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Aug 09, 2018
 |  BC Innovations  |  Targets & Mechanisms

Getting to function

How a new sarcopenia target could directly address muscle function deficits

A new target for sarcopenia that increases muscle function directly, in addition to adding muscle mass, could help address calls from patients and regulators to make functional recovery central to drug development in the indication.

Sarcopenia refers to age-related muscle wasting, and has only been classified as a disease by the CDC since 2016. Drug developers have started to trickle into the space over the last five years, but there’s growing evidence that their initial focus on muscle mass is too simplistic.

In 2010, the European Working Group on Sarcopenia in Older People (EWGSOP) published an analysis that concluded “defining sarcopenia only in terms of muscle mass is too narrow and may be of limited clinical value.”

Several factors play into a muscle’s strength besides its mass, and the relationship between mass or volume and strength is not linear, the group wrote. Instead, it recommends diagnosing the condition based on two criteria: low muscle mass plus either low muscle strength or performance.

Last year, FDA held a Patient-Focused Drug Discovery meeting on sarcopenia, in which fatigue and mobility stood out as two of the most important symptoms to patients. While the agency has not published guidance on sarcopenia trials, FDA spokesperson Theresa Eisenman told BioCentury, “therapies to treat sarcopenia, or any condition, should demonstrate a clinically meaningful benefit on how a patient feels, functions or survives.”

Few products have been tested in the clinic for the indication. Only three have completed a Phase II trial, all of which had muscle mass or volume as the sole or co-primary endpoint, according to a ClinicalTrials.gov search that excluded other forms of muscle wasting. But recent trials show companies are moving to include measures of function as well as muscle size.

Novartis AG’s bimagrumab blocks the myostatin receptor ACVR2, relieving its inhibition of protein synthesis, and thereby increasing muscle mass (see Figure: “Tapping Mitochondria”).


Figure: Tapping mitochondria

A University of Toulouse team has identified the peptide hormone APLN-13 as a new candidate for sarcopenia that could be more effective than first-generation therapies tested in the clinic, such as MSTN pathway inhibitors, because it directly boosts muscle function, in addition to increasing muscle mass. The university plans to start a Phase I trial of APLN-13 in January.

(1) When APLN-13 binds its receptor APLNR, the receptor activates at least two signaling axes: PI3K-AKT and AMPK-PGC-1α. PI3K-AKT induces protein synthesis, which helps build muscle mass. AMPK-PGC-1α increases mitochondrial biogenesis and respiratory capacity. Separately, AMPK also boosts cellular uptake of glucose through GLUT4 -- increasing intracellular availability of the energy substrate. Both effects of AMPK help boost muscle function.

(2) Sarconeos from Biophytis S.A. is another relatively new candidate for sarcopenia that stands to enhance muscle function and mass. Like APLN-13, the MAS receptor agonist feeds into both the PI3K-AKT and AMPK-PGC-1α pathways. The compound is in Phase II testing.

(3) Novartis AG’s bimagrumab is a first-wave therapy that increased muscle mass in a...

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