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Publication Number
US-11338013-B2
Publication Date
2022-05-24
Expiration Date
Abstract
In some aspects, the present invention provides certain combination therapies comprising compstatin analogs.
Core Innovation
The invention provides methods of inhibiting complement activation in a subject by administering an inhibitory nucleic acid agent (INAA) that inhibits expression of C3 together with a compstatin analog that comprises a clearance reducing moiety (CRM) and at least one compstatin analog moiety. The compstatin analog is positioned as a complement inhibiting therapy that includes a clearance reducing moiety to support the overall inhibition effect.
The methods further specify a dosing regimen in which the INAA and the compstatin analog are administered with a dosing interval of at least 2 days. The compstatin analog is administered in a smaller volume, using a lower concentration, or using a longer dosing interval, or any combination, relative to the volume, concentration, or dosing interval required to achieve a desired degree of complement inhibition if the compstatin analog were administered as a single complement inhibiting therapy.
The invention also defines efficacy targets and assay-based measures, including inhibiting serum complement activity by an average of no more than 95%, optionally between 50% and 95%, as measured using alternative pathway and/or classical pathway assays. The disclosure further includes compstatin analog structural and conjugation concepts, including CRM-containing long-acting compstatin analog architectures and targeted constructs.
Claims Coverage
The document provides four independent claims. Across these claims, the inventive coverage centers on combined complement inhibition using an INAA that inhibits C3 expression together with a CRM-containing compstatin analog, and on dosing and efficacy constraints that limit complement activity and compstatin exposure.
Combined c3 inhibition with crm-containing compstatin analog
Administering to a subject an INAA that inhibits expression of C3 and a compstatin analog that comprises a clearance reducing moiety (CRM) and at least one compstatin analog moiety.
At least 2-day dosing interval with reduced compstatin exposure
Administering each of the INAA and the compstatin analog according to a dosing regimen with a dosing interval of at least 2 days, wherein the compstatin analog is administered in a smaller volume, using a lower concentration, or using a longer dosing interval, or any combination, relative to the volume, concentration, or dosing interval required for desired complement inhibition if the compstatin analog were administered as a single complement inhibiting therapy.
Serum complement activity inhibition no more than 95%
Administering the INAA in an amount effective to inhibit serum complement activity by an average of no more than 95%, optionally between 50% and 95%, as measured using an alternative pathway assay, a classical pathway assay, or both.
Compstatin analog dose limit below about 300 mg/day
Administering the compstatin analog in an amount less than about 300 mg/day on average.
The independent claims collectively cover combined complement inhibition using an INAA that inhibits C3 expression together with a compstatin analog containing a clearance reducing moiety, constrained by a dosing interval of at least 2 days with reduced compstatin exposure, serum complement activity inhibition thresholds measured by alternative and/or classical pathway assays, and an average daily compstatin dose limit below about 300 mg/day.
Stated Advantages
Enables inhibition of complement activation while administering the compstatin analog in a smaller volume, lower concentration, and/or longer dosing interval than would be required for single complement inhibiting therapy.
Limits serum complement activity to an average of no more than 95%, optionally between 50% and 95%, as measured using alternative pathway and/or classical pathway assays.
Administers the compstatin analog at an average dose of less than about 300 mg/day.
Documented Applications
Methods of inhibiting complement activation in a subject.
Long-acting compstatin analog conjugates configured for clinical administration, including IV or subcutaneous administration.
Targeted compstatin analog constructs and click-functionalized compstatin conjugates incorporating external partners such as labels, affinity reagents, antibodies, targeting moieties, and device/surface functionalization.
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