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CA-2971800-C - SECUKINUMAB COMPOSITIONS, USES AND KITS THEREOF, AND PROCESSES FOR STABILIZING ANTIBODY FORMULATIONS

CA2971800CCA 2971800 CCA2971800 CCA 2971800CCA-2971800-C

Abstract

The disclosure is directed to pharmaceutical products and stable liquid compositions of IL-17 antibodies and antigen-binding fragments thereof, e.g., AIN457 (secukinumab), and processes of making these pharmaceutical products and compositions. The disclosure is also directed to the use of these pharmaceutical products and liquid compositions (e.g., as part of a kit having instructions for use) for the treatment of various IL-17-mediated disorders (e.g., autoimmune disorders, such as psoriasis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis).

Inventors

  • Susanne JOERG
  • Kathrin SERNO-SCHERSCH

Assignees

  • NOVARTIS AG

Dates

Publication Date
20260505
Application Date
20151221
Priority Date
20141222

Claims (20)

  1. 60 CLAIMS 1. A pharmaceutical product, comprising: a. a container having a headspace, wherein the oxygen content in the headspace is less than 12%, and b. a ready-to-use liquid pharmaceutical composition having a pH of about 5.2 to about 6.2 disposed within said container, said composition comprising: i. about 20 mg/ml to about 175 mg/ml secukinumab; ii. about 2.5 mM or at least 2.5 mM L-methionine; and iii. a non-ionic stabilizer, a surfactant selected from a polysorbate and a poloxamer, and a buffer.
  2. 2. The pharmaceutical product according to claim 1, wherein the concentration of L-methionine is about 2.5 mM, about 5 mM, about 10 mM, or about 20 mM.
  3. 3. The pharmaceutical product according to claim 2, wherein the concentration of L-methionine is about 2.5 mM.
  4. 4. The pharmaceutical product according to claim 2, wherein the concentration of L-methionine is about 5 mM.
  5. 5. The pharmaceutical product according to claim 2, wherein the concentration of L-methionine is about 10 mM.
  6. 6. The pharmaceutical product according to claim 2, wherein the concentration of L-methionine is about 20 mM.
  7. 7. The pharmaceutical product according to claim 1, wherein the concentration of L-methionine is no more than 134 mM.
  8. 8. The pharmaceutical product according to claim 7, wherein the concentration of L-methionine is no more than 67 mM.
  9. 9. The pharmaceutical product according to claim 8, wherein the concentration of 61 L-methionine is about 25 to about 30 mM.
  10. 10. The pharmaceutical product according to claim 9, wherein the concentration of Lmethionine is about 25 mM.
  11. 11. The pharmaceutical product according to claim 9, wherein the concentration of Lmethionine is about 30 mM.
  12. 12. The pharmaceutical product according to any one of claims 1-11, wherein the oxygen content in the headspace is less than 10%.
  13. 13. The pharmaceutical product according to any one of claims 1-12, wherein the oxygen content in the headspace is less than 8%.
  14. 14. The pharmaceutical product according to any one of claims 1-13, wherein the oxygen content in the headspace is less than 6%.
  15. 15. The pharmaceutical product according to any one of claims 1-14, wherein the ready-touse liquid pharmaceutical composition has a pH of about 5.5 to about 6.1.
  16. 16. The pharmaceutical product according to any one of claims 1-15, wherein the ready-touse liquid pharmaceutical composition has a pH of about 5.8.
  17. 17. The pharmaceutical product according to any one of claims 1-16, wherein the concentration of secukinumab is about 75 mg/ml to about 150 mg/ml.
  18. 18. The pharmaceutical product according to any one of claims 1-16, wherein the concentration of secukinumab is about 150 mg/ml.
  19. 19. The pharmaceutical product according to any one of claims 1-18, wherein the buffer is gluconate, histidine, citrate, phosphate, succinate, acetate, Tris, glycine, arginine, or a combination thereof.
  20. 20. The pharmaceutical product according to any one of claims 1-18, wherein the buffer 62 comprises gluconate.

Description

SECUKINUMAB COMPOSITIONS, USES AND KITS THEREOF, AND PROCESSES FOR STABILIZING ANTIBODY FORMULATIONS RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 62/095,210, filed on December 22, 2014. TECHNICAL FI;ELD The disclosure is directed to pharmaceutical products comprising stable liquid pharmaceutical compositions of IL-17 antibodies and antigen-binding fragments thereof, e.g .• AIN457 (secukinumab ), and processes of making such pharmaceutical products and liquid pharmaceutical compositions. BACKGROUND OF THE DISCLOSURE IL-17 A is the central lymphokine of a newly defined subset of inflammatory T cells. the Th 17 cells, which are pivotal in several autoimmune and inflammatory processes. IL-17 A neutralization is expected to treat the underlying pathophysiology of immune mediated disease. and as a consequence provide relief of symptoms. Secukinumab (AIN4S7) is a high--affinity fully human monoclonal anti-human antibody that inhibits IL-17 A activity, which has emerged as a potential treatment for patients with various autoimmune diseases, e.g., rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, diabetes, asthma, chronic plaque-type psoriasis, and multiple sclerosis. Several Phase Il and m studies have shown that secukinumab is superior to placebo in achievement of PASI 75 in treating chronic plaque-type psoriasis (e.g., secukinumab 3x150 mg and 3x75 mg were both superior to placebo in achievement of PASI 75 at Week 12 (81.5%and 57.1%, respectively, vs. 9.1%) in study CAIN457A2220. Secukinumab is currently used in global Phase IlI studies for the treatment of chronic plaque-type psoriasis, and has again shown superiority over placebo, and newly also over etanercept. International Patent Application PCT/EP2011/069476 provides sucrose-based lyophilized compositions of secuk.inumab, which are reconstituted with 1 mL water immediately prior to use. However, PCT/EP2011/069476 provides no disclosure of a ready-to-use pharmaceutical product J CA 02971800 2017-06•21 WO 2016/103153 PCT/1B2015/059836 or liquid pharmaceutical composition of secukinumab having long-term stability. Indeed, the marginal stability of proteins in liquid compositions often prevents long-term storage at room temperature or refrigerated conditions. In addition, various physical and chemical reactions can occur in solution (aggregation [covalent and noncovalent], deamidation, oxidation, clipping, isomerization, denaturation), leading to an increase in degradation product levels and/or loss of bioactivity. A commercial ready-to-use liquid antibody composition should provide sufficient physical and chemical stability of the antibody during shipping and handling to ensure that the dosage and product safety claims are met when the molecule is administered to a patient. Specifically, an acceptable liquid antibody composition must enhance stability and minimize protein degradation, especially protein aggregation, in order to avoid serious immunogenic reactions. Moreover, the composition must also be of acceptable osmolality and pH value for subcutaneous application and have low viscosity as a prerequisite for manufacturing (compounding, filtration, filling) and syringeability. Balancing these myriad requirements is difficult, making the production of a commercially viable aqueous biopharmaceutical composition a technical challenge. Regardless of the technical challenges outlined above, we have now successfully developed novel and beneficial ready-to-use pharmaceutical products and liquid pharmaceutical compositions of the IL-17 antibodies and antigen binding fragments disclosed herein, e.g., secukinumab. BRIEF SUMMARY OF fflE DISCWSURE The disclosure provides pharmaceutical products that include a container ( e.g., pen, syringe, vial, autoinjector) having a headspace with less than about 12% oxygen (e.g., less than about 10% oxygen, less than about 8% oxygen, less than about 6% oxygen, etc.), and a liquid composition disposed within the container. The liquid composition is not reconstituted from a lyophilisate, but rather is a ready-to-use liquid composition and broadly includes at least one of the disclosed IL-17 antibodies or antigen binding fragments thereof (e.g., secukinumab), a buffer, a surfactant, methionine, and a stabilizer, as well as subcombinations thereof. We have determined that the combined use of particular stabilizers with a low oxygen level in the heads pace of the container contributes significantly to long-term stability of the liquid 2 CA 02971800 2017-06•21 WO 2016/103153 PCT/1B2015/059836 pharmaceutical product, and prevents oxidation of the IL-17 antibody (e.g., secukinumab) included in the composition. These liquid compositions have excellent properties, e.g.: after 13 months storage at 25°C, aggregate formation as measured by SEC of::; 3.5 % for 2.5 mM methionine,::; 3.0 % for 5 mM; and::; 2.2 % for 20 mM methionine-containing compositions; and after 13 months storage at 25°