Both low and high doses of deflazacort (Marathon Pharmaceuticals) are effective in increasing muscle strength in children and adolescents with Duchenne muscular dystrophy (DMD), suggests results of a large phase 3 randomized controlled trial.
Remarkably, this trial was actually completed back in 1995. More than 20 years later, the findings were published online August 26 in Neurology thanks the efforts of the drug's current manufacturer, which took over rights to the study from the original sponsor.
Results showed that among 196 boys with DMD aged 5 to 15 years, those treated daily with 0.9 mg/kg or 1.2 mg/kg of deflazacort or 0.75 mg/kg of prednisone had greater changes in muscle strength between baseline and 12 weeks than those treated with placebo (the primary endpoint).
However, the two deflazacort cohorts also showed significantly less weight gain than the prednisone cohort after 12 and 52 weeks of use.
"The original excitement came after the original prednisone studies showed it was beneficial in Duchenne. The trouble was that the side effects were considerable," coinvestigator John T. Kissel, MD, Ohio State University Wexner Medical Center, Columbus, told Medscape Medical News.
Dr John T. Kissel
"Our hope was that we could get the same benefit with deflazacort with less side effects than prednisone. And that's what we found," said Dr Kissel.
On the basis of the findings, the US Food and Drug Administration (FDA) accepted the manufacturer's New Drug Application for deflazacort in August and has granted Priority Review for the drug. A decision regarding approval is expected in February 2017.
Muscle Strength Deterioration
DMD, which affects 1 in 5000 boys, typically presents before a child turns 5 years of age. "Without treatment, [these] boys require a wheelchair before their teen years due to deterioration of muscle strength," write the investigators.
Dr Kissel noted that the FDA recently turned down or delayed approval of two new DMD drugs, drisapersen (BioMarin Pharmaceutical Inc) and eteplirsen (Sarepta Therapeutics). However, those agents "are more meant to manipulate the genetics of the disease and correct the defects. That's an exciting type of therapy but also a much higher bar for approval," he said.
Prednisone and deflazacort "do not do anything about the underlying pathophysiology of the disease." Instead, they improve muscle strength in patients with the disease, he added.
A member of the oxazoline steroids drug class, deflazacort is a heterocyclic glucocorticoid with immunosuppressant and anti-inflammatory properties.
During the study, which was conducted between April 1993 and April 1995 at 4 US centers and 5 Canadian centers, the 196 participants (mean age, 8.8 years) were randomly assigned to 1 of the following 4 groups for 12 weeks of daily treatment:
Deflazacort, 0.9 mg/kg per day (n = 51);
Deflazacort, 1.2 mg/kg (n = 49);
Prednisone, 0.75 mg/kg (n = 46); or
Matching placebo (n = 50).
After this first phase, the placebo group members were then randomly assigned to one of the other treatment groups. They, along with the original active treatment cohorts, continued in the study for an additional 40 weeks.
Efficacy for All Active Treatments
The Medical Research Council scale was used to assess average muscle strength changes from baseline to 12 weeks.
All three of the active-treatment groups had a significant difference in this primary outcome measure vs the placebo group, which had a least-square (LS) mean difference of –0.1.
Table. Outcome With Deflazacort or Prednisone vs Placebo
| Treatment Group | LS Mean Differencea (95% Confidence Interval) | P Value |
| Deflazacort, 0.9 mg/kg/day | 0.25 (0.04 - 0.46) | .02 |
| Deflazacort, 1.2 mg/kg/day | 0.36 (0.14 - 0.57) | .0003 |
| Prednisone, 0.75 mg/kg/day | 0.37 (0.15 - 0.59) | .0002 |
| aLS mean difference vs placebo. |
||
Compared with placebo, there were also significant improvements at 12 weeks in the time needed to go from a supine to a standing position in the deflazacort high-dose (P = .0002) and low-dose (P = .002) groups, as well as in the prednisone group (P = .002).
In addition, all three active treatment groups had improved time to run or walk 30 feet and to climb 4 stairs (all vs placebo, P < .0001).
Phase 2 of the study showed more improvement in average muscle strength between 12 and 52 weeks for patients receiving 0.9 mg/kg of deflazacort than in those receiving prednisone (P = .04). And both deflazacort groups showed better time to climb 4 stairs vs the prednisone groups (P = .046 and .001, respectively).
Weight Gain Differences
As for weight gain, there was no significant difference at 12 weeks between either deflazacort group vs placebo.
On the other hand, the prednisone group had greater increase in weight (P = .0459) and body mass index (BMI) (P = .004) at this point than did the other groups. And they had greater weight and BMI increases at the 52-week mark compared with those receiving deflazacort.
The most commonly reported adverse event (AE) was cushingoid appearance (in 69% of all participants), followed by erythema (42%) and hirsutism (39%). All three were found more often in patients receiving prednisone than those receiving deflazacort and were more common in the high- vs low-dose deflazacort groups.
"Since similar efficacy was seen between the [deflazacort] groups with lower numerical incidence of AEs overall, the 0.9 mg/kg/d group was the proposed dose submitted to the Food and Drug Administration," report the investigators.
In addition, "the AEs observed…are consistent with known AEs associated with chronic corticosteroid therapy," they add.
Dr Kissel noted that this was a study that was "close to my heart" — and one of the first clinical trials he ever participated in. Although the study was fully completed, the pharmaceutical company that sponsored it decided not to continue development of the drug in the United States.
"This was a labor of love and it frustrated us all for a long time that we put in so much time and it wasn't getting published," he said. Now, he said, he's happy that it's being used to move forward approval for the drug in the United States.
A longer-term, randomized trial known as FOR DMD is now in progress.
Options Important
Valerie Cwik, MD, executive vice president and chief medical and scientific officer of the Muscular Dystrophy Association and a coinvestigator for the study, told Medscape Medical News that the results are important because these patients need options.
"Currently, prednisone is the only drug available to have shown an effect" in this condition, said Dr Cwik. "There have been a number of studies on deflazacort showing benefits for it as well, but the drug hasn't been available in the US. And families who wanted it have had to have it imported."
Versions of the drug are available in several countries outside the United States, although none are currently indicated for DMD.
Dr Cwik noted that although the study is old, it was rigorously done and one of the largest deflazacort trials conducted.
"It's gratifying to finally see this data published. And for our families to have deflazacort as an option, if it's approved, will be important," she said. "Clinicians need to make sure that they understand the risks and benefits of all the drugs available for Duchenne muscular dystrophy and to then share that information with families."
The study was funded by Nordic Merrill Dow and the Muscular Dystrophy Association. Dr Kissel has disclosed no relevant financial relationships. Disclosures for the coauthors are in the paper.
Neurology. Published online August 26, 2016. Abstract
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Cite this: Deflazacort Improves Muscle Strength in DMD, With Less Weight Gain Than Prednisone - Medscape - Sep 08, 2016.
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