WHAT HAPPENED
Duvyzat (givinostat) is a new drug indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older.
Duvyzat, developed by Italian Italfarmaco, is approved by the U.S. Food and Drug Administration (FDA) at the end of March 2024 [1] [2].
Italfarmaco was so confident that the FDA would deliver a favorable verdict on Duvyzat that it launched a U.S. division represented by ITF Therapeutics well in advance, although in late November 2023, the regulator gave notice of a postponement of the decision deadline previously set for late December 2023 [3] [4].
In early September 2024, the European Medicines Agency (EMA) started its regulatory review process of givinostat [5]. The drug will undoubtedly receive marketing authorization due to the high unmet medical need for new drugs for DMD.
Duvyzat oral suspension should be taken twice a day.
Duvyzat, which can be administered on the background of any therapy, provides a slowing of DMD progression by fibrosis inhibition and muscle regeneration activation.
Alternative brand names for givinostat include Duvistat, Duviken, Dusken, and Uviktos.
WHY IT MATTERS
Duchenne muscular dystrophy is still in desperate need of new treatment options. First, base therapy with corticosteroids such as prednisone/prednisolone, deflazacort, and vamorolone improves motor function, strength, and pulmonary function, delays the onset of cardiomyopathy, reduces the risk of scoliosis, slows the loss of ambulation, and prolongs survival [1] [2]. However, the nonspecificity of corticosteroids is echoed by a number of adverse events, including weight gain, decreased linear growth and short stature, hirsutism, cushingoid appearance, bone fractures, acne, and cataracts [1] [3] [4] [5].
Second, the specialty drugs Exondys 51 (eteplirsen), Vyondys 53 (golodirsen), and Amondys 45 (casimersen) prepared by Sarepta Therapeutics, as well as Viltepso (viltolarsen) by NS Pharma as part of Japan’s Nippon Shinyaku are only suitable for the treatment of those patients whose DMD is correctable by skipping exon 51, 53, or 45, respectively. These drugs, cumulatively covering approximately 30% of the patient population, have been referred to by some critics as a “scientifically elegant placebo”: there is no reliable evidence that they provide clinical benefit [6] [7].
Third, gene therapy Elevidys (delandistrogene moxeparvovec) by the same Sarepta is very expensive.
WHAT IT FOUND OUT
The EPIDYS (NCT02851797) phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) pivotal clinical trial enrolled outpatients (n=179) with Duchenne muscular dystrophy aged 6 years or older who were adherent to corticosteroid therapy and who were additionally administered oral twice-daily placebo or givinostat for 18 months.
In both groups, the results of the timed 4-stair climb test (4SC) worsened relative to baseline: the time required to complete it increased by 3.03 seconds and 1.25 seconds. However, the difference of 1.78 seconds between the placebo and givinostat groups was statistically significant (p=0.037). In other words, the use of givinostat resulted in a slowing of the rate of progression of muscle function deterioration [1].
According to the North Star Ambulatory Assessment (NSAA), givinostat provided a 40% slowing of disease progression (p=0.0209). According to magnetic resonance spectroscopy (MRS), administration of givinostat was reflected by a 30% reduction in the fat fraction in the vastus lateralis muscle of the thigh (p=0.0354); fatty infiltration of this muscle is a predictor of mobility loss. Positive trends were observed in favor of givinostat with respect to preservation of muscle strength and performance in the time to rise from floor test (TTR) and the six-minute walk test (6MWT).
Among the most common adverse events in response to givinostat administration: diarrhea (in 36% of subjects) and vomiting (29%).
In a prior phase 1/2 clinical trial NCT01761292 among outpatients (n=19) with DMD aged 7–10 years, the addition of givinostat to corticosteroid therapy resulted in significant improvements in muscle tissue histologicy, such as muscle fiber area fraction (MFAF), cross-sectional area (CSA), necrosis, hypercontractile (hyaline) fibers, fatty replacement, and fibrosis (total, endomysial, perimysial) [2].
Other beneficial effects of givinostat taken for over 7 years include delaying by 3.5 years the loss of the ability to walk independently and slowing the rate of deterioration of pulmonary function.
HOW IT WORKS
Givinostat (ITF-2357) is an oral small-molecule inhibitor of histone deacetylases (HDAC) classes I and II, which has anti-inflammatory, anti-angiogenic and antineoplastic activities. HDAC inhibition leads to accumulation of highly acetylated histones with subsequent induction of chromatin remodeling and changes in gene expression pattern. Givinostat suppresses the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin 1 (IL-1), interleukin 6 (IL-6), interferon gamma (IFN-γ) [1].
Pharmacological blockade of HDACs, which are constitutively active in Duchenne muscular dystrophy, restrains all processes that determine fibrotic muscle replacement (inflammation, necrosis, fatty infiltration, and fibrosis) and stimulates compensatory regeneration of muscle tissues [2] [3] [4].
WHAT’S NEXT
The phase 2/3 clinical trial NCT03373968 evaluating the long-term safety and tolerability of givinostat when administered to patients with DMD aged 7 years and older is ongoing. Givinostat is also being studied in more severe patients in the ULYSSES (NCT05933057) phase 3 clinical trial enrolling non-ambulatory DMD subjects aged 9–17 years.
WHAT’S MORE
In parallel, Italfarmaco is studying the applicability of givinostat in the treatment of Becker muscular dystrophy (BMD) and polycythemia vera (PV).
MEANWHILE
In late June 2023, Sarepta Therapeutics introduced Elevidys (delandistrogene moxeparvovec), a one-time gene therapy for DMD that has the potential to dramatically alter the course of this neuromuscular and deadly disease by delivering to the body a truncated but working variant of the dystrophin gene whose mutations are responsible for the development of the pathology. The cost of Elevidys is $3.2 million.
EXTRAS
Duvyzat (givinostat). Prescribing information. U.S. [PDF]