Deflazacort

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Deflazacort
Deflazacort structure.svg
Clinical data
Trade names Emflaza, Calcort, others
AHFS/Drugs.com International Drug Names
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 Renal (70%) and fecal (30%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.034.969 Edit this at Wikidata
Chemical and physical data
Formula C25H31NO6
Molar mass 441.517 g/mol
3D model (JSmol)
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Deflazacort (trade name Emflaza or Calcort among others) is a glucocorticoid used as an anti-inflammatory and immunosuppressant.

Medical uses[edit]

The manufacturer lists the following uses for deflazacort:[1]

In the United States, deflazacort is also FDA-approved for the treatment of Duchenne muscular dystrophy in people over the age of 5.[2]

Adverse effects[edit]

Deflazacort carries the risks common to all corticosteroids, including immune suppression, decreased bone density, and endocrine insufficiency. In clinical trials, the most common side effects (>10% above placebo) were Cushing's-like appearance, weight gain, and increased appetite.[3]

Pharmacology[edit]

Mechanism of action[edit]

Deflazacort is an inactive prodrug which is metabolized rapidly to the active drug 21-desacetyldeflazacort.[4]

Relative potency[edit]

Deflazacort's potency is around 70–90% that of prednisone.[5] 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.[6]

History in the US[edit]

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.[7] Although deflazacort was approved by the FDA for use in treatment of Duchenne muscular dystrophy on February 9, 2017,[8][9] 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.[10] 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.[11]

Deflazacort is sold in the United States under the trade name Emflaza after a company called PTC Therapeutics, Inc. acquired all rights to Emflaza on March 16, 2017.[12] Deflazacort is sold in the United Kingdom under the trade name Calcort;[5] in Brazil as Cortax, Decortil, 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.[13]

The U.S. Food and Drug Administration approved Emflaza (deflazacort) tablets and oral suspension to treat patients age 5 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.[14] NDA 208684 was approved on February 9, 2017 as a Type 1- new molecular entity with orphan status.[15]

Clinical Trials[edit]

Preclinical data showed Deflazacort had acute toxicity with an oral lethal dose (LD50) greater than 5,200 mg/kg in a mouse. The bioavailability was found to be around 70% and was 40% protein bound.[16] Clinical trials of Deflazacort were conducted in the United States and Canada. The first study was a 52-week double blind clinical trial. The main outcome of the study was to show how effectively Deflazacort treated Duchenne Muscular Dystrophy (DMD). The study had 196 male patients diagnosed with the dystrophin gene. The population of males ranged from ages 5 to 15 years old. The treatment of the patients was randomized for the first 12 weeks with patients receiving the Deflazacort (0.9 or 1.2 mg/kg/day), an active ingredient similar to Deflazacort, or placebo. After 12 weeks the patients receiving the placebo were re-randomized to receive one of the other two treatments. The trial was continued for 40 more weeks and the results showed that Deflzazacort had a greater effect on the muscle compared to the other two groups.

Commercial Aspect[edit]

Post-translational control (PTC) Therapeutics was founded in South Plainfield, New Jersey in 1998 by Dr. Stuart Peltz.[17] On June 30, 2017, PTC Therapeutics, Inc. had $133,011 in cash and cash equivalents.[18] As of October 30, 2017 the total equity for PTC Therapeutics was 82.13.[19] For 2013, PTC Therapeutics had $4.8 million in collaboration revenue.[20] In 2017, PTC Therapeutics, Inc. was authorized in the European Union to have provisional marketing authorization of the lead product candidate Translarna.[21] Translarna is used to treat nonsense mutation of Duchenne muscular dystrophy. PTC Therapeutics, Inc. filed for an extension of the trademark PTC Therapeutics on December 17, 2015.[22] PTC Therapeutics has 16 other trade marks including Translarna, Aperluri, Ilumerna, EmflazaCares, Emflaza, Kynzetix, Aldondis, Eurpizd, Aperluri, Ilumerna, and PTC124.[23] In 2017, PTC Therapeutics was covered by Bank of America, Barclays, Citi, Cowen and Company, Credit Suisse, J.P. Morgan Securities, RBC, and William Blair.[24]

Society and Culture[edit]

Patents[edit]

Patent No. EP0322630 was submitted by Lepetit Spa and was granted on October 6, 1993 for the process of preparing Deflazacort and other compounds.[25] Patent No. N208684 was filed on February 9, 2017 for PTC Therapeutics, Inc. to use the oral tablet in 6, 18, 30, and 36 mg.[26]

References[edit]

  1. ^ "Refla: deflazacort" (PDF). 
  2. ^ Commissioner, Office of the. "Press Announcements - FDA approves drug to treat Duchenne muscular dystrophy". www.fda.gov. Retrieved 18 February 2017. 
  3. ^ "Info" (PDF). www.accessdata.fda.gov. 2017. 
  4. ^ Möllmann, H; Hochhaus, G; Rohatagi, S; Barth, J; Derendorf, H (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. 
  5. ^ a b "Calcort". electronic Medicines Compendium. June 11, 2008.  Retrieved on October 28, 2008.
  6. ^ Luca Parente (2017). "Deflazacort: therapeutic index, relative potency and equivalent doses versus other corticosteroids". BMC Pharmacol Toxicol. doi:10.1186/s40360-016-0111-8. PMC 5216559Freely accessible. 
  7. ^ Ellen Jean Hirst (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 
  8. ^ "FDA approves drug to treat Duchenne muscular dystrophy". www.fda.gov. 2017-02-09. Retrieved 2017-02-10. 
  9. ^ "Marathon Pharmaceuticals to Charge $89,000 for Muscular Dystrophy Drug". www.wsj.com. 2017-02-10. Retrieved 2017-02-10. 
  10. ^ Joseph Walker and Susan Pulliam (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 
  11. ^ Clifton Sy Mukherjee (February 10, 2017). "Brainstorm Health Daily". Retrieved February 13, 2017. 
  12. ^ "PTC Therapeutics Completes Acquisition of Emflaza™ for the Treatment of Duchenne Muscular Dystrophy in the U.S." PTC Therapeutics, Inc. 
  13. ^ "Substâncias: DEFLAZACORT" (in Portuguese). Centralx. 2008.  Retrieved on October 28, 2008.
  14. ^ Commissioner, Office of the. "Press Announcements - FDA approves drug to treat Duchenne muscular dystrophy". www.fda.gov. 
  15. ^ "Drugs@FDA: FDA Approved Drug Products". www.accessdata.fda.gov. 
  16. ^ "Data" (PDF). www.accessdata.fda.gov. 2017. 
  17. ^ "PTC Therapeutics - Our History". 
  18. ^ "View Filing Data". www.sec.gov. 
  19. ^ "PTC Therapeutics Inc". www.marketwatch.com. 
  20. ^ "{title}". Archived from the original on 2017-11-07. Retrieved 2017-10-31. 
  21. ^ "Regulatory Updates on Duchenne MD and CF Drug Translarna Provided by PTC". 3 August 2016. 
  22. ^ "Apply for a Trademark. Search a Trademark". trademarkia.com. 
  23. ^ "Apply for a Trademark. Search a Trademark". trademarkia.com. 
  24. ^ "Analyst Coverage - PTC Therapeutics, Inc". PTC Therapeutics, Inc. 
  25. ^ Pubchem. "PROCESS FOR THE PREPARATION OF PREGNENO-OXAZOLINES - Patent EP0322630 - PubChem". pubchem.ncbi.nlm.nih.gov. 
  26. ^ "Information" (PDF). www.fda.gov.