15 e hōʻike ana i ka helu ʻokoʻa ulu 15.
Ma ka papa kuhikuhi, ʻoi aku ka nui o nā mea maʻi i ka ponsegromab 200 mg pūʻulu i hōʻike ʻole i ka emi ʻana o ka makemake; Ke hoʻohālikelike ʻia me kahi placebo, ua hōʻike nā poʻe maʻi i ka ponsegromab 100 mg a me 400 mg pūʻulu i ka hoʻomaikaʻi ʻana i ka makemake mai ka papa kuhikuhi i nā wiki he 12, me ka piʻi ʻana o nā helu FAACT-ACS o 4.12 a me 4.5077. ʻAʻohe ʻokoʻa koʻikoʻi ma nā helu FAACT-ACS ma waena o ka hui 200 mg a me ka hui placebo.
Ma muli o nā koi o ka wā lole a me nā pilikia o ka mīkini, 59 a me 68 mau mea maʻi, i hāʻawi ʻia i ka ʻikepili e pili ana i nā loli i ka hoʻoikaika kino a me nā hopena gait e pili ana i ka baseline. Ma waena o kēia mau maʻi, i hoʻohālikelikeʻia i ka hui placebo, ua hoʻonui ka poʻe maʻi i ka hui 400 mg i ka hana holoʻokoʻa ma nā wiki 12, me ka piʻiʻana o 72 mau minuke o ka hana kinoʻole i ka lā. Eia kekahi, ua hoʻonui pū ka hui 400 mg i ka helu ʻana o ka ʻiʻo ʻāʻī lumbar i ka pule 12.
ʻO ka nui o nā hanana ʻino he 70% i ka hui ponsegromab, i hoʻohālikelike ʻia me 80% i ka hui placebo, a ua loaʻa i 90% o nā mea maʻi e loaʻa ana i ka lāʻau anticancer systemic i ka manawa like. ʻOi aku ka haʻahaʻa o ka nausea a me ka luaʻi ʻana i ka hui ponsegromab.