Current status: corticosteroids are part of the standards of care

Marketing authorization is in place for vamorolone with EMA and FDA

Aim:
To suppress the immune system in order to reduce the formation of scar tissue.

Background:
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. Corticosteroids delay Duchenne disease progression and therefore they are part of the standards of care for DMD even though chronic use is associated with side effects.

Clinical trials:
Two types of corticosteroids are used by Duchenne patients: deflazacort and prednisone or its active metabolite prednisolone. Different doses and regimen are used, but the most frequently used regimen are daily deflazacort at 0. 9 mg/kg, daily prednisone or prednisolone at 0.75 mg/kg or a 10 days on 10 days off regimen of 0.75 mg/kg prednisone or prednisolone. Comparing the different regimen has occurred mainly in patient cohorts who had been treated for years (retrospective analysis). To compare the regimen in a more controlled prospective manner the FOR-DMD trial was conducted comparing the 3 most frequently used regimen. The results have recently been published. The study showed that steroid treatment in any regimen slows down disease progression. There was no difference between daily deflazacort and daily prednisone, while the on/off prednisone group did better than no steroids, but worse than those on daily steroids. No clear difference in side effects were seen in the different steroid regimen during the 3 year trial. Longer term follow up will reveal whether there is a difference after longer treatment.

To consider:

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.

Challenge 1:
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.

Clinical trial:
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.

Chronic use of corticosteroids is associated with side effects including reduced growth, weight gain, behavioral changes, increased risk of fractures and delayed puberty. Vamorolone (previously VBP15) is a dissociative steroid developed by Reveragen Biopharma. Vamorolone binds to the glucocorticoid receptor like prednisone and deflazacort and in this way can reduce inflammation. However, prednisone and deflazacort are agonists of the mineralcorticoid receptor, which leads to a high blood pressure. Furthermore, they can transfer to the cell nucleus, where they activate the expression of many gene. This is what underlies most steroid side effets. Vamorolone is an antagonist of the mineralcorticoid receptor, leading to a lower blood pressure (beneficial for patients with heart problems). Furthermore, vamorolone cannot transfer to the cell nucleus and is thus expected to lead to less side effects.

Development is currently coordinated by Santhera.. In the mdx mouse model vamorolone treatment was equally efficient as prednisone treatment, but did not result in stunted growth or osteoporosis. A phase 1 trial in healthy volunteers has been completed. A phase 2a trial in patients has been completed in the USA. Patients were enrolled in an open label study, of which results from 18 months follow up have now been published: dose dependent functional improvements have been observed in patients in the open label phase after 18 months of treatment compared to steroid naive patients from natural history datasets, while less side effects were seen than for steroid treated patients from natural history datasets. Phase 2b trials results have now been published where vamorolone treatment at 2 and 6 mg/kg/day was compared to placebo and prednisone treatment for 24 weeks This revealed that treatment with 2 or 6 mg/kg vamorolone improved muscle function compared to placebo and that 6 mg/kg vamorolone had equivalent effects as 0.75 mg/kg/day prednisone. Vamorolone treatment did not have an impact on height or bone turnover when compared to placebo, while prednisone treatment resulted in decreased growth and increased bone turnover. However, vamorolone treatment does have the same impact on weight gain as prednisone and deflazacort.

Based on these results marketing authorization was granted by the FDA and the EMA. The drug is sold under the tradename Agamree.

The company Antisense Therapeutics is developing ATL1102, an antisense oligonucleotide (ASO) compound (small piece of modified RNA) that targets CD49d, a protein that is elevated in Duchenne patients. The rationale is that reducing CD49d will result in a reduced immune response and thus a slower disease progression. A first clinical trial in Duchenne patients showed that weekly subcutaneous treatment was well tolerated and resulted in reduced levels of inflammatory cells in the blood.  A placebo-controlled trial to study this compound in non-ambulatory patients is currently ongoing.

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.

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 has been completed and results have been published. Unfortunately the primary endpoint was not reached: patients treated with edasalonexent for 48 weeks did not improve significantly compared to the placebo group for the North Star Ambulatory Assessment scale or timed function tests.

Background:
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.

Clinical trial:
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.

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 initiated a placebo-controlled clinical trial in DMD patients to test whether injections with MNK1411 have therapeutic effects. Due to poor enrollment this trial has been terminated.