Lyophilized factor IX formulations
Inventors
THOME, Brian M. • Parkhurst-Lang, Cherie • LEVEILLE, Brandon W.
Assignees
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Publication Number
US-12128092-B2
Publication Date
2024-10-29
Expiration Date
Abstract
The present invention provides, among other things, pre-lyophilization formulations, reconstituted formulations, and lyophilate powder compositions comprising a Factor IX (FIX) polypeptide. The present invention also provides lyophilization methods for producing lyophilate powder comprising a FIX polypeptide.
Core Innovation
The invention relates to a pre-lyophilization formulation in a vial for a chimeric Factor IX (FIX) polypeptide, where the FIX comprises FIX and a heterologous moiety that extends the half-life of the FIX. The formulation contains L-histidine, sucrose, mannitol, and polysorbate 20 at defined concentration ranges, and the vial fill volume is between 2 mL and 3 mL. The formulation is capable of being lyophilized into a lyophilate formulation with residual moisture below specified levels.
The formulation is defined to be lyophilizable using a lyophilization cycle with a cycle time of 4 days or less and a drying time of 25 hours or less. The lyophilate formulation has a residual moisture level below 2% in the broad formulation and residual moisture below 1% in refined embodiments. The document also describes improved stability and performance relative to reference higher-fill-volume formulations.
The invention further includes lyophilate powders and reconstituted formulations derived from the pre-lyophilization formulation. The document describes chimeric rFIXFc structures as FIX linked to Fc, including FIXFc-sc and Fc-sc with hinge disulfide bonds, and discusses FcRn-binding partner concepts in the context of half-life extension. Development is described as including evaluation using DOE to select a lyophilization cycle that achieves residual moisture targets while avoiding collapse, supported by example results.
Claims Coverage
The independent claims identified are clm-00001 and clm-00012. Both independent claims focus on a pre-lyophilization formulation in a vial with defined excipient concentrations, defined vial fill volume, and lyophilization performance limits defined by residual moisture and cycle/drying time, with clm-00012 further specifying a particular set of numeric concentrations.
Pre-lyophilization formulation for chimeric FIX lyophilization
A pre-lyophilization formulation within a vial comprising a chimeric Factor IX (FIX) polypeptide (FIX and a heterologous moiety that extends the half-life of the FIX) in an amount of about 2,000, about 3,000, or about 4,000 IU; L-histidine at 3 mg/ml to 15 mg/mL; sucrose at 10 mg/mL to 50 mg/mL; mannitol at 20 mg/mL to 100 mg/mL; and polysorbate 20 at 0.01 mg/ml to 5 mg/mL; wherein the formulation has a fill volume between 2 mL and 3 mL; and wherein the formulation is capable of being lyophilized into a lyophilate formulation having residual moisture below 2% using a lyophilization cycle with a cycle time of 4 days or less and a drying time of 25 hours or less.
Specific pre-lyophilization formulation concentrations with chimeric FIX
A pre-lyophilization formulation within a vial comprising about 2,000, about 3,000, or about 4,000 IU of a chimeric Factor IX (FIX) polypeptide comprising FIX and Fc; about 7.76 mg/ml of L-histidine; about 47.6 mg/ml of mannitol; about 23.8 mg/ml of sucrose; and about 0.2 mg/ml of polysorbate 20; wherein the formulation has a fill volume between 2 mL and 3 mL; and wherein the formulation is capable of being lyophilized into a lyophilate formulation having a residual moisture level below 2% using a lyophilization cycle with a cycle time of 4 days or less and a drying time of 25 hours or less.
Across the independent claims, the inventive scope is directed to lyophilization-capable pre-lyophilization vial formulations for a chimeric FIX half-life-extending construct, defined by excipient selection and concentration ranges or specific numeric concentrations, restricted vial fill volume between 2 mL and 3 mL, and lyophilization performance characterized by residual moisture below 2% with cycle time of 4 days or less and drying time of 25 hours or less.
Stated Advantages
Improves lyophilized FIX stability.
Reduces reconstitution time.
Reduces stopper splashing.
Shortens lyophilization cycle time.
Increases room-temperature shelf life versus a reference higher-fill-volume formulation.
Documented Applications
Production of lyophilized rFIXFc/long-acting FIX products, including lyophilate powders and reconstituted formulations derived from the pre-lyophilization formulation.
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