Product information and disease description Product description Product information Pharmacology

Pharmacodynamics

8 evidence topics · 3 sources

Pharmacodynamics in the prescribing information: exposure-response and QTc

“Lirafugratinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.” (opens the prescribing information at this quote)
“The largest mean increase in QTcF from baseline was 7 ms (upper confidence interval = 12 ms) after administration of LYRFIGTU 70 mg in patients with unresectable or metastatic cholangiocarcinoma or other advanced tumors.” (opens the prescribing information at this quote)

Preclinical: cellular potency and kinome selectivity

“The cellular potency (expressed as IC50) of RLY-4008 is 6 nmol/L (pFGFR) and 3 nmol/L (pERK), consistent with the observed biochemical potency on FGFR2.” (opens the source at this quote in a new tab)
“At the test concentration of 500 nmol/L (which resulted in 94.1% inhibition of FGFR2), only two additional kinases showed greater than 75% inhibition: MEK5 (92.4%) and MKNK2 (89%).” (opens the source at this quote in a new tab)
“In contrast to pan-FGFRi, RLY-4008 did not have strong inhibitory activity in FGFR1-, FGFR3-, or FGFR4-dependent cell lines.” (opens the source at this quote in a new tab)

Preclinical: tumor regression and target inhibition in FGFR2-altered xenograft models

“RLY-4008, administered orally, twice daily from 1 to 30 mg/kg, exhibited dose-dependent antitumor activity and induced tumor regression in all models (Fig. 3A, C, and E).” (opens the source at this quote in a new tab)
“In each model, at a dose of 30 mg/kg twice daily, RLY-4008 led to ≥90% pFGFR2 inhibition that was sustained throughout the 12-hour dosing interval and resulted in tumor regression.” (opens the source at this quote in a new tab)
“Pemigatinib and futibatinib, dosed to achieve exposures similar to those achieved at their recommended human doses of 13.5 mg and 20 mg, respectively (Supplementary Table S4), were less efficacious than 30 mg/kg of RLY-4008.” (opens the source at this quote in a new tab)

Preclinical: serum phosphate at efficacious exposures compared with pan-FGFR inhibitors

“All compounds caused tumor regression (Fig. 3G), whereas only pan-FGFRi demonstrated a statistically significant increase in serum phosphate, consistent with clinical observations (32%–47% over vehicle; P < 0.0001, one-way ANOVA; Fig. 3H).” (opens the source at this quote in a new tab)
“RLY-4008 led to tumor regression at doses of 10 and 30 mg/kg once daily without significantly altering serum phosphate levels (P > 0.2, one-way ANOVA), demonstrating that RLY-4008 is the only molecule tested that spares FGFR1 at efficacious exposures in vivo (Fig. 3H).” (opens the source at this quote in a new tab)

Preclinical: activity in a gatekeeper-mutant cholangiocarcinoma model after pan-FGFR inhibitor progression

“Strikingly, RLY-4008 caused rapid regression of ICC13-7–FGFR2V564F tumors at a dose of 2 mg/kg once daily (Fig. 4C), lower than that required to drive regression of ICC13-7 tumors (Fig. 3G).” (opens the source at this quote in a new tab)
“In contrast, pan-FGFRi were ineffective (Fig. 4C), consistent with the finding that they do not retain potency on FGFR2V564F (Fig. 4B).” (opens the source at this quote in a new tab)

Clinical mechanisms of resistance to lirafugratinib

“Circulating tumor DNA (ctDNA) samples from 28 patients treated with lirafugratinib (16 FGFR inhibitor-naive, 12 FGFR inhibitor-refractory) were analyzed using targeted next-generation sequencing.” (opens the source at this quote in a new tab)
“Polyclonal FGFR2 kinase domain mutations and receptor tyrosine kinase-mitogen activated protein kinase (RTK-MAPK) bypass alterations emerged as common lirafugratinib resistance mechanisms in the FGFR inhibitor-naive context (8/16 and 9/16 patients, respectively).” (opens the source at this quote in a new tab)
“Resistance profiles differed markedly from pan-FGFR inhibitors, with decreased FGFR2 V565F/L and N550H/K mutations, increased M538I and L618F mutations, and more frequent RTK-MAPK bypass alterations.” (opens the source at this quote in a new tab)
“Lirafugratinib retains activity against multiple mutations that confer clinical resistance to pan-FGFR inhibitors.” (opens the source at this quote in a new tab)

Nonclinical: phototoxicity and tissue distribution

“Lirafugratinib absorbs UV radiation and demonstrated phototoxic potential in an in vitro phototoxicity study in BALB/c-3T3 mouse fibroblast cells. In rat tissue distribution studies, lirafugratinib was present in skin and pigmented eyes.” (opens the prescribing information at this quote)

Nonclinical: carcinogenicity, genotoxicity, and fertility

“Carcinogenicity studies have not been conducted with lirafugratinib.” (opens the prescribing information at this quote)
“Lirafugratinib was not mutagenic in the bacterial reverse mutation (Ames) assay. Lirafugratinib was clastogenic in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes but not clastogenic in the in vivo peripheral blood reticulocyte micronucleus assay in rats.” (opens the prescribing information at this quote)
“Dedicated fertility studies with lirafugratinib have not been conducted.” (opens the prescribing information at this quote)
“Partial reversibility of these findings was observed following a recovery period.” (opens the prescribing information at this quote)