Safety and Efficacy of Givinostat for Patients with Muscular Dystrophy: A Systematic Review

Abstract

Introduction

Muscular dystrophy (MD) refers to a group of genetic disorders leading to progressive weakness and degeneration of skeletal muscle. Among them, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are the most common types. Histone deacetylase inhibitors (i.e., givinostat) is a recently approved therapy for DMD. In this systematic review, we aimed to evaluate givinostat in MD patients regarding safety and efficacy.

Methods

A systematic review was performed according to the PRISMA guidelines by searching through Medline, Embase, Cochrane Library, and Web of Science. Only randomized control trials comparing givinostat vs. placebo or other therapies are included. The primary outcomes were motor function alteration and histopathologic muscle changes and the secondary outcomes were the adverse reactions.

Results

A total of 188 records were identified, and after screening, two clinical trials met the inclusion criteria. In DMD patients, givinostat significantly slowed disease progression, improving four-stair climb times (p = 0.037) and reducing muscle fat infiltration. In BMD patients, fibrosis progression was not significantly different (p = 0.8282), but MRI showed reduced muscle fat replacement. Common adverse events included diarrhoea, thrombocytopenia, and hypertriglyceridemia, leading to dose reductions, though no new safety signals or treatment-related deaths were observed.

Conclusion

Givinostat seems to be effective in slowing disease progression in DMD but has little benefit in BMD. Its safety profile requires rigorous monitoring. Efficacy difference might be explained by the pathophysiology of the disease and the progression rate. Larger and longer follow-up trials are warranted to confirm longer term benefits and to optimize dosing strategies. Givinostat offers potential as a disease-modifying therapy for DMD but requires further investigation to establish its role in BMD.

Plain Language Summary

This study systematically reviews the safety and effectiveness of givinostat, a newly approved medication for Duchenne muscular dystrophy (DMD). Muscular dystrophies are inherited disorders causing progressive muscle weakness and deterioration. We analysed scientific studies based on trials of givinostat in patients. Givinostat works by targeting the way our genetic material is organized within the cells, helping reduce inflammation and prevent muscle cell death. The review found that in patients with DMD, which progresses rapidly, givinostat slowed down the worsening of symptoms, especially improving the ability to climb stairs. It also reduced fat buildup in muscles, showing it helps preserve muscle tissue. However, in Becker muscular dystrophy (BMD) patients, a milder form of the disease, givinostat did not significantly improve muscle scarring, though it may help prevent further fat replacement in muscles over time. Common side effects included diarrhoea, vomiting, and decreased blood platelet counts, which sometimes required reducing the dose. No serious safety concerns were identified, suggesting the medication is generally tolerable with proper monitoring. We conclude that givinostat shows promise for DMD patients, becoming the first non-steroid treatment approved for all genetic variants of the disease. For BMD patients, more research with longer follow-up periods is needed to determine its benefits. This medication represents an important advancement in treating these challenging conditions, offering new hope for patients and their families.

Introduction

Muscular dystrophy (MD) describes to a spectrum of genetic disorders that leads to progressive weakness and degeneration of skeletal muscle fibres. These disorders vary in their age of onset (usually diagnosed in childhood), severity, and the pattern of affected muscles. Almost all the variants of MD worsen in the long run because of progressive degeneration of the muscles, and the life expectancy in these patients differs based on the type of MD [1]. In most cases, MD is caused by genetic mutations like alteration in the DNA sequence that affects the proteins which constitute the muscle fibre. These mutations are usually inherited, but in certain situations, they also occur spontaneously and can later be inherited by a diseased individual’s offspring [1]. Mutations in the X-linked DMD gene, causing no or reduced production of dystrophin protein, finally manifest as muscular dystrophies [2]. There are several types of MD which can affect the mankind, the major types being Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), myotonic, limb-girdle, oculopharyngeal, facioscapulohumeral, distal, congenital, and Emery-Dreifuss [3]. Of all of these, DMD is the most common form of MD in children, affecting approximately 1 in every 5,000–7,000 male births globally. Predominantly affecting boys, DMD usually starts occurring in pre-schooler age group (3–5 years) [4]. Frameshifting or nonsense mutations of DMD gene leads to premature halting of translation or production of non-functional proteins due to abrupt appearance of stop codons causing early appearance of severe muscular weakness, loss of motor activities, and often fatal outcome in early adulthood due to cardiopulmonary complications [5, 6].

On the contrary, BMD is a comparatively minor form of MD occurring due to the same DMD gene mutations. The key difference is that the “in-frame mutation” maintains the reading frame, leading to the synthesis of shorter partially functional dystrophin proteins contributing to milder form of dystrophinopathies [7]. About 1 in every 18,000–30,000 individuals worldwide is affected by this condition with a male preponderance. BMD generally manifests later and has mild progression compared to DMD [8].

The available treatments for MD can decrease the severity of symptoms but are unable to alter the pathophysiology behind the disease. The treatment includes administration of glucocorticoids like prednisone or deflazacort and anticonvulsants for muscle spasms in MD [9]. Although corticosteroids have shown benefits in muscle strength and retaining ambulatory capacity for longer period [10], they come with a risk of adrenal insufficiency, osteoporotic fractures, delayed growth, obesity, and glucose intolerance, attenuating their effectiveness. However, drugs like vamorolone have emerged as a ray of hope in controlling symptoms with favourable safety profile found in some studies [11, 12].

Therefore, several research works are going on to find safer alternatives, modifying disease pathology in MD which includes some of the gene-based therapies. In a systematic review, Pascual-Morena et al. [13] has mentioned that drugs like eteplirsen and ataluren can be effective both in symptomatic management and progression halting. On March 21, 2024, the US Food and Drug Administration (US-FDA) approved givinostat, a histone deacetylase (HDAC) inhibitor, for individuals diagnosed with DMD from 6 years of age and above. HDAC is an enzyme playing a pivotal role in histone acetylation, which is a very well-defined post-translational modification, where hyperacetylation leads to increased gene expression as this relaxes the chromatin structure (shown in Fig. 1). On the other hand, hypoacetylation caused by HDAC decreases gene expression [14]. The balance between heterochromatin and euchromatin formation is greatly influenced by HDAC activity followed by altered genetic expression and [15] structural difference of HDAC has classified them into short-chain fatty acid, hydroxamic acid, benzamide, cyclic peptide, mercaptoketone, sirtuin inhibitors, and other compounds. Eighteen different isoforms have been identified and therefore organized into four classes (I, II, III, and IV) based on their homology to yeast proteins [16]. Among them, class I, II, and IV are zinc dependent, while class III is dependent on NAD+ for their [17] role of HDAC-4 in growth, and functioning of skeletal muscles is well established. Surplus presence in the skeletal muscle is found in several diseases like DMD and amyotrophic lateral sclerosis [18–20]. Research reveals HDACs regulate muscle fibre differentiation [21], size, innervation, development [19, 22–24], and exercise capacity [25–27], thus maintaining the skeletal muscle homoeostasis. Pertaining to this context, HDACi acts very selectively and amplifies myogenesis by hyperacetylating the genes regulated during development and undertaking their epigenetic bivalency [28]. This approach is very impactful in restoring the downstream pathways of myogenesis and muscle homoeostasis, leading to improved functional and morphological features of the affected muscles. It acts by targeting pathogenic processes involved in DMD to decrease inflammation and death of muscle fibres and is the first nonsteroidal drug approved for DMD that can be used regardless of the mutation in the DMD patients. Early clinical trials have shown promising results, with givinostat being used in patients with variants of MD like DMD [29]. Nonetheless, further investigation is required to fully comprehend the safety and effectiveness of givinostat in treating MD. Current articles have depicted contradictory outcomes, with some suggesting pertinent developments in muscle histology and function, while others failed to show significant clinical benefits [30]. To deal with these lacunae in current knowledge, we performed a systematic review of published studies to assess the safety and efficacy of givinostat in the treatment of MD patients. By summarizing the results from related clinical trials, our goal is to offer clinicians and policymakers evidence-based recommendations for the use of givinostat in managing MD. Additionally, our study will also add on to find significant areas for future research related to this drug, ultimately improving patient’s well-being, who are suffering from this devastating condition.

Fig. 1.

Schematic diagram of mechanism of action of givinostat.

Methods

This systematic review has been registered with PROSPERO (CRD42024542663) and is performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Cochrane Collaboration Handbook [31–33]. The completed PRISMA 2020 checklist is provided as online supplementary file (for all online suppl. material, see https://doi.org/10.1159/000547936).

Data Sources and Search Strategy

A comprehensive literature search was carried out till May 7th, 2024, by using electronic databases like Medline, Embase, Cochrane Library, and Web of Science using MeSH terms like “Givinostat” and “Muscular dystrophy.” Hand searching of the articles was also done. Articles published in English were included, with no restrictions on publication date or sample size. The comprehensive search strategies employed for these databases are outlined in online supplementary Table S1.

Abstract Screening

All studies identified through the systematic search were exported to reference management software Zotero for duplicate removal and to streamline the screening process. To ensure relevance according to the inclusion criteria, three reviewers independently assessed the articles, initially based on their titles and abstracts using Rayyan as the screening tool, followed by a detailed full-text review [34]. Conflicts, if any, were discussed with a fourth reviewer.

Inclusion and Exclusion Criteria

Strict criteria were followed for selection of the studies eligible for the review. Randomized clinical trials assessing efficacy and safety of givinostat in MD were selected after title and abstract screening followed by a thorough full-text screening. Details of inclusion and exclusion criteria in PICO format are mentioned in online supplementary Table S2.

Data Extraction

Three independent investigators extracted data from the included articles into an MS Excel sheet using structured questionnaire including the relevant details to be obtained from the selected studies. The outcomes of this systemic review were alteration of motor symptoms and histopathological findings in muscle fibres after treatment with givinostat for at least 6 months. Motor symptoms included functional mobility assessment, overall motor function score, cumulative loss of motor function, time to perform a mobility task, endurance/exercise capacity, knee muscle strength, and arm muscle strength. Histopathological findings in muscle fibres included change in overall fibrosis/scarring, change in fatty tissue infiltration, change in percentage of fibres with centralized nuclei, change in percentage of regenerating fibres, change in vastus lateralis fat fraction measured by magnetic resonance spectroscopy in certain muscles, and muscle fat infiltration. Secondary endpoints included the adverse events occurring because of givinostat therapy. Baseline characteristics were also obtained like mean age and type of dystrophin gene mutation in the included participants.

Data Synthesis

After extracting all efficacy, safety, and baseline data into an Excel workbook, two independent reviewers cross-checked the information. Continuous outcomes were documented as group mean ± SD or least square means (LSMs), often with 95% CIs, while dichotomous outcomes were recorded as event counts and risks. Key study-level variables like population and dosing were tabulated for easy comparison. Results were presented in detailed summary tables for each trial, showcasing point estimates and CIs for all key endpoints without pooling. A narrative synthesis highlighted consistencies and divergences across studies. A formal meta-analysis was not conducted due to significant clinical heterogeneity (different dystrophinopathies with distinct progression) and methodological heterogeneity (incomparable eligibility criteria and endpoints), which would have yielded uninterpretable results. This final manuscript was refined and grammar corrected with the assistance of Claude 3.5 Sonnet by Anthropic.

Results

After a thorough search across multiple databases (PubMed [6], Embase [16], Web of Science [148], CENTRAL in Cochrane Library [14]), 184 records were identified. Hand searching of other resources found 4 more records, making the total numbers of retrieved citations 188. After removal of duplicate records, remaining 161 articles were screened by title and abstract. Among them, a total of 157 articles were excluded for not meeting the screening criteria. Subsequently, 4 full-text articles were evaluated for eligibility, of which 2 were excluded with specific reasons, one due to unavailability of the full text and another due to study design issues. Finally, two studies that met all the inclusion criteria were included in the systematic review (shown in Fig. 2) [30, 35].

Fig. 2.

Methodology according to the PRISMA guideline.

Study Characteristics

Two clinical trials evaluated the safety and efficacy of givinostat in patients with MDs (Table 1). The EPIDYS Phase 3 trial focused on boys with DMD, enrolling 120 participants randomized in a 2:1 ratio (81 in the intervention group and 39 in the control group). The median age of participants was 9.8 years in the intervention group and 9.6 years in the control group. The most common genetic mutations were deletions (58 in the intervention group vs. 28 in the control group), followed by duplications and point mutations. Concomitant corticosteroid use was permitted, with deflazacort being the most frequently administered (77%), either as a daily oral regimen or intermittently. The primary efficacy endpoint was the change in the four-stair climb assessment from baseline to 72 weeks, evaluating the impact of givinostat on disease progression. Safety was assessed throughout the study, with a focus on adverse events and other clinically relevant parameters.

Table 1.

Baseline characteristics of included studies

Title	Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial	Givinostat for Becker muscular dystrophy: a randomized, placebo-controlled, double-blind study
First author, year of publication	Mercuri et al. [35], 2024	Comi et al. [30], 2023
Patients, n (intervention)	81	34
Patients, n (control)	39	17
Age – intervention group, years	Median (range):9.8 (8.0–10.9)	Mean (SD), range: 36.5 (11.56); 19–61
Age – control group, years	Median (range):9.6 (8.2–11.4)	Mean (SD), range: 39.2 (9.84); 24–58
Days of a symptom – intervention group, median (range)	5.5 (3.9–7.5)	​
Days of a symptom – control group, median (range)	5.3 (3.7–8.3)	​
Type of MD	DMD	BMD
Mutation type	Deletion (58 vs. 28), duplication (13 vs. 9), point mutation (10 vs. 2)	Mutated exon category: exon 45 (20 vs. 14), downstream from exon 45 (2 vs. 1), upstream of exon 45 (12 vs. 2)
Concomitant corticosteroid used	Yes	Yes
Details of corticosteroid used	Deflazacort daily regimen (60 vs. 25), deflazacort intermittent (6 vs. 4), other CS daily (9 vs. 6), other CS intermittently 96 vs. 4)	Deflazacort (2 vs. 0), prednisone (0 vs. 1)

The second trial, conducted by Comi et al. [30], investigated the effects of givinostat in patients with BMD. A total of 51 participants were randomized in a 2:1 ratio, with 34 in the intervention group and 17 in the control group. The median age was 36.5 years (SD 11.56) in the intervention group and 39.2 years (SD 9.84) in the control group. Similar to the DMD trial, the most common genetic mutations were deletions (32 in the intervention group vs. 16 in the control group), followed by duplications and point mutations, particularly around exon 45. Concomitant corticosteroid use, including deflazacort and prednisolone, was allowed for patients requiring additional therapies. The primary efficacy endpoint was the mean change in total fibrosis from baseline after 12 months of treatment, assessing the impact of givinostat on disease progression. Safety monitoring was conducted throughout the study, with a focus on adverse events and other relevant clinical outcomes.

Efficacy Outcomes

Primary Outcomes

In DMD, givinostat demonstrated a notable effect in slowing the progression of the disease compared to a placebo. Over 72 weeks, the average delay in the deterioration of the four-stair climb test was 1.25 s for the givinostat group, compared to 3.03 s for the placebo group (p = 0.037), highlighting its efficacy in preserving muscle function (Table 2). In context of velocity, LSM difference was 0.034 tasks per second which was also statistically significant (p = 0.029).

Table 2.

Comparison of efficacy outcomes of givinostat

Parameter (unit)	Intervention group (95% CI)	Control group (95% CI)	Mean difference (effect size)	Clinical impact of givinostat
DMD (EPIDYS) (Mercuri et al. [35], 2024)
Four-stair climb, s	1.27 (1.17 to 1.37)	1.48 (1.32 to 1.66)	−0.21	Reduced rate of functional decline in stair-climbing ability
MRS VLFF, %	7.63 (6.10 to 9.17)	10.56 (8.33 to 12.78)	−2.93	Attenuation of muscle fat infiltration, indicating slower disease progression
Time to rise, s	9.33 (5.82 to 12.84)	12.61 (7.49 to 17.72)	−3.28	Slower progression in the time required to rise from the floor
6-min walk test, m	−38.4 (−50.7 to −26.2)	−48.4 (−66.3 to −30.5)	+10.0	Improvement in walking endurance compared to the control group
Knee extension, N/kg	−0.32 (−0.44 to −0.20)	−0.50 (−0.68 to −0.33)	+0.18	Reduced loss of muscle strength in knee extension
Elbow flexion, N/kg	−0.10 (−0.17 to −0.03)	−0.19 (−0.29 to −0.09)	+0.09	Reduced loss of muscle strength in elbow flexion
NSAA: total score	−2.66 (−3.56 to −1.76)	−4.58 (−5.89 to −3.26)	+1.92	Lesser functional decline as measured by the (NSAA) score
BMD (Comi et al. [30], 2023)
Four-stair climb, s	0.87 (0.71 to 1.05)	0.88 (0.67 to 1.16)	−0.01	Comparable maintenance of stair-climbing ability between groups
MRS VLFF, %	1.02 (0.95 to 1.09)	1.07 (0.98 to 1.16)	−0.05	Stabilization of muscle fat fraction, suggesting slowed disease progression
Time to rise, s	1.39 (−0.97 to 3.75)	0.77 (−3.01 to 4.56)	+0.62	No significant difference observed in the time required to rise from the floor
6-min walk test, m	0.94 (0.89 to 1.00)	0.96 (0.88 to 1.04)	−0.02	No clinically meaningful difference observed in walking endurance between groups

MRS VLFF, vastus lateralis fat fraction measured by magnetic resonance spectroscopy.

In BMD, the mean fibrosis percentage did not change significantly from baseline in either group, with an LSM difference of 1.04% (p = 0.8282). However, MRI measures indicated less progression of muscle fat replacement with givinostat.

Secondary Outcomes

Secondary outcomes in DMD, including the North Star Ambulatory Assessment (NSAA), six-min walk test, and muscle strength measures, consistently favoured givinostat over placebo. MRS findings showed reduced fatty tissue infiltration in the muscles of the givinostat group (LSM difference in fat fraction –2.92%), suggesting a protective effect on muscle composition.

In BMD, MRS fat fraction analyses showed significant differences in the progression of muscle fat infiltration between givinostat and placebo. In the thigh, there is a significant LSM difference in fat fraction at 12 months in whole thigh (−1.35%) as well as in the quadriceps (−1.96%). Functional assessments such as the six-minute walk test and timed function tests showed no significant differences between groups.

Safety Outcomes

Treatment-Emergent Adverse Effects

In DMD study, patients from givinostat group experience adverse drug reactions more commonly, with diarrhoea (36%) and vomiting (29%) being the most frequent and almost twice compared to the placebo. Dose reductions were required for nearly half of the givinostat-treated participants due to complaints of diarrhoea, thrombocytopenia, and hypertriglyceridemia. SAE was found in 7% of the treatment group compared to the placebo (3%). A shift from normal to low platelet count was observed in 57% versus 5%, respectively. Dose reduction was required in both treatment regimens of givinostat (42% in regimen 1 and 16% in regime 2). Hypertriglyceridemia was more common with givinostat (23%) compared to placebo (7%); despite this, no new safety signals or treatment-related deaths were observed (Table 3).

Table 3.

Comparison of safety outcomes of givinostat

Parameter	Intervention group	Control group	Safety impact of givinostat
DMD (EPIDYS) (Mercuri et al. [35], 2024)
Most common AE	Diarrhoea (36%)	Nasopharyngitis (31%)	Different AE profiles
Treatment interruption	16 (14%)	4 (7%)	2-fold higher interruption rate
Treatment discontinuation	4 (3%)	Not reported	Slightly higher discontinuations
Severe AEs	5 (4%)	1 (2%)	Higher severe AE rate
BMD (Comi et al. [30], 2023)
Most common AE	Decreased platelet count (58.82%)	Hypertriglyceridemia (11.76%)	Higher rate of haematologic AEs
Treatment interruption	11 (32.35%)	1 (5.88%)	Significantly higher interruption rate
Severe AEs	5 (14.7%)	0 (0%)	Notable increase in severe AEs

AE, adverse event.

Givinostat’s safety profile in BMD was consistent with DMD findings, with thrombocytopenia and hypertriglyceridemia being the most common AEs. High-dose givinostat caused AEs in all patients, leading to dose reductions in over 50% of cases due to decreased platelets. Five participants experienced treatment-related SAEs.

Risk of Bias and Quality Assessment

Only randomized control trials (RCTs) were included and analysers used the Cochrane Risk of Bias Tool for RCTs (RoB 2) to assess the quality of included RCTs [36]. The articles were scrutinized according to their process of randomization, any variations from expected interventions, any kind of omitted outcome information and its measurement, and selection bias within published results. All studies were thoroughly screened and subsequently categorized as having “a low risk,” “some concerns,” or “a high risk” of bias. Three independent reviewers evaluated RoB 2 discrepancies that were resolved by discussion with the most senior reviewer. Details of the RoB 2 domains of these studies are outlined in online supplementary Table S3.

Both the RCTs included were assessed using the RoB 2 scale. The study conducted by Comi et al. [30] was found to have some concerns from the randomization process (D1 domain), and in the rest of the four domains, the risk of bias was low. Similarly, for the study conducted by Mercuri et al. [35], some concerns were found in missing outcome data (D3 domain) and the remaining four domains had low risk of bias. Overall, both the RCTs had some concerns (shown in Fig. 3).

Fig. 3.

ROB 2 assessment of the studies.

Discussion

Management of MDs mostly consists of symptomatic treatment with glucocorticoids, antispasmodics, etc. Disease-modifying therapies have often been found to be ineffective in long term. Genetic intervention has emerged as novel therapeutic approaches in this condition.

Antisense oligonucleotides like eteplirsen, casimersen, golodirsen has shown prominent effects. In 2023, delandistrogene moxeparvovec received accelerated approval and later got traditional approval in DMD for both ambulatory and non-ambulatory individuals aged 4 years and above with a confirmed mutation in the DMD gene on June 20, 2024 [37]. Stop codon read-through in DMD gene has been achieved by drugs like ataluren [13]. A recently published systematic review and meta-analysis by Pascual-Morena et al. [38] has discussed the efficacy and safety of the first approved gene therapy delandistrogene moxeparvovec, where they have highlighted modest improvement in motor outcomes not reaching statistical significance. The limitation of such gene-based therapies include requirement for technical expertise during administration, risk of increased incidence of adverse drug reactions due to complex genetic interactions, single lifetime therapy in dividing cells in progressive disease failing to reach statistical significance due to possible loss of transgene with time causing therapeutic failure in the long run, and risk of adverse effects as highlighted in a recent systematic review [39]. To avoid such complications with gene therapy, drugs like givinostat, which have prominent positive impact on efficacy outcomes, can be administered easily and can be given for longer time with lesser risk of adverse events.

The systematic review analysed safety and efficacy of givinostat in MDs like DMD and BMD as reported by the EPIDYS study and the study conducted by Comi and team [30], respectively. Though the EPIDYS study found the drug to be effective in slowing the functional decline (improvement in four-stair climb test), Comi et al. [30] found no significant improvement in primary endpoints in BMD patients. But there was potential stabilization of disease, which was measured by muscular fat fraction on MRI. Safety profiles were similar with major prevalence of gastrointestinal adverse effects and thrombocytopenia requiring dose adjustment. Variation in efficacy outcomes has highlighted the importance of givinostat in condition-adjusted therapeutic approaches; therefore, an “in-depth” understanding of its pharmacology as well as disease pathology are crucial for analysing its role as potential disease-modifying therapy in dystrophinopathies.

HDAC inhibitors are a group of medicines known as epigenetic regulators whose role is inhibition of the loss of acetyl groups from histones which makes the chromatin structure more relaxed as well as increase transcription. According to their specific site of action, pan-HDAC inhibitors (vorinostat and panobinostat) target groups of diseases involving multiple HDAC classes, and selective inhibitors (romidepsin and entinostat) are used to target specific HDAC classes [40]. Cellular effects of these drugs include halting of cell cycle, induction of apoptosis, differentiation, and anti-angiogenesis through p53-dependent and independent pathways, NF-κB signalling, and DNA damage response pathways [41]. Pan-HDAC inhibitors have been efficient in treating carcinomas with haematological origin, including T-cell lymphomas and multiple myeloma. Class-selective inhibitors, like entinostat which is class I specific, are safer with similar efficacy. Romidepsin, a selective HDAC1/2 inhibitor, can be used in management of cutaneous T-cell lymphoma. HDACi, apart from anticancer actions, show promising results in the treatment of neurodegenerative disorders due to their role in neuroprotection and anti-inflammatory mechanisms. In Alzheimer’s disease, selective HDAC2 inhibition improves cognitive decline in murine models. Class I HDAC inhibition shows potential in reducing mutant huntingtin cluster [42].

MD is a group of congenital disorders with worldwide incidence of 1 in 5,000 individuals, commonly diagnosed at childhood. Several therapeutic modalities have been implemented for the management of MDs. Though therapeutic focus is on relieving the symptoms, halting the progression of the disease, and improving the quality of life, there is scarcity of drugs that are efficient in slowing the progression of the disease or permanent cure. Antiarrhythmics like ACE inhibitors, flecainamide, and beta blockers can control cardiac complications. Sodium channel blockers, e.g., phenytoin, procainamide, mexiletine, can relieve myotonia. Due to the associated adverse effects of the chronic therapy, effectiveness of these drugs is often mild. As a result, corticosteroids remain the mainstay of treatment of MDs. Despite the risk of weight gain and risk of fractures, prominent positive impact is seen with early corticosteroid therapy [8]. Therapy with antisense oligonucleotides like golodirsen, which shows increased dystrophin production, is approved by the FDA in 2019 for the management of DMD [43, 44]. Still, an effective therapy for reversal of disease progression and muscular regeneration remains a challenge for most of the MD cases. Recently, in MDs in adults as well as children, HDAC inhibitors have emerged as promising pharmacotherapy by inducing muscle regeneration and inhibiting fibrosis and muscle displacement through enhancement of differentiation of myoblast, expression of utrophin (which can partially compensate for dystrophin deficiency), and inhibition of inflammatory markers. Studies with valproic acid and trichostatin A have demonstrated improved muscle strength and reduced muscle degeneration in preclinical models.

In March 2024, the FDA has approved givinostat as an oral therapy in DMD patients aged 6 years and above. It is the first nonsteroidal drug that got approval for all genetic variants of DMD. This orphan drug, an HDAC inhibitor, targets pathogenic processes to mitigate inflammation and prevent muscle wasting [45]. DMD is a severe X-linked recessive (Xp2.1) neuromuscular disorder predominantly affecting males. It is caused by the DMD gene mutations on chromosome 21, leading to the absence of dystrophin, a critical protein for muscle function. The lack of dystrophin results in progressive muscle weakening and atrophy. Most cases are diagnosed in young males between 3 and 5 years of age. Complications of the disease typically result in death by early adulthood, around 20 years of age [46].

In this systematic review, the safety and efficacy of givinostat has been assessed in both DMD and BMD. The trials analysed in this study provide insights into its potential role as a disease-modifying therapy, though the efficacy is variable across types of diseases and endpoints. Pathology and progression of the disease should be considered for selecting the therapy.

Mechanistic Considerations

The variability in efficacy of givinostat in both Duchenne and Becker disease may be attributed to distinct disease pathophysiology and stages of muscle degeneration. In DMD, inflammation and necrosis of muscle fibres is rapid, while in BMD, the disease progression is slower with existing fibrosis. Givinostat plays a pivotal role in gene expression and inflammation by inhibiting HDACs. Consalvi et al. found dose-dependent increase of muscle mass as well as remarkable fibrosis reduction and fatty infiltration in mdx mice models [47]. In another study by Licandro et al. [48], there is notable functional improvement in mdx murine models with dose-dependent increase in FNmax assessed in grip test as well as enhanced performance in treadmill exhaustion test. In 2016, the beneficial effects in animal models have also been successfully translated in humans, where Bettica et al. [49] found significant reduction of necrosed fibre, fat tissue replacement, and endomysial as well as perimysial fibrosis with the common adverse effects being depletion in platelet count and diarrhoea. These findings highlight the need for earlier intervention with givinostat in MDs and longer follow-up studies to identify longstanding safety and efficacy.

Efficacy in DMD and BMD

In DMD, givinostat has been proved to be efficacious in both preventing functional decline and preserving muscle mass as found by Mercuri et al. [35]. The primary outcome was to evaluate the effect of givinostat on disease progression, measured by the change in four-stair climb time. Givinostat demonstrated a significant reduction in the progression of functional impairment compared to placebo (p = 0.037) after 72 weeks, with noticeable improvements evident as early as 48 weeks. This was not only achieving the primary goal of the study but also particularly relevant in the clinical viewpoint as slower four climb implies lesser participation in physical and social activities which in turn might indicate loss of stair-climbing ability and in turn ambulatory power, indicating poor prognosis.

Key secondary outcomes, including NSAA and 6-min walk test, were consistent with the primary outcomes, though changes were not significant after multiplicity adjustments. Other outcomes including alteration in elbow flexion and knee extension over 72 weeks were apparently lower with givinostat. Importantly, MRI assessments revealed less fat infiltration in the muscles of patients receiving givinostat, further corroborating its protective role. MRI assessments also supported the above findings. Reduced fat infiltration in the vastus lateralis was observed at 72 weeks and the change was consistent at all time points.

In contrast, the study by Comi et al. [30] found no significant improvement in the primary outcome, total fibrosis in BMD patients. No alteration in the mean from baseline in treatment or placebo group was seen throughout the study period. Other secondary histological parameters also showed similar findings. The MRI findings revealed increased fat infiltration and less muscle preservation in the placebo group, whereas no worsening in the givinostat group suggests a potential role in preventing chronic progression of the disease, though not able to reverse the already established pathology. Functional endpoints, including the MFM score, timed function tests, 6-min walk test, and handheld myometry showed similar insignificant changes between groups, likely reflecting the study’s shorter duration and the milder disease phenotype in BMD.

This apparent inefficacy of givinostat therapy in BMD is in contrast with its murine DMD models. Though the general assumption is cross-efficacy between BMD and DMD, there are no specific animal models for BMD, and no pharmacotherapy, including corticosteroid therapy, was found to be equally efficacious between these two diseases. Possible explanations could be slower progression of the disease, imbalance at baseline between groups, and relative less sensitivity of histological and functional parameters.

Safety Profile

The safety profile of givinostat was similar in both studies, with tolerable adverse events. Most common adverse effects were diarrhoea, vomiting, nasopharyngitis, thrombocytopenia, and hypertriglyceridemia. Adverse events were consistent in both study and placebo groups in the DMD study. GI side effects were almost two times more prevalent in the givinostat group, including few serious adverse events of vomiting. Thrombocytopenia was observed in 57% of the treatment group with dose reduction required in 28%. Mean increase in triglyceride was observed in 59% of the givinostat group with adverse effects in 23%.

In the BMD study group, the findings were similar. In the group receiving givinostat, treatment-emergent adverse effect was found in 100% (high-dose) vs. 70% (low-dose) with treatment interruption in 41% (high-dose) vs. 23.5% (low-dose) and treatment-related SAE in 2 of the participants in both groups. In the placebo group, ADR was seen in 52% with 23% related to treatment with no SAE. Three participants required treatment withdrawal in the givinostat group compared to one in the placebo group. While no treatment-related deaths or serious adverse events were reported, the high frequency of dose adjustments highlights the importance of close monitoring and individualized dosing regimens to optimize tolerability.

Study Limitations

The systematic review has several limitations. After searching the databases, only two studies met the eligibility criteria. As effects of givinostat on two different clinical conditions with distinct pathophysiology and progression were investigated, comparative analysis between these two studies could not be performed. One common limitation of both these studies was small sample size due to the rarity of the diseases. Limited number of participants caused failure to meet endpoints and smaller effect size. The study by Comi et al. [30] also had baseline difference in the genetic mutation type and mutated exon category, making the treatment and placebo group unmatched and thus the interpretation challenging.

Clinical Implications

These findings from the studies demonstrate the potential role of givinostat as a disease-modifying therapy in MDs with rapid progression like DMD. For slow progressing diseases like BMD, as the radiological findings suggest improvement over time, givinostat has great potential in prevention of disease advancement, but larger trials with longer duration are needed to be conducted to evaluate its impact on functional and histological parameters. The results also highlight the importance of selecting appropriate endpoints based on disease characteristics. Functional assessments, such as the four-stair climb, appear more suitable for rapidly progressive diseases like DMD, whereas imaging-based measures may better capture early effects in slower progressing conditions like BMD.

Conclusion

This systematic review incorporates the promise of givinostat as a disease-modifying therapy for MDs, especially DMD. Clinical trials have demonstrated that it can retard the disease progression, maintain muscle mass, and reduce fat infiltration, although its efficacy in BMD is inconclusive. Although givinostat is generally a tolerable drug, adverse effects like thrombocytopenia and gastrointestinal symptoms require vigilant monitoring and personalized dosing regimens. With the heterogeneity of treatment response, additional large-scale, long-term studies will be required to further clarify patient selection criteria, dosing regimens, and its influence on long-term functional consequences. Ultimately, givinostat is a key step forward in the therapeutic management of MDs, with a new promise for patients and clinicians caring for these disabling disorders.

Statement of Ethics

Patients or the public were not involved in the design, conduct, reporting, or dissemination plans of our research. No ethical approval was required as this study is based exclusively on published literature.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Prasanjit Das: conceptualization, project administration, formal analysis, methodology, resources, visualization, writing – original draft, and data curation. Bisweswar Ojha: data curation, formal analysis, project administration, data synthesis, resources, supervision, visualization, writing – original draft, review, and editing. Alapan Das: data synthesis, data extraction, formal analysis, validation, visualization, and writing – review and editing. Bhairav Pathak: methodology, resources, writing – review and editing, and formal analysis. Kaushik Mukhopadhyay: project administration, resources, software, supervision, validation, and writing – review and editing.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

The data that support the findings of this study are openly available in PubMed at doi.org/10.1016/S1474-4422(24)00036-X [35], doi.org/10.3389/fneur.2023 [30].