One aspect where this is evident is with the underutilization of corticosteroids in DMD patients despite years of data demonstrating their benefits. While data from randomized controlled trials have shown benefit of corticosteroids on muscle strength and function, and data from nonrandomized trials have suggested longitudinal benefit, there is not a consensus on the most appropriate steroid regimen.
Currently, treatment recommendations lack comparative data on the efficacy of alternative dosing regimens. Relatively recent publications have uncovered differences between countries in the prescription patterns of steroids regimens. Deflazacort has been used for the treatment of DMD for over 20 years and published data demonstrates it to be a potentially safer and more effective alternative to prednisone. Deflazacort appears to have a positive impact on multiple aspects of the disease and could be used across the entire DMD population regardless of underlying genetic mutation.
Efforts to achieve approval for deflazacort from the FDA are close to being submitted for review. As deflazacort may be approved for DMD and available to patients in the US in early , this article summarizes the published literature on deflazacort to help inform DMD-treating physicians on its impact on the disease. In a cohort of 54 boys with DMD, where 30 received active treatment and 24 were untreated, Biggar et al.
Patients in the active deflazacort treatment group remained ambulatory for longer than untreated patients Another paper by Biggar et al. In a retrospective analysis, Schara 15 analyzed the outcome of longterm steroid therapy for DMD using results with an average follow up period of 65 months.
Nineteen male patients receiving deflazacort 0. Additionally, 13 of the 19 male patients were compared with an age-matched control group of 13 patients with DMD who were not receiving steroid treatment.
The results suggested diminished loss of muscle strength and function in deflazacort treated patients with DMD compared to the natural history and this was observed to be more apparent with increasing age in patients who started therapy early i.
The statistical analysis of 13 deflazacort treated and 13 age-matched untreated patients showed that the average muscle strength was significantly greater in the treated group p A randomized, double-blind study of two doses of deflazacort 0.
Bonifati et al. Patients were treated with either deflazacort 0. At 12 months, the effect of both steroids was examined by comparing the status of the treated patients with another group of untreated DMD patients that served as natural history control. Results demonstrated that both steroids were equally effective in improving motor function and functional performances.
After 12 months of treatment the prednisone group gained significantly more weight than the deflazacort group 5. In a battery of motor function tests, patients treated with either deflazacort or prednisone lost their ability to walk, get up, climb, stand, lift weights, and lift their hand at a significantly later age than untreated patients p Angelini et al. After six months of treatment, the deflazacort group showed significant improvement in climbing stairs p Houde et al.
Data were collected over an eight-year period, with the mean length of treatment reported to be 66 months. The results of this study demonstrated that boys who received long-term treatment with deflazacort stopped walking at A further paper was published by Biggar et al. A total of 37 and 32 boys with DMD between the ages of 8 and 15 years were treated with deflazacort for at least four years using the Naples and Toronto protocols, respectively, then compared with non-treatment groups containing 19 and 30 patients, respectively.
Deflazacort treatment started between four and eight years of age. The results were compared with age-matched controls in the two groups 19 for the Naples protocol and 30 for the Toronto protocol. No aids or leg braces were used for ambulation. Wang et al. Similarly, Bello 23 reported the results from the Cooperative International Neuromuscular Research Group CINRG which prospectively observed DMD patients aged two to 28 years who received treatment with different corticosteroid regimens involving both deflazacort and prednisolone.
Prednisolone was administered while ambulatory to participants Deflazacort was associated with later loss of ambulation than prednisolone median loss of ambulation with deflazacort at Scoliosis Untreated boys with DMD develop significant scoliosis, often requiring surgery. Hoffman EP et al. Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function. Neurology Sep 24; e Neurology Sep 24 Treatment of Duchenne muscular dystrophy with vamorolone, a modified corticosteroid, may provide benefit with reduced side effects.
Comment This brief open-label trial suggests that vamorolone has reduced side effects compared with prednisone in a historical control sample. Citation s : Hoffman EP et al. October 22, Internal Medicine. Wilmington, North Carolina. Unfortunately, high dosage or long-term use of prednisone is typically accompanied by mild to severe adverse effects that can impact the quality of life, reduce patient adherence and limit overall therapeutic outcomes in DMD sufferers.
These include: excessive weight gain [ 40 , 42 , 48 , 49 , 51 ], adrenal insufficiency [ 52 ], stunted growth [ 51 ], cushingoid appearance [ 48 , 49 ], behavioural changes [ 53 ], decreased bone mineral density [ 54 ] and increased incidence of fractures [ 46 , 55 ].
These adverse effects, in combination with the already progressive, terminal nature of DMD may further place undue strain on patients and their families, and in particular, increase parental stress. For this reason, short-term intermittent prednisone treatment has been investigated as an alternative to chronic therapy, with noticeably reduced adverse effects and family stress and no impact on therapeutic activity [ 40 ].
Deflazacort, an oxazoline derivative of prednisolone [ 56 ] was approved in for DMD patients aged 5 years and older. Similar to prednisone, deflazacort is also used to treat a variety of other diseases based on its anti-inflammatory and immunosuppressive effects. Deflazacort is purported as a steroid alternative with fewer adverse effects and possibly with less risk of weight gain compared to prednisone [ 46 , 47 , 58 , 61 ]. However, in comparison to prednisone it is associated with behavioural changes [ 53 ] and cataract formation [ 46 , 47 , 57 , 58 ].
The effects of deflazacort on development and bone health have been inconsistent. Balaban , Marden , Bello and Biggar associated deflazacort with higher frequencies of growth delay and bone fractures [ 46 , 47 , 57 , 58 ] whereas Mesa and Angelini reported fewer effects on bone mass and fractures [ 60 , 62 ] in comparison to prednisone, making it unclear how deflazacort affects bone health.
The cardiac effects of corticosteroid treatment in DMD patients are not well characterised, although their use was associated with benefits such as improved overall cardiac function and delayed onset of cardiomyopathy [ 63 , 64 , 65 ].
Long-term administration of glucocorticoids has also been associated with acceleration of protein breakdown and inhibition of protein synthesis [ 67 , 68 , 69 ], which may ultimately lead to skeletal muscle atrophy [ 70 , 71 , 72 ]. These catabolic effects appear to be mediated, at least in part, via modulation of insulin-like growth factor-1 IGF-1 signalling and pro-atrophy signalling through Atrogin-1 [ 69 , 73 ].
Despite atrophy being counterintuitive to the attenuation of muscle wasting, glucocorticoids are still able to ablate some clinical symptoms through anti-inflammatory function. While these studies contributed to our understanding concerning the impact of corticosteroid treatment on DMD patients, some are disadvantaged by their short duration and follow-up times highlighting the need for longitudinal studies to understand the full impact of long-term corticosteroid use.
Although there is ongoing research to establish the most effective dose and regimens for glucocorticoids, safer alternatives are needed that offer a better benefit to side effect profile. In this regard, a novel dissociative steroid has recently shown some promise. Vamorolone formerly VBP , is a first-in-class anti-inflammatory steroid analogue [ 74 ] that is currently being investigated as a replacement for traditional standard of care glucocorticoids in DMD.
The structure of vamorolone is similar to other glucocorticoids: it binds to the GR and retains the anti-inflammatory effects characteristic of traditional steroids, preferentially inducing transrepression with little-to-no transactivation or cis -repression Fig.
As such, it is purported to elicit fewer adverse effects [ 13 , 75 ]. Vamorolone is also a mineralocorticoid receptor MR antagonist [ 18 ], and thus has the potential to treat DMD-associated cardiomyopathy through modulation of blood pressure. Dystrophin-deficient hearts are especially sensitive to damage facilitated through MR activation [ 18 ] although specific MR antagonists e.
The development of vamorolone for DMD was initiated with a Phase I clinical trial NCT in healthy volunteers to assess its safety, tolerability and pharmacokinetics. Vamorolone was well-tolerated at all dose levels, with pharmacokinetic and metabolic profiles similar to that of prednisone but without the associated adverse effects and safety concerns of traditional glucocorticoids e. Similar to the Phase I trial, Vamorolone was reported to be safe and well-tolerated and met the primary efficacy outcome of improved muscle function without evidence of adverse effects [ 78 , 79 ].
Rather than transition back to glucocorticoids, all patients included in the study requested to continue treatment on vamorolone under the month long-term open-label extension study NCT , which was recently completed [ 80 ].
In this study, treatment with vamorolone was associated with improvements in some motor outcomes and a favourable safety profile as fewer adverse effects were reported less incidence of weight gain, behavioural changes and cushingoid appearance [ 80 ] compared to those previously reported with traditional corticosteroid use.
Importantly, vamorolone, did not repress growth, which is usually observed with SOC treatment. An ongoing Phase IIb randomised, double-blind trial NCT is designed to demonstrate efficacy and safety of vamorolone at different doses compared to prednisone and placebo over 24 weeks.
Based on the available data, vamorolone received orphan drug status in the United States and Europe and will likely establish itself as a safer and superior alternative to current SOC glucocorticoids to benefit DMD patients as well as patients diagnosed with other chronic inflammatory diseases.
Despite some advances, an unmet clinical need remains for DMD disease-modifying drugs that are well tolerated and effectively mitigate disease progression. Steroids have prevailed as the only disease modifying drugs against DMD for more than a decade, despite their propensity to promote muscular atrophy [ 70 , 71 , 72 ].
Presumably, their intense anti-inflammatory function is more influential to attenuate muscle wasting than their atrophic effect progresses it [ 81 ]. Particularly, chronic inflammation is a driver of fast type II muscle fibre loss, which is pronounced in DMD [ 82 ]. It is possible that other potent anti-inflammatory drugs could have equivalent, if not greater, beneficial effects on mitigating DMD without the associated side-effects—particularly those pertaining to muscle atrophy, which is clearly counterintuitive in DMD treatment.
There are a variety of other potent anti-inflammatory drugs on the market that are yet to be investigated in DMD and that could be therapeutically advantageous compared to the glucocorticoids. These drugs display robust safety profiles and comprehensive clinical utility for diseases characterised by inflammation and oxidative stress, and both of these are notorious drivers of DMD [ 94 , 95 , 96 , 97 , 98 , 99 , , , ].
The therapeutic efficacy of FAEs appear to be mediated through the dual activation of the nuclear factor erythroid 2-related factor 2 Nrf2 transcriptional pathway [ 88 , , , ] and the hydroxycarboxylic acid receptor 2 HCAR2 [ , ] Fig. Nrf2 regulates the essential cellular defence system that counteracts potentially harmful stimuli through the upregulation of antioxidants and cytoprotective response genes [ , ].
Over the last decade, several Nrf2 activating drugs have been developed and trialled in both clinical [ , , , , , ] and pre-clinical [ , , , ] settings highlighting the broad therapeutic utility of targeted Nrf2 activation against diseases associated with inflammation and oxidative stress [ ]. Given the safety and efficacy of FAEs and targeted Nrf2 activators established in other studies, further translational investigations should be undertaken to assess the therapeutic potential of novel and repurposed modulators of DMD pathology as corticosteroid alternatives.
This is particularly relevant since Nrf2 activation has additional benefits beyond the anti-inflammatory activity of glucocorticoids, which include energy re-balancing through mitochondrial biogenesis as well as muscle regeneration and repair [ ]. Through multiple mechanisms, FAEs can also modify a more extensive cytokine profile than glucocorticoids [ ]. In DMD, glucocorticoids represent the most frequently used drug class for the management of symptoms. More recently, research has focused on novel selective, dissociative steroids, such as vamorolone [ 74 , 77 , 78 , 79 ], which may provide a better alternative by reducing steroid-associated adverse effects.
Although novel dissociative steroids may be a superior substitute to glucocorticoids, other potential therapeutics should be explored. Repurposing or developing novel pharmacological therapies that are capable of addressing the many downstream consequences of dystrophin deficiency, such as FAEs and novel Nrf2 activators, respectively, may be a viable option to improve patient quality of life without severe adverse events like those observed with corticosteroid use.
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