Dosing regimens and related compositions and methods

Inventors

Grossi, Federico • Deschatelets, Pascal • Francois, Cedric • Johnson, Patrick • Vega, Carolina

Assignees

Jpharma Solutions GmbH • Apellis Pharmaceuticals Inc

Abstract

In some aspects, the present invention provides cell-reactive compstatin analogs and compositions comprising cell-reactive compstatin analogs. In some aspects, the invention further provides methods of using cell-reactive compstatin analogs, e.g., treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ. In some aspects, the invention provides long-acting compstatin analogs and compositions comprising long-acting compstatin analogs. In some aspects, the invention further provides methods of using long-acting compstatin analogs, e.g., to treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ. In some aspects, the invention provides targeted compstatin analogs and compositions comprising targeted compstatin analogs. In some aspects, the invention further provides methods of using targeted compstatin analogs, e.g., to treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ.

Core Innovation

The invention relates to long-acting compstatin analogs (LACA) for treating a subject in need of treatment of a complement-mediated disorder. The LACA comprises a clearance-reducing moiety attached to two compstatin analog moieties, and the compstatin analog moieties comprise a cyclic peptide comprising an amino acid sequence as set forth in SEQ ID NO: 28 extended by a lysine residue or having a lysine residue at the N-terminus, C-terminus, or both, where the lysine residue is separated from the cyclic portion by a spacer comprising 8-amino-3,6-dioxaoctanoic acid (AEEAc).

The clearance-reducing moiety comprises a polymer, and each end of the polymer is linked to one of the compstatin analog moieties by way of a carbamate linkage. The polymer is PEG having an average molecular weight of about 40 kD. The long-acting compounds extend plasma half-life and terminal half-life and are associated with PEG-based clearance reduction.

The disclosure further describes subcutaneous administration according to a dosing schedule, including about 20 mL at a concentration of between about 50 mg/mL to about 75 mg/mL thrice weekly, every three days, twice weekly, or weekly. The document further discusses complement inhibition, pharmacokinetics/pharmacodynamics, and comparison to eculizumab in the context of complement-mediated disease.

Claims Coverage

The independent claims are directed to a treatment method and a unit dose formulation for subcutaneous administration. Across the claims, the core structural concept is a PEG-based clearance-reducing moiety linked via carbamate to two compstatin analog moieties comprising SEQ ID NO: 28 with lysine and an AEEAc spacer, with the treatment claim adding a dosing schedule and the unit-dose claim fixing the amount and concentration.

Overall, the claim coverage centers on subcutaneous administration of a LACA built from two lysine-extended SEQ ID NO: 28 cyclic compstatin analog moieties separated by an AEEAc spacer, and a PEG clearance-reducing polymer (about 40 kD) linked at each end via carbamate linkages to the two peptide moieties, with the treatment claim specifying the about 20 mL dose volume, 50–75 mg/mL concentration, and thrice weekly/every three days/twice weekly/weekly schedules.

Stated Advantages

Documented Applications