Carfilzomib

Carfilzomib
Other names

PX-171-007
Identifiers
CAS number 868540-17-4
ChEMBL CHEMBL451887 Y
Jmol-3D images Image 1
Properties
Molecular formula C40H57N5O7
Molar mass 719.91 g mol−1
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Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Carfilzomib (CFZ) is a tetrapeptide epoxyketone and a selective proteasome inhibitor. It is an analog of epoxomicin.[1]

Contents

Discovery and Early Development

Carfilzomib was discovered and advanced to multiple Phase 1 and 2 clinical trials, including a pivotal Phase 2 clinical trial designed to seek accelerated approval, by Proteolix, Inc. Clinical trials for carfilzomib continue under Onyx Pharmaceuticals, which acquired Proteolix in 2009. In January 2011, the U.S. FDA granted carfilzomib fast-track status, allowing Onyx to initiate a rolling submission of its new drug application for carfilzomib. [2]

Mechanism

Carfilzomib irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome, an enzyme that degrades unwanted cellular proteins. Inhibition of proteasome-mediated proteolysis results in a build-up of polyubiquinated proteins, which may cause cell cycle arrest, apoptosis, and inhibition of tumor growth.[1]

Clinical trials

A phase 2 trial for multiple myeloma showed promising results.[3][4]

A single-arm, phase 2 trial of carfilzomib in patients with relapsed and refractory multiple myeloma showed that single-agent carfilzomib had durable responses in 36 percent of the 257 patients evaluated. [5][6]

In another phase 2 trial of patients with relapsed and/or refractory multiple myeloma, carfilzomib in combination with lenalidomide and dexamethasone demonstrated an overall response rate of 78 percent. Researchers found carfilzomib could be administered over a period of 14-23 months with no new or overlapping toxicities. [7][8]

In a phase 2 trial, carfilzomib had a 53 percent overall response rate among patients with relapsed and/or refractory multiple myeloma who had not previously received bortezomib. This study also found prolonged carfilzomib treatment is well-tolerated with approximately 22 percent of patients continuing treatment beyond one year. [9]

In phase 2 trials of carfilzomib, the most common grade 3 or higher treatment-emergent adverse events were thrombocytopenia, anemia, lymphoenia, neutropenia, pneumonia, fatigue and hyponatremia. [10]

A phase 3 trial comparing carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma is ongoing.[11]

References

  1. ^ a b Carfilzomib, NCI Drug Dictionary
  2. ^ "Onyx multiple myeloma drug wins FDA fast-track status". San Francisco Business Times. 2011-1-31. http://www.bizjournals.com/sanfrancisco/news/2011/01/31/onyx-multiple-myeloma-drug-wins.html. Retrieved 2011-09-01. 
  3. ^ Onyx Says Carfilzomib Results Promising, Drug Discovery & Development, July 27, 2010
  4. ^ "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.
  5. ^ "ASCO Showcasing Bay Area Cancer Therapies". San Francisco Business Times. 2011-06-2. http://www.bizjournals.com/sanfrancisco/blog/2011/06/asco-cancer-genentech-avastin.html. Retrieved 2011-09-01. 
  6. ^ "”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. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=81812. Retrieved 2011-09-01. 
  7. ^ "”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. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=81812. Retrieved 2011-09-01. 
  8. ^ "”Interim results from PX-171-006, a phase (Ph) II multicenter dose-expansion study of carfilzomib (CFZ), lenalidomide (LEN), and low-dose dexamethasone (loDex) in relapsed and/or refractory multiple myeloma (R/R MM)”". ASCO 2011; Abstract 8025. 2011. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=82679. Retrieved 2011-09-01. 
  9. ^ "“The effect of carfilzomib (CFZ) in patients (Pts) with bortezomib (BTZ)-naive relapsed or refractory multiple myeloma (MM): Updated results from the PX-171-004 study”". ASCO 2011; Abstract 8026. 2011. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=77577. Retrieved 2011-09-01. 
  10. ^ "” Siegel DS, Martin T, Wang, M, et al. 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. 2011-03-09. http://www.onclive.com/publications/obtn/2010/December-2010/ASH-2010-Carfilzomib-Shrinks-Tumors-in-More-Than-One-Third-of-Pretreated-Myeloma-Patients. Retrieved 2011-09-01. 
  11. ^ "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. http://clinicaltrials.gov/ct2/show/NCT01080391. Retrieved 2011-09-01.