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WO 2018/089540 Al 17 May 2018 (17.05.2018) W ! P O P C T

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WO 2018/089540 Al 17 May 2018 (17.05.2018) W ! P O P C T (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 2018/089540 Al 17 May 2018 (17.05.2018) W ! P O P C T (51) International Patent Classification: (74) Agent: ERLACHER, Heidi, A. et al; Cooley LLP, 1299 A61K 9/00 (2006.01) A61K 48/00 (2006.01) Pennsylvania Avenue, NW, Suite 700, Washington, District A61K 9/19 (2006.01) A61K 9/S1 (2006.01) of Columbia 20004-2400 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US20 17/060704 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (22) International Filing Date: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, 08 November 201 7 (08. 11.201 7) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (25) Filing Language: English 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, (26) Publication Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (30) Priority Data: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 62/419,459 08 November 2016 (08. 11.20 16) US 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. (71) Applicant: MODERNATX, INC. [US/US]; 200 Technol ogy Square, Cambridge, Massachusetts 02139 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventor: BRADER, Mark; ModernaTX, Inc., 200 Tech GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, nology Square, Cambridge, Massachusetts 02139 (US). 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, (54) Title: STABILIZED FORMULATIONS OF LIPID NANOP ARTICLES Segregation of constituents 00 © (57) Abstract: The disclosure features a lipid nanoparticle (LNP) formulation comprising a plurality of LNPs and a stabilizing agent that mitigates the degradation of the LNPs or a subpopulation thereof. Lipid nanoparticles further including therapeutics and/or prophylactics 00 such as RNA are useful in the delivery of therapeutics and/or prophylactics to mammalian cells or organs to, for example, regulate o polypeptide, protein, or gene expression. Methods of manufacturing LNP formulations and screening for a stabilizing agent are also disclosed. [Continued on nextpage] WO 2018/089540 Al llll II II 11III II I III 11II I II II III II I II TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: — as to applicant's entitlement to apply for and be granted a patent (Rule 4.1 7(H)) Published: — with international search report (Art. 21(3)) — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) STABILIZED FORMULATIONS OF LIPID NANOP ARTICLES RELATED APPLICATION [0001] This application claims priority to, and the benefit of, U.S. provisional application No. 62/419,459, filed November 8, 2016, the entire content of which is incorporated herein by reference in its entirety. BACKGROUND [0002] The effective targeted delivery of biologically active substances such as small molecule drugs, proteins, and nucleic acids represents a continuing medical challenge. In particular, the delivery of nucleic acids to cells is made difficult by the relative instability and low cell permeability of such species. Thus, there exists a need to develop methods and compositions to facilitate the delivery of therapeutics and/or prophylactics such as nucleic acids to cells. [0003] Lipid-containing nanoparticles or lipid nanoparticles, liposomes, and lipoplexes have proven effective as transport vehicles into cells and/or intracellular compartments for biologically active substances such as small molecule drugs, proteins, and nucleic acids. Though a variety of such lipid-containing nanoparticles have been demonstrated, improvements in safety, efficacy, and specificity are still lacking. SUMMARY [0004] In one aspect, the present disclosure provides a stabilized lipid nanoparticle (LNP) formulation comprising a plurality of LNPs and a stabilizing agent that mitigates the degradation of the LNPs or a subpopulation of the LNPs, wherein the LNPs comprise an ionizable lipid and a structural lipid, and the stabilizing agent comprises a cryoprotectant, a chelator, an antioxidant, or any combination thereof. In some embodiments, the stabilizing agent further comprises a surfactant. [0005] The stabilized LNP formulation may include one or more of the following features. [0006] For example, the formulation is an aqueous formulation or a frozen formulation thereof (e.g., an aqueous formulation being stored at about -20 °C or lower, such as at about -20 °C, -25 °C, -30 °C, -40 °C, -50 °C, -60 °C, -70 °C, or -80 °C). [0007] For example, the degradation comprises a phase separation of one or more LNP components (e.g., phase separation of a fraction of the structure lipid such as cholesterol or phase separation of a fraction of the ionizable lipid such as an ionizable amino lipid) from the remainder of LNP. For example, the formulation has a decreased fraction of the phase-separated structure lipid and/or ionizable lipid as compared to a corresponding formulation which does not comprise the stabilizing agent. For example, decrease in the fraction of the phase-separated structure lipid and/or ionizable lipid is about 20% or more (e.g., about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, or more) as compared to that of a corresponding formulation which does not comprise the stabilizing agent. [0008] For example, the degradation of LNPs is determined by dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), turbidity analysis, flow microscopy analysis, flow cytometry, FTIR microscopy, resonant mass measurement (RMM), Raman microscopy, filtration, laser diffraction, electron microscopy, atomic force microscopy (AFM), static light scattering (SLS), multi-angle static light scattering (MALS), field flow fractionation (FFF), analytical ultracentrifugation (AUC), or any combination thereof. [0009] For example, the degradation yields an increased average size of particles in the formulation. For example, the degradation yields an increase in LNP mean size of about 20% or less (e.g., about 15%, about 10%, about 5% or less) after storage at -20 °C or lower for at least one month, e.g., as measured dynamic light scattering (DLS). [0010] For example, the degradation yields an increase in LNP mean size of about 20% or less (e.g., about 15%, about 10%, about 5% or less) after up to 30 freeze/thaw cycles, e.g., as measured dynamic light scattering (DLS). [0011] For example, the degradation yields an increase in turbidity of about 20% or less (e.g., about 15%, about 10%, about 5% or less) after storage at -20 °C or lower for at least one month, e.g., via nephelometric turbidity analysis. [0012] For example, the degradation yields an increase in turbidity of about 20% or less (e.g., about 15%, about 10%, about 5% or less) after up to 30 freeze/thaw cycles, e.g., via nephelometric turbidity analysis. [0013] For example, the formulation has a decreased average size of particles (e.g., about 95% or less, about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, or about 30% or less) as compared to a corresponding formulation which does not comprise the stabilizing agent. [0014] For example, the formulation has a decreased number of particles (e.g., about 95% or less, about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, or about 30% or less) as compared to a corresponding formulation which does not comprise the stabilizing agent. [0015] For example, the cryoprotectant comprises a polyol (e.g., a diol or a triol such as propylene glycol, glycerol, (+/-)-2-methyl-2,4-pentanediol, 1,6-hexanediol, 2,3-butanediol, ethylene glycol, or diethylene glycol), a nondetergent sulfobetaine (e.g., NDSB-201 (3-(l-pyridino)-l- propane sulfonate), an osmolyte (e.g., L-proline or trimethylamine N-oxide dihydrate), a polymer (e.g., polyethylene glycol 200 (PEG 200), PEG 400, PEG 600, PEG 1000, PEG 3350, PEG 4000, PEG 8000, PEG 10000, polyethylene glycol monomethyl ether 550 (mPEG 550), mPEG 600, mPEG 2000, mPEG 3350, mPEG 4000, mPEG 5000, polyvinylpyrrolidone, pentaerythritol propoxylate, or polypropylene glycol P 400), an organic solvent (e.g., dimethyl sulfoxide (DMSO) or ethanol), a sugar (e.g., D-(+)-sucrose, D-sorbitol, trehalose, D-(+)-maltose monohydrate, meso- erythritol, xylitol, myo-inositol, D-(+)-raffinose pentahydrate, D-(+)-trehalose dihydrate, or D-(+)- glucose monohydrate) or any combination thereof. For example, the concentration of the cryoprotectant in the formulation ranges from about 0.05 % to about 50 % by weight (e.g., from about 0.05 % to about 25 % by weight, from about 1 % to 15 % by weight, from about 3 % to about 12.5 % by weight, from about 1 % to about 8 % by weight or from about 2 % to about 7 % by weight).
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