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WO 2018/067987 Al 12 April 2018 (12.04.2018) W !P O PCT

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WO 2018/067987 Al 12 April 2018 (12.04.2018) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/067987 Al 12 April 2018 (12.04.2018) W !P O PCT (51) International Patent Classification: Published: A61K 39/00 (2006.01) A61K 47/22 (2006.01) — with international search report (Art. 21(3)) (21) International Application Number: — with sequence listing part of description (Rule 5.2(a)) PCT/US2017/055620 (22) International Filing Date: 06 October 2017 (06.10.2017) (25) Filing Language: English (26) Publication Langi English (30) Priority Data: 62/404,861 06 October 2016 (06.10.2016) US (71) Applicant: AMGEN INC. [US/US]; One Amgen Center Drive, Thousand Oaks, CA 91320-1799 (US). (72) Inventors: TERAN, Alona; 13715 Shenandoah Way, Moorpark, CA 93021 (US). MUNAIM, Qahera; 21025 Lemarsh Street, Unit #G42, Chatsworth, CA 913 11 (US). KHALAF, Nazer; 14 Lauf Street, Worcester, MA 01602 _ (US). KAUSHIK, Rahul, Rajan; 1660 Glider Court, Thou- = sand Oaks, CA 91320 (US). CLOGSTON, Christi, L.; = 601 Country View Place, Camarillo, CA 93010 (US). = CHRISTIAN, Twinkle, R.; 519 W. Gainsborough Road, = Apt. 303, Thousand Oaks, CA 91360 (US). CALLAHAN, — William, J.; 1104 Woodridge Avenue, Thousand Oaks, CA = 91362 (US). — (74) Agent: HONG, Julie, J. et al; Marshall, Gerstein Borun = LLP, 233 S. Wacker Drive, 6300 Willis Tower, Chicago, IL = 60606-6357 (US). = (81) Designated States (unless otherwise indicated, for every — kind of national protection available): AE, AG, AL, AM, = AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, ≡ CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, = DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, = HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, ≡ KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, = MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, ≡ OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, = SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, ≡ TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. Ξ (84) Designated States (unless otherwise indicated, for every = kind of regional protection available): ARIPO (BW, GH, ≡ GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, = UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). I o 00 (54) Title: REDUCED VISCOSITY PROTEIN PHARMACEUTICAL FORMULATIONS (57) Abstract: Described herein are therapeutic protein formulations comprising N-methyl pyrrolidone (NMP), methods related to reducing viscosity of pharmaceutical formulations and methods related to stabilizing pharmaceutical formulations using NMP. REDUCED VISCOSITY PROTEIN PHARMACEUTICAL FORMULATIONS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application No. 62/404,861, filed October 6, 2016, the contents of which are incorporated by reference. SEQUENCE LISTING [0002] The present application is being filed with a sequence listing in electronic format. The sequence listing provided as a file titled, "A-2092-WO-PCT_sequence_listing_ST25.txt ", created October 5, 2017, and is 284 KB in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. BACKGROUND [0003] Pharmaceutically active proteins, such as antibodies, are frequently formulated in liquid solutions, particularly for parenteral injection. For products that need to be administered via a subcutaneous route, for example use in self-administration, formulations in delivery volumes greater than 1-2 milliliters are not well tolerated. In such cases, highly concentrated protein formulations are desirable to meet the limited dose volume. The high dose and small volume requirements of such administration means that the protein therapeutic can reach concentrations of upwards of 100 mg/m Lor more. Highly concentrated protein formulations can pose many challenges to the manufacturability and administration of protein therapeutics. One challenge posed by some highly concentrated protein formulations is increased viscosity. High viscosity formulations are difficult to handle during manufacturing, including at the bulk and filling stages. High viscosity formulations are also difficult to draw into a syringe and inject, making administration to the patient difficult and unpleasant. There is a need in the pharmaceutical industry to identify compounds that are useful for reducing viscosity of highly concentrated protein formulations, to develop methods of reducing the viscosity of such formulations, and to provide pharmaceutical formulations with reduced viscosity. SUMMARY [0004] Provided is N-methyl pyrrolidone (N P) at selected concentrations for use in reducing the viscosity of protein pharmaceutical formulations. NM P can be used with other excipients, such as for example, arginine, lysine, N-acetyl arginine (NAR), and mixtures thereof. Methods for reducing the viscosity of protein pharmaceutical formulations by combining a high concentration of a therapeutic protein with a viscosity-reducing concentration of NM P are provided herein. Also provided are lyophilized powders comprising a therapeutic protein and NM P, wherein NM P is present at a weight:weight concentration effective t o reduce viscosity upon reconstitution with a diluent. [0005] Provided herein are methods for reducing the viscosity of a liquid pharmaceutical formulation comprising a therapeutic protein at a concentration of at least about 100 mg/m L, such as about 100 mg/m Lto about 300 mg/m L (e.g., about 140 mg/mL), such as about 180 mg/mL to about 230 mg/m L, such as about 210 mg/m L, comprising the step of combining the therapeutic protein with a viscosity-reducing concentration of NM P. In one embodiment the viscosity of the formulation is reduced by at least about 5%. In another embodiment the viscosity of the formulation is reduced by at least about 10%. In another embodiment the viscosity of the formulation is reduced by at least about 20%. In another embodiment the viscosity of the formulation is reduced by at least about 30%. In another embodiment the viscosity of the formulation is reduced by at least about 40%. In another embodiment the viscosity of the formulation is reduced by at least about 50%. In another embodiment the viscosity of the formulation is reduced by at least about 60%. In another embodiment the viscosity of the formulation is reduced by at least about 70%. In another embodiment the viscosity of the formulation is reduced by at least about 80%. In some embodiments, the therapeutic protein is an antibody (such as an IgGl or lgG2 monoclonal antibody) or antigen-binding fragment thereof, such as, for example, an anti-PCSK9 antibody or antigen- binding fragment thereof. An example of an anti-PCSK9 antibody is evolocumab. In a related embodiment, pharmaceutical formulations produced by such methods are provided. Other excipients can be used in combination with NM P, such as arginine, lysine, NA , and mixtures thereof. [0006] Also provided is a pharmaceutical formulation comprising a therapeutic protein at a concentration of at least about 100 mg/m L, such as about 100 mg/m Lto about 300 mg/m L (e.g., about 140 mg/m L), such as about 180 mg/mL to about 230 mg/mL, such as about 210 mg/mL, and NM P. In one embodiment, the concentration of NM P is from about 1.0 mM to about 1000 mM . In a related embodiment the concentration of NM P is from about 100 mM to about 500 mM . In another related embodiment the concentration of NM P is from about 300 mM to about 425 mM . In another related embodiment the concentration of NM P is about 340 mM. In another related embodiment the concentration of NM P is about 425 mM. In a related embodiment the concentration of NM P is greater than about 300 mM, greater than about 500 mM, greater than about 800 mM, about 1000 mM . Also provided are such pharmaceutical formulations having a pH between about 4.0 to about 6.0. In a related embodiment, the pH is about 4.8 t o about 5.4. In some embodiments, the pH is about 5.0. In yet other related embodiments, the therapeutic protein is an antibody (such as an IgGl or lgG2 monoclonal antibody) or antigen-binding fragment thereof, such as, for example, an anti- PCSK9 antibody or antigen-binding fragment thereof. An exam ple of an anti-PCSK9 antibody is evolocumab. [0007] In one preferred aspect, a pharmaceutical formulation comprises at least about 100 mg/m L, such as about 100 mg/m Lt o about 300 mg/m L (e.g., about 140 mg/m L), such as about 180 mg/m Lt o about 230 mg/m L, such as about 210 mg/m L of a therapeutic protein, e.g., an antibody (such as an IgGl or lgG2 monoclonal antibody; an example of an antibody is an anti-PCSK9 antibody, such as evolocumab) or an antigen-binding fragment thereof, about 370-600 mM N P, and about 0.05-0.2% PLU RON IC® F-68 (polyoxyethylene-polyoxypropylene block copolymer); in related aspects, the pharmaceutical formulation further comprises a buffer, such as about 5-20 m M acetate; in yet further aspects, the pharmaceutical formulation has a pH of about 4.5-5.5. In one embodiment, the pharmaceutical formulation comprises at least about 100 mg/m L, such as about 100 mg/m Lt o about 300 mg/m L (e.g., about 140 mg/m L), such as about 180 mg/m L t o about 230 mg/mL, such as about 210 mg/m L of an antibody (such as an IgGl or lgG2 monoclonal antibody) or antigen-binding fragment thereof (e.g., an anti-PCSK9 antibody, such as evolocumab), about 425 mM NM P, and about 0.10% PLURON IC® F-68; in related aspects, the pharmaceutical formulation further comprises a buffer, such as about 10 m M acetate; in yet further aspects, the pharmaceutical formulation has a pH of about 5.0.
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