Carfilzomib

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Systematic (IUPAC) name
(S)-4-Methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide
Clinical data
Trade names Kyprolis
Licence data US FDA:link
Pregnancy cat. D (US)
Legal status ℞-only (US)
Routes Intravenous
Identifiers
CAS number 868540-17-4
ATC code  ?
PubChem CID 11556711
ChemSpider 9731489
KEGG D08880
Synonyms PX-171-007
Chemical data
Formula C40H57N5O7 
Mol. mass 719.91 g mol

Carfilzomib (CFZ, marketed under the tradename Kyprolis) is a tetrapeptide epoxyketone and a selective proteasome inhibitor. It is an analog of epoxomicin.[1]

The US FDA approved it for relapsed and refractory multiple myeloma on 20 July 2012.

Contents

Discovery, early development and regulatory approval [edit]

Carfilzomib is derived from epoxomicin, a natural product that was shown by the laboratory of Craig Crews at Yale University to inhibit the proteasome.[2] The Crews laboratory subsequently invented a more specific derivative of epoxomicin named YU101,[3] which was licensed to Proteolix, Inc.. Scientists at Proteolix modified YU101 to create carfilzomib, which they advanced to multiple Phase 1 and 2 clinical trials, including a pivotal Phase 2 clinical trial designed to seek accelerated approval. Clinical trials for carfilzomib continue under Onyx Pharmaceuticals, which acquired Proteolix in 2009.[4]

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.[5] In December 2011, the FDA granted Onyx standard review designation, [6][7] 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.[8]

Carfilzomib was approved by the FDA for use in patients with relapsed and refractory multiple myeloma on 20 July 2012.[9] Onyx expects to launch the drug in the U.S. on 1 August 2012. When it launches, it will cost $10,000 per 28-day cycle, making it the most expensive FDA-approved drug for multiple myeloma.[10]

Mechanism [edit]

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 [edit]

A phase 2 trial (-007) for multiple myeloma showed promising results.[11][12]

A single-arm, phase 2 trial (-003-A1) 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.[13][8]

In another phase 2 trial (-006) 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.[8][14]

In a phase 2 trial (-004), 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.[15]

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.[16]

In a frontline phase 1/2 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.[17]

Ongoing [edit]

A phase 3 trial comparing carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma is ongoing.[18] It is no longer recruiting and should report in 2014.

References [edit]

  1. ^ a b Carfilzomib, NCI Drug Dictionary
  2. ^ Meng, L; Mohan, R., Kwok, B.H., Elofsson, M., Sin, N., Crews, C.M. (1999). "Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity". Proc Natl Acad Sci USA 96 (18): 10403–8. doi:10.1073/pnas.96.18.10403. PMC 17900. PMID 10468620. 
  3. ^ Myung, J; Kim, K.B., Lindsten, K., Dantuma, N.P., Crews, C.M. (2001). "Lack of proteasome active site allostery as revealed by subunit-specific inhibitors". Mol Cell 7 (2): 411–20. doi:10.1016/S1097-2765(01)00188-5. PMID 11239469. 
  4. ^ Carfilzomib: From Discovery To Drug
  5. ^ "Onyx multiple myeloma drug wins FDA fast-track status". San Francisco Business Times. 2011-01-31. Retrieved 2011-09-01. 
  6. ^ "Beacon Breaking News – Carfilzomib to Get Standard, Not Priority, FDA Review". The Myeloma Beacon. Retrieved 2012-02-27. 
  7. ^ "Fast Track, Accelerated Approval and Priority Review; Accelerating Availability of New Drugs for Patients with Serious Diseases". FDA. Retrieved 2012-02-27. 
  8. ^ a b c "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. Retrieved 2011-09-01. 
  9. ^ "FDA approves Kyprolis for some patients with multiple myeloma". U.S. Food and Drug Administration. 
  10. ^ "FDA Approves Kyprolis (Carfilzomib) For Relapsed And Refractory Multiple Myeloma". The Myeloma Beacon. Retrieved 2012-07-20. 
  11. ^ Onyx Says Carfilzomib Results Promising, Drug Discovery & Development, July 27, 2010
  12. ^ "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.
  13. ^ "ASCO Showcasing Bay Area Cancer Therapies". San Francisco Business Times. 2011-06-02. Retrieved 2011-09-01. 
  14. ^ "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. Retrieved 2011-09-01. 
  15. ^ "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. Retrieved 2011-09-01. 
  16. ^ "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. Retrieved 2011-09-01. 
  17. ^ "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. 
  18. ^ "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. 
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