Corticosteroids (prednisone, deflazacort etc)
To suppress the immune system in order to reduce the formation of scar tissue.
Corticosteroids are a group of drugs that can suppress the immune system. When muscle tissue is damaged, this will elicit an immune response (the body does not know what causes the damage – it could well be a virus, bacteria etc). While the immune response has the best intensions (to protect the body from infections), in this case the immune system increases the severity of the disease. Immune cells excrete toxic substances (aimed to kill bacteria etc), which further increase muscle damage and enhance the formation of scar tissue.
By suppressing the immune system with corticosteroids, muscle damage will be less severe and less scar tissue will be formed.
Not that many trials have been done to compare patients treated with corticosteroids and those without, or to compare one corticosteroid to another (e.g. prednisone to deflazacort), but the general consensus is that corticosteroids delay the disease progression and therefore they are part of the standards of care for DMD. Long term analyses have revealed treatment will delay wheelchair dependency by ~1-3 years, will improve muscle strength and function, will delay the loss of respiratory function and improve survival.
It is very likely that corticosteroids work on other levels than only immune suppression (it is thought they can increase expression of utrophin and/or stabilize muscle fibers, so they are less sensitive to damage). This is still under investigation. However, the finding that drugs that only suppress the immune system are less effective than corticosteroids (see e.g. below in the section on cyclosporine),
underlines this idea.
Corticosteroids have to be taken regularly and chronically. This results in side effects in most patients. The most common are weight gain, depression, behavioral problems, growth retardation, delayed puberty and loss of bone mass but many more have been described.
For some patients side effects can be reduced by an “on-off” treatment regime. Steroids are e.g. taken only every other week, or only during weekdays and not weekends or high doses are taken only during the weekends.
Some patients cannot tolerate chronic treatment with corticosteroids. If the side effects outweigh the benefits (e.g. weight gain to such an extent it impairs rather than enhances muscle functionality) it may be best to stop treatment (this should of course only be done after discussion with the treating clinician because abruptly stopping steriod treatment can lead to severe side effects and even death).
Many different corticosteroid treatment regimes are in use by different patients. It is not yet known whether one regime is more optimal than others. Furthermore, for clinical trials testing therapeutic approaches, it would be preferred if a more standardized regime would be used by all patients in the trial.
The FOR-DMD trial compares beneficial effects and side effects of the most used dosing regimes of prednisolone (daily treatment vs. 10 days on – 10 days off) and daily treatment with deflazacort. The study takes place in at least 40 muscle clinics in the USA, Canada, UK, Germany and Italy. This study is fully recruited.
It is unknown when best to start with corticosteroids. Due to the adverse effects (stunting growth, obesity and increased osteoporosis) most clinicians do not start before age 3-4 years.
To test whether starting before age 3 years is beneficial, a clinical trial is ongoing in 1-30 month old DMD patients. Patients take high doses of prednisone only twice per week to lower the chance of side effects.
Vamorolone (previously VBP15) is a non-steroid compound developed by Reveragen Biopharma. The hope is that this compound induces the beneficial effects of corticosteroids, but not the side effects. In the mdx mouse model this was indeed observed. A phase 1 trial in healthy volunteers has been completed. A phase 2a trial in patients has been completed in the USA. Dose dependent functional improvements have been observed in patients in the open label phase after 6 months of treatment compared to untreated patients from natural history datasets. Phase 2b trials are currently ongoing in the USA and Europe where vamorolone treatment is compared to placebo and prednisone treatment.
CAT1004 (edasalonexent) is an anti-inflammatory drug developed by Catabasis. It has been tested in healthy adults. A two stage phase 1/2 study in DMD patients has recently been completed. Edasalonexent was safe and well tolerated. No anti-inflammatory effect could be picked up by MRI when comparing placebo and treatment groups after 12 weeks of treatment. All boys were then switched to the high dose group. After 48-60 weeks of treatment, muscle function seems to be stabilized compared to the progression before treatment initiation. Patients still receive treatment in an open label phase. A phase 3 confirmatory trial is currently ongoing. Results are expected in the second half of 2020.
MNK1411 (cosyntropin) is a manmade hormone that has similar anti-inflammatory effects as corticosteroids. Results in mdx mice suggest that MNK1411 treatment results in less inflammation. The company Mallinckrodt Pharmaceuticals is currently running a placebo-controlled clinical trial in DMD patients to test whether injections with MNK1411 have therapeutic effects.
Marathon Pharmaceuticals has conducted an open label study for deflazacort in the US in DMD patients which was at the time not marketed. They have obtained approval for treatment of DMD in the US by the FDA. PTC has obtained the rights to deflazacort in the US and is currently marketing the drug.
Tested but found ineffective
Cyclosporin is a drug that suppresses the immune system. When muscle tissue is damaged, this will elicit an immune response (the body does not know what causes the damage – it could well be a virus, a bacteria etc). While the immune response has the best intensions (to protect the body from infections), in this case the immune system increase the pathology. Immune cells excrete toxic substances (aimed to kill bacteria etc), which further increases muscle damage and enhances the formation of scar tissue.
By suppressing the immune system with cyclosporin, muscle damage will thus be less severe and less scar tissue will be formed. It is thought to induce less side effects than corticosteroids.
A clinical trial was performed in Germany (Rudolf Korinthenberg in Freiburg) to assess whether cyclosporine treatment indeed is beneficial for patients. Unfortunately, no difference was observed between patients treated with and without cyclosporine.