Low-viscosity, high concentration evolocumab formulations and methods of making the same
Provided herein are formulations of PCSK9-binding polypeptides, such as those comprising evolocumab, that comprise N-acetyl arginine and have reduced viscosities when compared to formulations lacking N-acetyl arginine. Provided herein are also methods of formulating such compositions that are advantageous in that they conserve certain components. Such formulations comprising PCSK9-binding polypeptides can be administered to patients to treat and/or prevent PCSK9-related diseases, conditions, and disorders.
1. A pharmaceutical composition comprising
a. a proprotein convertase subtilisin/kexin type 9 (PCSK9)-binding polypeptide selected from the group consisting of:
i. a monoclonal antibody comprising a heavy chain polypeptide having an amino acid sequence of SEQ ID NO:1 and a light chain polypeptide having an amino acid sequence of SEQ ID NO:2 (evolocumab), or an antigen-binding fragment thereof; and
ii. a monoclonal antibody, comprising:
1. a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO:14; a heavy chain CDR2 that is a CDR2 in SEQ ID NO:14; a heavy chain CDR3 that is a CDR3 in SEQ ID NO:14, and
2. a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO:15; a light chain CDR2 that a CDR2 in SEQ ID NO:15; and a light chain CDR3 that is a CDR3 in SEQ ID NO:15; and
b. N-acetyl arginine,
wherein the pharmaceutical composition has a viscosity of no more than 80 centipoise (cP), and wherein the composition comprises high molecular weight aggregates or oligomers of the PCSK9-binding polypeptide at no more than 3% of the PCSK9-binding polypeptide.
2. The pharmaceutical composition of claim 1 , wherein the PCSK9-binding polypeptide is a monoclonal antibody comprising a heavy chain polypeptide and a light chain polypeptide comprising the following complementarity determining regions (CDRs):
a. heavy chain CDR1, CDR2, and CDR3 having an amino acid sequence of SEQ ID NOs:7, 8, and 9, respectively; and
b. light chain CDR1, CDR2, and CDR3 having an amino acid sequence of SEQ ID NOs:4, 5, and 6, respectively.
3. The pharmaceutical composition of claim 1 , wherein the PCSK9-binding polypeptide is present at a concentration of 140 mg/mL to 260 mg/mL.
4. The pharmaceutical composition of claim 1 , wherein the PCSK9-binding polypeptide concentration is 190 mg/mL to 210 mg/mL.
5. The pharmaceutical composition of claim 1 , wherein the N-acetyl arginine is present at a concentration from 25 mM to 230 mM.
6. The pharmaceutical composition of claim 1 , further comprising a buffer.
7. The pharmaceutical composition of claim 1 , further comprising a surfactant.
8. The pharmaceutical composition of claim 1 , further comprising proline.
9. The pharmaceutical composition of claim 1 , further comprising an arginine salt.
10. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is liquid.
11. A kit, comprising the pharmaceutical composition of claim 1 and a delivery device selected from the group consisting of a syringe, an injector pen, a body injector, and an autoinjector.
12. A method of treating a subject in need thereof, comprising administering the pharmaceutical composition of claim 1 .