What is Duvyzat (Givinostat)?

For individuals with Duchenne muscular dystrophy (DMD), adults and children six years of age and older, the U.S. has approved the oral treatment duvyzat (givinostat). It was created by Italfarmaco with the intention of reducing DMD patients’ inflammation and muscle atrophy, ultimately slowing the disease’s progression. [Read more: What is Duchenne Muscular Dystrophy?]

Another kind of muscular dystrophy called Becker muscular dystrophy (BMD) is also being treated with small molecules. Phase 2 trial testing was done on it.

Does Duvyzat Work in DMD and BMD?

The dystrophin protein connects the intracellular skeletal structure in the muscle cell to molecules outside the cell. This increases the strength of the muscle cell. The DMD gene provides instructions for dystrophin production. The interruption of the instructions in the gene either stops dystrophin production completely or allows it to be produced in small amounts. If dystrophin production stops, this is called DMD. If some production continues, the genetic disease called BMD occurs.

If dystrophin production is insufficient, the muscles of those with this disease become more susceptible to damage, which causes the gradual loss of muscle mass and strength that characterizes each type of disease.

Duvyzat is the first nonsteroidal anti-inflammatory drug approved to treat patients with all genetic variants of DMD. It is a histone deacetylase (HDAC) inhibitor that works by targeting pathogenic processes to reduce inflammation and muscle wasting.

Duvyzat is a small molecule designed to block histone deacetylase (HDAC) enzymes that play a role in shutting down gene activity.

Blocking HDAC enzymes can turn on a gene that codes for a protein called follistatin. Follistatin helps build muscle mass by counteracting the effects of myostatin, a protein that causes scar tissue to form in muscles and prevents their growth and repair.

Treatment with Duvyzat is expected to alleviate muscle loss and inflammation in DMD, thus slowing the progression of the disease.

Who can use Duvyzat?

Duvyzat was approved by the FDA (United States Department of Health and Human Services, Bureau of Food, Dietary Supplements, Drugs, Biological Medical Products, Blood Products, Medical Devices, Radiating Devices, Veterinary Devices, and Cosmetics) in March 2024. It can be used to treat adults and children ages 6 and older with DMD. It is also expected to be approved in Europe, where the drug has been granted orphan drug status, for use as a treatment for Duchenne. [Source: FDA]

Who should not use Duvyzat?

According to the prescription information published by Duvyzat, there is no indication that it should not be used. It is only emphasized that treatment should not be started if the DMD patient has less than 150,000 platelets per microliter of blood. The main reason for this is that Duvyzat can cause thrombocytopenia or a decrease in the number of platelets in the blood. Platelets in the body help the blood to clot, and having too few platelets can increase the risk of bleeding or bruising.

In addition, patients at high risk of ventricular arrhythmias or irregular heartbeats should avoid treatment with Duvyzat.

How is Duvyzat administered?

Duvyzat is available as an oral suspension that should be taken orally twice a day with food. The dosage is determined by body weight; individuals weighing 10 kg to less than 20 kg (22 pounds to less than 44 pounds) should take the lowest dose of 22.2 mg (2.5 mL) twice daily. The maximum dosage for individuals weighing 60 kg (132 pounds) or more is 53.2 mg (6 mL) twice daily.

The oral suspension comes in a bottle with 140 mL of a white to off-white or slightly pink liquid with a peach flavor, and 8.86 mg/mL of suspension. Flip the bottle 180 degrees and shake the oral suspension for at least 30 seconds before using. It is necessary to measure the specified volume.

It might be necessary to lower the dosage if a patient:

has more than 300 mg of triglycerides (a type of fat) per deciliter of blood in two tests done one week apart while fasting, which should cause the levels of triglycerides to decrease. has less than 150,000 platelets per microliter of blood in two tests done one week apart. develops moderate or severe diarrhea.

Depending on the patient’s body weight, the dose may need to be further lowered if side effects continue after it has been adjusted. After the second adjustment, Duvyzat medication should be discontinued if side effects still occur.

Duvyzat in experimental studies

Based on the outcomes of a Phase 3 clinical research evaluating the safety and effectiveness of duvyzat in walking boys with DMD, the medication was approved.

DMD clinical trials

The therapy’s pharmacokinetics—or how it enters, moves through, and exits the body—as well as its safety and tolerability were initially evaluated in an open-label, two-part Phase 1/2 clinical trial (NCT01761292). Twenty young boys with DMD, aged 7 to 10, were included in the study, which also assessed Duvyzat’s effects on muscular tissue. Every boy who took part in the study was taking corticosteroids at a consistent dosage.

The boys’ muscle fibers had increased by a mean of 78% and occupied 29% more space within muscle tissue after taking Duvyzat for a year or longer. Less scar tissue and fat were also seen. Although Duvyzat was not shown to improve muscular function, the researchers pointed out that this might be because there was insufficient data from the study to make any firm conclusions. The only dose-limiting adverse effect of duvyzat was a decrease in platelet count, which was safe and well tolerated.

Next, in 179 walkable boys with DMD aged 6 to 17, a pivotal Phase 3 clinical trial named EPIDYS (NCT02851797) evaluated the safety and effectiveness of Duvyzat versus a placebo. For a minimum of six months, all boys were administered corticosteroids, such as Emflaza (deflazacort), at a consistent dosage. Depending on the weight of the child, the participants were randomized to receive either the placebo (10 mg/mL) or Duvyzat (10 mg/mL) twice daily for a duration of 18 months or 1.5 years.

When compared to baseline—the beginning of the clinical trial—duvyzat was demonstrated to slow the deterioration in muscular function. When boys were given Duvyzat instead of a placebo, it took them 1.78 seconds less on average to ascend four stairs. A faster time equals a better outcome in that four-stair climb test.

During a follow-up period of eighteen months, Duvyzat also prevented a drop in the North Star Ambulatory Assessment score, a motor function test where a higher score denotes better performance. those using Duvyzat scored 1.91 points better on average than those taking a placebo.

In addition, boys using Duvyzat did not develop as much muscle fat as boys in the placebo group did. For instance, in a thigh muscle, the percentage of fat tissue grew by 7.6% in males taking Duvyzat and 10.6% in those receiving a placebo, a 3% difference.

The most frequent adverse effects associated with Duvyzat were thrombocytopenia, diarrhea, abdominal pain, and elevated blood triglyceride levels. Ninety-five percent had mild to moderate adverse effects; three boys stopped taking Duvyzat because of one of these side effects.

Ongoing medical research

Boys were encouraged to continue in an ongoing extension research (NCT03373968) after completing the 18-month clinical trial. Every participant in this phase will keep receiving Duvyzat at the same starting dosage that they had during the EPIDYS clinical trial. A year or so will be spent tracking any side effects.

ULYSSES (NCT05933057), another Phase 3 clinical trial, will evaluate the treatment in boys who have lost their ability to walk. Up to 138 boys with DMD who are non-ambulatory and between the ages of 9 and 17 will be enrolled in ULYSSES. The trial is scheduled to last until 2028 and is anticipated to occur at several clinical locations across Europe and Canada.

Duvyzat will be compared against a placebo, same like in EPIDYS, and patients will be on a consistent corticosteroid dosage. A shift in the Performance of Upper Limb 2.0 total score, a test used to assess upper extremity function, is the main outcome measure in ULYSSES. Assessments will also be made of adverse effects, vital signs, and lung function.

BMD clinical trial

Additionally, more clinical trials for givinostat are planned in Becker, MD. 51 males with BMD participated in a Phase 2 clinical trial (NCT03238235), which was finished in 2021 and evaluated the safety, tolerability, and effectiveness of givinostat versus a placebo. The volunteers, who were between the ages of 18 and 65, could walk 200 to 450 meters in six minutes, or 219 to 492 yards. Everyone received givinostat or a placebo twice a day for a duration of 12 months, or one year, at random.

Givinostat stopped the accumulation of fat tissue in muscles, even if the clinical trial’s primary objective of lowering scarring after 12 months when compared with the placebo was not achieved. It also stopped muscular tissue from being lost.

Common adverse reactions to Duvyzat

Those with DMD who take Duvyzat most frequently experience the following negative effects:

• diarrhea
• abdominal pain
• thrombocytopenia, or reduced numbers of platelets in the blood
• nausea
• vomiting
• high levels of triglycerides in the blood
• fever.

Thrombocytopenia

Dosage-related myelosuppression, which happens when the bone marrow becomes less active and generates fewer blood cells, can be brought on by duvyzat. Anemia, neutropenia, and thrombocytopenia may ensue from this. Anemia is defined as having insufficient hemoglobin or red blood cells to supply oxygen to the body’s tissues, whereas neutropenia is defined as having insufficient neutrophils, or white blood cells.

For the first two months of treatment, blood counts should be examined every two weeks. After that, they should be checked monthly for the first three months and then every three months after that. Should thrombocytopenia arise, Duvyzat dosage adjustments or discontinuation of treatment may be necessary.

Excessive bleeding from cuts, easy bruising, blood in the urine or feces, and petechiae—small red or purple spots on the skin—are all signs of thrombocytopenia. It is important to get medical assistance if any of these symptoms are observed.

Triglycerides rising

Triglyceride levels in the blood can rise as a result of duvyzat, increasing the risk of heart disease and stroke. Triglyceride levels should be monitored at one, three, and six months into Duvyzat treatment, and then every six months after that. Triglycerides may need to be taken at a higher dose or cease treatment entirely if they rise above 300 mg per deciliter of blood.

Digestive issues

Duvyzat may result in diarrhea and vomiting. Patients should stay hydrated and record the frequency and intensity of their symptoms if they arise. If antidiarrheal or antiemetic (against vomiting and nausea) drugs are ineffective in treating these adverse effects, the dosage of Duvyzat may need to be changed, or treatment may need to be discontinued.

Cardiac issues

The corrected QT (QTc) interval, which is an electrocardiogram (ECG) measure of the heart’s electrical activity, can be prolonged by duvyzat. The cardiac muscle’s recovery time between contractions is represented by this measurement. An extended QTc interval raises the possibility that an irregular cardiac rhythm originating in the ventricles is the cause of the heart’s longer than usual recharging period.

Before beginning Duvyzat, patients with underlying cardiac illness or those taking drugs that can cause QT prolongation should have an ECG. Patients with congenital long QT syndrome, coronary artery disease, or electrolyte disturbance—which happens when the levels of specific minerals in the blood go too high or too low—should not receive treatment because they are at a greater risk of developing ventricular arrhythmias. It should also be avoided by anyone taking other drugs that are known to lengthen the QT interval.

Patients should alert their doctor if they faint, feel lightheaded, or lose consciousness. If the QTc interval is more than 500 milliseconds (ms) or the difference from baseline is more than 60 ms, Duvyzat treatment should be discontinued.

Use in pregnancy and breastfeeding

Males and boys are most typically affected with DMD. As a result, insufficient information exists to recommend the use of Duvyzat in expectant or nursing mothers. On the other hand, research on pregnant rats and rabbits revealed that Duvyzat therapy led to decreased fetal weight, an increased rate of stillbirths, and neurobehavioral abnormalities in the offspring. It is unknown if Duvyzat is safe for a breastfed child or if it enters breast milk.