Givinostat Data Point to Delayed Loss of Ambulation, Preserved Muscle Tissue in DMD

Longer-term treatment with givinostat (Duvyzat; ITF Therapeutics) plus standard-of-care corticosteroids may delay the age at which patients with Duchenne muscular dystrophy (DMD) lose the ability to walk, according to an updated interim analysis of the drug's ongoing open-label extension study (NCT03373968). These findings were recently presented at the 2026 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting, held September 29 to October 2, in Orlando, Florida.¹

Givinostat is an oral histone deacetylase inhibitor that was evaluated in the phase 3, randomized, double-blind, placebo-controlled EPIDYS trial (NCT02851797). In a 2021 interim analysis of the OLE, givinostat-treated patients showed a delay in median age at persistent loss of ambulation (LoA) compared with a matched, natural history control group.¹ The current analysis used data through a 2023 cutoff. It included a larger patient population and an additional 2 years of follow-up.

Presented by senior author Eugenio Mercuri, MD, PhD, and colleagues, the ongoing OLE enrolled patients aged 6 years and older who had completed a prior phase 2 givinostat study (NCT01761292) or EPIDYS, as well as patients who were screened but not randomized in EPIDYS. All patients who received at least 1 month of givinostat in combination with corticosteroids were included. Investigators calculated median age at persistent LoA, meaning a permanent inability to walk independently, using Kaplan-Meier survival analysis.

Among 225 patients, 78 (34.7%) experienced persistent loss of ambulation (LoA), at a median age of 17.3 years (95% CI, 15.5-18.1). Compared with published estimates of 11.0 to 13.4 years among patients treated with corticosteroids alone, the findings suggest givinostat may delay LoA.

MRI Data Show Less Muscle Loss With Givinostat

A second poster at the meeting reported quantitative MRI measures of muscle composition from EPIDYS. Contractile cross-sectional area (cCSA) reflects the amount of functional muscle tissue available to generate force, and fat fraction (FF) reflects the replacement of muscle by fat. Both are noninvasive, quantitative measures of DMD progression.²

EPIDYS randomized ambulant boys aged 6 years and older with genetically confirmed DMD 2:1 to givinostat or placebo, each in addition to corticosteroids, for 72 weeks. Patients were prespecified into subgroups based on baseline vastus lateralis fat fraction (VLFF). A target population with VLFF greater than 5% to 30% or less was chosen to capture patients who were not at risk of sudden, complete loss of ambulation but who would be expected to decline over the study period if receiving placebo.

Of 179 enrolled patients, 120 met the target population criteria (givinostat, n = 81; placebo, n = 39), and 113 completed imaging at week 48 and at the end of the study (givinostat, n = 76; placebo, n = 37). Investigators measured cCSA and FF with 8-point Dixon MRI in 5 lower limb muscle groups: the biceps femoris long head, hamstrings, quadriceps, semitendinosus, and vastus lateralis. In the main trial, givinostat met its primary end point, slowing decline on the 4-stair climb vs placebo (least squares [LS] mean difference, −1.78 seconds; P = .037).^2,3

At the end of the study, givinostat-treated patients had less decline in cCSA than placebo-treated patients across all 5 muscle groups. LS mean differences ranged from 0.43 cm² in the biceps femoris long head (95% CI, 0.14-0.73; nominal P = .005) to 1.20 cm² in the quadriceps (95% CI, 0.16-2.23; nominal P = .02). The largest relative effect was in the hamstrings, at 1.02 cm² (95% CI, 0.47-1.58; nominal P < .001). FF increased less with givinostat across all muscle groups, with LS mean differences ranging from −3.43% in the semitendinosus (95% CI, −5.80 to −1.06; nominal P = .005) to −4.60% in the biceps femoris long head (95% CI, −8.22 to −0.99; nominal P = .01).

Differences in FF were already evident at week 48 in all 5 muscle groups. Differences in cCSA at week 48 reached nominal significance in the biceps femoris long head, hamstrings, and quadriceps but not in the semitendinosus or vastus lateralis. "Givinostat treatment appears to be associated with significantly less decline in muscle contractile area and reduced fat infiltration compared with placebo, suggesting attenuation of muscle loss in patients with DMD," senior author Mercuri, professor of pediatric neurology at the Catholic University in Rome, Italy and colleagues wrote.²

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The OLE findings build on a previously published long-term analysis of 194 patients. In that analysis, post hoc, propensity-matched comparisons with the ImagingDMD and CINRG natural history datasets suggested that givinostat added to corticosteroids delayed loss of ambulation, loss of the ability to rise from the floor, and loss of the ability to complete the 4-stair climb. Median delays ranged from 2.0 to 3.3 years across these milestones.⁴

Givinostat is approved for patients with DMD aged 6 years and older in several regions, including the US, EU, UK, and United Arab Emirates, with differences in ambulatory status criteria across regions.⁵

Both analyses have important limitations. The OLE is single arm and open label, and its comparison with published natural history estimates is cross-study rather than a matched or randomized comparison. Published LoA estimates vary with cohort characteristics, corticosteroid regimen, and era of care. For example, the matched natural history cohort in an earlier OLE analysis had a median age at LoA of 15.2 years, considerably higher than the 11.0- to 13.4-year range cited here.⁶ Only about one-third of OLE patients had reached the LoA end point, so the median estimate may shift with further follow-up.

The MRI analysis was randomized, but the imaging end points were exploratory, and the nominal P values were presented for descriptive purposes only, without adjustment for multiple comparisons. The analysis was also limited to the target population with VLFF of 5% to 30%. It did not directly link the imaging changes to functional outcomes. The LoA analysis was previously presented at the 2026 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference and the 2026 International Congress on Neuromuscular Diseases (ICNMD). The MRI data were previously presented at MDA 2026, the AIM 2026 National Congress, and ICNMD 2026.^2,5,6

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REFERENCES
1. Gómez Andrés D, Sansone V, Parodi A, et al. Open-label extension analysis shows potential delay in age at loss of ambulation in patients with Duchenne muscular dystrophy treated with givinostat. Presented at: 2026 AANEM Annual Meeting; September 29-October 2, 2026; Orlando, FL. Abstract 137.
2. Vandenborne K, Willcocks R, Bettica P, Cazzaniga S, Alessi F, Mercuri E. Givinostat reduces the decline of contractile cross-sectional area and decreases fat infiltration in patients with Duchenne muscular dystrophy. Presented at: 2026 AANEM Annual Meeting; September 29-October 2, 2026; Orlando, FL. Abstract 138.
3. Mercuri E, Vilchez JJ, Boespflug-Tanguy O, et al. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2024;23(4):393-403. doi:10.1016/S1474-4422(24)00036-X
4. McDonald CM, Guglieri M, Vucinic D, et al. Long-term evaluation of givinostat in Duchenne muscular dystrophy, and natural history comparisons. Ann Clin Transl Neurol. 2025;12(11):2335-2348. doi:10.1002/acn3.70165
5. Presentation of new clinical data on givinostat in Duchenne muscular dystrophy at ICNMD 2026. News release. Italfarmaco S.p.A. July 7, 2026. Accessed October 1, 2026. https://www.globenewswire.com/news-release/2026/07/07/3322957/0/en/Presentation-of-New-Clinical-Data-on-Givinostat-in-Duchenne-Muscular-Dystrophy-at-ICNMD-2026.html
6. ITF Therapeutics LLC presents new data and analyses on givinostat for treatment of Duchenne muscular dystrophy at 2026 MDA Clinical and Scientific Conference. News release. ITF Therapeutics. March 2026. Accessed October 1, 2026. https://www.prnewswire.com/news-releases/itf-therapeutics-llc-presents-new-data-and-analyses-on-givinostat-for-treatment-of-duchenne-muscular-dystrophy-at-2026-mda-clinical-and-scientific-conference-302707870.html