Deflazacort

Last updated
Deflazacort
Deflazacort structure.svg
Clinical data
Trade names Emflaza, Calcort, others
AHFS/Drugs.com Monograph
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 40%
Metabolism By plasma esterases, to active metabolite
Elimination half-life 1.1–1.9 hours (metabolite)
Excretion Kidney (70%) and fecal (30%)
Identifiers
  • (11β,16β)-21-(Acetyloxy)-11-hydroxy-2′-methyl-5′H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.034.969 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C25H31NO6
Molar mass 441.524 g·mol−1
3D model (JSmol)
  • O=C(OCC(=O)[C@]25/N=C(\O[C@@H]5C[C@H]1[C@H]4[C@H]([C@@H](O)C[C@@]12C)[C@]/3(/C=C\C(=O)\C=C\3CC4)C)C)C
  • InChI=1S/C25H31NO6/c1-13-26-25(20(30)12-31-14(2)27)21(32-13)10-18-17-6-5-15-9-16(28)7-8-23(15,3)22(17)19(29)11-24(18,25)4/h7-9,17-19,21-22,29H,5-6,10-12H2,1-4H3/t17-,18-,19-,21+,22+,23-,24-,25+/m0/s1 X mark.svgN
  • Key:FBHSPRKOSMHSIF-GRMWVWQJSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Deflazacort (trade name Calcort among others) is a glucocorticoid belonging to acetonides or O-isopropylidene derivative. [1] It is used as an anti-inflammatory and was patented in 1969 [1] and approved for medical use in 1985. [2] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication for Duchenne Muscular Dystrophy. [3]

Contents

Medical uses

The manufacturer lists the following uses for deflazacort: [4]

In the United States, deflazacort is approved for the treatment of duchenne muscular dystrophy in people over the age of two. [5]

Adverse effects

Deflazacort carries the risks common to all corticosteroids, including immune suppression, decreased bone density, steroid induced muscle atrophy, myopathy and endocrine insufficiency. In clinical trials, the most common side effects (>10% above placebo) were Cushing's-like appearance, weight gain, and increased appetite. [6]

Pharmacology

Mechanism of action

Deflazacort is an inactive prodrug which is metabolized rapidly to the active drug 21-desacetyldeflazacort. [7]

Relative potency

Deflazacort's potency is around 70–90% that of prednisone. [8] A 2017 review found its activity of 7.5 mg of deflazacort is approximately equivalent to 25 mg cortisone, 20 mg hydrocortisone, 5 mg of prednisolone or prednisone, 4 mg of methylprednisolone or triamcinolone, or 0.75 mg of betamethasone or dexamethasone. The review noted that the drug has a high therapeutic index, being used at initial oral doses ranging from 6 to 90 mg, and probably requires a 50% higher dose to induce the same demineralizing effect as prednisolone. Thus it has "a smaller impact on calcium metabolism than any other synthetic corticosteroid, and therefore shows a lower risk of growth rate retardation in children and of osteoporosis" in the elderly, and comparatively small effects on carbohydrate metabolism, sodium retention, and hypokalemia. [9]

History

Deflazacort was first introduced in 1969 to treat rheumatoid arthritis, nephritic syndrome, SLE, transplantation, polymyalgia rheumatica, sarcoidosis and juvenile chronic arthritis. [1]

In January 2015, the FDA granted fast track status to Marathon Pharmaceuticals to pursue approval of deflazacort as a potential treatment for Duchenne muscular dystrophy, a rare, "progressive and fatal disease" that affects boys. [10] Although deflazacort was approved by the FDA for use in treatment of Duchenne muscular dystrophy on February 9, 2017, [11] [12] Marathon CEO announced on February 13, 2017, that the launch of deflazacort (Emflaza) would be delayed amidst controversy over the steep price Marathon was asking for the drug in the United States - $89,000 per year, which is "roughly 70 times" more than it would cost overseas. [13] Because deflazacort is an older drug which has been long-approved in some other countries, it is now available in many places as an inexpensive generic. For example, in Canada deflazacort can be purchased for around $1 per tablet. [14]

Deflazacort is sold in the United States under the brand name Emflaza after PTC Therapeutics, Inc. acquired all rights to Emflaza on March 16, 2017. [15] Deflazacort is sold in the United Kingdom under the trade name Calcort; [8] in Brazil as Cortax, Decortil, Defcort and Deflanil; in India as Moaid, Zenflav, Defolet, DFZ, Decotaz, and DefZot; in Bangladesh as Xalcort; in Panama as Zamen; Spain as Zamene; and in Honduras as Flezacor. [16]

The U.S. Food and Drug Administration approved deflazacort to treat people age five years and older with Duchenne muscular dystrophy (DMD), a rare genetic disorder that causes progressive muscle deterioration and weakness. Emflaza is a corticosteroid that works by decreasing inflammation and reducing the activity of the immune system. [5] NDA 208684 was approved on February 9, 2017, as a Type 1- new molecular entity with orphan status. [17]

Related Research Articles

<span class="mw-page-title-main">Giant cell arteritis</span> Medical condition

Giant cell arteritis (GCA), also called temporal arteritis, is an inflammatory autoimmune disease of large blood vessels. Symptoms may include headache, pain over the temples, flu-like symptoms, double vision, and difficulty opening the mouth. Complications can include blockage of the artery to the eye with resulting blindness, as well as aortic dissection, and aortic aneurysm. GCA is frequently associated with polymyalgia rheumatica. It can be confirmed by biopsy of the temporal artery in about 90% of people.

<span class="mw-page-title-main">Prednisone</span> Steroid medication

Prednisone is a glucocorticoid medication mostly used to suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium due to cancer and adrenal insufficiency along with other steroids. It is taken by mouth.

<span class="mw-page-title-main">Duchenne muscular dystrophy</span> Type of muscular dystrophy

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.

Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.

<span class="mw-page-title-main">Polymyalgia rheumatica</span> Medical condition

Polymyalgia rheumatica (PMR) is a syndrome experienced as pain or stiffness, usually in the neck, shoulders, upper arms, and hips, but which may occur all over the body. The pain can be sudden or can occur gradually over a period. Most people with PMR wake up in the morning with pain in their muscles; however, cases have occurred in which the person has developed the pain during the evenings or has pain and stiffness all day long.

<span class="mw-page-title-main">Methylprednisolone</span> Corticosteroid medication

Methylprednisolone is a synthetic glucocorticoid, primarily prescribed for its anti-inflammatory and immunosuppressive effects. It is either used at low doses for chronic illnesses or used concomitantly at high doses during acute flares. Methylprednisolone and its derivatives can be administered orally or parenterally.

<span class="mw-page-title-main">Ataluren</span> Duchenne muscular dystrophy medication

Ataluren, sold under the brand name Translarna, is a medication for the treatment of Duchenne muscular dystrophy. It was designed by PTC Therapeutics.

<span class="mw-page-title-main">PTC Therapeutics</span> Pharmaceutical company

PTC Therapeutics is a US pharmaceutical company focused on the development of orally administered small molecule drugs and gene therapy which regulate gene expression by targeting post-transcriptional control (PTC) mechanisms in orphan diseases.

Givinostat, sold under the brand name Duvyzat is a medication used for the treatment of Duchenne muscular dystrophy. It is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities. It is a histone deacetylase (HDAC) inhibitor that works by targeting pathogenic processes to reduce inflammation and loss of muscle.

<span class="mw-page-title-main">Eteplirsen</span> Medication

Eteplirsen is a medication to treat, but not cure, some types of Duchenne muscular dystrophy (DMD), caused by a specific mutation. Eteplirsen only targets specific mutations and can be used to treat about 14% of DMD cases. Eteplirsen is a form of antisense therapy.

<span class="mw-page-title-main">Marathon Pharmaceuticals</span> Former U.S. rare disease drug company

Marathon Pharmaceuticals LLC was a privately held biopharmaceuticals company focused on drugs for people with rare diseases. The Illinois-based company developed and manufactured therapeutics and brought them to market. It employed 100 people in four global locations. In 2017, PTC Therapeutics acquired rights to Marathon Pharmaceuticals' drug Emflaza (deflazacort) for $140 million after criticism about their plan to sell the drug at a list price of $89,000 per year to sufferers despite the fact that the same drug was available in Canada and the UK for around $1,000 per year.

<span class="mw-page-title-main">Ezutromid</span> Chemical compound

Ezutromid is an orally administered small molecule utrophin modulator involved in a Phase 2 clinical trial produced by Summit Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). DMD is a fatal x-linked recessive disease affecting approximately 1 in 5000 males and is a designated orphan disease by the FDA and European Medicines Agency. Approximately 1/3 of the children obtain DMD as a result of spontaneous mutation in the dystrophin gene and have no family history of the disease. Dystrophin is a vital component of mature muscle function, and therefore DMD patients have multifarious forms of defunct or deficient dystrophin proteins that all manifest symptomatically as muscle necrosis and eventually organ failure. Ezutromid is theorized to maintain utrophin, a protein functionally and structurally similar to dystrophin that precedes and is replaced by dystrophin during development. Utrophin and dystrophin are reciprocally expressed, and are found in different locations in a mature muscle cell. However, in dystrophin-deficient patients, utrophin was found to be upregulated and is theorized to replace dystrophin in order to maintain muscle fibers. Ezutromid is projected to have the potential to treat all patients suffering with DMD as it maintains the production of utrophin to counteract the lack of dystrophin to retard muscle degeneration. Both the FDA and European Medicines Agency has given ezutromid an orphan drug designation. The FDA Office of Orphan Products and Development offers an Orphan Drug Designation program (ODD) that allows drugs aimed to treat diseases that affect less than 200,000 people in the U.S. monetary incentives such as a period of market exclusivity, tax incentives, and expedited approval processes.

<span class="mw-page-title-main">Vamorolone</span> Chemical compound

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.

Golodirsen, sold under the brand name Vyondys 53, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). It is an antisense oligonucleotide drug of phosphorodiamidate morpholino oligomer (PMO) chemistry.

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.

<span class="mw-page-title-main">Cure Rare Disease</span>

Cure Rare Disease is a non-profit biotechnology company based in Boston, Massachusetts that is working to create novel therapeutics using gene therapy, gene editing and antisense oligonucleotides to treat people impacted by rare and ultra-rare genetic neuromuscular conditions.

<span class="mw-page-title-main">Ultragenyx</span> American biopharmaceutical company

Ultragenyx is an American biopharmaceutical company involved in the research and development of novel products for treatment of rare and ultra-rare genetic diseases for which there are typically no approved treatments and high unmet medical need. The company works with multiple drug modalities including biologics, small molecule, gene therapies, and ASO and mRNAs in the disease categories of bone, endocrine, metabolic, muscle and CNS diseases.

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.

Delandistrogene moxeparvovec, sold under the brand name Elevidys, is a recombinant gene therapy used for the treatment of Duchenne muscular dystrophy. It is designed to deliver into the body a gene that leads to production of Elevidys micro-dystrophin that contains selected domains of the dystrophin protein present in normal muscle cells. It is an adeno-associated virus vector-based gene therapy that is given by injection into a vein.

References

  1. 1 2 3 Nayak, Surajit; Acharjya, Basanti (December 19, 2008). "Deflazacort versus other glucocorticoids: A comparison". Indian Journal of Dermatology. 53 (4): 167–170. doi: 10.4103/0019-5154.44786 . PMC   2763756 . PMID   19882026.
  2. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 486. ISBN   9783527607495.
  3. ↑ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Retrieved 16 September 2020.
  4. ↑ "Refla: deflazacort" (PDF).
  5. 1 2 "FDA approves drug to treat Duchenne muscular dystrophy". U.S. Food and Drug Administration (Press release). Retrieved 18 February 2017.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  6. ↑ "Emflaza- deflazacort tablet Emflaza- deflazacort suspension". DailyMed. 29 January 2020. Retrieved 17 September 2020.
  7. ↑ Möllmann H, Hochhaus G, Rohatagi S, Barth J, Derendorf H (July 1995). "Pharmacokinetic/pharmacodynamic evaluation of deflazacort in comparison to methylprednisolone and prednisolone". Pharmaceutical Research. 12 (7): 1096–100. doi:10.1023/a:1016287104656. PMID   7494809. S2CID   9920545.
  8. 1 2 "Calcort". electronic Medicines Compendium. June 11, 2008. Archived from the original on December 24, 2012. Retrieved on October 28, 2008.
  9. ↑ Parente L (January 2017). "Deflazacort: therapeutic index, relative potency and equivalent doses versus other corticosteroids". BMC Pharmacology & Toxicology. 18 (1): 1. doi: 10.1186/s40360-016-0111-8 . PMC   5216559 . PMID   28057083.
  10. ↑ Hirst EJ (January 19, 2015), Duchenne muscular dystrophy drug could get OK for U.S. sales in 2016, The Chicago Tribune, retrieved February 13, 2017, has been shown to prolong lives ... a progressive and fatal disease that has no drug treatment available in the US
  11. ↑ "FDA approves drug to treat Duchenne muscular dystrophy". www.fda.gov. 2017-02-09. Retrieved 2017-02-10.
  12. ↑ "Marathon Pharmaceuticals to Charge $89,000 for Muscular Dystrophy Drug". www.wsj.com. 2017-02-10. Archived from the original on 2017-02-10. Retrieved 2017-02-10.
  13. ↑ Walker J, Pulliam S (February 13, 2017), Marathon Pharmaceuticals to Charge $89,000 for Muscular Dystrophy Drug After 70-Fold Increase, The Wall Street Journal, retrieved February 13, 2017, FDA-approved deflazacort treats rare type of disease affecting boys
  14. ↑ Mukherjee CS (February 10, 2017). "Brainstorm Health Daily" . Retrieved February 13, 2017.
  15. ↑ "PTC Therapeutics Completes Acquisition of Emflaza for the Treatment of Duchenne Muscular Dystrophy in the U.S." PTC Therapeutics, Inc.
  16. ↑ "Substâncias: DEFLAZACORT" (in Portuguese). Centralx. 2008. Retrieved on October 28, 2008.
  17. ↑ "Drugs@FDA: FDA Approved Drug Products". U.S. Food and Drug Administration (FDA).
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