Difference between revisions of "Ixazomib (Ninlaro)"

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(FDA approval)
m (Text replacement - "please refer to your preferred pharmacopeias such as [http://www.thomsonhc.com/home/dispatch Micromedex], [https://online.lexi.com/lco/action/login UpToDate Lexidrug], [http://www.utdol.com/online/content/search.do UpToDate (courtesy of Lexicomp)], or the prescribing information" to "please refer to your preferred pharmacopeias or the prescribing information")
 
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==General information==
 
==General information==
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Class/mechanism: Second-generation reversible proteasome inhibitor; preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.  Ixazomib interferes with degradation of ubiquitinated proteins, which disrupts normal homeostatic mechansims, leading to cell death.  The tissue distribution profile of ixazomib may be different than [[Bortezomib (Velcade)]] due to a shorter 20S proteasome dissociation half-life.  Upon exposure to aqueous solutions, ixazomib/MLN9708 hydrolyzes to MLN2238, the active form.<ref name=insert>[http://www.ninlarohcp.com/downloads/Prescribing-Information.pdf Ixazomib (Ninlaro) package insert]</ref><ref>[[Media:Ixazomib.pdf|Ixazomib (Ninlaro) package insert (locally hosted backup)]]</ref><ref>[http://www.ninlarohcp.com/ Ninlaro manufacturer's website]</ref><ref>Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, Yu J, Yang Y, Hales P, Bruzzese F, Liu J, Blank J, Garcia K, Tsu C, Dick L, Fleming P, Yu L, Manfredi M, Rolfe M, Bolen J. [http://cancerres.aacrjournals.org/content/70/5/1970.long Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer]. Cancer Res. 2010 Mar 1;70(5):1970-80. Epub 2010 Feb 16. [http://www.ncbi.nlm.nih.gov/pubmed/20160034 PubMed]</ref><ref>Siegfried Janz, Brian G Van Ness, Vishala Neppalli, Ray Liu, Michael D Pickard, Jennifer Terkelsen, Daniel Bradley, Ling Hu, Erik Kupperman, Mark Manfredi, and Edmund Lee. [http://ash.confex.com/ash/2009/webprogram/Paper17365.html The Novel Proteasome Inhibitor MLN9708 Demonstrates Efficacy in a Genetically-Engineered Mouse Model of De Novo Plasma Cell Malignancy]. 2009 ASH Annual Meeting oral poster/abstract 3849.</ref><ref>Aisha Masood, MD, Kasyapa Chitta, PhD, Kiersten M Miles, PhD, Nazmul H Khan, PhD, Remi Adelaiye, Drusilla Akhtar, Taimur Sher, MD, and Asher A. Chanan-Khan, MD. [http://ash.confex.com/ash/2010/webprogram/Paper34596.html An Investigational Proteasome Inhibitor MLN9708 (MLN2238) Induces Apoptosis In Human Multiple Myeloma Cells In Vitro]. 2010 ASH Annual Meeting oral poster/abstract 3066.</ref><ref>Paul G. Richardson, MD, Rachid Baz, MD, Luhua Wang, MD, Andrzej J Jakubowiak, MD, PhD, Deborah Berg, RN, MSN, Guohui Liu, PhD, Neeraj Gupta, PhD, Alessandra Di Bacco, PhD, Ai-Min Hui, MD, and Sagar Lonial, MD. [http://ash.confex.com/ash/2011/webprogram/Paper37860.html Investigational Agent MLN9708, An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (MM): Results From the Expansion Cohorts of a Phase 1 Dose-Escalation Study]. 2011 ASH Annual Meeting oral poster/abstract 301.</ref>
+
Class/mechanism: Second-generation reversible proteasome inhibitor; preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.  Ixazomib interferes with degradation of ubiquitinated proteins, which disrupts normal homeostatic mechansims, leading to cell death.  The tissue distribution profile of ixazomib may be different than [[Bortezomib (Velcade)]] due to a shorter 20S proteasome dissociation half-life.  Upon exposure to aqueous solutions, ixazomib/MLN9708 hydrolyzes to MLN2238, the active form.<ref name=insert>[http://www.ninlarohcp.com/downloads/Prescribing-Information.pdf Ixazomib (Ninlaro) package insert]</ref><ref>[[:File:Ixazomib.pdf|Ixazomib (Ninlaro) package insert (locally hosted backup)]]</ref><ref>[http://www.ninlarohcp.com/ Ninlaro manufacturer's website]</ref><ref>Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, Yu J, Yang Y, Hales P, Bruzzese F, Liu J, Blank J, Garcia K, Tsu C, Dick L, Fleming P, Yu L, Manfredi M, Rolfe M, Bolen J. [http://cancerres.aacrjournals.org/content/70/5/1970.long Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer]. Cancer Res. 2010 Mar 1;70(5):1970-80. Epub 2010 Feb 16. [https://pubmed.ncbi.nlm.nih.gov/20160034/ PubMed]</ref><ref>Siegfried Janz, Brian G Van Ness, Vishala Neppalli, Ray Liu, Michael D Pickard, Jennifer Terkelsen, Daniel Bradley, Ling Hu, Erik Kupperman, Mark Manfredi, and Edmund Lee. [http://ash.confex.com/ash/2009/webprogram/Paper17365.html The Novel Proteasome Inhibitor MLN9708 Demonstrates Efficacy in a Genetically-Engineered Mouse Model of De Novo Plasma Cell Malignancy]. 2009 ASH Annual Meeting oral poster 3849.</ref><ref>Aisha Masood, MD, Kasyapa Chitta, PhD, Kiersten M Miles, PhD, Nazmul H Khan, PhD, Remi Adelaiye, Drusilla Akhtar, Taimur Sher, MD, and Asher A. Chanan-Khan, MD. [http://ash.confex.com/ash/2010/webprogram/Paper34596.html An Investigational Proteasome Inhibitor MLN9708 (MLN2238) Induces Apoptosis In Human Multiple Myeloma Cells In Vitro]. 2010 ASH Annual Meeting oral poster 3066.</ref><ref>Paul G. Richardson, MD, Rachid Baz, MD, Luhua Wang, MD, Andrzej J Jakubowiak, MD, PhD, Deborah Berg, RN, MSN, Guohui Liu, PhD, Neeraj Gupta, PhD, Alessandra Di Bacco, PhD, Ai-Min Hui, MD, and Sagar Lonial, MD. [http://ash.confex.com/ash/2011/webprogram/Paper37860.html Investigational Agent MLN9708, An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (MM): Results From the Expansion Cohorts of a Phase 1 Dose-Escalation Study]. 2011 ASH Annual Meeting oral poster 301.</ref><ref>[http://www.takeda.com/news/2015/20151106_7181.html Takeda to Present Data from Ixazomib's <nowiki>[TOUR­MA­LINE MM-1] Phase 3 Study in Relapsed/Refractory Multiple Myeloma at Upcoming [2015]</nowiki> American Society of Hematology Annual Meeting]</ref>
 
<br>Route: PO
 
<br>Route: PO
 
<br>Extravasation: n/a
 
<br>Extravasation: n/a
  
−
For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias such as [http://www.thomsonhc.com/home/dispatch Micromedex], [http://online.lexi.com/ Lexicomp], [http://www.utdol.com/online/content/search.do UpToDate (courtesy of Lexicomp)], or the prescribing information.<ref name="insert"></ref>
+
For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias or the prescribing information.<ref name="insert"></ref>
  
 
==Diseases for which it is used==
 
==Diseases for which it is used==
 +
*[[Light-chain (AL) amyloidosis]]
 
*[[Multiple myeloma]]
 
*[[Multiple myeloma]]
−
 
+
*[[Waldenström macroglobulinemia]]
−
==Preliminary data==
 
−
===[[Multiple myeloma]]===
 
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# Kumar SK, Bensinger WI, Zimmerman TM, Reeder CB, Berenson JR, Berg D, Hui AM, Gupta N, Di Bacco A, Yu J, Shou Y, Niesvizky R. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014 Aug 14;124(7):1047-55. Epub 2014 Jun 5. [http://www.bloodjournal.org/content/124/7/1047.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/24904120 PubMed]
 
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# Richardson PG, Baz R, Wang M, Jakubowiak AJ, Laubach JP, Harvey RD, Talpaz M, Berg D, Liu G, Yu J, Gupta N, Di Bacco A, Hui AM, Lonial S. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014 Aug 14;124(7):1038-46. Epub 2014 Jun 11. [http://www.bloodjournal.org/content/124/7/1038.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/24920586 PubMed]
 
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# Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-12. Epub 2014 Nov 14. [http://www.ncbi.nlm.nih.gov/pubmed/25456369 PubMed]
 
−
 
 
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==Clinical trials==
 
−
*[http://clinicaltrials.gov/ct2/show/NCT01217957 A Study of MLN9708 Administered in Combination With Lenalidomide and Low-Dose Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma]
 
−
*[http://clinicaltrials.gov/ct2/show/NCT01454076 Phase 1 Study of Oral MLN9708 in Patients With Advanced Nonhematologic Malignancies or Lymphoma]
 
−
*[http://clinicaltrials.gov/ct2/show/NCT01415882 Proteasome Inhibitor MLN9708 in Treating Patients With Relapsed Multiple Myeloma That Is Not Refractory to Bortezomib]
 
−
*[http://clinicaltrials.gov/ct2/show/NCT00893464 A Study of MLN9708 in Adult Patients With Lymphoma]
 
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*[http://clinicaltrials.gov/ct2/show/NCT01318902 Study of Oral MLN9708 in Adult Patients With Relapsed or Refractory Light Chain Amyloidosis]
 
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*[http://clinicaltrials.gov/ct2/show/NCT00963820 Study Evaluating the Safety and Tolerability of Weekly Dosing of Oral MLN9708 in Adult Patients With Relapsed and Refractory Multiple Myeloma]
 
  
 
==Patient drug information==
 
==Patient drug information==
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==History of changes in FDA indication==
 
==History of changes in FDA indication==
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*11/20/2015: [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm473804.htm FDA approved] "in combination with [[Lenalidomide (Revlimid)|lenalidomide]] and [[Dexamethasone (Decadron)|dexamethasone]] for the treatment of patients with [[multiple myeloma]] who have received at least one prior therapy.<ref name="insert"></ref>
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*2015-11-20: [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm473804.htm FDA approved] in combination with [[Lenalidomide (Revlimid)|lenalidomide]] and [[Dexamethasone (Decadron)|dexamethasone]] for the treatment of patients with [[multiple myeloma]] who have received at least one prior therapy. ''(Based on TOURMALINE-MM1)''
 +
==History of changes in EMA indication==
 +
*2016-11-21: Initial conditional approval
 +
==History of changes in Health Canada indication==
 +
*2016-08-04: Initial notice of compliance
 +
==History of changes in PMDA indication==
 +
*2017-03-30: Initial approval for the treatment of relapsed or refractory [[multiple myeloma]].
 +
*2020-03-25: New indication and a new dosage for the maintenance treatment of [[multiple myeloma]] in patients after autologous hematopoietic stem-cell transplantation.
 +
*2021-05-27: New indication for the maintenance therapy of [[multiple myeloma]].
  
 
==Also known as==
 
==Also known as==
−
MLN2238, MLN9708
+
*'''Code names:''' MLN-2238, MLN-9708
 +
*'''Brand name:''' Ninlaro
  
 
==References==
 
==References==
 
<references/>
 
<references/>
  
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[[Category:Drug index]]
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[[Category:Drugs]]
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[[Category:Chemotherapy]]
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[[Category:Oral medications]]
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[[Category:Oral chemotherapy]]
 
  
 
[[Category:Proteasome inhibitors]]
 
[[Category:Proteasome inhibitors]]
  
 +
[[Category:Light-chain (AL) amyloidosis medications]]
 
[[Category:Multiple myeloma medications]]
 
[[Category:Multiple myeloma medications]]
 +
[[Category:Waldenström macroglobulinemia medications]]
  
−
[[Category:Drugs FDA approved in 2015]]
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[[Category:FDA approved in 2015]]
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[[Category:EMA approved in 2016]]
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[[Category:Health Canada approved in 2016]]
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[[Category:PMDA approved in 2017]]

Latest revision as of 01:00, 29 June 2024

General information

Class/mechanism: Second-generation reversible proteasome inhibitor; preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome. Ixazomib interferes with degradation of ubiquitinated proteins, which disrupts normal homeostatic mechansims, leading to cell death. The tissue distribution profile of ixazomib may be different than Bortezomib (Velcade) due to a shorter 20S proteasome dissociation half-life. Upon exposure to aqueous solutions, ixazomib/MLN9708 hydrolyzes to MLN2238, the active form.[1][2][3][4][5][6][7][8]
Route: PO
Extravasation: n/a

For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias or the prescribing information.[1]

Diseases for which it is used

Patient drug information

History of changes in FDA indication

History of changes in EMA indication

  • 2016-11-21: Initial conditional approval

History of changes in Health Canada indication

  • 2016-08-04: Initial notice of compliance

History of changes in PMDA indication

  • 2017-03-30: Initial approval for the treatment of relapsed or refractory multiple myeloma.
  • 2020-03-25: New indication and a new dosage for the maintenance treatment of multiple myeloma in patients after autologous hematopoietic stem-cell transplantation.
  • 2021-05-27: New indication for the maintenance therapy of multiple myeloma.

Also known as

  • Code names: MLN-2238, MLN-9708
  • Brand name: Ninlaro

References

  1. ↑ 1.0 1.1 1.2 Ixazomib (Ninlaro) package insert
  2. ↑ Ixazomib (Ninlaro) package insert (locally hosted backup)
  3. ↑ Ninlaro manufacturer's website
  4. ↑ Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, Yu J, Yang Y, Hales P, Bruzzese F, Liu J, Blank J, Garcia K, Tsu C, Dick L, Fleming P, Yu L, Manfredi M, Rolfe M, Bolen J. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 2010 Mar 1;70(5):1970-80. Epub 2010 Feb 16. PubMed
  5. ↑ Siegfried Janz, Brian G Van Ness, Vishala Neppalli, Ray Liu, Michael D Pickard, Jennifer Terkelsen, Daniel Bradley, Ling Hu, Erik Kupperman, Mark Manfredi, and Edmund Lee. The Novel Proteasome Inhibitor MLN9708 Demonstrates Efficacy in a Genetically-Engineered Mouse Model of De Novo Plasma Cell Malignancy. 2009 ASH Annual Meeting oral poster 3849.
  6. ↑ Aisha Masood, MD, Kasyapa Chitta, PhD, Kiersten M Miles, PhD, Nazmul H Khan, PhD, Remi Adelaiye, Drusilla Akhtar, Taimur Sher, MD, and Asher A. Chanan-Khan, MD. An Investigational Proteasome Inhibitor MLN9708 (MLN2238) Induces Apoptosis In Human Multiple Myeloma Cells In Vitro. 2010 ASH Annual Meeting oral poster 3066.
  7. ↑ Paul G. Richardson, MD, Rachid Baz, MD, Luhua Wang, MD, Andrzej J Jakubowiak, MD, PhD, Deborah Berg, RN, MSN, Guohui Liu, PhD, Neeraj Gupta, PhD, Alessandra Di Bacco, PhD, Ai-Min Hui, MD, and Sagar Lonial, MD. Investigational Agent MLN9708, An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (MM): Results From the Expansion Cohorts of a Phase 1 Dose-Escalation Study. 2011 ASH Annual Meeting oral poster 301.
  8. ↑ Takeda to Present Data from Ixazomib's [TOUR­MA­LINE MM-1] Phase 3 Study in Relapsed/Refractory Multiple Myeloma at Upcoming [2015] American Society of Hematology Annual Meeting
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