| Candidate ID: | R1434 |
| Source ID: | DB12147 |
| Source Type: | approved; investigational |
| Compound Type: |
small molecule
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| Compound Name: |
Erdafitinib
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| Synonyms: |
Erdafitinib
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| Molecular Formula: |
C25H30N6O2
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| SMILES: |
COC1=CC(=CC(OC)=C1)N(CCNC(C)C)C1=CC=C2N=CC(=NC2=C1)C1=CN(C)N=C1
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| Structure: |
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| DrugBank Description: |
In early April of 2019, the US FDA approved Janssen Pharmaceutical Companies' brand name Balversa (erdafitinib) as the first-ever fibroblast growth factor receptor (FGFR) kinase inhibitor indicated for patients with locally advanced or metastatic urothelial carcinoma, with susceptible FGFR3 or FGFR2 genetic alterations, that has progressed during or following platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy . At the same time, the FDA also approved the therascreen FGFR RGQ RT-PCR Kit (Qiagen) for utilization as a companion diagnostic with erdafitinib for selecting patients for the indicated therapy .
Erdafitinib's innovation lies in the fact that it is the first personalized treatment targeting susceptible FGFR genetic alterations for patients with metastatic bladder cancer, which demonstrates the design of erdafitinib in developing more personalized and precision medicines with the capacity to target cancer treatment to a patient's specific genetic mutation . Considering urothelial cancer is statistically the fourth most common kind of cancer in the world , the introduction of erdafitinib offers a welcome new option in the ever-expanding therapeutic tool kit to treat such prevalent medical conditions.
Nevertheless, although erdafitinib was granted Breakthrough Therapy designation and Accelerated Approval from the FDA so as to allow the agency to focus on and expedite the approval process for a medication indicated for a serious condition that fills an unmet medical need using clinical trial data that is believed to predict a genuine clinical benefit for patients with the given condition, such designations mean further ongoing clinical trials are necessary to confirm the clinical benefit of erdafitinib going forward .
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| CAS Number: |
1346242-81-6
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| Molecular Weight: |
446.555
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| DrugBank Indication: |
Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor that is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has:
i) susceptible FGFR3 or FGFR2 genetic alterations and has ,
ii) progressed during or following at least one line of prior platinum-containing chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy .
The selection of patients for the treatment of locally advanced or metastatic urothelial carcinoma with erdafitinib should be based on the presence of susceptible FGFR genetic alterations in tumor specimens as detected by an FDA-approved companion diagnostic like the FDA approved therascreen FGFR RGQ RT-PCR Kit as developed by QIAGEN .
This above indication is approved under accelerated approval by the US FDA based on tumor response rate . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials .
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| DrugBank Pharmacology: |
Upon administration, it was observed that erdafitinib increased serum phosphate level as a consequence of FGFR inhibition . Erdafitinib should be increased to the maximum recommended dose to achieve target serum phosphate levels of 5.5– 7.0 mg/dL in early cycles with continuous daily dosing .
Subsequently, in erfatinib clinical trials, the use of drugs which could increase serum phosphate levels, such as potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas or laxatives, and medications known to have phosphate as an excipient were prohibited unless no alternatives existed . To manage phosphate elevation, phosphate binders were utilized . Additionally, the concomitant use of agents that can alter serum phosphate levels before the initial erfatinib dose increase period based on serum phosphate levels was also avoided .
Furthermore, based on the evaluation of QTc interval in an open-label, dose escalation, and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval .
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| DrugBank MoA: |
Urothelial cancer is statistically the fourth most common kind of cancer in the world . In general, such urothelial cancers originate in the urothelium - or the transitional epithelium - a membrane that covers the renal pelvis to the ureter, the bladder, and the proximal two-thirds of the urethra . While 90 to 95% of urothelial cancers are bladder cancers and the other 5 to 10% are upper tract urothelial cancers, the bladder cancers can also be either superficial or invasive (either not having or having invaded the deeper layers of the bladder) .
Moreover, fibroblast growth factor receptor (FGFR) is a transmembrane protein that is expressed ubiquitously in normal tissues and is involved in various endogenous bio-physiological processes including the homeostasis of phosphate and vitamin D, cell proliferation, cell anti-apoptotic signaling, and cell migration in a variety of cell types . Concurrently, genetic mutations or changes like deregulation of FGFR pathways and FGFR aberrations such as gene amplification, point mutations, and chromosomal translocations have been implicated in the pathogenesis of urothelial cancer, including the possibility of such changes to all four FGFR genes (FGFR1, FGFR2, FGFR3, and FGFR4) . Changes to the FGFR genes are consequently thought to promote cell proliferation, migration, angiogenesis, and anti-apoptosis in many cancers including urothelial cancer .
Erdafitinib is subsequently an oral selective pan-FGFR kinase inhibitor that binds to and inhibits the enzymatic activity of expressed FGFR1, FGFR2, FGFR3, and FGFR4 based on in vitro data . In particular, erdafitinib demonstrates inhibition of FGFR phosphorylation and signaling as well as decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions . Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer .
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| Targets: |
Fibroblast growth factor receptor 1 inhibitor; Fibroblast growth factor receptor 2 inhibitor; Fibroblast growth factor receptor 3 inhibitor; Fibroblast growth factor receptor 4 inhibitor; RET proto-oncogene substrate; Macrophage colony-stimulating factor 1 receptor substrate; Platelet-derived growth factor receptor alpha substrate; Platelet-derived growth factor receptor beta substrate; Mast/stem cell growth factor receptor Kit substrate; Vascular endothelial growth factor receptor 2 substrate
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| Inclusion Criteria: |
Therapeutic strategy associated
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