DMD treatment Agamree may avoid issues of traditional steroids
Biological action different from that of corticosteroids, researchers say
Data from two clinical trials confirm that Agamree (vamorolone), an approved anti-inflammatory treatment for people with Duchenne muscular dystrophy (DMD), blocks the action of a receptor involved in regulating the balance of salt and water in the body, and may have advantages over traditional corticosteroids.
A study found the biological action of Agamree, which also interacts with corticosteroid receptors, is distinctly different from that of traditional DMD medications.
The study, “Mineralocorticoid receptor antagonism of vamorolone: Evidence from LIONHEART and VISION-DMD clinical trials,” was published in the journal Steroids. Two of the study’s authors are former employees of Santhera Pharmaceuticals, which sponsored the LIONHEART trial. Catalyst Pharmaceuticals holds the North American marketing rights to Agamree under an agreement with Santhera.
Corticosteroids are potent anti-inflammatory medications commonly prescribed in DMD. It’s thought these drugs — such as prednisone and Emflaza (deflazacort) — help preserve muscle tissue by easing inflammation. But their long-term use is associated with a wide range of side effects, including weight gain, high blood pressure, and irregular heartbeats.
Cell, mouse studies show receptor blocking
Agamree is a so-called dissociative steroid approved to preserve muscle function and ease inflammation in people with DMD, ages 2 and older. It’s designed to activate cortisol receptors in a way that promotes anti-inflammatory activity, while minimizing the side effects of traditional corticosteroids.
Unlike prednisone, Agamree was found to block the action of the mineralocorticoid receptor (MR) in a dose-dependent manner in cells. The activation of the MR leads to the production of proteins that regulate the reabsorption of sodium and the excretion of potassium, thereby maintaining normal salt levels in the body.
The action of Agamree against the MR was further demonstrated in a mouse model of DMD. Animals treated with prednisolone also developed cardiac hypertrophy, characterized by thickened heart muscle, but those given Agamree did not.
But “the activity of [Agamree] on the MR has yet to be investigated in humans,” wrote researchers who analyzed data from two clinical trials: LIONHEART (NCT06649409), a Phase 1 mechanistic study in healthy volunteers, and VISION-DMD (NCT03439670), a Phase 2b study that helped support Agamree’s approval.
“This potential differentiating activity of [Agamree] is of particular interest in patients with DMD for whom cardiac involvement can begin before the age of 10 years and affects all patients with advanced disease,” the team wrote.
In LIONHEART, 30 healthy adult volunteers were randomly assigned to a single dose of Agamree, a single dose of eplerenone, or no treatment. Eplerenone, a medication used to treat heart failure and high blood pressure, was used as a positive control because it’s known to block the MR in humans. The outcome was the ratio of urinary sodium to potassium, as determined under fludrocortisone challenge, which induces sodium retention.
The data showed that Agamree significantly increased the sodium-to-potassium ratio compared with no treatment, as did eplerenone, “indicating that the [sodium retention] effect of fludrocortisone was reversed and thus confirming the [MR blocking] effect of [Agamree],” the team noted.
At the same time, the levels of potassium in urine were similar between the Agamree group and the no-treatment group, but were slightly reduced with eplerenone.
Blocking effect supported in patient trial
The VISION-DMD trial enrolled 121 boys, ages 4-6, with DMD who could walk. They were given oral Agamree, prednisone, or a placebo once daily for 24 weeks, or about six months. Thereafter, all participants either started or continued treatment with Agamree for up to 24 weeks.
From blood samples collected throughout the study, the team measured the levels of proteins, such as klotho and renin, as well as fetuin A and B, which are known to increase with MR blockade.
At 12 and 24 weeks, klotho and renin levels rose significantly in the Agamree group relative to the placebo group. After that, renin and klotho levels in the prednisone and placebo groups also increased when these participants switched to Agamree. Similarly, fetuin A and fetuin B increased significantly with Agamree treatment compared with the placebo, but prednisone had no effect. After patients switched to Agamree, blood fetuin A and B rose significantly.
No adverse events related to excessive potassium levels were reported in the trial, and no changes in blood sodium levels were observed in any of the groups.
“The [MR blocking] effect of [Agamree] was confirmed in healthy subjects in the mechanistic LIONHEART study and further supported by serum protein data from the DMD patients treated with [Agamree] …in the VISION-DMD study,” the researchers wrote.
“It remains to be further investigated if the unique mode of action of [Agamree] that combines anti-inflammatory effects via [glucocorticoid receptor activation], and MR [blocking] could provide additional cardioprotective benefits in patients with DMD,” they added.
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