We all understand that Duchenne muscular dystrophy is characterized by muscle wasting and associated loss of function and that there are considerable efforts underway to develop drugs and biologics (cell and gene therapy) to address the primary problem in Duchenne—the absence of dystrophin. Restoring dystrophin or replacing dystrophin with replacement protein are considered foundational therapies.
That said, the Duchenne community is well aware of the need for combination therapies. Combinations would include compounds that target what is referred to as the ‘downstream pathology’ or the changes that occur because dystrophin is absent. This includes anti-inflammatories, anti-fibrotics, factors that control muscle regeneration and fiber size, compounds that improve circulation to muscle, and compounds that improve mitochondrial function (mitochondria are considered the powerhouses of cells). We are all hopeful that by combining several of these targeted therapies, we could end Duchenne, stop progression for every individual. This is the dream of precision or personalized medicine. The right drug, at the right time, in the right dose for the right person. It requires planning and it will require combinations.
Regeneration of muscle and improving muscle fiber size is thought to be an important piece of the puzzle
Muscle regeneration is regulated by insulin-like growth factor 1 (IGF-1), which is a protein that in humans is encoded by the IGF1 gene, and myostatin. IGF-1 is the positive regulator of muscle. Myostatin is the negative regulator of muscle. Muscle growth and regeneration is controlled in a push-pull fashion. That is, there are factors that promote or restrict the process of satellite cell expansion and their incorporation into new or existing muscle fibers.
Myostatin (also known as Growth Differentiation Factor 8 or GDF8) is one of these regulators of muscle regeneration. Myostatin is normally secreted by muscle cells to act on surrounding muscle cells by inhibiting or stopping muscle growth and differentiation. Inhibiting or blocking this pathway results in an increase in regeneration and fiber size.
There are a number of ways to target the myostatin pathway
Follistatin is one possibility. PPMD supported Jerry Mendell’s first study of follistatin in Becker patients and Dr. Mendell has now expanded the study to Duchenne. The approach is to deliver follistatin via gene therapy into the quadriceps muscle. Follistatin is a naturally occurring protein that plays a role in blocking the myostatin pathway.
Blocking myostatin via the GDF8 pathway is another possibility. Thus, myostatin itself, as well as the molecular pathways that regulate myostatin, are potentially important targets for development of therapies to optimize muscle regeneration and thus delay the progression of Duchenne.
Currently, there are clinical trials that target the myostatin or GDF8 pathway
Both of these trials are exploring an antibody strategy to inactivate the myostatin-based signaling cascade and thereby enhance muscle regeneration and delay the progression of muscle weakness in Duchenne.
Many of you are likely familiar with prior efforts by Wyeth (MYO-029; failed to show efficacy in trials in Becker and other types of muscular dystrophy) and Acceleron (ACE-031; stopped because of adverse events experienced by participants), earlier generation drugs targeted at myostatin inhibition. These were the first attempts on the myostatin target. Learning from the experiences in designing MYO-029 and ACE-031 has been important in moving forward.
BMS’s and Pfizer’s trials build on lessons learned about the myostatin pathway and will be a good test of the hypothesis that myostatin inhibition can delay the progression of Duchenne.
Bristol Myers-Squibb is an educational partner of PPMD.