Vamorolone for treatment of Duchenne muscular dystrophy

Summary

Corticosteroid therapy is currently the only therapeutic option for the treatment of Duchenne muscular dystrophy. However, long-term corticosteroid therapy is associated with numerous and serious side effects. At the end of 2023, the European Medicines Agency approved vamorolone, a partial agonist of the glucocorticoid receptor, which promises to maintain an anti-inflammatory effect while reducing the side effects of glucocorticoids. The article provides an overview of preclinical and clinical studies. The results show that vamorolone, especially at higher doses (6 mg/kg/day), has comparable efficacy to prednisone in maintaining muscle strength, has a demonstrably more favorable profile in maintaining growth rate, and potentially a lower incidence of undesirable psychological, bone, immunosuppressive, and cardiological effects, while body mass index values are comparable to prednisone, they do not increase over time.

Keywords:

Duchenne muscular dystrophy – vamorolone – corticotherapy

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

Introduction

Duchenne muscular dystrophy (DMD) is a progressive congenital muscle disorder. It is caused by the absence of dystrophin, which is encoded by the DMD gene located on the X chromosome. With an incidence of approximately 1 in 5,000 boys, it is the most common form of muscular dystrophy in childhood. The disease leads to a reduction in the mechanical strength of muscle fibers; their gradual degeneration triggers an inflammatory cascade in the muscle and results in the progressive remodeling of skeletal muscle into connective and adipose tissue. Clinically, DMD manifests as progressive muscle weakness with loss of the ability to walk independently by age 13 without treatment. There is also a gradual weakening of upper limb strength and respiratory muscles, with the development of chronic pulmonary insufficiency, as well as myocardial involvement due to dilated cardiomyopathy. This is a fatal disease for which there is currently no causal therapy.

Long-term treatment with glucocorticoids has been shown to be effective in DMD. It allows patients to maintain the ability to walk independently for 2–3 years longer and delays the need for mechanical ventilation [1,2]. Unfortunately, this effect is accompanied by serious adverse effects [3].

Glucocorticoids suppress inflammation, which in DMD is triggered by the breakdown of muscle fibers, thereby producing the desired positive effects on the course of the disease [1].

Glucocorticoids significantly influence the regulation of the body’s inflammatory and metabolic processes, and through cross-reactivity with the mineralocorticoid receptor (MR), they can also affect the body’s water and mineral balance. As a result, they have very broad therapeutic potential; unfortunately, they also have a very wide range of adverse effects, including serious and long-term ones [4], such as adrenal axis suppression, obesity, secondary osteoporosis, delayed puberty, growth arrest, increased risk of insulin resistance and type 2 diabetes mellitus, non-alcoholic fatty liver disease, arterial hypertension, cataracts or glaucoma, and behavioral problems [3,5]. Given that there is still no effective, universally applicable causal therapy for DMD, efforts are focused on finding gentler methods of corticosteroid therapy. The current standard of care is prednisone at an initial dose of 0.75 mg/kg/day, or deflazacort at a dose of 0.9 mg/kg/day, which has a more favorable profile, particularly regarding obesity [6]. Both have a comparable effect on slowing disease progression, but both are also associated with a significant incidence of the aforementioned adverse effects [6].

Vamorolon was launched on the European market at the end of 2023. It is a synthetic dissociative steroidal anti-inflammatory drug whose pharmacological properties suggest a lower potential for affecting metabolism and a more targeted approach to suppressing inflammation.

The aim of this review article is to familiarize readers with the available information from preclinical and clinical studies on vamorolon, which is available to patients with DMD in the Czech Republic under the exceptional reimbursement scheme pursuant to Section 16 of the Public Health Insurance Act.

 

Overview of the Mechanism of Action of Glucocorticoids

Corticosteroids occur naturally primarily in the form of hydrocortisone and cortisol. Hydrocortisone has predominantly mineralocorticoid effects, meaning it regulates water and mineral balance and acts primarily through the MR. Cortisol acts via the glucocorticoid receptor (GR) and influences, among other things, the stress response, the body’s metabolic regulation, and inflammatory processes. Both corticosteroids bind to the MR and GR with similar affinity. Tissue-specific enzymes, 11-b -hydroxydeshydrogenase (11-b -HSD), help ensure selective action. In tissues where regulation by hydrocortisone is required, such as the kidneys or pancreas, 11-b -HSD2 is highly active, rapidly degrading cortisol into inactive cortisone. This frees the MR for the action of hydrocortisone, which occurs in the body at significantly lower concentrations. In contrast, 11-b -HSD1 is present in all tissues sensitive to glucocorticoids. It converts inactive cortisone to cortisol, thereby increasing glucocorticoid activity. Furthermore, cortisone is bound in plasma to glucocorticoid-binding globulin (CBG) and, to a lesser extent, to albumin, so that only about 5% of the total amount is biologically active. In contrast, synthetic corticosteroids generally have low affinity for CBG and 11-b -HSD2; their bioavailability is therefore higher, and their effect on the MR receptor is orders of magnitude greater than that of cortisol [3–5]. Vamorolone is not a substrate for 11-b -HSD1, so it does not accumulate in tissues [7].

Glucocorticoids are small lipophilic molecules that easily cross cell membranes. After binding to intracellular or membrane-bound GR, they can exert their effects rapidly within minutes by influencing cell membrane fluidity, releasing cytoplasmic proteins, and activating second messengers (cyclic adenosine monophosphate [cAMP], phosphokinases). These mechanisms rapidly influence cellular metabolism toward a stress response (glycogenolysis, lipolysis, reduced insulin secretion, and others) and affect the physical properties of cell membranes [8]. Among the adverse effects caused by this pathway, we can observe, for example, the development of diabetes mellitus or metabolic syndrome. Another mechanism is a pathway that is slow, taking hours to days, in which the ligand-receptor complex forms dimers that penetrate the nucleus, where they act as a transcription factor, binding to specific DNA nucleotide sequences known as glucocorticoid response elements (GREs). The GR-ligand complex can also interact with other transcription factors. Depending on its interaction with various cofactors, it either activates or suppresses gene expression. Through this pathway, glucocorticoids influence the body’s long-term homeostasis, reduce inflammation, and stimulate the storage of fatty acids in adipose tissue, which leads, for example, to obesity and the development of Cushingoid features. Their anti-inflammatory action is due to a broad influence on cellular expression in favor of anti-inflammatory proteins, and conversely, the suppression of pro-inflammatory factors (cytokines, chemokines, etc.), many of which are induced by the transcription factor NF-k B (nuclear factor kappa B), whose expression is inhibited by glucocorticoids [9].

In dystrophic muscles, corticosteroids increase the resistance of the muscle membrane to mechanical damage, improve metabolic efficiency (via upregulation of Krüppel-like factor 15 [KLF15]), temporarily increase calcium influx during contraction, and reduce the inflammatory response and fibrosis of muscle tissue (among other things, by inhibiting NF-k B, which leads to a reduction in the expression of tumor necrosis factor alpha (TNF-alpha)) [8,9].

In addition to their effects via the GR, glucocorticoids can also bind to the MR, particularly when present in excess. Its activation leads to sodium and water retention and potentially to arterial hypertension and other cardiovascular adverse effects.

 

Preclinical studies

Vamorolone (VPB15) is a synthetic dissociative glucocorticoid belonging to the group ofD 9,11 glucocorticoid analogs [10]. Vamorolone retains a high affinity for the glucocorticoid receptor (GR) [8]. However, after binding, it interacts less effectively with cofactors and exhibits reduced dimerization capacity [10], which leads to limited binding of the vamorolone-GR complex to the GRE region of chromatin. Its effect on the direct activation of gene transcription (leading, for example, to the suppression of adrenocorticotropic hormone or the expression of factors promoting fibrosis) is lower than that of classical glucocorticoids [8,11], although it is not entirely absent [6], and is dependent on the vamorolone dose [8]. The repressive activity of vamorolone via secondary transcription factors remains intact [7,11]; in particular, it effectively inhibits the transcription factor NF-k B [6,8,10], to an extent comparable in vitro to the effects of prednisone [6,8]. Overall, an effect on gene expression favoring anti-inflammatory responses has been demonstrated [12,13]. Conversely, the expression of genes associated with the adverse effects of corticosteroids was not induced to the same extent [13]. Treatment with vamorolone further increased the mechanical resistance and regenerative capacity of cell membranes following laser damage compared to prednisone [8], which could play a significant role given the pathophysiology of DMD.

These properties were tested in animal models of various autoinflammatory diseases, glioma, and acute muscle injury in intensive care, where vamorolone demonstrated a lower incidence of adverse effects compared to prednisone at relatively high doses (30–40 mg/kg) [7,14–19].

In mouse models of DMD (dmx mice), vamorolone was tested against prednisolone, dexamethasone, and deflazacort. Vamorolone doses ranged from 5 mg/kg to 45 mg/kg, and both desired and adverse effects were dose-dependent.

Its efficacy was confirmed in DMX mice treated both presymptomatically and after symptom onset, where vamorolon increased muscle strength [6,8] and reduced serum creatine kinase [8] and inflammatory activity in muscle tissue [9]. The anti-inflammatory activity was mediated by inhibition of the NF-k B pathway [8]. Vamorolone was also tested in a mouse model of Becker muscular dystrophy, where daily administration at a dose of 20 mg/kg increased muscle strength. This increase was, however, slightly lower compared to prednisone at a dose of 5 mg/kg [20]. Furthermore, it improved findings in muscle biopsies, reduced the expression of inflammatory and profibrotic genes in both muscle and heart, and even increased dystrophin levels slightly more than prednisone [20].

Regarding the safety profile, vamorolone, unlike prednisone, had almost no effect on the differential lymphocyte count and did not reduce their numbers [6,21]; thus, lower immunosuppressive effects can be expected while maintaining the anti-inflammatory effect. Furthermore, unlike prednisone [6,8] and deflazacort [6], it did not affect the growth of long bones or their trabecular and mineral density, even at high doses.

On the other hand, at effective concentrations (30–45 mg/kg), vamorolone also exhibited adverse effects such as increased blood glucose levels and suppression of the adrenocorticotropic axis; it influenced gene expression in the CNS, and, comparable to prednisone, symptoms of depression were observed in mice during vamorolone therapy [6]. Psychological effects were not observed in mouse models of Becker muscular dystrophy, where the effect of vamorolone on anxiety symptoms was, conversely, comparable to placebo [20].

A major advantage of vamorolone is its low affinity for the androgen receptor [8] and its antagonistic effect on the mineralocorticoid receptor (MR), comparable to that of eplerenone or spironolactone [22,23]. A cardioprotective effect can therefore be anticipated, as suggested by studies in mdx mice, where, unlike prednisolone and placebo, it did not cause myocardial fibrosis or hypertrophy [8,22].

 

Clinical Studies

The pharmacokinetics of vamorolone were tested in healthy adult men and boys with DMD. The drug reaches maximum plasma concentrations 2–4 hours after administration, and its elimination half-life is 2 hours. No accumulation occurs with once-daily dosing. Its bioavailability increases slightly when administered with a fatty meal [24–26].

Five clinical studies were conducted, as summarized in Table 1. Studies VBP15-001, 002, 003, and LTE were open-label. Study VBP-004 was a double-blind, placebo -⁠ and prednisone-controlled trial.

In study VBP15-001, vamorolone was well tolerated in healthy volunteers [26]. The maximum dose tested was 20 mg/kg/day for 14 days.

The Phase 2 study consisted of three parts: the first (VPB15-002) was a 14-day safety study [25], the second (VPB15-003) sought the optimal dose of vamorolone over 6 months [27], and this was followed by a 24-month extension study, VPB15-LTE [28,29], which was completed by 41 boys with an average age of 5.83 years.

The results were compared against historical cohorts from the CINRG and DNHS, from which boys were selected who matched as closely as possible in the monitored parameters, including age, performance on specific tests, and duration of corticosteroid therapy at the start of the study. Efficacy was evaluated against boys without corticosteroid therapy as well as those on corticosteroid therapy, and adverse effects were compared against a historical cohort treated with prednisone [25–29].

In the VPB15-002 and VPB15-003 studies, the boys were divided into four groups based on the administered doses (0.25, 0.75, 2.0, and 6.0 mg/kg/day). To improve the efficacy of vamorolone at doses above 2 mg/kg/day, boys from the lower-dose group were switched to a dose of at least 2 mg/kg/day during the extension phase (VPB15-LTE). For the 30-month efficacy analysis, a cohort was used that had a dose higher than 2.0 mg/kg/day throughout the study and initially consisted of 23 boys, 21 of whom completed the study.

Patients taking vamorolone at doses higher than 2 mg/kg/day showed improvement in the first 24 weeks on specific scales (Time to Stand test [TTS], 6-minute walk test [6MWT], and The North Star Ambulatory Assessment [NSAA]). These effects increased in patients receiving higher doses, most notably at 6 mg/kg/day [27]. In the subsequent phase, a plateau was reached, which persisted for 18 months of treatment [28]. The results were comparable to those of a historical cohort treated with traditional corticosteroids [28] and persisted even after 30 months of treatment in the timed tests evaluated (TTS, Time to Run/Walk 10 m [TTRW], 6MWT, Time to Climb [TTCLIMB] 4 stairs) as well as in the NSAA [29].

Vamorolone also underwent a double-blind randomized study, VISION-DMD [30,31], where it was compared with placebo and prednisone. The first phase of the study lasted 24 weeks and included 121 boys, 114 of whom completed the study [30]. This phase was followed by a 4-week transition period, and the second part of the study examined the efficacy of vamorolone after switching from prednisone or placebo to vamorolone and lasted another 20 weeks.

The protocol included timed physiological tests, cortisol stimulation tests, biochemical markers of bone remodeling, densitometry (DEXA), and lateral spinal radiographs.

Vamorolone was effective compared to placebo at both doses studied, but the 6 mg/kg/day dose showed better results than the 2 mg/kg/day dose, where the overall peak in scores was lower and was reached later, and in some tests the difference from placebo did not reach statistical significance (TTRW). The effect of prednisone (0.75 mg/kg/day) was comparable to that of vamorolone at a dose of 6 mg/kg/day; the lower dose showed a poorer effect in some of the tests (TTRW and TTCLIMB 4 steps) [30,31]. In the second phase of the study, patients on prednisone and placebo were switched to vamorolone with a randomly assigned dose of 2 or 6 mg/kg/day. The treatment effect observed in the first part was maintained in the group treated with the higher dose through 48 weeks of follow-up, while the 2 mg/kg/day dose showed a slight decline in most parameters between weeks 24 and 48 of treatment. However, compared to the placebo group, which was discontinued at week 24, the values in the lower-dose group were significantly better even after 48 weeks. The group that switched from placebo to a high dose of vamorolone showed significant improvement in performance on physical tests during the follow-up period in the second part, comparable to the first part. The switch to a lower dose showed greater variability, and in some tests (TTRW, TTCLIMB), a slight decline continued [31].

Suppression of the adrenocorticotropic axis was observed with vamorolone at doses of 9 mg/kg/day in healthy adults [26] and in a small percentage (8.2%) as low as 0.75 mg/kg/day in children with DMD [27,30]. The incidence increased with the daily dose; at a dose of 6 mg/kg/day, it was observed in up to 89% of children and was slightly more significant than in children treated with prednisone at 0.75 mg/kg/day [27,30]. Vamorolone did not affect glycemia and did not alter lymphocyte counts [25,26]. In children, a mild increase in insulin was observed at higher doses [25], along with inconsistent decreases or increases in markers of bone resorption and formation [25,27]. These effects were dose-dependent [25,27,30]. The impact on bone metabolism was minimal in other studies [26,30,31], and it normalized after switching from prednisone to vamorolone [31]. In the VPB15-003 study, a total of 13% of participants had a clinically significant fracture after 30 months of vamorolone treatment [29], none occurred in the vamorolone group during one year of treatment in a controlled study [31], and according to densitometry, patient groups did not differ by treatment except for total lean mass (amount of tissue excluding fat), which had a better profile with prednisone than with vamorolone [30].

Unlike prednisone, vamorolone did not consistently cause growth impairment [28,30,31]. Bone age was reduced by only 1.1 years after 30 months of treatment [29]. The growth retardation observed in a randomized study during 6 months of prednisone treatment was reversible after switching to vamorolone, with partial catch-up growth initiated after the switch [31]. However, comparable to prednisone, vamorolone increased the body mass index (BMI) [27,28,30,31]. A total of 24% of participants in the placebo-uncontrolled study (all dose groups at baseline, n = 41) had to reduce the dose from 6 to 2 mg/kg/day due to weight gain. In 6 out of 10 boys, the dose reduction helped stabilize weight [29].

Regarding behavioral problems, a questionnaire survey [31] suggested a trend toward a better profile for low-dose vamorolone compared to prednisone, but not with regard to depression and anxiety [32]. Regarding safety, the total number of adverse events was highest in the prednisone-treated group and lowest in the placebo-treated group. In Phase 2 of the VISION DMD study, the number of adverse events was comparable to that in Phase 1 and was higher at the higher dose of vamorolone. However, adverse effects associated with corticosteroid use occurred less frequently during the second half of the study and did not increase in patients switching from prednisone to vamorolone [31]. A post hoc analysis of serum samples from the latter study suggested an antagonistic effect of vamorolone on the mineralocorticoid receptor [23].

 

Discussion

Based on the conducted studies, the efficacy profile of vamorolone appears favorable. The effect of vamorolone is comparable to that of prednisone at higher doses, which, however, may not always be tolerated by patients. We particularly note the increase in BMI, which is comparable to that observed in studies with prednisone.

In studies, vamorolone has repeatedly demonstrated a reduced impact on growth retardation. Short stature is often a factor that troubles patients with DMD [33,34]. Therefore, we consider this effect of vamorolone to be beneficial. Conversely, obesity is a significant adverse effect [35] that has been consistently observed with vamorolone, which may limit the use of the most effective doses.

With regard to its effect on bone health, vamorolone has been shown not to suppress markers of bone remodeling compared to prednisone. In preclinical studies, it improved trabecular bone density, a key indicator of bone health, and, with the exception of the lean mass index, densitometry parameters did not differ from those of prednisone. The clinical significance of these findings is currently unclear, and therefore longer-term follow-up will be needed to record the incidence of fractures, particularly vertebral fractures, which are often the first manifestation of secondary osteoporosis in DMD. It should also be noted that most patients in the studies were under 10 years of age, and corticosteroid therapy was administered for a maximum of 2.5 years, a period during which pathological fractures may not yet have manifested [36]. Therefore, more long-term data will need to be collected. Preliminary data recently released by Santhera suggest that the number of vertebral fractures during a 5-year follow-up is lower with vamorolone [37].

One of the more demonstrable advantages of vamorolone over traditional corticosteroids is its mineralocorticoid receptor antagonism. This effect appears to be cardioprotective, as suggested by mouse models of DMD and biochemical analyses in clinical trials. Furthermore, studies consistently show a lower immunosuppressive effect of vamorolone while maintaining its anti-inflammatory effect.

Overall, we conclude that vamorolone has the potential to provide therapeutic benefits with fewer adverse effects; however, long-term data still need to be collected, particularly regarding necessary and tolerable effective doses (especially due to obesity, secondary osteoporosis, and cardioprotection).

 

Grant Support

This study was supported by project GAUK 586120.

 

Conflict of interest

The authors declare that they have no conflict of interest regarding the subject of the study.

 

Table 1. Summary of clinical studies.

STUDY	PHASE	NUMBER OF PARTICIPANTS, CHARACTERISTICS	DOSE, DURATION	RESULT
VBP15-001, PMC6136660	P1	healthy volunteers, adult males, n = 86	placebo vs.: 0.1, 0.3, 1.0, 3.0, 8.0, 20.0 mg/kg; 14 days	No serious ADRs. Most common: headache, nausea, vertigo, 10-fold lower cortisol suppression, 1 case of elevated liver enzymes, no alteration in bone markers.
VBP15-002, PMC6218284	P2a	ambulatory boys with DMD, age 4–7 years, n = 48 (4 groups of 12 for each dose)	vamorolon 0.25, 0.75, 2.0, and 6.0 mg/kg/day, open-label, 14 days of treatment + 14 days of follow-up	No serious ADRs; does not affect ECG, blood glucose, insulin, or liver function tests. In children, dose-dependent shift in bone markers, dose-dependent suppression of the adrenocortical axis (18% at 2.0 mg/kg/day and 60% at 6.0 mg/kg/day). A dose-dependent decrease in CK was observed
VBP15-003, PMID: 31451516	P2, open-label	walking boys with DMD from the VBP-002 study, age 4–7 years, n = 48 (4 × 12 for each dose) comparison with participants in studies NCT00468832 (without corticosteroid therapy) and NCT00110669 (with prednisolone) –⁠ DNHS and CINRG	vamorolone 0.25, 0.75, 2.0, and 6.0 mg/kg/day, open-label, 24 weeks	Improved performance in TTS, 6MWT (compared to baseline and the steroid-naive cohort), NSAA (compared to baseline), increase in osteocalcin (= marker of bone formation) –⁠ but not in the 6 mg/kg/day cohort compared to baseline, increase in C-terminal telopeptide (= marker of bone resorption) dependent on dose and duration of therapy, suppression of the HPA axis starting at 0.75 mg/kg/day, dose-dependent, dose-dependent increase in insulin, without affecting blood glucose or glycated hemoglobin. Increase in BMI comparable to prednisolone at a dose of 6 mg/kg/day
VBP15-LTE, PMID: 32956407	P2, open-label	ambulatory boys with DMD from the VBP-003 study, age 4–7 years, n = 46, 41 completed. Doses escalated to 2, 4, or 6 mg/kg/day based on tolerance. Comparison with participants from studies NCT00468832 (on corticosteroids for at least 6 months) and PMC4752678 (for NSAIDs, at least 6 months on corticosteroids).	Vamorolon 0.25, 0.75, 2.0, and 6.0 mg/kg/day, with gradual escalation to 6 mg/kg/day, reduction to 4 or 2 mg/kg/day in case of ADRs; open-label, 24 months	Performance in TTS, TTCLIMB, 6MWT, NSAA, and TTWR 10 m showed no significant difference between baseline and the final follow-up, even when compared with historical cohorts. The most common adverse events were obesity (24% requiring dose reduction) and clinically significant fracture (13%)—patients were under 10 years of age at the time of study completion. Mean BMI was not significantly higher compared to other control groups. Significantly higher height percentiles in boys on vamorolone compared to other control groups; bone age delayed by only 1.1 years.
VBP15-004, Part 1 (interim analysis) PMID: 36036925	P3, double-blind, placebo -⁠ and prednisone-controlled	ambulatory boys with DMD, 4–7 years, n = 114. Vamorolone 2 mg/kg/day, 6 mg/kg/day, placebo, prednisone 0.75 mg/kg/day. Duration 24 weeks.	Vamorolone vs. placebo and prednisone, 24 weeks	Performance with vamorolone 6 mg/kg/day was better than with placebo; 2 mg/kg/day was also better except for TTCLIMB and TTRW. No vertebral fractures in those treated with vamorolone; vamorolone did not cause growth impairment, but prednisone did; favorable biomarkers of bone remodeling; DEXA scans comparable to prednisone. At low doses, possibly better management of anxiety and depression. Suppression of the adrenergic axis: vamorolone 6 mg/kg/day > prednisone > vamorolone 2 mg/kg/day
VBP15-004, Part 2 PMID: 38335499	P3, double-blind, 2 doses of vamorolone	walking boys with DMD, 4–7 years old, n = 114. Vamorolone 2 mg/kg/day, 6 mg/kg/day, placebo >>> vamorolone 2 or 6 mg/kg/day, prednisone 0.75 mg/kg/day >>> vamorolone 2 or 6 mg/kg/day. Duration 24 weeks >>> 4-week washout period >>> 20 weeks.	A follow-up to the previous study, involving a switch from placebo and prednisone to vamorolone, 24 weeks	At a dose of 6 mg/kg/day, the effect was maintained; at a dose of 2 mg/kg/day, there was already a decline in exercise test results, but values remained more favorable compared to placebo. The safety profile was favorable, comparable to the previous study, with fewer new adverse events associated with corticosteroid therapy compared to the first 6 months of treatment

6MWT –⁠ 6-minute walk test; BMI –⁠ body mass index; CK –⁠ creatine kinase; DMD –⁠ Duchenne muscular dystrophy; CS –⁠ corticosteroids; n –⁠ number; NSAA –⁠ The North Star Ambulatory Assessment; AEs –⁠ adverse events; TTCLIMB –⁠ Time to Climb; TTS –⁠ Time to Stand; TTRW –⁠ Time to Run/Walk