US 2017/0304397 A1 · TREATMENT OF CARDIOVASCULAR DISEASE USING ACTRII LIGAND TRAPS

A method for treating and/or preventing cardiovascular disease in a subject, comprising administering to the subject a pharmaceutically effective dose of an activin receptor type II (ActRII) signaling inhibitor, wherein the subject has:

(a) elevated levels of runt-related transcription factor 2 (Runx2) as compared to levels of Runx2 in a reference population;
(b) elevated levels of alkaline phosphatase (Alp) as compared to levels of Alp in a reference population;
(c) elevated levels of snail homolog 1 (Snai1) as compared to levels of Snai1 in a reference population;
(d) elevated levels of phosphosmad2 as compared to levels of phosphosmad2 in a reference population;
(e) elevated levels of dickkopf homolog 1 (Dkk1) as compared to levels of Dkk1 in a reference population;
(f) elevated levels of collagen type 1 alpha 1 (col1a1) as compared to levels of col1a1 in a reference population;
(g) elevated levels of activin as compared to levels of activin in a reference population;
(h) elevated levels of bone-specific alkaline phosphatase (BSAP) as compared to levels of BSAP in a reference population;
(i) elevated levels of CTX as compared to levels of CTX in a reference population;
(j) elevated levels of Osterix as compared to levels of Osterix in a reference population;
(k) decreased levels of Klotho as compared to levels of Klotho in a reference population;
(l) decreased levels of alpha smooth muscle actin (alpha-SMA) as compared to levels of alpha-SMA in a reference population;
(m) decreased levels of myocardin (MYOCD) as compared to levels of MYOCD in a reference population;
(n) decreased levels of smooth muscle protein 22-alpha (Sm22-alpha) as compared to levels of Sm22-alpha in a reference population
(o) elevated levels of phosphosmad3 as compared to levels of phosphosmad3 in a reference population;
(p) elevated levels of urinary protein as compared to levels of urinary protein in a reference population;
and/or
(q) decreased levels of ActRIIA as compared to levels of ActRIIA in a reference population.

15 more elements

A method for treating and/or preventing vascular calcification in a subject, comprising administering to the subject a pharmaceutically effective dose of an ActRII signaling inhibitor, wherein the subject has:

(a) elevated levels of Runx2 as compared to levels of Runx2 in a reference population;
(b) elevated levels of Alp as compared to levels of Alp in a reference population;
(c) elevated levels of Snai1 as compared to levels of Snai1 in a reference population;
(d) elevated levels of phosphosmad2 as compared to levels of phosphosmad2 in a reference population;
(e) elevated levels of Dkk1 as compared to levels of Dkk1 in a reference population;
(f) elevated levels of col1a1 as compared to levels of col1a1 in a reference population;
(g) elevated levels of activin as compared to levels of activin in a reference population;
(h) elevated levels of BSAP as compared to levels of BSAP in a reference population;
(i) elevated levels of CTX as compared to levels of CTX in a reference population;
(j) elevated levels of Osterix as compared to levels of Osterix in a reference population;
(k) decreased levels of Klotho as compared to levels of Klotho in a reference population;
(l) decreased levels of alpha-SMA as compared to levels of alpha-SMA in a reference population;
(m) decreased levels of MYOCD as compared to levels of MYOCD in a reference population;
(n) decreased levels of Sm22-alpha as compared to levels of Sm22-alpha in a reference population;
(o) elevated levels of phosphosmad3 as compared to levels of phosphosmad3 in a reference population;
(p) elevated levels of phosphosmad2 as compared to levels of phosphosmad2 in a reference population;
and/or
(q) decreased levels of ActRIIA as compared to levels of ActRIIA in a reference population.

15 more elements

A method for treating and/or preventing cardiovascular disease in a subject, comprising administering to the subject a pharmaceutically effective dose of an ActRII signaling inhibitor, wherein the subject has:

(a) elevated levels of Runx2 as compared to levels of Runx2 in a reference population;
(b) elevated levels of Alp as compared to levels of Alp in a reference population;
(c) elevated levels of Snai1 as compared to levels of Snai1 in a reference population;
(d) elevated levels of phosphosmad2 as compared to levels of phosphosmad2 in a reference population,
(e) elevated levels of Dkk1 as compared to levels of Dkk1 in a reference population;
(f) elevated levels of col1a1 as compared to levels of col1a1 in a reference population;
(g) elevated levels of activin as compared to levels of activin in a reference population;
(h) elevated levels of BSAP as compared to levels of BSAP in a reference population;
(i) elevated levels of CTX as compared to levels of CTX in a reference population;
(j) elevated levels of Osterix as compared to levels of Osterix in a reference population;
(k) decreased levels of Klotho as compared to levels of Klotho in a reference population;
(l) decreased levels of alpha-SMA as compared to levels of alpha-SMA in a reference population;
(m) decreased levels of MYOCD as compared to levels of MYOCD in a reference population;
and/or
(n) decreased levels of Sm22-alpha as compared to levels of Sm22-alpha in a reference population;
(o) elevated levels of phosphosmad3 as compared to levels of phosphosmad3 in a reference population
(p) elevated levels of urinary protein as compared to levels of urinary protein in a reference population;
and/or
(q) decreased levels of ActRIIA as compared to levels of ActRIIA in a reference population;
and
wherein the cardiovascular disease is associated with and/or results from vascular calcification.

18 more elements

A method for treating and/or preventing elevated levels of arterial stiffness in a subject, comprising administering to the subject a pharmaceutically effective dose of an ActRII signaling inhibitor, wherein the subject has:

(a) elevated levels of Runx2 as compared to levels of Runx2 in a reference population;
(b) elevated levels of Alp as compared to levels of Alp in a reference population;
(c) elevated levels of Snai1 as compared to levels of Snai1 in a reference population;
(d) elevated levels of phosphosmad2 as compared to levels of phosphosmad2 in a reference population;
(e) elevated levels of Dkk1 as compared to levels of Dkk1 in a reference population;
(f) elevated levels of col1a1 as compared to levels of col1a1 in a reference population;
(g) elevated levels of activin as compared to levels of activin in a reference population;
(h) elevated levels of BSAP as compared to levels of BSAP in a reference population;
(i) elevated levels of CTX as compared to levels of CTX in a reference population;
(j) elevated levels of Osterix as compared to levels of Osterix in a reference population;
(k) decreased levels of Klotho as compared to levels of Klotho in a reference population;
(l) decreased levels of alpha-SMA as compared to levels of alpha-SMA in a reference population;
(m) decreased levels of MYOCD as compared to levels of MYOCD in a reference population;
and/or
(n) decreased levels of Sm22-alpha as compared to levels of Sm22-alpha in a reference population;
(o) elevated levels of phosphosmad3 as compared to levels of phosphosmad3 in a reference population;
(p) elevated levels of urinary protein as compared to levels of urinary protein in a reference population;
and/or
(q) decreased levels of ActRIIA as compared to levels of ActRIIA in a reference population.

16 more elements

A method for treating and/or preventing cardiovascular disease in a subject, comprising administering to the subject a pharmaceutically effective dose of an ActRII signaling inhibitor, wherein the subject has:

(a) elevated levels of Runx2 as compared to levels of Runx2 in a reference population;
(b) elevated levels of Alp as compared to levels of Alp in a reference population;
(c) elevated levels of Snai1 as compared to levels of Snai1 in a reference population;
(d) elevated levels of phosphosmad2 as compared to levels of phosphosmad2 in a reference population;
(e) elevated levels of Dkk1 as compared to levels of Dkk1 in a reference population;
(f) elevated levels of col1a1 as compared to levels of col1a1 in a reference population;
(g) elevated levels of activin as compared to levels of activin in a reference population;
(h) elevated levels of BSAP as compared to levels of BSAP in a reference population;
(i) elevated levels of CTX as compared to levels of CTX in a reference population;
(j) elevated levels of Osterix as compared to levels of Osterix in a reference population;
(k) decreased levels of Klotho as compared to levels of Klotho in a reference population;
(l) decreased levels of alpha-SMA as compared to levels of alpha-SMA in a reference population;
(m) decreased levels of MYOCD as compared to levels of MYOCD in a reference population;
and/or
(n) decreased levels of Sm22-alpha as compared to levels of Sm22-alpha in a reference population;
(o) elevated levels of phosphosmad3 as compared to levels of phosphosmad3 in a reference population;
(p) elevated levels of urinary protein as compared to levels of urinary protein in a reference population;
and/or
(q) decreased levels of ActRIIA as compared to levels of ActRIIA in a reference population,
wherein the cardiovascular disease is associated with and/or results from elevated levels of arterial stiffness.

17 more elements

A method for treating and/or preventing left ventricular hypertrophy (LVH) in a subject, comprising administering to the subject a pharmaceutically effective dose of an ActRII signaling inhibitor, wherein the subject has:

(a) elevated levels of Runx2 as compared to levels of Runx2 in a reference population;
(b) elevated levels of Alp as compared to levels of Alp in a reference population;
(c) elevated levels of Snai1 as compared to levels of Snai1 in a reference population;
(d) elevated levels of phosphosmad2 as compared to levels of phosphosmad2 in a reference population;
(e) elevated levels of Dkk1 as compared to levels of Dkk1 in a reference population;
(f) elevated levels of col1a1 as compared to levels of col1a 1 in a reference population;
(g) elevated levels of activin as compared to levels of activin in a reference population;
(h) elevated levels of BSAP as compared to levels of BSAP in a reference population;
(i) elevated levels of CTX as compared to levels of CTX in a reference population;
(j) elevated levels of Osterix as compared to levels of Osterix in a reference population;
(k) decreased levels of Klotho as compared to levels of Klotho in a reference population;
(l) decreased levels of alpha-SMA as compared to levels of alpha-SMA in a reference population;
(m) decreased levels of MYOCD as compared to levels of MYOCD in a reference population;
and/or
(n) decreased levels of Sm22-alpha as compared to levels of Sm22-alpha in a reference population;
(o) elevated levels of phosphosmad3 as compared to levels of phosphosmad3 in a reference population;
(p) elevated levels of urinary protein as compared to levels of urinary protein in a reference population;
and/or
(q) decreased levels of ActRIIA as compared to levels of ActRIIA in a reference population.

16 more elements

A method for treating and/or preventing cardiovascular disease in a subject, comprising administering to the subject a pharmaceutically effective dose of an ActRII signaling inhibitor, wherein the subject has:

(a) elevated levels of Runx2 as compared to levels of Runx2 in a reference population;
(b) elevated levels of Alp as compared to levels of Alp in a reference population;
(c) elevated levels of Snai1 as compared to levels of Snai1 in a reference population;
(d) elevated levels of phosphosmad2 as compared to levels of phosphosmad2 in a reference population;
(e) elevated levels of Dkk1 as compared to levels of Dkk1 in a reference population;
(f) elevated levels of col1a1 as compared to levels of col1a1 in a reference population;
(g) elevated levels of activin as compared to levels of activin in a reference population;
(h) elevated levels of BSAP as compared to levels of BSAP in a reference population;
(i) elevated levels of CTX as compared to levels of CTX in a reference population;
(j) elevated levels of Osterix as compared to levels of Osterix in a reference population;
(k) decreased levels of Klotho as compared to levels of Klotho in a reference population;
(l) decreased levels of alpha-SMA as compared to levels of alpha-SMA in a reference population;
(m) decreased levels of MYOCD as compared to levels of MYOCD in a reference population;
and/or
(n) decreased levels of Sm22-alpha as compared to levels of Sm22-alpha in a reference population;
(o) elevated levels of phosphosmad3 as compared to levels of phosphosmad3 in a reference population;
(p) elevated levels of urinary protein as compared to levels of urinary protein in a reference population;
and/or
(q) decreased levels of ActRIIA as compared to levels of ActRIIA in a reference population;
wherein the cardiovascular disease is associated with and/or results from left ventricular hypertrophy.

17 more elements

A method for treating and/or preventing cardiovascular disease in a subject, comprising administering to the subject a pharmaceutically effective dose of an ActRII signaling inhibitor, wherein the subject has:

(a) elevated levels of Runx2 as compared to levels of Runx2 in a reference population;
(b) elevated levels of Alp as compared to levels of Alp in a reference population;
(c) elevated levels of Snai1 as compared to levels of Snai1 in a reference population;
(d) elevated levels of phosphosmad2 as compared to levels of phosphosmad2 in a reference population;
(e) elevated levels of Dkk1 as compared to levels of Dkk1 in a reference population;
(f) elevated levels of col1a1 as compared to levels of col1a1 in a reference population;
(g) elevated levels of activin as compared to levels of activin in a reference population;
(h) elevated levels of BSAP as compared to levels of BSAP in a reference population;
(i) elevated levels of CTX as compared to levels of CTX in a reference population;
(j) elevated levels of Osterix as compared to levels of Osterix in a reference population;
(k) decreased levels of Klotho as compared to levels of Klotho in a reference population;
(l) decreased levels of alpha-SMA as compared to levels of alpha-SMA in a reference population;
(m) decreased levels of MYOCD as compared to levels of MYOCD in a reference population;
and/or
(n) decreased levels of Sm22-alpha as compared to levels of Sm22-alpha in a reference population;
(o) elevated levels of phosphosmad3 as compared to levels of phosphosmad3 in a reference population;
(p) elevated levels of urinary protein as compared to levels of urinary protein in a reference population;
and/or
(q) decreased levels of ActRIIA as compared to levels of ActRIIA in a reference population;
and
wherein the cardiovascular disease is associated with and/or results from renal disease.

18 more elements

A method for reducing bone resorption in a subject, comprising administering to the subject a pharmaceutically effective dose of an ActRII signaling inhibitor, wherein the subject has:

(a) elevated levels of Runx2 as compared to levels of Runx2 in a reference population;
(b) elevated levels of Alp as compared to levels of Alp in a reference population;
(c) elevated levels of Snai1 as compared to levels of Snai1 in a reference population;
(d) elevated levels of phosphosmad2 as compared to levels of phosphosmad2 in a reference population;
(e) elevated levels of Dkk1 as compared to levels of Dkk1 in a reference population;
(f) elevated levels of col1a1 as compared to levels of col1a1 in a reference population;
(g) elevated levels of activin as compared to levels of activin in a reference population;
(h) elevated levels of BSAP as compared to levels of BSAP in a reference population;
(i) elevated levels of CTX as compared to levels of CTX in a reference population;
(j) elevated levels of Osterix as compared to levels of Osterix in a reference population;
(k) decreased levels of Klotho as compared to levels of Klotho in a reference population;
(l) decreased levels of alpha-SMA as compared to levels of alpha-SMA in a reference population;
(m) decreased levels of MYOCD as compared to levels of MYOCD in a reference population;
(n) decreased levels of Sm22-alpha as compared to levels of Sm22-alpha in a reference population
(o) elevated levels of phosphosmad3 as compared to levels of phosphosmad3 in a reference population;
(p) elevated levels of urinary protein as compared to levels of urinary protein in a reference population;
and/or
(q) decreased levels of ActRIIA as compared to levels of ActRIIA in a reference population.

15 more elements

A method for treating and/or preventing vascular calcification in a subject, wherein the method comprises:

(a) administering to the subject an initial dose of an ActRII signaling inhibitor to the subject;
(b) taking a first measurement of the level of Snai1, phosphosmad2, phosphosmad3, urinary protein, Dkk1, col1a1, activin, Runx2, Alp, BSAP, CTX, Osterix, Klotho, alpha-SMA, MYOCD, ActRIIA, Axin2, and/or Sm22-alpha in the subject;
(c) after a period of time, taking a second measurement of the level of Snai1, phosphosmad2, phosphosmad3, urinary protein, Dkk1, col1a1, activin, Runx2, Alp, BSAP, CTX, Osterix, Klotho, alpha-SMA, MYOCD, ActRIIA, Axin2, and/or Sm22-alpha in the subject;
and
(d) administering to the subject an adjusted dose of the activin receptor type II signaling inhibitor, wherein the first measurement is taken prior to the commencement of the treatment or within at most 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week, 2 weeks, 3 weeks, 4 weeks, or 2 months thereof, and wherein the adjusted dose is based on the detected change between the first measurement and the second measurement, thereby treating and/or preventing said vascular calcification.

2 more elements