Givinostat Delays Duchenne Muscular Dystrophy Progression by 2 Years, Simulation Model Shows

Chamindra Laverty, MD

(Credit: University of California, San Diego)

Givinostat (Duvyzat; Italfarmaco SpA), an oral histone deacetylase inhibitor recently approved by the FDA for Duchenne muscular dystrophy (DMD) in patients aged 6 years and older, was associated with a significant delay in disease progression, according to a new analysis using the Duchenne Regulatory Science Consortium’s (D-RSC) Clinical Trial Simulation tool.¹

The analysis incorporated data from the phase 3 EPIDYS study (NCT02851797) and an ongoing long-term safety and tolerability study (LTSE) to assess the impact of givinostat on the 4-stair climb (4SC) end point, a key measure of functional decline in DMD. Findings showed that patients receiving the recently approved therapy experienced a 2-year delay in disease progression compared with those receiving standard of care (SoC), with treated patients demonstrating faster stair-climbing ability at age 14.

Recently presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 16-19 in Dallas, Texas, the study used a nonlinear mixed-effects modeling approach to update the D-RSC disease progression model with new data from 357 patients, 296 treated with givinostat and 61 with SoC. Authors noted that patients with missing baseline data or those who became nonambulant were excluded from the analysis.

To validate the model, researchers transformed 4SC measurements into climb velocity (1/s) and confirmed that the original disease progression model accurately predicted observed data in SoC-treated patients. The model was then updated and re-estimated using givinostat data, with visual predictive checks confirming strong alignment between model predictions and real-world observations.

Simulations were conducted on 1000 virtual patients over 5 years. Results indicated that starting at age 9, givinostat delayed disease progression by approximately 2 years. At age 14, patients on givinostat had a higher 4SC velocity (0.1 1/s) than those receiving SoC, suggesting preserved mobility for a longer period.

Presented by lead author Chamindra Laverty, MD, clinical professor of neurosciences at University of California, San Diego, these findings demonstrated that givinostat significantly slowed the functional decline in DMD compared with standard care, supporting its role as a disease-modifying therapy. Future research may further refine simulation models to assess long-term treatment benefits of givinostat in DMD.

READ MORE: SHIELD-DMD to Evaluate Therapeutic Potential of IL-6 Receptor Satralizumab in Duchenne Muscular Dystrophy

Following evidence that givinostat can delay mobility loss in DMD, new simulations suggested the therapy may also help preserve lung function. Using the D-RSC validated clinical trial simulation tool, another study presented at MDA 2025 reported that patients over age 15 who were treated with givinostat had a significantly lower risk of severe respiratory decline compared with those on SoC.²

The analysis, which also incorporated data from the phase 3 EPIDYS study and an ongoing LTSE, assessed differences in forced vital capacity (FVC), a known key measure of respiratory function. Findings showed that only 3.1% of patients receiving givinostat had critically low FVC (<1L) compared with 12.5% of those on SoC—indicating a 4-fold greater risk of severe respiratory impairment in untreated patients.

Since there were a limited number of givinostat-treated patients in the long-term study showing FVC decline, researchers were unable to apply a full disease progression model. Instead, they compared observed FVC data in givinostat-treated patients over age 15 with simulated projections for those on SoC, using the validated DMD progression model.

Simulations were conducted using NONMEM (version 7.5.1) across 500 virtual patient replicates, incorporating demographic data from EPIDYS and LTSE. Visual predictive check diagnostics confirmed strong alignment between observed and simulated SoC data, validating the model’s reliability for comparative assessment.

Presented by lead author Erika L Finanger, MD, MS, professor of pediatrics at Oregon Health and Science University, the results demonstrated that among patients older than 15, those on givinostat were far less likely to experience severe respiratory decline. Only 3.1% had an FVC below 1L, compared with 12.5% in the SoC group (95% CI, 6.2%-20.3%). This translated to a 4-fold greater likelihood (95% CI, 2.0-6.5) of reaching critical FVC thresholds in patients receiving SoC.

These findings suggest that givinostat may help delay respiratory decline in DMD, further supporting its role as a disease-modifying therapy. However, researchers cautioned that limited long-term data in older patients may necessitate further validation of these results. Thus, future studies could be critical in confirming the long-term respiratory benefits of givinostat in DMD management.

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REFERENCES
1. Laverty C, Mercuri E, Alessi F, et al. Disease progression modeling in Duchenne muscular dystrophy: delayed decay in four-stair climb with givinostat compared with standard of care. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19. Dallas, TX. Abstract P76
2. Finanger EL, Laverty C, Alessi F, et al. Modeling disease progression in Duchenne muscular dystrophy: reduced decline in forced vital capacity with givinostat compared with standard of care. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19. Dallas, TX. Abstract P85