Abemaciclib

Abemaciclib, sold under the brand name Verzenio among others, is a medication for the treatment of advanced or metastatic breast cancers. It was developed by Eli Lilly and it acts as a CDK inhibitor selective for CDK4 and CDK6.[2]

Abemaciclib
Clinical data
Pronunciation/əˌbɛməˈsaɪklɪb/
ə-BEM-ə-SY-klib
Trade namesVerzenio, Verzenios, others
Other namesLY2835219
AHFS/Drugs.comConsumer Drug Information
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability45%
Protein binding96.3%
Elimination half-life18.3 hrs
Excretion81% via feces, 3% via urine
Identifiers
IUPAC name
  • N-[5-[(4-Ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-2-pyrimidinamine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.233.787
Chemical and physical data
FormulaC27H32F2N8
Molar mass506.606 g·mol−1
3D model (JSmol)
SMILES
  • CCN1CCN(CC1)Cc2ccc(nc2)Nc3ncc(c(n3)c4cc5c(c(c4)F)nc(n5C(C)C)C)F
InChI
  • InChI=1S/C27H32F2N8/c1-5-35-8-10-36(11-9-35)16-19-6-7-24(30-14-19)33-27-31-15-22(29)25(34-27)20-12-21(28)26-23(13-20)37(17(2)3)18(4)32-26/h6-7,12-15,17H,5,8-11,16H2,1-4H3,(H,30,31,33,34)
  • Key:UZWDCWONPYILKI-UHFFFAOYSA-N

It was designated as a breakthrough therapy for breast cancer by the U.S. Food and Drug Administration (FDA) in October 2015.[3]

On 28 September 2017, it was approved for use in the United States by the FDA for the treatment of certain breast cancers.[4]

Medical uses

Since September 2017 Abemaciclib is approved in the US for "adult patients who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient's hormones".[4]

In studies that compared fulvestrant plus abemaciclib to fulvestrant plus placebo in breast cancer patients, progression-free survival under abemaciclib therapy was 16.4 months on average, as compared to 9.3 months under the placebo arm.

Side effects

Side effects that occurred in 20% or more of patients in studies were diarrhea, nausea and vomiting, leukopenia (low white blood cell count) including neutropenia, anemia (low red blood cell count), thrombocytopenia (low platelet count), stomach pain, infections, fatigue, decreased appetite, and headache.[5][6]

Interactions

As abemaciclib is mainly metabolized by the liver enzyme CYP3A4, inhibitors of this enzyme (such as ketoconazole) are expected to increase its blood plasma concentrations. Conversely, CYP3A4 inducers lower plasma concentrations of abemaciclib, as has been shown in a study with rifampicin.[6]

Pharmacology

Mechanism of action

Like the related drugs palbociclib and ribociclib, abemaciclib inhibits the enzymes cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6).[6] These enzymes are responsible for phosphorylating and thus deactivating the retinoblastoma protein, which plays a role in cell cycle progression from the G1 (first gap) to the S (synthesis) phase.[7] Blocking this pathway prevents cells from progressing to the S phase, thereby inducing apoptosis (cell death).[6] In vitro analysis using cancer cell lines, it is reported that abemaciclib induces non‐apoptotic cell death characterized by formation of cytoplasmic vacuoles derived from lysosomes. This result suggest that there may be a mechanism of action other than inhibition of a cyclin-dependent kinase.[8]

Pharmacokinetics
N-desethylabemaciclib (M2), the main metabolite

After oral intake, absolute bioavailability is 45%. Highest blood plasma concentrations are reached after 8 hours on average (range: 4.1–24.0 hours). When in the circulation, 96.3% of abemaciclib is bound to plasma proteins. The substance is mainly metabolized by the liver enzyme CYP3A4 to N-desethylabemaciclib (M2), and to a lesser extent to hydroxy derivatives (M18, M20) and another oxidative metabolite (M1). These metabolites have high plasma protein binding rates similar to the parent substance.[6]

Abemaciclib is excreted mainly via the feces (81%) and to a small extent via the urine (3%). Its elimination half-life is 18.3 hours on average.[6]

Clinical trials

Successful Phase I[9] and Phase II[10] trials against breast cancer were announced in May and December 2014 respectively.

As of early 2016, abemaciclib was involved in 3 Phase III clinical trials:

  • The JUNIPER Study[11] is comparing abemaciclib against erlotinib in patients with stage IV non-small-cell lung carcinoma[12] Due to collect data until September 2017.[11]
  • The MONARCH 2 study is investigating the effectiveness of abemaciclib in combination with fulvestrant for women with breast cancer.[13] It is due to end in Feb 2017.[14] In March 2017, Eli Lilly announced that it had met its primary endpoint of superior progression-free survival (PFS) over placebo plus fulvestrant in patients with estrogen receptor positive and HER2 negative advanced or metastatic breast cancer.[15] This result led to the September 2017 FDA approval.[16]
  • The MONARCH 3 study[17] is investigating the effectiveness of abemaciclib, plus either anastrozole or letrozole, as a first-line treatment for women with breast cancer.[18] The trial is expected to end in June 2017.[17]

Chemistry

Abemaciclib may be synthesized in a four step manner using a Suzuki coupling, followed by a Buchwald–Hartwig amination with the final step being a reductive amination using the Leuckart reaction.[19]

References
  1. "Summary Basis of Decision (SBD) for Verzenio". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  2. Lu J (August 2015). "Palbociclib: a first-in-class CDK4/CDK6 inhibitor for the treatment of hormone-receptor positive advanced breast cancer". Journal of Hematology & Oncology. 8 (1): 98. doi:10.1186/s13045-015-0194-5. PMC 4534142. PMID 26264704.
  3. Digiulio, Sarah (8 October 2015). "FDA's Breakthrough Therapy Designation to Abemaciclib for Breast Cancer". Oncology Times. LWW Journals. Retrieved 30 March 2016.
  4. "FDA approves new treatment for certain advanced or metastatic breast cancers" (Press release). Food and Drug Administration. 28 September 2017.
  5. Drugs.com: Abemaciclib Monograph. Accessed 2017-11-22.
  6. "Highlights of Prescribing Information for Verzenio" (PDF). September 2017.
  7. Goodrich DW, Wang NP, Qian YW, Lee EY, Lee WH (October 1991). "The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle". Cell. 67 (2): 293–302. doi:10.1016/0092-8674(91)90181-w. PMID 1655277. S2CID 12990398.
  8. Hino H, Iriyama N, Kokuba H, et al. (June 2020). "Abemaciclib induces atypical cell death in cancer cells characterized by formation of cytoplasmic vacuoles derived from lysosomes". Cancer Sci. 111 (6): 2132–2145. doi:10.1111/cas.14419. PMC 7293084. PMID 32304130.
  9. LY2835219 Shows Strong Single-Agent Activity in Preliminary Study in Metastatic Breast Cancer
  10. Clinical Activity of Abemaciclib (LY2835219), a Cell Cycle Inhibitor Selective for CDK4 and CDK6, in Patients with Relapsed or Refractory Mantle Cell Lymphoma
  11. A Study of Abemaciclib (LY2835219) in Participants With Previously Treated KRAS Mutated Lung Cancer (JUNIPER)
  12. Goldman JW, Shi P, Reck M, Paz-Ares L, Koustenis A, Hurt KC (January 2016). "Treatment Rationale and Study Design for the JUNIPER Study: A Randomized Phase III Study of Abemaciclib With Best Supportive Care Versus Erlotinib With Best Supportive Care in Patients With Stage IV Non-Small-Cell Lung Cancer With a Detectable KRAS Mutation Whose Disease Has Progressed After Platinum-Based Chemotherapy". Clinical Lung Cancer. 17 (1): 80–4. doi:10.1016/j.cllc.2015.08.003. PMID 26432508.
  13. Llombart A, Toi M, Klise SR, Frenzel M, Chan EM, Sledge GW (30 April 2015). "Abstract OT1-1-07: A phase III study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (MONARCH 2)". Cancer Research. 75 (9 Supplement): OT1–1–07–OT1–1–07. doi:10.1158/1538-7445.SABCS14-OT1-1-07.
  14. A Study of Abemaciclib (LY2835219) Combined With Fulvestrant in Women With Hormone Receptor Positive HER2 Negative Breast Cancer (MONARCH 2)
  15. Lilly Announces Phase 3 MONARCH 2 Breast Cancer Study of Abemaciclib Met Primary Endpoint of Progression-Free Survival, Eli Lilly, 20 March 2017
  16. Abemaciclib Receives FDA Approval for Certain Metastatic Breast Cancers. Sept 2017
  17. A Study of Nonsteroidal Aromatase Inhibitors Plus Abemaciclib (LY2835219) in Postmenopausal Women With Breast Cancer (MONARCH 3)
  18. Goetz MP, Toi M, Klise S, Frenzel M, Bourayou N, Di Leo A (2015). "MONARCH 3: A randomized phase III study of anastrozole or letrozole plus abemaciclib, a CDK4/6 inhibitor, or placebo in first-line treatment of women with HR+, HER2-locoregionally recurrent or metastatic breast cancer (MBC)". Journal of Clinical Oncology. 33 (15_suppl): TPS624. doi:10.1200/jco.2015.33.15_suppl.tps624. Archived from the original on 7 April 2016. Retrieved 30 March 2016.
  19. Frederick MO, Kjell DP (February 2015). "A synthesis of abemaciclib utilizing a Leuckart–Wallach reaction". Tetrahedron Letters. 56 (7): 949–951. doi:10.1016/j.tetlet.2014.12.082.
  • "Abemaciclib". Drug Information Portal. U.S. National Library of Medicine.
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