TW201703792A - 用於治療代謝症候群之醫藥組成物 - Google Patents
用於治療代謝症候群之醫藥組成物 Download PDFInfo
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- TW201703792A TW201703792A TW105119851A TW105119851A TW201703792A TW 201703792 A TW201703792 A TW 201703792A TW 105119851 A TW105119851 A TW 105119851A TW 105119851 A TW105119851 A TW 105119851A TW 201703792 A TW201703792 A TW 201703792A
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Abstract
本發明係關於一種含有至少一種FGF-21(纖維母細胞生長因子21)化合物、至少一GLP-1R(類升糖素肽-1受體)激動劑以及選擇性地至少一抗糖尿病藥物和/或至少一DPP-4(二肽基肽酶-4)抑制劑的醫藥組成物供用於治療至少一代謝症候群和/或動脈粥樣硬化,特別是糖尿病、異常血脂症、肥胖和/或脂肪過多。
Description
本發明係關於一種含有至少一種FGF-21(纖維母細胞生長因子21)化合物、至少一GLP-1R(類升糖素肽-1受體)激動劑以及選擇性地至少一抗糖尿病藥物和/或至少一DPP-4(二肽基肽酶-4)抑制劑的醫藥組成物供用於治療至少一代謝症候群和/或動脈粥樣硬化,特別是糖尿病、異常血脂症(dyslipidemia)、肥胖和/或脂肪過多(adipositas)。
糖尿病的特徵在於其臨床表現,亦即非胰島素依賴型或成年發病型(又知曉為第2型糖尿病)以及胰島素依賴型或幼年發病型(又知曉為第1型糖尿病)。第2型糖尿病與潛在肥胖的臨床症狀的表現通常在超過40歲時出現,相反地,第1型糖尿病通常在30歲以前顯示快速發病。這個疾病在人類體內是一種代謝異常,在一般族群中的盛行率為1%,其中四分之一是第1型糖尿病,四分之三是第2型糖尿病。第2型糖尿病是一種特徵在於高循環血糖、胰島素與皮質類固醇濃度的疾病。
現今,有各種用於治療第2型糖尿病的藥理學方法,它們可獨立或組合來使用,且其經由不同的作用模式來作用:1)磺醯脲(sulfonylurea)刺激胰島素分泌;2)雙胍(biguanides)(甲福明(metformin))藉由促進葡萄糖利用、降低肝臟葡萄糖生成以及減少腸葡萄糖排出來作用;
3)oc-葡萄糖苷酶抑制劑(阿卡波糖、米格列醇(miglitol))減緩醣類消化以及後續從腸吸收並且減低餐後高血糖症;4)噻唑烷二酮(thiazolidinedione)(曲格列酮(troglitozone))增強胰島素作用,因而促進葡萄糖在週邊組織中的使用;以及5)胰島素刺激組織葡萄糖使用並且抑制肝臟葡萄糖排出。
但是,大多數藥物的效力有限,而且無法處理最為重要的問題:β-細胞功能降低以及相關的肥胖。
肥胖是一種在現代社會中高度盛行的慢性疾病,而且與許多醫學問題(包括糖尿病、胰島素抗性、高血壓、高膽固醇血症(hypercholesterolemia)與冠狀動脈心臟病)相關。它與糖尿病和胰島素抗性更是高度相關,後者通常伴隨著高胰島素血症(hyperinsulinemia)或高血糖症(hyperglycemia),或兩者。此外,第2型糖尿病與2至4倍風險冠狀動脈疾病有關。
第1型糖尿病典型顯示非常低或無法計得的血漿胰島素以及升高的升糖素。因為β-細胞分泌胰島素,特定針對對抗β-細胞的免疫反應會導致第1型糖尿病。現今針對第1型糖尿病的治療攝生法試著將因為缺乏天然胰島素所致的高血糖症降至最低。
纖維母細胞生長因子21(FGF21)是一種新穎的代謝調節劑,主要是由肝臟製造,它在肥胖以及第2型糖尿病的動物模型中展現出強效抗糖尿病以及降低脂肪的效用。這個激素提供體重調節並且在小鼠體內涉入對營養剝奪(nutritional deprivation)與產酮狀態(ketogenic state)的反應。FGF21代謝作用的主要位置是脂肪組織、肝臟以及胰臟。實驗研究已顯示,在FGF21投藥之後,於糖尿病小鼠以及靈長類動物體內會增進糖尿病補償以及異常血脂症(dyslipidemia)(Dostalova et al.2009)。已顯示在存在與不存在胰島素下,FGF21在小鼠3T3-L1脂肪細胞中會刺激葡萄糖攝取,且在ob/ob與db/db小鼠與8週大olf ZDF大鼠體內會以劑量依賴的方式來降低飽食與禁食血糖、三酸甘油酯與升糖素濃度,因而提供使用FGF-21作
為用於治療糖尿病以及肥胖的療法之基礎(參見例如WO03/011213)。
纖維母細胞生長因子(FGFs)在發育以及成體組織中是廣為表現的多肽。現今FGF家族是由22個成員所組成,FGF-1至FGF-23。就脊椎動物物種間的基因結構以及胺基酸序列這兩者來說,FGF家族的成員是高度守恆的。有18種哺乳動物纖維母細胞生長因子(FGF1-FGF10以及FGF16-FGF23),它們依據序列同源性以及譜系(phylogeny)而被分成6個子家族。沒有被分派至子家族-FGF同源因子(先前知曉為FGF11-FGF14)-的編號「FGFs」與FGF家族具有高度序列同一性,但不會活化FGF受體(FGFRs),而因此一般不被視為是FGF家族的成員。
儘管大多數的FGFs作用有如細胞生長以及分化的局部調節劑,近來的研究指出,FGF19次家族成員(包括FGF15/19、FGF21與FGF23)藉由內分泌的方式(endocrine fashion)發揮重要的代謝影響。FGF19次家族的成員調節不會受到典型FGFs所影響的多樣化生理學過程。這些內分泌因子的廣泛多樣的代謝活性包括調節膽酸、醣類與脂質代謝以及磷、鈣和維生素D恆定(Tomlinson et al.2002,Holt et al.2003,Shimada et al.2004,Kharitonenkov et al.2005,Inagaki et al.2005,Lundasen et al.2006)。
FGF21原先是從小鼠胚胎分離而來。FGF21 mRNA在肝臟中被大量表現,而在胸腺中表現較少的程度(Nishimura et al.2000)。人類FGF21與小鼠FGF21是高度相似的(約75%胺基酸同一性)。在人類FGF家族成員之中,FGF21與FGF19是最為相似的(約35%胺基酸同一性)(Nishimura et al.2000)。FGF21沒有增生以及致瘤效用(Kharitonenkov et al.2005,Huang et al.2006,Wente et al.2006),這些作用對於FGF家族的大多數成員來說是典型的(Ornitz and Itoh 2001,Nicholes et al.2002,Eswarakumar et al.2005)。
在口服葡萄糖耐受性試驗中,將FGF21投藥給肥胖的瘦素-缺乏ob/ob以及瘦素受體-缺乏db/db小鼠與肥胖的ZDF大鼠會明顯降低血
糖以及三酸甘油酯,降低禁食胰島素濃度和改善葡萄糖清除。在投藥2週的期間,FGF21不會影響糖尿病或精瘦小鼠與大鼠的食物攝入或體重/組成。重要的是,在任何測試劑量下,FGF21於糖尿病或健康動物體內或當在轉殖小鼠體內過度表現時都不會誘發有絲分裂、低血糖症(hypoglycemia)或增重(Kharitonenkov et al.2005)。過度表現FGF21的轉殖小鼠對膳食誘發的肥胖有抗性。
將FGF21投藥給糖尿病恆河猴歷時6週會降低禁食血漿葡萄糖、果胺糖、三酸甘油酯、胰島素以及升糖素濃度。重要的是,儘管有明顯的降低葡萄糖效用,在研究期間並未發現到低血糖症。FGF21投藥也會明顯降低LDL-膽固醇並且增加HDL-膽固醇,與小鼠的結果呈對比(Kharitonenkov et al.2005),略為但明顯會降低體重(Kharitonenkov et al.2007)。
更多資訊可以自下列參考文件取得:
1. DOSTALOVA I. et al.: Fibroblast Growth Factor 21: A Novel Metabolic Regulator With Potential Therapeutic Properties in Obesity/Type 2 Diabetes Mellitus. Physiol Res 58:1-7, 2009.
2. ESWARAKUMAR V.P. et al.: Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16: 139-149, 2005.
3. HOLT J.A. et al.: Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev 17: 1581-1591, 2003.
4. HUANG X. et al.: Forced expression of hepatocytespecific fibroblast growth factor 21 delays initiation of chemically induced hepatocarcinogenesis. Mol Carcinog 45: 934-942, 2006.
5. INAGAKI T. et al.: Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell
Metab 5: 415-425, 2007.
6. KHARITONENKOV A. et al.: FGF-21 as a novel metabolic regulator. J Clin Invest 115: 1627-1635, 2005.
7. KHARITONENKOV A. et al.: The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148: 774-781, 2007.
8. LUNDÅSEN T. et al.: Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Intem Med 260: 530-536, 2006.
9. NICHOLES K. et al.: A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 160: 2295-2307, 2002.
10. NISHIMURA T. et al.: Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta 1492: 203-206, 2000.
11. ORNITZ D.M. et al.: Fibroblast growth factors. Genome Biol 2: REVIEWS3005, 2001.
12. SHIMADA T. et al.: FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19: 429-435, 2004.
13. TOMLINSON E. et al.: Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 143: 1741-1747, 2002.
14. WENTE W. et al.: Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular
signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 55: 2470-2478, 2006.
腸肽類升糖素肽-1(GLP-1)是一種腸促胰液素激素,而且是以一種營養依賴型的方式被分泌。它會刺激葡萄糖依賴型胰島素分泌。GLP-1也會促進β-細胞增生,並且經由對於葡萄糖感應器、抑制胃排空、食物攝入以及升糖素分泌的額外作用來控制血糖。此外,GLP-1在帶有第2型糖尿病的人類個體體內會刺激胰島素分泌並且降低血糖。投予具有生物活性的外源性GLP-1、GLP-1(7-27)或GLP-1(7-36醯胺)會隨著劑量升高血漿濃度至生理餐後濃度約3-4倍,令第2型糖尿病患者的禁食高血糖症完全正常化(Nauck,M.A.et al.(1997)Exp Clin Endocrinol Diabetes,105,187-197)。人類GLP-1受體(GLP-1R)是一個463個胺基酸七螺旋G蛋白-偶合的受體,在胰島、腎臟、肺臟、心臟以及週邊與中樞神經系統的多個區域被廣為表現。在胰島內,GLP-1R主要位在島β-細胞中。活化GLP-1傳訊會起始分化朝向更為類內分泌表現型的程式,特別是衍生自人類胰島的前驅細胞分化成有功能的β-細胞(Drucker,D.J.(2006)Cell Metabolism,3,153-165)。
不幸的是,FGF-21以及有生物活性的GLP-1這兩者,與其他已知的藥物因為它們在第2型糖尿病或其他代謝障礙中可以發現到有複雜以及多因性代謝障礙而效力有限。這也適用於藉由該等化合物本身來降低血糖濃度的效力。
依據本發明,已意外地發現到,組合FGF-21以及GLP-1R激動劑會以協同的方式顯著降低血糖濃度至正常血糖濃度。
因此,本發明的一個具體例是有關於一種醫藥組成物,其含有至少一種FGF-21(纖維母細胞生長因子21)化合物以及至少一GLP-1R(類升糖素肽-1受體)激動劑。
「FGF-21化合物”」被定義為一種顯示出FGF-21活性的化合
物,特別是包含有(i)天然FGF-21,尤其是人類FGF-21,特別是如SEQ ID NO:1所示的人類FGF-21,或(ii)一具有FGF-21活性的FGF-21仿效物。
「FGF-21活性」通常是在一個習於該項技藝者一般所熟知的FGF-21活性分析中測量。FGF-21活性分析是例如在Kharitonenkov,A.et al.(2005),115;1627,No.6中所述的「葡萄糖攝取分析」。關於葡萄糖攝取分析的一個實例,脂肪細胞在DMEM/0.1%BSA中受飢歷時3小時,以FGF-21刺激歷時24小時,而且以KRP緩衝液(15mM HEPES、pH 7.4、118mM NaCl、4.8mM KCl、1.2mM MgSO4、1.3mM CaCl2、1.2mM KH2PO4、0.1%BSA)洗滌2次,並將含有2-去氧基-D-[14C]葡萄糖(2-DOG)(0.1μCi,100μM)的100μl KRP緩衝液加入各小孔中。對照小孔含有100μl的KRP緩衝液(具有2-DOG)(0.1μCi,10mM)以供監測非專一性。攝取反應在37℃下進行歷時1小時,藉由加入細胞遲緩素B(cytochalasin B;20μM)來終止,並且使用Wallac 1450 MicroBeta計數器(PerkinElmer,USA)來測量。
FGF-21仿效物的實例是(a)相對於SEQ ID NO:1所示的胺基酸序列具有至少約96%,特別是99%胺基酸序列同一性並且具有FGF-21活性的蛋白質、(b)FGF-21融合蛋白質或(c)FGF-21接合物(conjugate),例如FGF-21突變蛋白、FGF-21-Fc融合蛋白質、FGF-21-HSA融合蛋白質或PEG化FGF-21。
FGF-21突變蛋白的實例描述於例如WO2005/061712、WO2006/028595、WO2006/028714、WO2006/065582或WO2008/121563。例示性突變蛋白是例如在酵母菌中表現時,相較於野生型人類FGF-21,在O-醣化方面的能力降低的突變蛋白,例如在位置167處(絲胺酸)有取代的人類FGF-21,例如具有下列取代之一者的人類FGF-21:Ser167Ala、Ser167Glu、Ser167Asp、Ser167Asn、Ser167Gln、Ser167Gly、Ser167Val、Ser167His、Ser167Lys或Ser167Tyr。另一個實例是一個相較於野生型人類FGF-21顯示降低去醯胺化的突變蛋白,例如在人類FGF-21的位置121處(天門冬醯胺酸)
有取代的突變蛋白,例如Asn121Ala、Asn121Val、Asn121Ser、Asn121Asp或Asn121Glu。替換性突變蛋白是具有一或多個非天然編碼胺基酸的人類FGF-21,例如依據WO2008/121563的申請專利範圍第29項中所述的通式。其他的突變蛋白包含以帶電胺基酸(例如天門冬胺酸、麩胺酸)或極性但不帶電胺基酸(例如絲胺酸、蘇胺酸、天門冬醯胺酸、麩醯胺酸)分別來置換例如極性但不帶電或帶電胺基酸。實例為Leu139Glu、Ala145Glu、Leu146Glu、Ile152Glu、Gln156Glu、Ser163Glu、Ile152Glu、Ser163Glu或Gln54Glu。另一個突變蛋白是一種在例如酵母菌中表現時,相較於人類FGF-21,顯示對蛋白分解的感受性降低的突變蛋白,特別是具有Leu153以選自於Gly、Ala、Val、Pro、Phe、Tyr、Trp、Ser、Thr、Asn、Asp、Gln、Glu、Cys或Met的胺基酸予以置換的人類FGF-21。較佳的FGF-21突變蛋白是依據SEQ ID NO:2的突變FGF-21,其帶有人類FGF-21的胺基酸1-28的刪除(SEQ ID NO:1)並且在N-端含有一個額外的甘胺酸。
FGF-21融合蛋白質的實例描述於例如WO2004/110472或WO2005/113606,例如FGF-21-Fc融合蛋白質或FGF-21-HSA融合蛋白質。「Fc」表示免疫球蛋白的Fc部分,例如IgG4的Fc部分。「HSA」表示人類血清白蛋白。
FGF-21接合物的實例描述於例如WO2005/091944、WO2006/050247或WO2009/089396,例如乙二醇-連結的FGF-21化合物。此等乙二醇-連結的FGF21化合物通常帶有一個聚乙二醇(PEG),例如在半胱胺酸或離胺酸胺基酸殘基或在引入N-連結或O-連結之醣化位置處(在此意指為「PEG化FGF-21」)。這些PEG化FGF-21化合物相較於人類FGF-21通常會顯示作用時間延長。適當的PEGs具有約20,000至40,000道耳頓的分子量。
「GLP-1R激動劑」定義為一種結合並且活化GLP-1受體的化合物,例如GLP-1(類升糖素肽1)。GLP-1和/或GLP-1R激動劑的生理作用描述於例如Nauck,M.A.et al.(1997)Exp.Clin.Endocrinol.
Diabetes,105,187-195。這些生理作用在正常個體體內,特別是人類,包括例如胰島素分泌的葡萄糖依賴型刺激、抑制升糖素分泌、刺激(原)胰島素生合成、降低食物攝入、減緩胃排空和/或不確定的胰島素敏感性。
找到GLP-1R激動劑的適當分析描述於例如Thorkildsen,Chr.et al.(2003),Journal of Pharmacology and Experimental Therapeutics,307,490-496;Knudsen,L.B.et al.(2007),PNAS,104,937-942,No.3;Chen,D.et al.(2007),PNAS,104,943-948,No.3;或US2006/0003417 A1(參見例如實施例8)。簡言之,在「受體結合分析」中,在有例如人類GLP-1(例如GLP-1(7-36)醯胺,被標示有例如125I(例如80kBq/pmol))存在下,將具有例如人類重組型GLP-1受體之真核細胞(例如CHO、BHK或HEK293細胞)的純化細胞膜部分與測試化合物或化合物等一起培育。使用慣常不同濃度的測試化合物或化合物等,並且隨著減少人類GLP-1專一性結合的濃度來決定IC50數值。在「受體功能性分析」中,製備源自於真核細胞的分離血漿細胞膜,例如上述(表現例如人類GLP-1受體)並且與測試化合物一起培育。該功能性分析是藉著測定cAMP作為因為測試化合物刺激的反應來進行。在「報導子基因分析」中,真核細胞,像是如上所述(表現例如人類GLP-1受體並且含有例如多個反應要素/cAMP反應要素-驅動螢光素酶報導子質體)在有測試化合物的存在下培養。cAMP反應要素-驅動螢光素酶活性被測量為對因為測試化合物刺激的反應。
適當的GLP-1R激動劑選自於具有生物活性的GLP-1、GLP-1類似物或GLP-代用品,像是例如描述於Drucker,D.J.(2006)Cell Metabolism,3,153-165;Thorkildsen,Chr.(2003;上文);Chen,D.et al.(2009;上文);Knudsen,L.B.et al.(2007;上文);Liu,J.et al.(2007)Neurochem Int.,51,361-369,No.6-7;Christensen,M.et al.(2009),Drugs,12,503-513;Maida,A.et al.(2008)Endocrinology,149,5670-5678,No.11以及US2006/0003417。例示性化合物為
GLP-1(7-37)、GLP-1(7-36)醯胺、毒蜥外泌肽(extendin-4)、利拉魯肽(liraglutide)、CJC-1131、阿必魯泰(albugon)、阿必魯泰(albiglutide)、艾塞那肽(exenatide)、艾塞那肽-LAR(exenatide-LAR)、調酸素(oxyntomodulin)、利希拉來(lixisenatide)、京尼平苷(geniproside)、AVE-0010、具有GLP-1R激動活性的短肽和/或具有GLP-1R激動活性的小有機化合物。
詳言之,人類GLP-1(7-37)具有SEQ ID NO:3的胺基酸序列。人類GLP-1(7-36)醯胺具有SEQ ID NO:4的胺基酸序列。毒蜥外泌肽(extendin-4)具有SEQ ID NO:5的胺基酸序列。艾塞那肽(exenatide)具有SEQ ID NO:6的胺基酸序列,而調酸素具有SEQ ID NO:7的胺基酸序列。利希拉來的胺基酸序列顯示於SEQ ID NO:8。利希拉來的結構是以在C-端以6個額外離胺酸殘基修飾的毒蜥外泌肽(exendin-4)(1-37)為基礎而能夠耐受DPP-4(二肽基肽酶-4)的立即生理分解。AVE0010的胺基酸序列顯示於SEQ ID NO:9。
利拉魯肽的化學結構顯示於第1圖中。利拉魯肽是藉由將GLP-1(7-37)的Lys34置換為Arg,以及藉由使用γ-麩胺酸間隔子在位置26處加入一個C16脂肪酸而獲得。化學名為[N-ε(γ-L-麩胺醯基(N-α-十六醯基)-Lys26,Arg34-GLP-1(7-37)]。
CJC-1131的化學結構顯示於第2圖中。白蛋白接附在GLP-1的C-端,在位置8處帶有d-丙胺酸置換。CJC-1131顯示出非常良好的安定性以及生物活性的組合。
其他具有GLP-1R激動劑活性的肽例示性地描述於US 2006/0003417,而具有GLP-1R激動活性的小有機化合物例示性地描述於Chen et al.2007,PNAS,104,943-948,No.3或Knudsen et al.,2007,PNAS,104,937-942。
在本發明的另一具體例中,該醫藥組成物額外含有至少一種抗糖尿病藥物和/或至少一種DPP-4抑制劑。
例示性抗糖尿病藥物為a)胰島素,
b)噻唑烷二酮,例如羅格列酮(rosiglitazone)或吡格列酮(pioglitazone)(參見例如WO2005/072769)、甲福明(N,N-二甲基亞胺基二碳醯亞胺-二胺),或c)磺醯脲,諸如氯磺丙脲(chlorpropamide)(4-氯-N-(丙基胺甲醯基)-苯磺醯胺)、妥拉磺脲(tolazamide)(N-[(氮平-1-基胺基)羰基]-4-甲基-苯磺醯胺)、格列齊特(gliclazide)(N-(六氫環庚[c]吡咯-2-(1H)-基-甲醯基)-4-甲基苯磺醯胺)或格列美脲(glimepiride)(3-乙基-4-甲基-N-(4-[N-((1r,4r)-4-甲基環己基甲醯基)-胺磺醯基)苯乙基)-2-側氧基-2,5-二氫-1H-吡咯-1-甲醯胺)。
依據本發明,「胰島素」表示天然存在的胰島素、經修飾的胰島素或胰島素類似物,包括其鹽類及它們的組合,例如經修飾的胰島素與胰島素類似物(例如具有胺基酸置換/刪除/添加以及更多諸如醯化或其他化學修飾的修飾)的組合。這類型化合物的一個實例是胰島素地特(detemir),亦即LysB29-十四醯基/des(B3)人類胰島素。另一個實例是併入非天然胺基酸或通常在真核細胞中是非編碼胺基酸(諸如D-胺基酸)的胰島素(Geiger,R.et al.,Hoppe Seylers Z.Physiol.Chem.(1976)357,1267-1270;Geiger,R.et al.,Hoppe Seylers Z.Physiol.Chem.(1975)356,1635-1649,No.10;Krail,G.et al.,Hoppe Seylers Z.Physiol.Chem.(1971)352,1595-1598,No.11)。又其他的實例是胰島素類似物,其中A-鏈或B-鏈或這兩者的C-端羧酸置換為一個醯胺。
「經修飾的胰島素」較佳的是選自於具有胰島素活性的經醯基化胰島素,特別是其中胰島素的A和/或B鏈中的一或多個胺基酸(等)被醯基化,較佳的是在位置B29處被醯基化的人類胰島素(Tsai,Y.J.et al.(1997)Journal of Pharmaceutical Sciences,86,1264-1268,No.11)。其他醯基化胰島素是desB30人類胰島素或B01牛胰島素(Tsai,Y.J.et al.,上文)。其他醯基化胰島素的實例例如描述於US 5,750,497以及US 6,011,007。關於經修飾胰島素的結構-活性關係的概述在
Mayer,J.P.et al.(2007)Biopolymers,88,687-713,No.5中提供。經修飾胰島素典型地是藉由化學和/或酵素操作胰島素,或適當的胰島素前驅物(諸如前胰島素原、胰島素原或其截短的類似物)來製備。
「胰島素類似物」較佳地是選自於具有胰島素活性的胰島素,其具有一或多個突變、置換、刪除和/或添加,特別是在A和/或B鏈中有C-和/或N-端截短或延伸的胰島素,較佳的是des(B30)胰島素、PheB1胰島素、B1-4胰島素、AspB28人類胰島素(天門冬胺胰島素)、LysB28/ProB29人類胰島素(賴脯胰島素)、LysB03/GluB29人類胰島素(格魯辛胰島素;insulin glulisine)或GlyA21/ArgB31/ArgB32人類胰島素(甘精胰島素)。胰島素類似物的唯一先決要件在於它要具有足夠的胰島素活性。胰島素類似物的結構-活性關係的概述,連同有關哪個胺基酸置換、刪除和/或添加是可容許的討論,在Mayer,J.P.et al.(2007;上文)中提供。胰島素類似物較佳地是其中一或多個天然存在的胺基酸殘基,較佳地它們有1、2或3個被另一個胺基酸殘基所置換。胰島素類似物的更多實例是C-端截短的衍生物,諸如des(B30)人類胰島素;B-鏈N-端截短的胰島素衍生物,諸如des PheB1胰島素或des B1-4胰島素;胰島素類似物,其中A-鏈和/或B鏈具有N-端延伸,包括所謂「前胰島素」,其中B鏈具有N-端延伸;以及胰島素類似物,其中A-鏈和/或B鏈具有C-端延伸。例如,1或2個Arg可以被添加至位置B1處。胰島素類似物的實例描述下列專利案及其等同文件:US 5,618,913、EP 0 254 516 A2以及EP 0 280 534 A2。胰島素纇似物在臨床應用上的概述在Mayer,J.P.et al.(2007;上文)中提供。胰島素類似物或其前驅物典型是使用為那些習於該技藝者所熟知的基因科技技術來製備,典型地是在細菌或酵母菌中,若需要,後續使用酵素或合成操作。或者,胰島素類似物可以在化學上來製備(Cao,Q.P.et al.(1986)Biol.Chem.Hoppe Seyler,367,135-140,No.2)。特定胰島素類似物的實例是天門冬胺胰島素(亦即AspB28人類胰島素);賴脯胰島素(亦即LysB28,ProB29人類胰島素);格魯辛胰島素(亦即LysB03,GluB29人類胰島素);以及甘精胰島素(亦即
GlyA21,ArgB31,ArgB32人類胰島素)。
例示性DPP-4抑制劑為西他列汀(sitagliptin):(R)-4-側氧基-4-[3-(三氟甲基)-5,6-二氫[1,2,4]三唑[4,3-a]吡-7(8H)-基]-1-(2,4,5-三氟苯基)丁烷-2-胺,維格列汀(vildagliptin):(S)-1-[N-(3-羥基-1-金剛烷基)甘胺醯基]吡咯啶-2-腈,沙格列汀(saxagliptin):(1S,3S,5S)-2-[(2S)-2-胺基-2-(3-羥基-1-金剛烷基)-乙醯基]-2-偶氮二環[3.1.0]己烷-3-腈,利拉利汀(linagliptin):8-[(3R)-3-胺基哌啶-1-基]-7-(丁-2-炔-1-基)-3-甲基-1-[(4-甲基-喹唑啉-2-基)甲基]-3,7-二氫-1H-嘌呤-2,6-二酮),阿洛利汀(adogliptin):2-({6-[(3R)-3-胺基哌啶-1-基]3-甲基-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基}甲基)-苯甲腈),以及小蘗鹼(berberine),選自於由在小檗(Berberis)、金印草屬(goldenseal)(白毛茛(Hydrastis canadensis))以及黃連(Coptis chinensis)之根、根莖、莖以及樹皮中發現到的異喹啉生物鹼的四級銨鹽(cuaternary ammonium salt)。
本發明之醫藥組成物的個別化合物可以組合在一個調配物或包含在數個調配物中以供例如同時或接續,亦即相繼投藥(等)或其組合。
依據本發明,如同在實施例中使用動物模型所示般,至少一種FGF-21化合物以及至少一種GLP-1R激動劑的組合出乎意料地會在降低血漿葡萄糖濃度上造成協同效用。動物模型為ob/ob或肥胖小鼠以及db/db小鼠。ob/ob小鼠是一種突變小鼠,牠無法製造調節食慾的激素受素。因此,ob/ob小鼠吃的過量而變得過胖。牠是一種用於高血糖症、胰島素耐受性以及肥胖的標準動物模型。另一種用於糖
尿病的標準動物模型是帶有缺陷瘦素受體活性的db/db小鼠。這種小鼠的特徵也是肥胖、高血糖症以及胰島素抗性。
本發明的醫藥組成物含有治療有效數量的個別化合物以及一般來說可接受的藥學載劑、稀釋劑或賦形劑,例如無菌水、生理食鹽水、抑菌食鹽水(亦即含有約0.9%mg/ml苄醇的食鹽水)、磷酸鹽緩衝食鹽水、漢克氏(Hank)溶液、林格氏(Ringer)溶液、乳糖、右旋糖、蔗糖、海藻糖、山梨糖醇、甘露糖醇以及類似物。該組成物通常是一種溶液或懸浮液。它可以口服地、皮下地、肌肉內地、肺部地、藉由吸入被投藥和/或透過持續釋放投藥。較佳地,該組成物是皮下地被投藥。
術語「治療有效數量」通常表示一化合物會造成所欲治療和/或預防效果而不會造成無法接受的副作用的數量。典型劑量範圍是從每天約0.01mg至每天約1000mg。就各個治療有效化合物來說,較佳的劑量範圍是從每天約0.1mg至每天約100mg,而最佳的劑量範圍是從約1.0mg/天至約10mg/天,特別是約1-5mg/天。
在接續投藥(等)的情況下,該醫藥組成物的各個化合物在時間期間內被投藥,其中仍可在「葡萄糖耐受性試驗」中測得FGF-21化合物以及GLP-1R激動劑的協同效用,像是例如在實施例中所示。葡萄糖耐受性試驗是一種在投予葡萄糖之後決定葡萄糖有多快從血液中清除的試驗。葡萄糖大部分通常是口服給予(「口服葡萄糖耐受性試驗」或「OGTT」)。有關於各個化合物接續投藥的時間期間,特別是FGF-21化合物以及GLP-1R激動劑,通常是在1小時內,較佳地在半小時內,最佳地在15分鐘內,尤其是在5分鐘內。
一般而言,每天將醫藥組成物施用予患者1或數次,或1週1或數次,或甚至在更長的時間期間內,端視情況而定。本發明之醫藥組成物的最佳施用是以組合劑量每天皮下施用1至3次。
本發明的醫藥組成物會藉由更快並更有效率地使用葡萄糖來降低血糖濃度至高達正常血糖濃度,並且增加能量消耗,而因此可用於治療至少一種代謝症候群和/或動脈粥樣硬化,特別是第1型或第2
型糖尿病、異常血脂症、肥胖和/或脂肪過多,尤其是第2型糖尿病。
因此,本發明亦有關於使用所述醫藥組成物(等)用於製備供治療至少一種上述疾病或障礙的醫藥品,以及一種用以治療一患者體內的至少一種上述疾病的方法。該患者特別是選自於第1型糖尿病患者、第2型糖尿病患者,特別是膳食治療的第2型糖尿病患者、磺醯脲治療的第2型糖尿病患者、極晚期階段的第2型糖尿病患者和/或胰島素長期治療的第2型糖尿病患者。該醫藥品可以藉由一習於該技藝者所熟知的方法來製備,例如藉由將藥學有效數量的化合物或化合物等與一可接受的藥學載劑、稀釋劑或賦形劑(如上所述)混合。
下列圖式以及實施例是僅供說明之用,而非意欲要限制本發明。
第1圖顯示利拉魯肽的化學結構。
第2圖顯示CJC-1131的化學結構。
第3圖顯示在FGF-21與AVE0010一起皮下注射之後,隨著時間於ob/ob小鼠體內的血漿葡萄糖濃度。所有的數據是平均值±SEM,每組n=6。
第4圖顯示在FGF-21與AVE0010一起皮下注射10天之後,於ob/ob小鼠體內的口服葡萄糖耐受性試驗(OGTT)結果。所有的數據是平均值±SEM,每組n=6。
第5圖顯示在FGF-21皮下注射與西他列汀口服治療10天之後於ob/ob小鼠體內的肝臟三酸甘油酯濃度。所有的數據是平均值±SEM,每組n=6,* P<0.05;*** P<0.001相對於媒劑治療的肥胖對照組。
第6圖顯示在FGF-21與AVE0010一起皮下注射之後,隨著時間於db/db小鼠體內的血漿葡萄糖濃度。所有的數據是平均值±SEM,每組n=6。
第7圖顯示在FGF-21與AVE0010一起皮下注射21天之後,於db/db小鼠體內的OGTT結果。所有的數據是平均值±SEM,每組n=6。
第8圖顯示在FGF-21與AVE0010或艾塞那肽一起皮下注射之後的8週期間內,於db/db小鼠體內的血漿葡萄糖濃度。所有的數據是平均值±SEM,每組n=6。
第9圖顯示在FGF-21與AVE0010或艾塞那肽一起皮下注射之後的8週期間內,於db/db小鼠體內的血漿HbA1c濃度。所有的數據是平均值±SEM,每組n=6。
第10圖顯示在FGF-21與AVE0010或艾塞那肽一起皮下注射8週之後,db/db小鼠體內的體溫。所有的數據是平均值±SEM,每組n=6,** P<0.01;*** P<0.001相對於媒劑治療的肥胖對照組。
第11圖顯示DIO小鼠在FGF-21與AVE0010一起皮下注射16天之後的胰島素耐受性試驗(ITT)結果。所有的數據是平均值±SEM,每組n=8,* P<0.05相對於媒劑治療的HFD對照組。
第12圖顯示DIO小鼠在FGF-21與AVE0010一起皮下注射3週之後的體重變化。所有的數據是平均值±SEM,每組n=8,* P<0.05相對於媒劑治療的HFD對照組。
雌性ob/ob小鼠(B6.V-LEP OB/J,6週大)是得自於Charles Rivers實驗室(Sulzfeld,德國)。將小鼠隨機分成治療組或媒劑組,並且隨機化是依據體重以及飽食血糖濃度來分級。每6隻為1群的動物被豢養23℃下以及12小時光照-黑暗週期。所有的實驗操作步驟是依據德國動物保護法來進行。小鼠在藥物治療期間可任意地食用標準齧齒動物食物。在整個研究期間每隔1天記錄體重,且1週測量食物攝入1次。
以媒劑(PBS)、0.05mg.kg-1.天-1 AVE0010、0.75mg.kg-1.天-1重組型人類FGF-21(SEQ ID NO:2)或FGF-21(SEQ ID NO:2)與AVE0010(0.75+0.05mg.kg-1.天-1)的組合劑量來治療ob/ob小鼠。第
1次治療前1天以及在研究第10天於飽食狀況下藉由尾端採血來測量血糖。如第3圖中所示,經治療的小鼠的血糖濃度變成正常血糖。在研究第8天進行葡萄糖耐受性試驗(OGTT)。以2g.kg-1葡萄糖口服刺激禁食小鼠。在指定時間點於沒有麻醉的情況下藉由尾端採血來測量血糖。OGTT的結果顯示於第4圖。與僅投藥FGF-21或僅投藥AVE0010相較之下,葡萄糖耐受性明顯地透過組合治療而被強烈改善。經組合治療的肥胖動物對於葡萄糖要比精瘦的對照組動物更能耐受。
在另一個實驗中,以媒劑(PBS),或0.75mg.kg-1.天-1重組型人類FGF-21(SEQ ID NO:2)皮下,或5mg.kg-1.天-1西他列汀每天或每天1次,或FGF-21 s.c.(SEQ ID NO:2)與西他列汀p.o.(0.75+5mg.kg-1.天-1)的組合劑量來治療雌性ob/ob小鼠。在第10天收取肝臟供脂肪分析。進行肝臟脂肪萃取並且測量脂肪含量。當與以媒劑治療的小鼠或單獨投藥FGF-21或西他列汀相較之下,在以FGF-21皮下注射組合DDPIV抑制劑西他列汀口服投藥治療歷時10天之後,於ob/ob小鼠的肝臟中發現脂肪累積明顯降低(第5圖)。
以媒劑(PBS)、0.05mg.kg-1.天-1 AVE0010、0.75mg.kg-1.天-1重組型人類FGF-21(SEQ ID NO:2)或FGF-21(SEQ ID NO:2)與AVE0010(0.75+0.05mg.kg-1.天-1)的組合劑量皮下地來治療雌性db/db小鼠(BKS.Cg-m +/+ Leprdb/J,6週大)每天1次。小鼠可任意地進食。在第1次治療前、1週與4週後於飽食狀況下來測量血糖以及HbA1c。在治療21天之後開始口服葡萄糖耐受性試驗(OGTT)。以2g.kg-1葡萄糖溶液口服刺激禁食小鼠並且在指定時間點測量血糖。結果顯示於第6與7圖中。與經媒劑處理的肥胖對照組相較之下,FGF21加上AVE0010組合投藥會造成血糖正常化以及大為改善血糖耐受性。另一方面,與組合相較之下,單獨以FGF21或AVE0010治療僅會抑制血糖增加以及少許地改善血糖耐受性。
在另一個實驗中,以媒劑(PBS),或0.05mg.kg-1.天-1AVE0010,
或0.04mg.kg-1.天-1艾塞那肽,或0.75mg.kg-1.天-1重組型人類FGF-21(SEQ ID NO:2),或FGF-21(SEQ ID NO:2)與AVE0010(0.75+0.05mg.kg-1.天-1)的組合劑量,或FGF-21(SEQ ID NO:2)與艾塞那肽(0.75+0.04mg.kg-1.天-1)皮下治療雌性db/db小鼠(BKS.Cg-m +/+ Leprdb/J,12週大)每天1次歷時8週。在飽食狀況下分析血糖濃度以及HbA1c。在治療8週之後測量直腸體溫。
當與FGF-21組合時,GLP-1R激動劑AVE0010以及艾塞那肽這兩者全部會使得血糖濃度正常化並且令HbA1c停止增加,而單獨治療就沒那麼有效,結果顯示於第8圖以及第9圖中。以FGF-21加上AVE0010或艾塞那肽的組合來治療在db/db小鼠體內的結果為,體重往精瘦對照組動物的生理正常值增加1-1.6℃,單獨治療如第10圖中所示較不有效。
在另一個實驗中,雌性C57bI6小鼠接受22週高脂膳食以誘發肥胖(DIO)。之後,以媒劑(PBS),或0.05mg.kg-1.天-1AVE0010,或0.75mg.kg-1.天-1重組型人類FGF-21(SEQ ID NO:2)或FGF-21(SEQ ID NO:2)與AVE0010(0.75+0.05mg.kg-1.天-1)的組合劑量來治療小鼠。
在整個研究期間每隔1天記錄體重,並且1週測量食物攝入1次。
於16天治療之後在未禁食動物中藉由進行胰島素耐受性試驗(ITT)來分析胰島素敏感性。i.p.注射胰島素(0.75單位.kg-1)以並且在指定時間點測量血糖(第11圖)。接著藉著小鼠胰島素ELISA套組(Mercodia,Uppsala,Sweden)來測量血清胰島素。
以FGF-21與AVE0010的組合來治療歷時16天的小鼠在飽食狀態下顯示要比接受媒劑或單獨治療的小鼠更能明顯改善胰島素敏感性並且降低基礎血糖濃度。與媒劑或單獨治療的小鼠相較之下,如同在第12圖中所示般觀察到體重劇烈下降。
人類FGF-21(SEQ ID NO:1):
突變的FGF-21(G+FGF21 H29-S209;SEQ ID NO:2):
人類GLP-1(7-37)(SEQ ID NO:3):HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG-NH2
人類GLP-1(7-36)NH2(SEQ ID NO:4):HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2
毒蜥外泌肽(SEQ ID NO:5):HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
艾塞那肽(SEQ ID NO:6):HGEGTFTSDLSKQMEEEAVRLFIETLKNGGPSSGAPPPS-NH2
調酸素(SEQ ID NO:7):HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA-NH2
利希拉來(SEQ ID NO:8):HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2
AVE0010(SEQ ID NO:9):HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2
<110> 賽諾菲阿凡提斯
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Claims (20)
- 一種醫藥組成物,包含至少一種FGF-21(纖維母細胞生長因子21)化合物以及至少一種GLP-1R(類升糖素肽-1受體)激動劑,其中組合FGF-21化合物及GLP-1R激動劑於一調配物中。
- 如申請專利範圍第1項的醫藥組成物,其中該組成物包含至少一種另一抗糖尿病藥物。
- 如申請專利範圍第2項的醫藥組成物,其中該至少一種另一抗糖尿病藥物為DPP-4(二肽基肽酶-4)抑制劑。
- 如申請專利範圍第3項的醫藥組成物,其中該組成物進一步含有至少一種額外的抗糖尿病藥物。
- 如申請專利範圍第2項的醫藥組成物,其中該至少一種另一抗糖尿病藥物被包含於同一或另一調配物中。
- 如申請專利範圍第5項的醫藥組成物,其中包含FGF-21化合物及GLP-1R激動劑之調配物與包含另一抗糖尿病藥物的另一調配物適用於同時或接續投藥。
- 如申請專利範圍第1項的醫藥組成物,其中該FGF-21化合物選自於FGF-21或FGF-21仿效物,其中該FGF-21仿效物選自由下列組成之群組:相對於SEQ ID NO:1中所示的胺基酸序列具有至少約96%胺基酸序列同一性並且具有FGF-21活性的蛋白質、FGF-21融合蛋白質、FGF-21接合物、FGF-21突變蛋白、FGF-21-Fc融合蛋白質、FGF-21-HSA融合蛋白質及PEG化FGF-21。
- 如申請專利範圍第1項的醫藥組成物,其中該GLP-1R激動劑選自於具有生物活性的GLP-1、GLP-1類似物或GLP-1代用品。
- 如申請專利範圍第8項的醫藥組成物,其中該GLP-1R激動劑選自於GLP-1(7-37)、GLP-1(7-36)醯胺、毒蜥外泌肽(extendin-4)、利拉魯肽(liraglutide)、CJC-1131、阿必魯泰(albugon)、阿必魯泰(albiglutide)、艾塞那肽(exenatide)、艾塞那肽-LAR(exenatide-LAR)、調酸素(oxyntomodulin)、利希拉來(lixisenatide)、京尼平苷(geniproside)、AVE-0010(SEQ ID NO:9)、具有GLP-1R激動活性的短肽和/或具有GLP-1R激動活性的小有機化合物。
- 如申請專利範圍第2項的醫藥組成物,其中該抗糖尿病藥物選自於甲福明、噻唑烷二酮、磺醯脲和/或胰島素。
- 如申請專利範圍第3項的醫藥組成物,其中該DPP-4抑制劑選自於西他列汀(sitagliptin)、維格列汀(vildagliptin)、沙格列汀(saxagliptin)、利拉利汀(linagliptin)、阿洛利汀(adogliptin)和/或小蘗鹼。
- 一種醫藥組成物,其含有根據SEQ ID NO:2之FGF-21(纖維母系胞生長因子21)、視情況之至少一種另一FGF-21化合物及至少一種GLP-1R(類升糖素肽-1受體)激動劑。
- 如申請專利範圍第1-12項中一項的醫藥組成物,其用於治療至少一種代謝症候群和/或動脈粥樣硬化之。
- 如申請專利範圍第13項的醫藥組成物,其中該代謝症候群是選自於糖尿病、異常血脂症、肥胖和/或脂肪過多。
- 如申請專利範圍第13項的醫藥組成物,其中該代謝症候群為2型糖尿病。
- 一種如申請專利範圍第1-12項中至少一項的醫藥組成物於製備醫藥品的用途,該藥品用於治療患者的至少一種代謝症候群和/或動脈粥樣硬化。
- 如申請專利範圍第16項的用途,其中該代謝症候群選自於糖尿病、異常血脂症、肥胖和/或脂肪過多。
- 如申請專利範圍第16項的用途,其中該代謝症候群為第2型糖尿病。
- 如申請專利範圍第16、17或18項的用途,其中該患者為第1型糖尿病患者或第2型糖尿病患者。
- 如申請專利範圍第19項的用途,其中該第2型糖尿病患者係選自由下列組成之群組:膳食治療的第2型糖尿病患者、磺醯脲治療的第2型糖尿病患者、極晚期階段的第2型糖尿病患者和/或胰島素長期治療的第2型糖尿病患者。
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Families Citing this family (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RS56632B1 (sr) | 2008-10-17 | 2018-03-30 | Sanofi Aventis Deutschland | Kombinacija insulina i glp-1-agonista |
CN102711804B (zh) | 2009-11-13 | 2015-09-16 | 赛诺菲-安万特德国有限公司 | 包含glp-1激动剂和甲硫氨酸的药物组合物 |
AU2010317995B2 (en) | 2009-11-13 | 2014-04-17 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a GLP-1 agonist, an insulin, and methionine |
JP6199186B2 (ja) | 2010-08-30 | 2017-09-20 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | 2型糖尿病の治療用の医薬の製造のためのave0010の使用 |
US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
AU2012279237B2 (en) | 2011-07-01 | 2016-09-29 | Ngm Biopharmaceuticals, Inc. | Compositions, uses and methods for treatment of metabolic disorders and diseases |
EP2548570A1 (en) * | 2011-07-19 | 2013-01-23 | Sanofi | Pharmaceutical composition for treating a metabolic syndrome |
TWI559929B (en) | 2011-09-01 | 2016-12-01 | Sanofi Aventis Deutschland | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
TW201315742A (zh) | 2011-09-26 | 2013-04-16 | Novartis Ag | 治療代謝病症之雙功能蛋白質 |
SG11201500682WA (en) * | 2012-09-07 | 2015-02-27 | Sanofi Sa | Fusion proteins for treating a metabolic syndrome |
US9290557B2 (en) | 2012-11-28 | 2016-03-22 | Ngm Biopharmaceuticals, Inc. | Compositions comprising variants and fusions of FGF19 polypeptides |
WO2014085365A2 (en) | 2012-11-28 | 2014-06-05 | Ngm Biopharmaceuticals, Inc. | Compositions and methods for treatment of metabolic disorders and diseases |
JP6403685B2 (ja) | 2012-12-27 | 2018-10-17 | エヌジーエム バイオファーマシューティカルス,インコーポレーテッド | 胆汁酸ホメオスタシス調整並びに胆汁酸障害及び疾患の治療の方法 |
US9273107B2 (en) | 2012-12-27 | 2016-03-01 | Ngm Biopharmaceuticals, Inc. | Uses and methods for modulating bile acid homeostasis and treatment of bile acid disorders and diseases |
NZ718962A (en) | 2013-10-28 | 2019-12-20 | Ngm Biopharmaceuticals Inc | Cancer models and associated methods |
US9738716B2 (en) | 2014-01-24 | 2017-08-22 | Ngm Biopharmaceuticals, Inc. | Beta klotho binding proteins and methods of use thereof |
WO2015121457A1 (en) * | 2014-02-13 | 2015-08-20 | Westphal Sören | Fgf-8 for use in treating diseases or disorders of energy homeostasis |
EP3125921B1 (en) | 2014-03-11 | 2020-07-08 | Novartis AG | Fgf21 variants for use in treating hiv-haart induced partial lipodystrophy |
EP3139948B1 (en) * | 2014-05-07 | 2020-03-04 | Novo Nordisk A/S | Treatment of diabetes type 1 using glp-1 and anti-il-21 |
US10398758B2 (en) | 2014-05-28 | 2019-09-03 | Ngm Biopharmaceuticals, Inc. | Compositions comprising variants of FGF19 polypeptides and uses thereof for the treatment of hyperglycemic conditions |
AU2015277438B2 (en) | 2014-06-16 | 2020-02-27 | Ngm Biopharmaceuticals, Inc. | Methods and uses for modulating bile acid homeostasis and treatment of bile acid disorders and diseases |
CN104383523A (zh) * | 2014-10-22 | 2015-03-04 | 山西医科大学 | Cjc-1131降糖药物在治疗阿尔茨海默病的用途 |
RU2729161C2 (ru) | 2014-10-23 | 2020-08-04 | ЭнДжиЭм БАЙОФАРМАСЬЮТИКАЛЗ, ИНК. | Фармацевтические композиции, содержащие варианты пептидов, и способы их применения |
US10434144B2 (en) | 2014-11-07 | 2019-10-08 | Ngm Biopharmaceuticals, Inc. | Methods for treatment of bile acid-related disorders and prediction of clinical sensitivity to treatment of bile acid-related disorders |
MX2017007699A (es) | 2014-12-12 | 2017-09-18 | Sanofi Aventis Deutschland | Formulacion de proporcion fija de insulina glargina/lixisenatida. |
TWI748945B (zh) | 2015-03-13 | 2021-12-11 | 德商賽諾菲阿凡提斯德意志有限公司 | 第2型糖尿病病患治療 |
TW201705975A (zh) | 2015-03-18 | 2017-02-16 | 賽諾菲阿凡提斯德意志有限公司 | 第2型糖尿病病患之治療 |
US10800843B2 (en) | 2015-07-29 | 2020-10-13 | Ngm Biopharmaceuticals, Inc. | Beta klotho-binding proteins |
US10744185B2 (en) | 2015-11-09 | 2020-08-18 | Ngm Biopharmaceuticals, Inc. | Methods of using variants of FGF19 polypeptides for the treatment of pruritus |
US11370841B2 (en) | 2016-08-26 | 2022-06-28 | Ngm Biopharmaceuticals, Inc. | Methods of treating fibroblast growth factor 19-mediated cancers and tumors |
RU2019122785A (ru) | 2016-12-22 | 2021-01-22 | Санофи | Комбинации соединения на основе fgf21/агониста glp-1r с оптимизированным соотношением активности |
JP2018110304A (ja) | 2016-12-28 | 2018-07-12 | パナソニックIpマネジメント株式会社 | 監視システム、監視方法、及びプログラム |
US20220127322A1 (en) * | 2017-03-14 | 2022-04-28 | Sunshine Lake Pharma Co., Ltd. | Dual-target fusion proteins comprising the fc portion of an immunoglobulin |
SG11202006903WA (en) * | 2018-01-31 | 2020-08-28 | Sanofi Sa | Modified lipidated relaxin b chain peptides and their therapeutic use |
EP3749683A4 (en) | 2018-02-08 | 2022-03-16 | Sunshine Lake Pharma Co., Ltd. | FGF21 VARIANT, FUSION PROTEIN AND USE THEREOF |
WO2019243557A1 (en) | 2018-06-21 | 2019-12-26 | Sanofi | Fgf21 compound / glp-1r agonist combinations with optimized activity ratio |
CN113728013B (zh) | 2020-01-11 | 2022-06-14 | 北京质肽生物医药科技有限公司 | Glp-1和fgf21的融合蛋白的缀合物 |
KR20210149366A (ko) * | 2020-06-02 | 2021-12-09 | 주식회사 고바이오랩 | Icam-2에 결합하는 물질을 유효성분으로 포함하는 대사질환 예방 또는 치료용 약학 조성물 |
US20220010021A1 (en) | 2020-07-02 | 2022-01-13 | Sanofi | FGFR1/KLB Targeting Agonistic Antigen-Binding Proteins and Conjugates Thereof with GLP-1R Agonistic Peptides |
CN114712488B (zh) * | 2021-01-04 | 2023-12-26 | 华领医药技术(上海)有限公司 | Dorzagliatin和胰高血糖素样肽-1类似物的药物组合物 |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK347086D0 (da) | 1986-07-21 | 1986-07-21 | Novo Industri As | Novel peptides |
PH25772A (en) | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
IE62879B1 (en) | 1987-02-25 | 1995-03-08 | Novo Nordisk As | Novel insulin derivatives |
US6011007A (en) | 1993-09-17 | 2000-01-04 | Novo Nordisk A/S | Acylated insulin |
BR9407508A (pt) | 1993-09-17 | 1997-01-07 | Novo Nordisk As | Derivado de insulina composição farmaceutica e processo para o tratamento de diabete em um paciente com necessidade deste tratamento |
UA65549C2 (uk) * | 1996-11-05 | 2004-04-15 | Елі Ліллі Енд Компані | Спосіб регулювання ожиріння шляхом периферійного введення аналогів та похідних glp-1 (варіанти) та фармацевтична композиція |
JP2002112772A (ja) * | 2000-07-10 | 2002-04-16 | Takeda Chem Ind Ltd | 新規ポリペプチドおよびそのdna |
US6689385B2 (en) * | 2000-11-03 | 2004-02-10 | Chronorx Llc | Formulations for the treatment of insulin resistance and type 2 diabetes mellitus |
WO2003011213A2 (en) | 2001-07-30 | 2003-02-13 | Eli Lilly And Company | Method for treating diabetes and obesity |
AR036711A1 (es) | 2001-10-05 | 2004-09-29 | Bayer Corp | Peptidos que actuan como agonistas del receptor del glp-1 y como antagonistas del receptor del glucagon y sus metodos de uso farmacologico |
CA2497794A1 (en) * | 2002-09-06 | 2004-03-18 | Bayer Pharmaceuticals Corporation | Modified glp-1 receptor agonists and their pharmacological methods of use |
ES2298785T3 (es) | 2003-06-12 | 2008-05-16 | Eli Lilly And Company | Proteinas de fusion. |
EA200601121A1 (ru) | 2003-12-10 | 2006-10-27 | Эли Лилли Энд Компани | Мутеины фактора роста фибробластов 21 |
WO2005072769A1 (en) | 2004-01-26 | 2005-08-11 | Eli Lilly And Company | Use of fgf-21 and thiazolidinedione for treating type 2 diabetes |
EP1735340A2 (en) | 2004-03-17 | 2006-12-27 | Eli Lilly And Company | Glycol linked fgf-21 compounds |
US7576190B2 (en) | 2004-05-13 | 2009-08-18 | Eli Lilly And Company | FGF-21 fusion proteins |
US7622445B2 (en) | 2004-09-02 | 2009-11-24 | Eli Lilly And Company | Muteins of fibroblast growth factor 21 |
EP2161281A1 (en) | 2004-09-02 | 2010-03-10 | Eli Lilly & Company | Muteins of fibroblast growth factor 21 |
SI2586456T1 (sl) | 2004-10-29 | 2016-05-31 | Ratiopharm Gmbh | Preoblikovanje in glikopegliacija fibroblastnega rastnega faktorja (FGF) |
US7655627B2 (en) | 2004-12-14 | 2010-02-02 | Eli Lilly And Company | Muteins of fibroblast growth factor 21 |
WO2008019143A2 (en) * | 2006-08-04 | 2008-02-14 | Amylin Pharmaceuticals, Inc | Use of exendins and glp-i receptor agonists for altering lipoprotein particle size and subclass composition |
TW200843794A (en) * | 2006-12-21 | 2008-11-16 | Centocor Inc | Use of long-acting GLP-1 receptor agonists to improve insulin sensitivity and lipid profiles |
BRPI0809583B1 (pt) * | 2007-03-30 | 2022-02-22 | Ambrx, Inc | Polipeptídeo fgf-21 modificado, composição compreendendo o mesmo, método para produzir o referido polipetídeo fgf-21 e célula compreendendo um polinucleotídeo |
ES2646614T3 (es) * | 2007-08-03 | 2017-12-14 | Eli Lilly And Company | Uso de un compuesto de FGF 21 y un compuesto de GLP 1 para el tratamiento de la obesidad |
GB0716385D0 (en) * | 2007-08-22 | 2007-10-03 | Camurus Ab | Formulations |
JP5647899B2 (ja) | 2008-01-08 | 2015-01-07 | ラツィオファルム ゲーエムベーハーratiopharm GmbH | オリゴサッカリルトランスフェラーゼを使用するポリペプチドの複合糖質化 |
WO2010006214A1 (en) * | 2008-07-09 | 2010-01-14 | Ambrx, Inc. | Fgf-21 neutralizing antibodies and their uses |
US20120052069A1 (en) * | 2009-05-05 | 2012-03-01 | Amgen Inc | Fgf21 mutants and uses thereof |
EP2440235A1 (en) * | 2009-06-11 | 2012-04-18 | Novo Nordisk A/S | Glp-1 and fgf21 combinations for treatment of diabetes type 2 |
EP2548570A1 (en) * | 2011-07-19 | 2013-01-23 | Sanofi | Pharmaceutical composition for treating a metabolic syndrome |
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