JP-7856872-B2 - Treatment methods for tissue calcification

Inventors

• クイン，アンソニー
• シア，ネルソン
• カーン，タイェバ
• アスキュー，キム リネット
• グラボウスキ，グレゴリー
• チェン，ジリアン
• オニール，ダブリュ．チャールズ

Assignees

• バイオマリン ファーマシューティカル インコーポレイテッド

Dates

Publication Date

20260512

Application Date

20210913

Priority Date

20141219

Claims (20)

1. A pharmaceutical composition for treating, as needed, a disease caused by a mutation in the gene encoding the MRP6 protein in a subject , wherein the pharmaceutical composition comprises isolated recombinant human sNPP1, a fragment or fusion protein containing the NPP1 domain essential for exhibiting its pyrophosphatase and/or phosphodiesterase activity , and the pharmaceutical composition is for reducing vascular calcification in the subject.
2. A pharmaceutical composition according to claim 1, characterized in that the subject is a human patient.
3. A pharmaceutical composition according to claim 1 or 2, characterized in that a fragment or fusion protein containing the isolated recombinant human sNPP1, the NPP1 domain essential for exhibiting its pyrophosphatase and/or phosphodiesterase activity is administered in an amount of about 0.10 to about 50 mg/kg.
4. A pharmaceutical composition according to claim 3, characterized in that the amount is approximately 0.5 mg/kg.
5. A pharmaceutical composition according to claim 3, characterized in that the amount is approximately 1 mg/kg.
6. A pharmaceutical composition according to claim 3, characterized in that the amount is approximately 5.0 mg/kg.
7. A pharmaceutical composition according to claim 3, characterized in that the amount is approximately 6.0 mg/kg.
8. A pharmaceutical composition according to claim 3, characterized in that the amount is approximately 10 mg/kg.
9. A pharmaceutical composition according to claim 3, characterized in that the amount is approximately 15 mg/kg.
10. A pharmaceutical composition according to claim 3, characterized in that the amount is approximately 20 mg/kg.
11. A pharmaceutical composition according to any one of claims 1 to 10, characterized in that it is administered approximately once a week.
12. A pharmaceutical composition according to any one of claims 1 to 10, characterized in that it is administered approximately once every two weeks.
13. A pharmaceutical composition according to any one of claims 1 to 10, characterized in that it is administered approximately once a month.
14. A pharmaceutical composition according to any one of claims 1 to 10, characterized in that it is for intravenous, subcutaneous, intrathecal, or intraperitoneal administration.
15. A pharmaceutical composition according to any one of claims 1 to 10, characterized in that it is for intravenous administration.
16. A pharmaceutical composition according to any one of claims 1 to 10, characterized in that it is for subcutaneous administration.
17. A pharmaceutical composition according to any one of claims 1 to 10, characterized in that it is for administration sufficient to normalize the blood level of PPi in the subject.
18. A pharmaceutical composition according to any one of claims 1 to 10, characterized in that it is sufficient for administration to prevent calcification of the affected tissue in the subject.
19. A pharmaceutical composition according to any one of claims 1 to 18 , characterized in that the pharmaceutical composition contains the fusion protein of the isolated recombinant human sNPP1 .
20. A pharmaceutical composition according to claim 19 , characterized in that the isolated recombinant human sNPP1 fusion protein includes the Fc region of an immunoglobulin.

Description

Related Applications This application claims the benefits of U.S. Provisional Application No. 62/094,943, filed on 19 December 2014, and U.S. Provisional Application No. 62/249,781, filed on 2 November 2015. The entire teachings of the above applications are incorporated herein by reference. Reference to Electronically Submitted Sequence Listings The entire contents of the electronically submitted sequence listings in the ASCII text file (name: 081245-0208_ascii.txt; size: 88,556 bytes; and creation date: December 15, 2015) filed with this application are incorporated herein by reference. Vascular calcification can be characterized by the formation of very small dispersed crystals of hydroxyapatite (HA) and by large calcified deposits in vascular tissue, such as arteries. (Amann, K. Clin J Am Soc Nephrol 2008, 3, 1599-605). Extracellular pyrophosphates (PPi) are important endogenous inhibitors of vascular calcification by inhibiting HA formation. (Lomashville, K.A. et al., J Am Soc Nephrol 2004, 15, 1392-1401; Fleisch, H. et al., Nature 1966, 212, 901-903). Ectonucleotide pyrophosphatase pyrophosphorylase (NPP1) is an ectoenzyme that cleaves ATP to produce extracellular pyrophosphate (PPi). Pyrophosphate is a potent inhibitor of hydroxyapatite formation and, under normal conditions, functions to inhibit vascular calcification. NPP1 deficiency in humans leads to decreased circulating PPi levels and is associated with conditions such as arterial calcification and infantile systemic arterial calcification (GACI) (Rutsch, F. et al., Am J Pathol 2001, 158, 543-554). When fed a high-phosphate diet, NPP1-deficient mice (Enpp1 -/- ) also show decreased PPi levels and exhibit a phenotype similar to that of NPP1-deficient humans (Harmey, D. et al., Am J Pathol 2004, 164, 1199-1209). Vascular calcification is also a well-recognized common complication in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) and is associated with increased morbidity and mortality. (Giachelli, C.J Am Soc Nephrol 2004, 15, 2959-64; Raggi, P. et al., J Am Coll Cardiol 2002, 39, 695-701). Ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1/ENPP1/PC-1) deficiency is a rare disorder caused by mutations in the type II transmembrane glycoprotein NPP1. NPP1 cleaves various substrates, including phosphodiester bonds and pyrophosphate bonds between nucleotides and nucleotide sugars. NPP1 deficiency has been associated with idiopathic infantile arterial calcification (IIAC), insulin resistance, hypophosphatemic rickets, and ossification of the posterior longitudinal ligament of the spine. IIAC is a rare, autosomal recessive, almost certainly fatal disorder characterized by stenosis of the muscular arteries due to calcification of the internal elastic membrane and proliferation of intimal smooth muscle cells. Over 160 cases of IIAC have been reported worldwide. Symptoms of this disease almost always appear by early infancy, and the disease generally leads to death by six months of age due to complications such as ischemic cardiomyopathy and other obstructive arteriovenous disorders, including renal artery stenosis. Despite the association of NPP1 protein deficiency with serious conditions such as IIAC, there are currently no available treatments for patients with this disease, or for other calcification disorders resulting from abnormal bone metabolism leading to high systemic loadings of calcium and phosphorus; low levels of circulating and locally produced inhibitors for phosphate producers; or impaired renal excretion. Current treatment options for preventing vascular calcification have limited efficacy and undesirable and/or unacceptable side effects. For example, very large doses of exogenous PPi are required for efficacy, and other inhibitors of hydroxyapatite formation inhibit bone calcification, potentially leading to osteomalacia. In particular, direct administration of exogenous PPi has been found to prevent calcification in uremic animal models (O'Neil, W.C. et al., Kidney Int 2011, 79, 512-517; Riser, B.L. et al., Nephrol Dial Transp 2011, 26, 3349-3357). However, this approach requires high doses due to the short half-life of PPi, leading to PPi reaching hyperphysiological plasma levels and causing local irritation. Bisphosphonates, non-hydrolyzable analogs of PPi, are used, for example, to treat vascular calcification in animal models (Fleisch, H. et al., Europ J Clin Invest 1970, 1, 12-18; Price, P.A. et al., Arteriosclerosis Throm and Vas Bio 2001, 21, 817-824; Price, P.A. et al., Kidney Int 2006, 70, 1577-1583; Lomashville, K.A. et al., Kidney Int 2009, 75, 617-625). However, bisphosphonates also inhibit bone formation. Bisphosphonates can delay calcification in GACI subjects, but they cannot prevent it (Rutsch, F. et al., Circ Cardiovasc Genet 2008, 1, 133-140), and can lead to osteomalacia, as seen in animals (Otero, J.E., et al., J Bone Miner Res 2013, 28, 419-430). Braddock, D. et al. (WO2014/12696