Acceleron Initiates Phase 1 Clinical Trial For ACE-031 To Treat Diseases Involving Muscle Loss

Acceleron Pharma announced the initiation of a Phase 1 clinical study of ACE-031, its lead compound for treating diseases involving the loss of muscle mass and function.

Explain this trial?

Acceleron will start phase I clinical trials, using a new compound, ACE-031. This phase I trial will be a randomized, placebo-controlled single dose and escalating dose study in humans to evaluate the effect of ACE-031 on muscle growth and strength. The study will be conducted in Canada.  It is unclear in which types of muscular dystrophy the drug will be tried, nor is it clear which mouse models were used in preclinical trials.  I will send an email to Acceleron and post their response as I would like to know if they tested the drug in any of the CMD mouse models. To read more about ACE-031….


ACE-031 works by blocking molecules from attaching to activin receptor type IIB (ActRIIB). The activin receptor is integral to the activin and myostatin signaling pathway.  Myostatin binds to the ActRIIB receptor as well. When myostatin binds to the ActRIIB receptor, it triggers negative regulation of muscle, meaning decreased muscle size and regeneration.  In the last research news, I discussed:

  1. myostatin action can be blocked by using a myostatin propeptide
  2. myostatin antibodies (MYO-029) were used in a clinical trial by Wyeth that was terminated prematurely. 
  3. The only trial looking at myostatin in CMD, crossed myostatin null mice with merosin deficient mice. The mice had larger muscles but no increased regeneration and no decreased fibrosis.  This differs from the results seen using myostatin in Duchenne mouse model, in that myostatin increases regeneration and decreases fibrosis.  What would the effect be of myostatin in other CMD mouse models? Would a less drastic approach, ie, myostatin inhibition through antibodies in the merosin deficient mouse have different results?


Losartan also blocks TGF beta through a different mechanism, ie, not the ActRIIB receptor, but through binding to the angiotensin II type 1 receptor (AT1). Losartan has been shown in Marfan’s, a connective tissue disease, to decrease fibrosis, upregulate muscle regeneration and repair. In a series of studies done by Dr. Cohn and Dr. Dietz, et al., it was shown that an increase in TGF beta can severely inhibit skeletal muscle cell growth and regeneration.  AT1 receptor inhibition has been shown in heart and kidney to block TGF beta signaling. A subsequent study was done by Dr. Cohn and Dr. Dietz, looking at using losartan in the Duchenne mouse model (mdx).  Losartan decreases muscle fibrosis and increases regeneration in the mdx mouse model. Cohn et al. Nature, 2007 January. Dietz et al. Science.2006 April; (312):117-121.


Bottom line: Myostatin and TGF Beta signaling or upregulation, leads to muscle breakdown, fibrosis and decreased regeneration. Losartan, myostatin propeptide, myostatin antibody (MYO-029) and ACE-031 block that effect in Duchenne MD.


Are there any studies looking at TGF Beta signaling in CMD?

There is a study looking at TGF beta in merosin deficient CMD. In this study, 5 patient populations had their muscle biopsies surveyed for level of TGF beta mRNA expression: 4 merosin negative, 4 merosin positive, 7 partial merosin deficient, Duchenne patients and normal controls. mRNA expression of TGF beta was highest in DMD, then in merosin negative and merosin positive and not elevated in partial merosin deficiency.  The conclusion is that TGFbeta is involved in CMD muscle fibrosis, but not to the same extent as in Duchenne. Bernasconi et al. Neuromuscul Disord.1999 Jan;9(1):28-33.


Are there any studies looking at fibrosis in CMD?

There is a study looking a fibrosis in Fukuyama (dystroglycanopathy) and merosin deficient CMD.  This study looked at what genes were upregulated and downregulated. In general, the genes that were upregulated dealt with the extracellular matrix (outside the muscle cell) and led to increased fibrosis. The genes that were downregulated dealt with structural components within the muscle cell.  Their conclusion was that extracellular fibrosis plays a greater role in the CMDs and there is less muscle cell regeneration when compared to muscle biopsy samples from Duchenne.  What is unclear is what is driving the active fibrosis if TGF beta plays less of a role in CMDs than Duchenne? Would Losartan work in CMDs? Toda et al. Biochem Biophys Res Commun. 2006, April 7;342 (2):489-502.


Where do the drugs or hormones exert their effect? “x” marks the binding location



AT1 receptor


Who did study?


 X study done in adult MD, with varied population. Found to be safe but no improvement of disease. Unclear if prevented progression.



Dr. Kathryn Wagner, Wyeth

Study population: adult MD including LGMD, Becker

Myostatin propeptide: delivered by adenovirus vector

X injected in Duchenne dog model; increased muscle mass, decreased fibrosis



Dr. Quio

Study population: Duchenne dog model



X used in Marfans and mdx mouse model: increased muscle mass, decreased fibrosis


Dr. Ron Cohn, Dr. Harry Dietz

Study population: Duchenne mouse model (mdx)

ACVR2B (soluble form of part of the ActRIIB receptor)



X injected into non MD mice, increased muscle mass

Dr. Se-Jin Lee

Study population: non muscular dystrophy mice




X Current phase I clinical trial by Acceleron in Canada


Study population: validated in ? animal models

myostatin, also called GDF-8

(growth differentiation factor)



X this is not a trial, but myostatin does bind to this receptor


Myostatin null mice

 X Bred myostatin null mice with merosin deficient mice; increased muscle mass, but no decrease in inflammation, strength not measured



Dr. Eva Engvall


Study population: merosin negative mouse model (dy/dy)

TGF beta







X binds here, blocked by losartan

X binds here, blocked by ACE-031 or ACVR2B

Bernasconi- TGF beta mRNA examined in merosin neg and pos. patients compared with DMD, less TGF elevation, though more than controls

Toda- Dystroglycanopathy and merosin neg, a more prominent fibrosis, less regeneration than Duchenne. Is fibrosis mediated through different pathway than TGFbeta?


TGF Beta superfamily is starting to play a big role as a therapeutic target as it has been shown to be involved in accelerating muscle degeneration and increasing fibrosis.  There are multiple targets within the TGF Beta superfamily, some by blocking the receptors it binds to.


How does TGF beta interact with muscle cells and how does blocking its effect, downregulate muscle cell growth, repair and fibrosis?  It is unclear if the main effect of TGF beta involves the satellite cell population.  Satellite cells are naturally occurring stem cell islands amidst the muscle cells that serve as a replenishing source of muscle cells. These new muscle cells replace damaged muscle cells in all of us. If one understood how the TGB beta up or down regulation affected the muscle cells one might be able to direct more focused therapy. TGB beta fulfills many functions in the body so inhibiting its effect may have secondary effects or cause side effects.


What is the relevance to CMD? This is unclear. It remains to be seen if myostatin inhibition and blocking TGF beta will have a similar effect in the CMDs, with increased muscle mass, decreased fibrosis and increased muscle regeneration. It is also important to assess gains in functional strength not simply increases in muscle mass.  An understanding of how Duchenne MD muscle breakdown progresses when compared with CMDs will be helpful to address new targets and distinguish which targets might work in Duchenne but not CMD.


To read more about Acceleron ACE-031 trial….




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  • Congenital Muscular Dystrophy

    A group of diseases causing muscle weakness at birth. Several defined genetic mutations cause muscles to break down faster than they can repair or grow. A child with CMD may have various neurological or physical impairments. Some children never gain the ability to walk, while others lose the ability as they grow older. Learn more...

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