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Trade names | Duvyzat |
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Routes of administration | By mouth |
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ECHA InfoCard | 100.258.524 |
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Formula | C24H27N3O4 |
Molar mass | 421.497 g·mol−1 |
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Givinostat, sold under the brand name Duvyzat is a medication used for the treatment of Duchenne muscular dystrophy. [1] [2] It is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities. [3] It is a histone deacetylase (HDAC) inhibitor that works by targeting pathogenic processes to reduce inflammation and loss of muscle. [2]
The most common side effects include diarrhea, abdominal pain, a decrease in platelets—which can lead to increased bleeding—nausea/vomiting, an increase in triglycerides (a type of fat in the body) and fever. [2]
Givinostat was approved for medical use in the United States in March 2024. [2] Givinostat is the first nonsteroidal medication approved by the FDA to treat people with all genetic variants of Duchenne Muscular Dystrophy. [2]
Givinostat is indicated for the treatment of Duchenne muscular dystrophy in people six years of age and older. [1] [2]
In clinical trials of givinostat as a salvage therapy for advanced Hodgkin's lymphoma, the most common adverse reactions were fatigue (seen in 50% of participants), mild diarrhea or abdominal pain (40% of participants), moderate thrombocytopenia (decreased platelet counts, seen in one third of patients), and mild leukopenia (a decrease in white blood cell levels, seen in 30% of patients). One-fifth of patients experienced prolongation of the QT interval, a measure of electrical conduction in the heart, severe enough to warrant temporary suspension of treatment. [4]
Givinostat inhibits class I and class II histone deacetylases (HDACs) and several pro-inflammatory cytokines. This reduces expression of tumour necrosis factor (TNF), interleukin 1α and β, and interleukin 6. [5]
It also has activity against cells expressing JAK2(V617F), a mutated form of the janus kinase 2 (JAK2) enzyme that is implicated in the pathophysiology of many myeloproliferative diseases, including polycythaemia vera. [6] [7] In patients with polycythaemia, the reduction of mutant JAK2 concentrations by givinostat is believed to slow down the abnormal growth of erythrocytes and ameliorate the symptoms of the disease. [8]
Givinostat is in numerous phase II clinical trials (including for relapsed leukemias and myelomas), [9] and has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis, [10] polycythaemia vera. [8] and Duchenne muscular dystrophy.
A preclinical study produced early results suggesting the molecule might help with diastolic dysfunction. [11]
ITF2357 was discovered at Italfarmaco of Milan, Italy. It was patented in 1997 and first described in the scientific literature in 2005. [12] [5]
The efficacy of givinostat for the treatment of Duchenne muscular dystrophy was evaluated in a randomized, double-blind, placebo-controlled 18-month phase III study. [2] The primary endpoint was the change from baseline to month 18 using a four stair climb to measure muscle function. [2] All participants continued to receive a standard of care steroid regimen throughout the study and, after 18 months of treatment, participants treated with givinostat showed statistically significant less decline in the time it took to climb four stairs compared to placebo. [2] The mean change from baseline to month 18 in time to climb four stairs was 1.25 seconds for participants receiving givinostat compared to 3.03 seconds for participants receiving placebo. [2] A secondary efficacy endpoint was the change from baseline to month 18 in physical function as assessed by the North Star Ambulatory Assessment (NSAA)—a scale commonly used to rate the motor function in boys with Duchenne muscular dystrophy who are capable of walking. [2] Compared to placebo, participants treated with givinostat saw less worsening in their NSAA score after 18 months. [2] The US Food and Drug Administration (FDA) granted the application for givinostat priority review, fast track, orphan drug, and rare pediatric disease designations. [2] The FDA granted the approval of Duvyzat to Italfarmaco S.p.A. [2]
Givinostat is the international nonproprietary name. [13]
In oncology, polycythemia vera (PV) is an uncommon myeloproliferative neoplasm in which the bone marrow makes too many red blood cells. The majority of cases are caused by mutations in the JAK2 gene, most commonly resulting in a single amino acid change in its protein product from valine to phenylalanine at position 617.
Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy predominantly affecting boys. The onset of muscle weakness typically begins around age four, with rapid progression. Initially, muscle loss occurs in the thighs and pelvis, extending to the arms, which can lead to difficulties in standing up. By the age of 12, most individuals with Duchenne muscular dystrophy are unable to walk. Affected muscles may appear larger due to an increase in fat content, and scoliosis is common. Some individuals may experience intellectual disability, and females carrying a single copy of the mutated gene may show mild symptoms.
Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. Myelo refers to the bone marrow, proliferative describes the rapid growth of blood cells and neoplasm describes that growth as abnormal and uncontrolled.
Deflazacort is a glucocorticoid belonging to acetonides or O-isopropylidene derivative. It is used as an anti-inflammatory and was patented in 1969 and approved for medical use in 1985. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication for Duchenne Muscular Dystrophy.
Vorinostat (rINN), also known as suberoylanilide hydroxamic acid, is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities.
Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, a severe form of arthritis in children, and COVID‑19. It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.
Histone deacetylase inhibitors are chemical compounds that inhibit histone deacetylases. Since deacetylation of histones produces transcriptionally silenced heterochromatin, HDIs can render chromatin more transcriptionally active and induce epigenomic changes.
Lestaurtinib is a tyrosine kinase inhibitor structurally related to staurosporine. This semisynthetic derivative of the indolocarbazole K252a was investigated by Cephalon as a treatment for various types of cancer. It is an inhibitor of the kinases fms-like tyrosine kinase 3 (FLT3), Janus kinase 2 (JAK2), tropomyosin receptor kinase (trk) A (TrkA), TrkB and TrkC.
Panobinostat, sold under the brand name Farydak, is a medication used for the treatment of multiple myeloma. It is a hydroxamic acid and acts as a non-selective histone deacetylase inhibitor.
Romidepsin, sold under the brand name Istodax, is an anticancer agent used in cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs). Romidepsin is a natural product obtained from the bacterium Chromobacterium violaceum, and works by blocking enzymes known as histone deacetylases, thus inducing apoptosis. It is sometimes referred to as depsipeptide, after the class of molecules to which it belongs. Romidepsin is branded and owned by Gloucester Pharmaceuticals, a part of Celgene.
A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes, thereby interfering with the JAK-STAT signaling pathway in lymphocytes.
Ruxolitinib, sold under the brand name Jakafi among others, is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the bone marrow; polycythemia vera, when there has been an inadequate response to or intolerance of hydroxyurea; and steroid-refractory acute graft-versus-host disease. Ruxolitinib is a Janus kinase inhibitor. It was developed and marketed by Incyte Corp in the US under the brand name Jakafi, and by Novartis elsewhere in the world, under the brand name Jakavi.
Fedratinib, sold under the brand name Inrebic, is an anti-cancer medication used to treat myeloproliferative diseases including myelofibrosis. It is used in the form of fedratinib hydrochloride capsules that are taken by mouth. It is a semi-selective inhibitor of Janus kinase 2 (JAK-2). It was approved by the FDA on 16 August 2019.
Baricitinib, sold under the brand name Olumiant among others, is an immunomodulatory medication used for the treatment of rheumatoid arthritis, alopecia areata, and COVID-19. It acts as an inhibitor of janus kinase (JAK), blocking the subtypes JAK1 and JAK2.
Pracinostat (SB939) is an orally bioavailable, small-molecule histone deacetylase (HDAC) inhibitor based on hydroxamic acid with potential anti-tumor activity characterized by favorable physicochemical, pharmaceutical, and pharmacokinetic properties.
Resminostat is an orally bioavailable inhibitor of histone deacetylases (HDACs), of which inhibitors are antineoplastic agents.
Rimeporide is an experimental drug for the treatment of Duchenne muscular dystrophy, being developed by the EspeRare foundation. it has been granted orphan drug status by the European Medicines Agency.
Vamorolone, sold under the brand name Agamree, is a synthetic corticosteroid, which is used for the treatment of Duchenne muscular dystrophy. It is taken by mouth. It is a dual atypical glucocorticoid and antimineralocorticoid.
Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen is a Morpholino antisense oligonucleotide.
Casimersen, sold under the brand name Amondys 45, is an antisense oligonucleotide medication used for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping. It is an antisense oligonucleotide of phosphorodiamidate morpholino oligomer (PMO). Duchenne muscular dystrophy is a rare disease that primarily affects boys. It is caused by low levels of a muscle protein called dystrophin. The lack of dystrophin causes progressive muscle weakness and premature death.