Treatment of diuretic resistant heart failure patients having at least one copy of the TMPRSS6 rs855791 allele

Inventors

Testani, Jeffrey • Rao, Veena • Kakkar, Rahul • Devalaraja, Madhav N. • Lo, Chih-Hung

Assignees

Novo Nordisk AS • Yale University

Abstract

The present disclosure provides methods of treating diuretic resistance by administering an IL-6 antagonist to patients who require diuresis. In typical embodiments, the patient has heart failure. Optionally, the patient has elevated urine levels of IL-6, plasma levels of IL-6, or both urine and plasma levels of IL-6.

Core Innovation

The invention relates to treating diuretic resistant heart failure and related cardiorenal syndrome by administering an IL-6 antagonist to a patient who requires diuresis but is resistant to diuretics. The treated patient has at least one copy of the TMPRSS6 rs855791 allele, and the IL-6 antagonist is administered in combination with a diuretic.

The disclosed approach uses IL-6 as a biomarker context, including urine IL-6 and plasma IL-6. The document describes an association between urine IL-6 and renal impairment metrics, and urine IL-6 is described as correlating with diuretic efficiency and eGFR and as predicting mortality risk patterns, including an explanation involving genotype-restricted prediction of responsiveness.

The document further describes that, in analyses including a 129-patient dataset, inverse associations between IL-6 and diuretic efficiency occur only in patients with at least one TMPRSS6 rs855791 major allele (AG+GG). The disclosed findings include a mechanistic discussion in which IL-6 increases ion transporter expression (NKCC2, ENaC-beta, NCC), and JAK inhibition blocks this increase, consistent with the IL-6 antagonist approach targeting IL-6 signaling via STAT3/JAK pathways.

Claims Coverage

The independent claim defines one central inventive concept with approximately four claim-embedded inventive feature directions: patient selection by TMPRSS6 rs855791 allele status, combination therapy pairing an IL-6 antagonist with a diuretic, and IL-6 antagonism defined by multiple specific classes, with additional dependents narrowing the treated indication to acute heart failure and/or cardiorenal syndrome.

Across the independent claim and its refinements, coverage centers on treating diuretic resistant heart failure patients selected by TMPRSS6 rs855791 allele status using an IL-6 antagonist administered in combination with a diuretic, with dependent features specifying IL-6 antagonism via STAT3 inhibitors, anti-IL-6 antibodies (including antigen-binding fragments/derivatives), or anti-IL-6R antibodies (including antigen-binding fragments/derivatives), and additional narrowing to acute heart failure and/or cardiorenal syndrome.

Stated Advantages

Documented Applications