Exon-skipping therapies for DMD in Kazakhstan: Progress and challenges

Abstract

Background

Duchenne muscular dystrophy (DMD) progression has been evaluated in clinical trials; however, some ethnic populations—including Kazakhstan, a country with a genetically unique population—are still underrepresented. While the prevalence of DMD in Kazakhstan has yet to be reported, Kazakhstan is one of the only central Asian countries with access to exon-skipping therapies for DMD. Although these therapies have been provided through regional budget and public funds since 2021, due to high costs and inconsistent support, accessibility remains challenging.

Objective

To describe the disease progression of exon-skipping–treated patients with DMD in Kazakhstan and discuss treatment management challenges.

Methods

Data from exon-skipping–treated patients (January 2021–April 2025) were provided to an expert council for review every 6 months. Functional outcomes (Scott scale, Vignos scale, 6-minute walk test, and 4-stair climb) were extracted and analyzed.

Results

A total of 46 patients received eteplirsen (n = 24), golodirsen (n = 14), and casimersen (n = 8). Median ages at eteplirsen, golodirsen, and casimersen initiation were 9.1, 9.6, and 10.3 years, respectively. During the follow-up period, 10 of 46 patients discontinued their exon-skipping therapy, and one patient died (decompensated cardiomyopathy). Functional assessments showed that patients were generally stable or improved over time. Approximately one-third of patients experienced treatment interruptions or were anticipated to be unable to maintain their prescribed exon-skipping therapy due to inadequate funding.

Conclusions

These data reflect the challenges patients with DMD experience in Kazakhstan, and the need for improved funding to maximize the therapeutic potential of exon-skipping therapies.

Introduction

Duchenne muscular dystrophy (DMD) is a degenerative X-linked recessive disease that affects approximately 1 in 5,000 to 1 in 6,000 live male births.^1–6 DMD is caused by specific pathogenic variants in the DMD gene that disrupt the messenger RNA open reading frame, resulting in an absence or the production of nonfunctional dystrophin protein in muscles.^2,3,6–9 While there is no cure for DMD, several therapies target the underlying cause of the disease and may delay its progression.^1,3,10–12 Clinical trials demonstrated that exon-skipping therapies restored the dystrophin open reading frame and allowed the production of a shortened, functional form of dystrophin,^{1,6,10,13–16} which led to the approval by the US Food and Drug Administration (FDA) and the Japanese Ministry of Health, Welfare, and Labour (MHWL) of four exon-skipping therapies: eteplirsen (targeting exon 51; FDA), casimersen (targeting exon 45; FDA), golodirsen (targeting exon 53; FDA), and viltolarsen (targeting exon 53; FDA and MHWL).^17–21 While approvals were based on an increase in dystrophin, the effectiveness of these therapies to slow the progression of the disease is still being evaluated in clinical trials.

In recent years, a growing awareness of a lack of diversity and representation in clinical trials has arisen. Kazakhstan, a country in Central Asia with a genetically unique background, remains underrepresented in clinical trials. Although the prevalence of DMD in Kazakhstan and Central Asia has yet to be reported, Kazakhstan is one of the only countries in Central Asia with access to exon-skipping therapies for DMD, including eteplirsen, golodirsen, and casimersen. ²² While eteplirsen and golodirsen first became available in Kazakhstan in 2021, followed by casimersen in 2022, very little data are available on the disease progression in treated Kazakhstani patients.

In Kazakhstan, DMD treatment is mainly provided to patients through the Kazakhstan Khalkyna Public Fund and 2 regional funds, distributed by the Ministry of Health and regional administration. However, as observed in other middle-income countries,^23,24 access to treatment remains challenging due to funding deficits, limited awareness of rare neuromuscular diseases among Kazakhstani healthcare professionals, and the lack of a standardized multidisciplinary care system. ²²

This study aims to describe the progression of disease among Kazakhstani patients with DMD receiving exon-skipping therapies in clinical practice and discuss the challenges preventing the effective management of this rare disease in Kazakhstan. Additionally, the point prevalence of DMD in Kazakhstan was estimated.

Methods

This was a retrospective analysis of data extracted from Kazakhstani patients receiving treatment for DMD during routine clinical practice at the hospital of their place of residence.

The Expert Advisory Council on Neuromuscular Diseases (Astana, Kazakhstan) includes 10 members who specialize in neuromuscular disorders and are responsible for overseeing the treatment of patients with DMD and assessing their suitability for exon-skipping therapies based on the manufacturers’ indications. Upon identification of a patient with muscle weakness and high creatine phosphokinase levels, genetic testing using multiplex ligation-dependent probe amplification is carried out at Kazakhstani laboratories (KF University Medical Center and the Presidential Administration Hospital) to search for deletions or duplications in the DMD gene. The Expert Advisory Council reviews genetic test results, patient documents, and video recordings of movements and functional tests, confirms the diagnosis of DMD if appropriate, prescribes therapy specific to the patient’s pathogenic variant (in addition to prednisone) according to the manufacturer’s instructions, and manages ongoing treatment.

The prevalence of DMD in Kazakhstan was estimated based on the number of patients overseen by the Expert Advisory Council on Neuromuscular Diseases as of September 2024. In addition, data are reported for all patients with a confirmed diagnosis of DMD and amenable pathogenic variants for exon-skipping therapies who were assessed by the Expert Advisory Council between January 2021 and April 2025. Data were collected per routine clinical practice by the treating neurologists, who had been trained in administering clinical scales relevant to DMD, and provided to the Expert Advisory Council for review every 6 months over the course of 4 years. At the initial visit, physicians collected patients’ place of residence, nationality, age at presentation, at disease onset, at confirmed diagnosis of DMD, and at therapy initiation, as well as mutation type and ambulatory status at presentation and therapy initiation. At the initial and subsequent visits, functional outcomes were assessed, which included the Vignos scale (graded 1–10, with lower scores indicating better lower extremity function), ²⁵ 6-minute walk test (6MWT; total distance walked in 6 minutes), and 4-stair climb (time taken to climb 4 standard steps) assessments, and the Scott scale (total score 0–40, with higher scores representing better motor ability). ²⁶ In Kazakhstan, specialists are untrained to the use of the North Star Ambulatory Assessment, instead the Scott scale is broadly implemented in clinical practice. The Scott scale is a 20-item scale based upon gross motor developmental process providing nominal level data with a degree of hierarchy between and within elements (weighted at 0, 1, or 2 upon performance). Scoring for elements is summed up to give a final total with a maximum score of 40.^26,27 Loss of ambulation was determined based on functional outcomes and was defined by the inability to walk independently without support. All data were analyzed descriptively.

Results

Prevalence of DMD in Kazakhstan

The point prevalence of DMD in Kazakhstan was estimated by calculating the incidence of DMD in September 2024. As of September 2024, a total of 191 patients in Kazakhstan with genetically confirmed DMD were being overseen by the Expert Advisory Council on Neuromuscular Diseases. Of these, 142 patients were in the ambulatory stages of the disease and 49 were non-ambulatory. The estimated overall point prevalence of DMD in the Republic of Kazakhstan was 2.8 cases per 100,000 children, and 5.5 cases per 100,000 boys. The estimated point prevalence of DMD varied by region, ranging from 9.5 cases per 100,000 boys in Kyzylorda to 1.1 cases per 100,000 boys in East Kazakhstan (Figure 1).

Figure 1.

Estimated point prevalence of DMD in September 2024 in Kazakhstan by region. DMD, Duchenne muscular dystrophy.

Patients assessed for treatment with exon-skipping therapies

Between January 2021 and April 2025, the Expert Advisory Council evaluated 58 patients with DMD for potential treatment with exon-skipping therapies, resulting in 46 patients receiving treatment across 14 of Kazakhstan’s 17 regions (Figure 2). All patients aged >4 years at the time of DMD diagnosis received glucocorticosteroid treatment, which was continued upon initiation of exon-skipping therapies.

Figure 2.

Regional distribution of patients treated with eteplirsen, golodirsen, and casimersen in Kazakhstan between January 2021 and April 2025. Symbols do not denote the exact locations of patients. The density of Kazakhstan population is a 2023 estimate based on the census from 2009. ²⁸ .

Eteplirsen (n = 27). A total of 27 patients with pathogenic variants amenable to therapy with eteplirsen (Table S1) were identified, of whom 24 received treatment (Table 1). Two ambulatory patients were recommended for therapy but could not proceed due to budget constraints, and one patient (late ambulatory) declined the medication.

Table 1.

Patient disposition and characteristics at baseline ^a and follow-up data.

Patients with pathogenic variants amenable to therapy	Eteplirsen	Golodirsen	Casimersen
	n = 27	n = 18	n = 13
Therapy not initiated, n (%)	3 (11.1)	4 (22.2)	5 (38.5)
Treated, n (%)	24 (88.9)	14 (77.8)	8 (61.5)
Discontinued therapy, n	7	2	1
Died, n	1 b	0	0

6MWT, 6-minute walk test; SD, standard deviation.

^aBaseline indicates the start of exon-skipping therapy.

^bThe patient died from decompensated cardiomyopathy caused by physical overload from inadequate physical activity at a private rehabilitation center.

^cPercentages may not total 100% due to rounding.

^dAll patients aged >4 years received glucocorticosteroid treatment.

At the initiation of eteplirsen therapy, patients (n = 24) were aged 3 to 12 years, and 16 (67%) were ambulatory (Table 1). Patients were followed for up to 42 months with a mean time of 22.89 months.

During the follow-up period, 17 of 24 patients remained on eteplirsen. One patient died from decompensated cardiomyopathy caused by physical overload from inadequate physical activity at a private rehabilitation center, and seven patients discontinued treatment (Tables 1 and 2). In addition to those who discontinued treatment, three patients had a treatment interruption of ≤3 months, and one patient was anticipated to discontinue eteplirsen after their last follow-up visit due to insufficient funding.

Table 2.

Summary of discontinuations among patients receiving exon-skipping therapies.

Parameters, n (%)	Eteplirsen n = 24	Golodirsen n =14	Casimersen n = 8
Total discontinuation	7 (29.2)	2 (14.3)	1 (12.5)
Non-ambulatory at treatment initiation	6 (25.0)	2 (14.3)	-
“Lack of medical expediency of continuing therapy”	4 (16.7) a	-	​
Parental refusal of medical care	1 (4.2)	-	​
Extended interruption in therapy	1 (4.2)	-	​
Lack of functional improvement as deemed by clinician	-	1 (7.1)	​
Seizures	-	1 (7.1)b	​
Ambulatory at treatment initiation	1 (4.2)	-	1 (12.5)
“Medically inappropriate”	1 (4.2) c	-	​
Progression of the disease despite exon-skipping therapy	-	-	1 (12.5) a

^aAs deemed by the clinician.

^bSeizures were due to known concomitant epilepsy; relationship to study treatment is unknown.

^cPatient discontinued after losing ambulation during the study, at which point treatment was considered “medically inappropriate” by the clinician.

Functional outcomes among the 24 patients receiving eteplirsen. Of 16 patients who were ambulatory at initiation of eteplirsen therapy, 12 remained ambulatory throughout the follow-up period (Table 3). This included one patient aged 13.9 years and one patient aged 13.7 years at their last assessment.

Table 3.

Summary of time to loss of ambulation among treated patients ambulatory at treatment initiation.

Parameters, n (%)	Eteplirsen n = 16	Golodirsen n = 9	Casimersen n = 8
Patients who remained ambulatory through follow-up	12 (75.0)	9 (100)	7 (87.5)
Last available visit
Before the 12-month visit	3 (18.8)	2 (22.2)	1 (12.5)
12-month visit	2 (12.5)	3 (33.3)	2 (25.0)
18-month visit	-	3 (33.3)	1 (12.5)
24-month visit	-	-	3 (37.5)
30-month visit	1 (6.3)	-	-
36-month visit	4 (25.0)	1 (11.1)	-
42-month visit	2 (12.5)	-	-
Patients who lost ambulation during the study	4 (25.0)	0	1 (12.5)
First visit recording loss of ambulation
Before the 12-month visit	-	-	-
12-month visit	1 (6.3) a	-	1 (12.5) b
18-month visit	1 (6.3) c	-	-
24-month visit	-	-	-
30-month visit	2 (12.5) d	-	-
36-month visit	-	-	-
42-month visit	-	-	-

^aPatient initiated eteplirsen at age 9.5 years.

^bPatient initiated casimersen at age 11.1 years.

^cPatient initiated eteplirsen at age 6.5 years; at the 18-month visit, when loss of ambulation was recorded, eteplirsen treatment was discontinued following the clinician’s decision due to the parents’ refusal of prednisone treatment and failure to follow the clinician’s recommendations.

^dPatients initiated eteplirsen at ages 8.0 and 11.7 years, respectively.

Six-monthly assessments showed no clear trend in Scott scale scores over ≤42 months of treatment, whereas Vignos scale grades generally increased over time (Figure 3). One patient experienced a marked decrease in Scott scale and an increase in Vignos grade followed by a decrease, which was due to two fractures involving surgical correction and immobilization, leading to temporary loss of ambulation. Time to complete the 4-stair climb was generally stable or increased over time, and 6MWT distance generally remained stable or decreased over time (Figure 3).

Figure 3.

Functional outcomes among the 24 patients receiving eteplirsen therapy. Not all patients had available data for each assessment and at each visit. Data from non-ambulatory patients at baseline were included. The number of patients with available data for each visit appears below the x-axis. 6MWT, 6-minute walk test.

Golodirsen (n = 18). A total of 18 patients with a pathogenic variant amenable to treatment with golodirsen were identified between January 2021 and April 2025 (Table S1), of whom 14 were treated (Table 1). Two ambulatory patients were “recommended for therapy” but did not initiate golodirsen due to lack of funding. In addition, golodirsen was not considered appropriate by the Expert Advisory Council for one patient as they were in the late non-ambulatory stage, and the decision regarding therapy was not documented for one patient (who has since become non-ambulatory).

At treatment initiation, patients were aged 3 to 11 years (Table 1). Four patients were non-ambulatory, and one patient’s ambulatory status was unknown. Patients were followed for up to 36 months, with a mean time of 15.00 months. During the follow-up period, 12 patients remained on golodirsen, and two patients discontinued treatment as decided by the Expert Advisory Council (Table 2).

Owing to a lack of funding, three patients experienced at least one treatment interruption. One patient had a 3-month gap in golodirsen treatment; another had a 10-month treatment interruption and was anticipated to have a second gap following their last follow-up visit; and the third patient had two separate 5-month treatment interruptions, with a 2-month period of resumed therapy between them.

Functional outcomes among the 14 patients receiving golodirsen. All nine patients who were ambulatory at the start of golodirsen treatment remained ambulatory throughout the follow-up period, including one who was 13.3 years of age at last assessment (Table 3). Scott and Vignos scale scores were generally stable up to 36 months of follow-up (Figure 4). One patient (10.0 years of age at treatment initiation) had a marked increase in Vignos grade (3 to 6) over 18 months of follow-up, which was caused by damage to the ankle joints. Four-stair climb times were generally stable over time, and no clear trend was seen in 6MWT distance (Figure 4).

Figure 4.

Functional outcomes among the 14 patients receiving golodirsen therapy. Not all patients had available data for each assessment and at each visit. Data from non-ambulatory patients at baseline were included. The number of patients with available data for each visit appears below the x-axis. 6MWT, 6-minute walk test.

Casimersen (n = 13). A total of 13 patients with a pathogenic variant amenable to treatment with casimersen were identified (Table S1), of whom eight were treated and five were “recommended” for treatment (Table 1). Of the patients who did not initiate casimersen, one patient (2 years of age) was “too small” according to the clinician and had a delay in psychomotor development, two patients were unable to start therapy due to a lack of funding, and for the other two patients, the reason for the delay in therapy initiation was not documented.

At casimersen treatment initiation, patients were aged 8 to 13 years and all were ambulatory (Table 1). The mean time of follow-up was 15.8 months. One patient (aged 10.3 years at treatment initiation) discontinued casimersen after 24 months of treatment (Table 2). Owing to a lack of funding, one patient had a treatment interruption for 3 months before resuming therapy, with a second interruption anticipated after their last follow-up visit; and four patients were anticipated to discontinue casimersen therapy after their last follow-up visit.

Functional outcomes among the 8 patients receiving casimersen. Most (7 of 8) treated patients remained ambulatory during follow-up, of whom one was 13.6 years of age and one was 15.0 years of age at their last assessment (Table 3). The patient who lost ambulation was 11.1 years of age at casimersen initiation and had loss of ambulation at the 12-month visit. Scott and Vignos scale scores, 4-stair climb time, and 6MWT distance were generally stable up to 24 months of treatment with casimersen (Figure 5).

Figure 5.

Functional outcomes among the 8 patients receiving casimersen therapy. Not all patients had available data for each assessment and at each visit. Data from non-ambulatory patients at baseline were included. The number of patients with available data for each visit appears below the x-axis. 6MWT, 6-minute walk test.

Discussion

This is the first report of an estimated point prevalence of DMD in Kazakhstan. While the estimated rate of 5.5 cases per 100,000 boys was much lower than the observed global birth prevalence of 1 in 5,000 to 6,000 male births,^1,2,4,5 it was within the range of point prevalence observed in other countries, such as France (10.9 cases), USA (1.9 cases), UK (2.2 cases), or Canada (6.1 cases). ⁷ However, the point prevalence described in this present study was estimated among male patients aged <18 years. When comparing with a similar population (males younger than 18 or 24 years), studies tend to find higher point prevalences (Canada, 10.3; USA, 10.2–14.3; Norway, 16.2). ⁷ This difference likely reflects underdiagnosis of DMD due to the lack of DMD specialists in Kazakhstan despite the efforts made since 2020 to increase DMD awareness among healthcare professionals with the creation of the national Expert Advisory Council on Neuromuscular Diseases. ²² Additionally, it is likely that not all children with DMD were considered by the Expert Advisory Council, contributing to a potential lower estimated point prevalence observed. The estimated point prevalence of DMD in Kazakhstan varied up to ∼9-fold across regions. This observed regional variation was likely influenced by low population density in certain areas, as well as differing levels of disease awareness among local physicians, likely leading to misdiagnosis and underreporting of DMD.

Management guidelines for DMD in Kazakhstan recommend the prescription of glucocorticosteroid therapy. Since June 2021, eteplirsen and golodirsen have been added to the Kazakhstan’s approved clinical protocol for the treatment of DMD, while casimersen and viltolarsen were added to a draft protocol in 2024. Of these therapies, only viltolarsen received regulatory approval in December 2024. Eteplirsen, golodirsen, and casimersen are available to patients solely under orphan drug status. Between January 2021 and April 2025, a total of 58 patients in Kazakhstan were assessed by the Expert Advisory Council as having a DMD pathogenic variant amenable to exon-skipping therapy with eteplirsen, golodirsen, or casimersen, of whom 46 patients received their recommended treatment.

Similarly to other studies, a general stabilization of the disease progression was observed among the exon-skipping–treated patients.^29–31 Notably, five of the patients who remained ambulant throughout the follow-up period were ≥13 years of age at their last assessment. The few patients who discontinued exon-skipping therapies mainly did due to lack of funding or efficacy, indicating treatment was generally safe and well tolerated, which was consistent with other studies.^15,30–32 While most functional assessments were conducted similarly to other studies (6MWT and Vignos scale), the use of the Scott scale is less broadly used in clinical trials. Implementation of the North Star Ambulatory Assessment in the Kazakhstani guidelines for DMD management would facilitate comparisons with other studies. Moreover, the lack of facilities to perform morphologic assessments in Kazakhstan, such as muscle biopsies, prevents the assessment of dystrophin expression following treatment. Dystrophin quantification is not a routine assessment in real-world clinical practice and dystrophin quantification methods are not universal. Assessment of functional outcomes and delay of milestones are needed to evaluate treatment effectiveness.

The treatment of patients with DMD in Kazakhstan is challenging for several reasons. Limited awareness of rare neuromuscular diseases among physicians in Kazakhstan may lead to delays in diagnosis and suboptimal management. ²² In addition, the absence of a standardized multidisciplinary care system means that many patients do not receive proactive treatment and lack access to quality cardiac care. To address these issues, the Expert Advisory Council on Neuromuscular Diseases was established to provide guidance on diagnostics and therapeutic strategies. ²² Nonetheless, access to specialized medical facilities and qualified healthcare professionals capable of delivering comprehensive care for patients with DMD remains scarce, particularly in rural areas, which can lead to premature death, as documented for at least one of the 46 children reported in this study (decompensated cardiomyopathy due to physical overload from inadequate physical activity). An improvement in access to multidisciplinary care and qualified healthcare professionals in Kazakhstan is crucial to prolong the survival rate and quality of life of children with DMD. Additionally, implementation of patient advocacy groups could have a significant impact on increasing awareness and education on DMD, among patients as well as emotional support for the patients. ³³

Despite these developments, access to exon-skipping therapies is limited due to funding deficits. In Kazakhstan, drugs with orphan status can be financed through three public sources: the Kazakhstan Khalkyna Public Charity Foundation, regional local budgets, and the Guaranteed Amount of Free Medical Care. In 2021, some regions began funding exon-skipping therapies through local budgets. For example, in Almaty, funding was available for a 3-month drug supply in January 2021 and resumed in May of that year. Since mid-2022, most patients have relied on support from the charitable Kazakhstan Khalkyna Public Fund to access exon-skipping therapies; however, this support was discontinued for new patients in January 2024 and ceased entirely for existing patients in early 2025. While some regional administrations have found additional funding, allowing some patients to resume treatment, there is currently no consistent supply of exon-skipping therapies in Kazakhstan. In our analysis, approximately one-third of patients experienced treatment interruptions or were anticipated to be unable to maintain their prescribed treatment due to inadequate funding. Repeated administration of exon-skipping therapies is required to sustain therapeutic levels and support continuous dystrophin production, with the aim of slowing disease progression in patients with DMD. Consequently, treatment gaps may compromise the long-term effectiveness of these therapies.

Early identification and treatment of DMD are essential to maximize the therapeutic potential of exon-skipping therapies and delay the irreversible muscle damage that occurs as the disease progresses.^11,12,34 The average age of clinical onset of DMD in Kazakhstani patients is approximately 3 years. ²² However, the median age of patients initiating exon-skipping therapies in the ∼4 years since their introduction in January 2021 was >9 years. Loss of ambulation typically occurs between the ages of 12 and 14 years, including in corticosteroid-treated patients. ³⁵ In our study, some patients began exon-skipping therapies during the late ambulatory stage of DMD, and approximately 26% had already transitioned to the non-ambulatory stage. An increased awareness of the disease among clinicians and families could favorize early diagnosis of the disease, and therefore, could allow for an earlier access to treatment, which could be highly important for improved outcomes.

This study has several limitations. The small number of patients receiving each therapy reflects the rarity of DMD and limits the generalizability of the results. Detailed information on patient demographics, treatment history, and concomitant therapies is lacking, and the evaluation of the effectiveness of exon-skipping therapies was constrained by missing or incomplete functional assessment data at baseline and follow-up. This likely reflects variability in clinical awareness and documentation practices among local neurologists, particularly regarding the importance of standardized monitoring of DMD. Additionally, the lack of a national general registry and the absence of clinical trials involving Kazakhstani patients and data on muscle biopsies prevent drawing independent conclusions on safety and efficacy. Due to the high cost of treatment and the criteria of effectiveness not implying full restoration of function or significant improvement in the quality of life of patients, government agencies often face challenges in recognizing the need to allocate funds for the treatment of orphan diseases, including DMD, which led to gaps in coverage of the patients included in this analysis. Consequently, the interruptions in therapy due to a lack of funding may have influenced treatment outcomes and contributed to variability in response. Finally, loss of ambulation was not consistently documented and was therefore inferred through review of functional data from each visit, leading to an unknown exact date of ambulation loss, and a timing based on the visit at which the patient was first identified as non-ambulatory using available data.

Despite these limitations, this study provides real-world evidence regarding the treatment of DMD with exon-skipping therapies in Kazakhstan. The reported data reflect the challenges experienced by patients with DMD and physicians in Kazakhstan, and the need for improved management to maximize the therapeutic potential of exon-skipping therapies.

Ethical considerations

The data collected for this study was anonymized and came from open sources. As such, ethics approval was not required.

Data Availability Statement

Data generated from this study are available from the corresponding author upon request.*