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(12) Patent Application Publication (10) Pub. No.: US 2015/0184142 A1 Hong Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0184142 A1 Hong Et Al US 2015O184142A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0184142 A1 Hong et al. (43) Pub. Date: Jul. 2, 2015 (54) PROCOAGULANT COMPOUNDS Publication Classification (71) Applicant: Biogen Idec MA Inc., Cambridge, MA (51) Int. Cl. (US) CI2N 9/64 (2006.01) A638/48 (2006.01) (72) Inventors: Vu Phong Hong, Cambridge, MA (US); (52) U.S. Cl. Adam R. Mezo, Carmel, IN (US); Joe CPC .......... CI2N 9/6437 (2013.01); A61 K38/4846 E.W. R.E. Rober (2013.01); C12N 9/6432 (2013.01) s s (57) ABSTRACT (73) Assignee: BiogenUS) Idec MA Inc., Cambridge, MA agulantAs present compounds till comprising provides aPrsity procoagulant polypeptide,G. ( e.g., a procoagulant peptide and/or clotting factor, and a linker comprising a protease-cleavable Substrate (e.g., a syn (21) Appl. No.: 14/406,163 thetic thrombin Substrate) and a self-immolative spacer (e.g., (22) PCT Filed: Jun. 7, 2013 p-amino benzyl carbamate). Upon cleavage of the protease cleavable Substrate by a protease (e.g., thrombin), the self (86). PCT No.: PCT/US13A44841 immolative spacer cleaves itself from the procoagulant polypeptide such that the polypeptide is in an underivatized S371 (c)(1), and active form. Also provided are pharmaceutical composi (2) Date: Dec. 5, 2014 tions, methods for treating bleeding disorders using the dis closed compounds, methods of enhancing in vivo efficacy of Related U.S. Application Data procoagulant polypeptides, methods of increasing the effi .S. App cacy of proteolytic cleavage of compounds comprising pro (60) Provisional application No. 61/657,688, filed on Jun. coagulant polypeptides, methods of activating procoagulant 8, 2012, provisional application No. 61/800,626, filed polypeptides, and methods of releasing a procoagulant on Mar. 15, 2013. polypeptide from a heterologous moiety such as PEG. Patent Application Publication Jul. 2, 2015 Sheet 1 of 22 US 201S/O1841-42 A1 Patent Application Publication Jul. 2, 2015 Sheet 2 of 22 US 201S/O1841-42 A1 Patent Application Publication Jul. 2, 2015 Sheet 3 of 22 US 201S/O1841-42 A1 ?3paraeodw?o?y? Patent Application Publication Jul. 2, 2015 Sheet 5 of 22 US 201S/O1841-42 A1 *********~~~~&&&&&&&&&&&&&&~~~ zpunodwuod **** Patent Application Publication Jul. 2, 2015 Sheet 6 of 22 US 201S/O1841-42 A1 3 S. S. S 9 s A pris Patent Application Publication Jul. 2, 2015 Sheet 7 of 22 US 201S/O1841-42 A1 & & s S. 8. S& is S. S.8 Ys. s: xxxx-xx-x S&asssssss&xas& SSNXSSX is: Patent Application Publication Jul. 2, 2015 Sheet 8 of 22 US 201S/O1841-42 A1 &~~~~~~~~~~~--~~~~~~••••••• ~~~~); 00|| (%) pe. Patent Application Publication Jul. 2, 2015 Sheet 9 of 22 US 201S/O1841-42 A1 punoduop&? 09Tl{}{}{090 punoduuoo Patent Application Publication Jul. 2, 2015 Sheet 11 of 22 US 201S/O1841-42 A1 passa/dx= ?apoy Patent Application Publication Jul. 2, 2015 Sheet 12 of 22 US 201S/O1841-42 A1 Patent Application Publication Jul. 2, 2015 Sheet 13 of 22 US 201S/O1841-42 A1 passaudx= Patent Application Publication Jul. 2, 2015 Sheet 14 of 22 US 201S/O1841-42 A1 Patent Application Publication Jul. 2, 2015 Sheet 15 of 22 US 201S/O1841-42 A1 0998.I-II/A-1-\fL98T-IMAH OWNTIS Patent Application Publication US 201S/O1841-42 A1 Jul. 2, 2015 Sheet 17 of 22 US 201S/O1841-42 A1 33 Patent Application Publication Jul. 2, 2015 Sheet 18 of 22 US 201S/O1841-42 A1 O f *------ CC Patent Application Publication Jul. 2, 2015 Sheet 19 of 22 US 201S/O1841-42 A1 Patent Application Publication Jul. 2, 2015 Sheet 20 of 22 US 201S/O1841-42 A1 Patent Application Publication US 201S/O1841-42 A1 OWTIS Patent Application Publication Jul. 2, 2015 Sheet 22 of 22 US 201S/O1841-42 A1 u?quod?LJ???eÁeSSV0?uÐ30Uuou?OeX ZTO-X-H-VLJOuO??e^{10\/ ZZ"91: GOt, W US 2015/O 184142 A1 Jul. 2, 2015 PROCOAGULANT COMPOUNDS Some embodiments, the present disclosure provides A proco agulant compound having a formula: BACKGROUND (Het2)-(Pep2)-(Het1)-(L)-Zy-Bx-Pep1 (Formula I) 0001 1. Field of the Disclosure wherein, 0002 The present invention relates to procoagulant com 0007 Het1 is a first heterologous molecule, which is either pounds useful for the treatment of bleeding diseases or dis absent or present; orders. 0008 Het2 is a second heterologous molecule, which is 0003 2. Background either absent or present; 0004. The blood coagulation pathway, in part, involves the 0009 L is a linker, which is either absent or present; formation of an enzymatic complex of Factor VIIIa (FVIIIa) 00.10 Zy is a protease-cleavable substrate; and Factor IXa (FIXa) (Xase complex) on the surface of 0011 Bx is a self-immolative spacer; platelets. FIXa is a serine protease with relatively weak cata 0012 Pep1 is a polypeptide; and, lytic activity without its cofactor FVIIIa. The Xase complex 0013 Pep2 is a polypeptide, which is either absent or cleaves Factor X (FX) into Factor Xa (FXa), which in turn present; interacts with Factor Va (FVa) to cleave prothrombin and wherein, Pep 1 or Pep2 comprises a clotting factor or a frag generate thrombin. Hemophilia A is a bleeding disorder ment thereof, or a synthetic procoagulant peptide. caused by mutations and/or deletions in the factor VIII 0014. In some embodiments, the self-immolative spacer in (FVIII) gene resulting in a deficiency of FVIII activity (Pey the procoagulant compound of the invention undergoes 1.4 vandi et al. 2006). Hemophilia B (also known as Christmas elimination after the enzymatic cleavage of the protease disease) is one of the most common inherited bleeding disor cleavable substrate. In some embodiments, the self-immola ders in the world. It results in decreased in vivo and in vitro tive spacer in the procoagulant compound of the invention blood clotting activity and requires extensive medical moni undergoes 1.6 elimination after the enzymatic cleavage of the toring throughout the life of the affected individual. protease-cleavable substrate. In some embodiments, the self 0005 Treatment of hemophilia is by replacement therapy immolative spacer is a p-amino benzyl carbamate (PABC), a targeting restoration of clotting activity. There are plasma p-aminobenzyl ether (PABE), or a p-aminobenzyl carbonate. derived and recombinant clotting factor products available to In certain embodiments, the self-immolative spacer com treat bleeding episodes on-demand or to prevent bleeding prises an aromatic group. In some embodiments, the aromatic episodes from occurring by treating prophylactically. Based group is selected from the group consisting of benzyl, cin on the half-life of these products, treatment regimens require namyl, naphthyl, and biphenyl. In some embodiments, the frequent intravenous administration. Such frequent adminis aromatic group is heterocyclic. In other embodiments, the tration is painful and inconvenient. Strategies to extend the aromatic group comprises at least one substituent. In some half-life of clotting factors include pegylation (Rostin J, et al., embodiments, at least one substituent is selected from F, Cl, I, Bioconi. Chem. 2000: 11:387-96), glycopegylation (Sten Br, OH, methyl, methoxy, NO, NH, NO", NHCOCH, nicke HR, et al., Thromb. Haemost. 2008: 100:920-8), for N(CH), NHCOCF, alkyl, haloalkyl, C-C alkylhalide, mulation with pegylated liposomes (Spira J. et al., Blood carboxylate, Sulfate, Sulfamate, Sulfonate, or any combina 2006; 108:3668-3673, Pan J, et al., Blood 2009; 114:2802 tions thereof. In other embodiments, at least one C in the 2811) and conjugation with albumin (Schulte S., Thromb. aromatic group is substituted with N, O, or C R, wherein Res. 2008: 122 Suppl 4:S14-9). However, modification of R is independently selected from H. F. Cl. I, Br, OH, methyl, coagulation factors and procoagulant peptides with half-life methoxy, NO, NH, NO"NHCOCH, N(CH), extending moieties (e.g., PEG) and other similar strategies to NHCOCF, alkyl, haloalkyl, C-C alkylhalide, carboxylate, extend their half-lives can lead to compromised activity. In Sulfate, Sulfamate, and Sulfonate. order to rescue their activity, a cleavable linker can be inserted 0015. In some embodiments, the protease-cleavable sub between the protein orpeptide of interest and its modifier. The strate in the procoagulant compound of the invention com chosen cleavable linker must be cleaved efficiently and rap prises a coagulation cascade protease Substrate. In some idly by a protease, for example, a protease involved in the embodiments, the coagulation cascade protease is selected coagulation cascade. Thrombin being the activator of many from thrombin, thromboplastin, Factor Va., Factor VIIa, Fac clotting factors is the most popular choice. However, all tor Villa, Factor IXa, Factor Xa, Factor XIa, Factor XIIa, or known Substrate sequences composed of natural amino acids any combinations thereof. In other embodiments, the coagu (e.g., LVPR, ALRPR (SEQ ID NO: 7), etc.) are not optimal lation cascade protease Substrate is a thrombin Substrate. In substrates. Furthermore, covalent binding of the cleavable Some embodiments, the thrombin Substrate is a synthetic linker to a coagulation factors or procoagulant peptide can thrombin substrate. In other embodiments, the synthetic result in Steric hindrances (e.g., due to the presence of amino thrombin substrate comprises the sequence of D-Phe-Pip acids such as such as proline, isoleucine or arginine C-termi Arg. In some embodiments, the thrombin Substrate is selected nal to the cleavage site) that can prevent an efficient enzy from D-Phe-Pro-Arg, D-Ala-Leu-Val-Pro-Arg (SEQID NO: matic cleavage reaction. 17), Ala-Leu-Val-Pro-Arg (SEQ ID NO: 17), Leu-Val-Pro Arg (SEQ ID NO: 18), or Ala-Leu-Arg-Pro-Arg (SEQ ID BRIEF SUMMARY NO:90). 0016. In some embodiments, the protease-cleavable sub 0006.
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