Carfilzomib

Carfilzomib (marketed under the trade name Kyprolis, developed by Onyx Pharmaceuticals) is an anti-cancer drug acting as a selective proteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin.[2]

Carfilzomib
Clinical data
Trade namesKyprolis
Other namesPX-171-007
License data
Pregnancy
category
  • AU: C
  • US: D (Evidence of risk)
    Routes of
    administration    		Intravenous
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Protein binding97%[1]
    MetabolismExtensive; CYP plays a minor role
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.219.957
    Chemical and physical data
    FormulaC40H57N5O7
    Molar mass719.924 g·mol−1
    3D model (JSmol)

    The U.S. Food and Drug Administration (FDA) approved it on 20 July 2012 for use in patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy (such as lenalidomide) and have demonstrated disease progression on or within 60 days of completion of the last therapy. Initial approval was based on response rate.[3] Data demonstrating an Overall Survival (OS) benefit was later demonstrated in the ENDEAVOR trial and approved by the FDA.[4]

    The abbreviation CFZ is common for referring to carfilzomib, but abbreviating drug names is not best practice in medicine.

    History

    Carfilzomib is derived from epoxomicin, a natural product that was shown by the laboratory of Craig Crews at Yale University to inhibit the proteasome.[5] The Crews laboratory subsequently invented a more specific derivative of epoxomicin named YU101,[6] which was licensed to Proteolix, Inc. Scientists at Proteolix invented a new, distinct compound that had potential use as a drug in humans, known as carfilzomib. Proteolix advanced carfilzomib to multiple Phase 1 and 2 clinical trials, including a pivotal phase 2 clinical trial designed to seek accelerated approval.[7] Clinical trials for carfilzomib continue under Onyx Pharmaceuticals, which acquired Proteolix in 2009.[7]

    In January 2011, the FDA granted carfilzomib fast-track status, allowing Onyx to initiate a rolling submission of its new drug application for carfilzomib.[8] In December 2011, the FDA granted Onyx standard review designation,[9][10] for its new drug application submission based on the 003-A1 study, an open-label, single-arm phase 2b trial. The trial evaluated 266 heavily-pretreated patients with relapsed and refractory multiple myeloma who had received at least two prior therapies, including bortezomib and either thalidomide or lenalidomide.[11] It costs approximately $10,000 per 28-day cycle.[12]

    Mechanism

    Carfilzomib covalently [13] irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome, an enzyme that degrades unwanted cellular proteins. Carfilzomib displays minimal interactions with non-proteasomal targets, thereby improving safety profiles over bortezomib.[13] Inhibition of proteasome-mediated proteolysis results in a build-up of polyubiquitinated proteins, which may cause cell cycle arrest, apoptosis, and inhibition of tumor growth.[2]

    Clinical trials & side effects

    Completed

    A single-arm, Phase II trial (003-A1) of carfilzomib in patients with relapsed and refractory multiple myeloma showed that single-agent carfilzomib demonstrated a clinical benefit rate of 36% in the 266 patients evaluated and had an overall response rate of 22.9% and median duration of response of 7.8 months. The FDA approval of carfilzomib was based on results of the 003-A1 trial.[14]

    In a Phase II trial (004), carfilzomib had a 53% overall response rate among patients with relapsed and/or refractory multiple myeloma who had not previously received bortezomib. This study also included a bortezomib-treated cohort. Results were reported separately.[15] This study also found prolonged carfilzomib treatment was tolerable, with approximately 22% of patients continuing treatment beyond one year. The 004 trial was a smaller study originally designed to investigate the impact of carfilzomib treatment in relationship to bortezomib treatment in less heavily pretreated (1–3 prior regimens) patients.[16]

    A Phase II trial (005), which assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of carfilzomib, in patients with multiple myeloma and varying degrees of renal impairment, where nearly 50% of patients were refractory to both bortezomib and lenalidomide, demonstrated that pharmacokinetics and safety were not influenced by the degree of baseline renal impairment. Carfilzomib was tolerable and demonstrated efficacy.[17]

    In another Phase II trial (006) of patients with relapsed and/or refractory multiple myeloma, carfilzomib in combination with lenalidomide and dexamethasone demonstrated an overall response rate of 69%.[18]

    A Phase II trial (007) for multiple myeloma and solid tumors showed promising results.[19][20]

    In Phase II trials of carfilzomib, the most common grade 3 or higher treatment-emergent adverse events were hematologic toxicity [21] with thrombocytopenia, anemia, lymphopenia, neutropenia, pneumonia, fatigue and hyponatremia.[22]

    In a frontline Phase I/II study, the combination of carfilzomib, lenalidomide, and low-dose dexamethasone was highly active and well tolerated, permitting the use of full doses for an extended time in newly diagnosed multiple myeloma patients, with limited need for dose modification. Responses were rapid and improved over time, reaching 100% very good partial response.[23]

    Furthermore, gastrointestinal disturbances, including diarrhea and nausea are non hematologic group of side effects commonly reported with proteasome inhibitors.[21] Additionally, cardiovascular toxicity may be an outcome of Carfilzomib treatment due to the effects on proteasomes in the myocardium.[21] Thus, patient evaluation and risk assessment prior to initiation of therapy with carfilzomib is crucial.[24]

    ASPIRE trial

    A phase III confirmatory clinical trial, known as the ASPIRE trial, comparing carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma is ongoing.[25] Its results were presented at an American Society of Hematology meeting in December 2014. They indicated that significantly more patients responded to the three-drug regimen than responded to the two-drug regimen.[26][27] Interim results of the ASPIRE trial have been published in the New England Journal of Medicine.[28]

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    References
    1. "Kyprolis (carfilzomib) for Injection, for Intravenous Use. U.S. Full Prescribing Information" (PDF). Onyx Pharmaceuticals, Inc.
    2. Carfilzomib, NCI Drug Dictionary
    3. "FDA Approves Kyprolis for Some Patients with Multiple Myeloma". FDA. 2012-07-20. Retrieved 2013-07-23.
    4. FDA Approves Carfilzomib Label Update in Myeloma | OncLive | ,
    5. Meng L, Mohan R, Kwok BH, Elofsson M, Sin N, Crews CM (August 1999). "Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity". Proceedings of the National Academy of Sciences of the United States of America. 96 (18): 10403–8. Bibcode:1999PNAS...9610403M. doi:10.1073/pnas.96.18.10403. PMC 17900. PMID 10468620.
    6. Myung J, Kim KB, Lindsten K, Dantuma NP, Crews CM (February 2001). "Lack of proteasome active site allostery as revealed by subunit-specific inhibitors". Molecular Cell. 7 (2): 411–20. doi:10.1016/S1097-2765(01)00188-5. PMID 11239469.
    7. "Carfilzomib: From Discovery To Drug". Chemical & Engineering News. 2012-08-27. Retrieved 2013-07-30.
    8. "Onyx multiple myeloma drug wins FDA fast-track status". San Francisco Business Times. 2011-01-31. Retrieved 2011-09-01.
    9. "Beacon Breaking News – Carfilzomib to Get Standard, Not Priority, FDA Review". The Myeloma Beacon. Retrieved 2012-02-27.
    10. "Fast Track, Accelerated Approval and Priority Review; Accelerating Availability of New Drugs for Patients with Serious Diseases". FDA. Retrieved 2012-02-27.
    11. "PX-171-003-A1, an open-label, single-arm, phase (Ph) II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (R/R MM): Long-term follow-up and subgroup analysis". ASCO 2011; Abstract 8027. 2011. Archived from the original on 2012-03-23. Retrieved 2011-09-01.
    12. "FDA Approves Kyprolis (Carfilzomib) For Relapsed And Refractory Multiple Myeloma". The Myeloma Beacon. Retrieved 2012-07-20.
    13. Park JE, Park J, Jun Y, Oh Y, Ryoo G, Jeong YS, et al. (May 2019). "Expanding therapeutic utility of carfilzomib for breast cancer therapy by novel albumin-coated nanocrystal formulation". Journal of Controlled Release. 302: 148–159. doi:10.1016/j.jconrel.2019.04.006. PMC 6638563. PMID 30954620.
    14. "Carfilzomib Prescribing Information". NCI Drug Dictionary. Retrieved 2013-07-23.
    15. Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, et al. (September 2012). "An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib". British Journal of Haematology. 158 (6): 739–48. doi:10.1111/j.1365-2141.2012.09232.x. PMC 5818209. PMID 22845873.
    16. Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, et al. (June 2012). "An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma". Blood. 119 (24): 5661–70. doi:10.1182/blood-2012-03-414359. PMC 4123327. PMID 22555973.
    17. Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, et al. (August 2013). "Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety". Leukemia. 27 (8): 1707–14. doi:10.1038/leu.2013.29. PMC 3740399. PMID 23364621.
    18. "European Hematology Association (EHA) 18th Congress. June 13-16, 2013". The Myeloma Beacon. 2013. Retrieved 2013-07-13.
    19. "Nikoletta Lendval, MD PhD et al. Phase II Study of Infusional Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma". Presented at: 54th ASH Annual Meeting and Exposition: December 2012. Retrieved 2013-07-23.
    20. "Phase II results of Study PX-171-007: A phase Ib/II study of carfilzomib (CFZ), a selective proteasome inhibitor, in patients with selected advanced metastatic solid tumors" - ASCO 2009; Abstract 3515.
    21. Guerrero-Garcia TA, Gandolfi S, Laubach JP, Hideshima T, Chauhan D, Mitsiades C, et al. (December 2018). "The power of proteasome inhibition in multiple myeloma". Expert Review of Proteomics. 15 (12): 1033–1052. doi:10.1080/14789450.2018.1543595. PMID 30427223.
    22. Siegel DS, Martin T, Wang M, et al. (2011-03-09). "Results of PX-171- 003-A1, an open-label, single-arm, phase 2 study of carfilzomib in patients with relapsed and refractory multiple myeloma. Presented at: 52nd ASH Annual Meeting and Exposition; December 4-7, 2010; Orlando, Florida". OncLive.com. Retrieved 2011-09-01.
    23. "Final Results of a Frontline Phase 1/2 Study of Carfilzomib Lenalidomide, and Low-Dose Dexamethasone (CRd) in Multiple Myeloma (MM)". ASH 20111; Abstract 631. Retrieved 2012-02-27.
    24. Efentakis P, Kremastiotis G, Varela A, Nikolaou PE, Papanagnou ED, Davos CH, et al. (February 2019). "Molecular mechanisms of carfilzomib-induced cardiotoxicity in mice and the emerging cardioprotective role of metformin". Blood. 133 (7): 710–723. doi:10.1182/blood-2018-06-858415. PMID 30482794.
    25. "Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) Versus Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma". ClinicalTrials.gov. 2011-08-04. Retrieved 2011-09-01.
    26. Berkrot, Bill (6 December 2014). "Addition of Amgen drug boosts benefits in relapsed myeloma: study". Reuters. Retrieved 6 December 2014.
    27. "Dr. Stewart Discusses the Efficacy of Carfilzomib in the ASPIRE Trial". onclive. December 6, 2014.
    28. Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, et al. (January 2015). "Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma". The New England Journal of Medicine. 372 (2): 142–52. doi:10.1056/NEJMoa1411321. PMID 25482145.
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