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AXPAXLI (axitinib intravitreal implant)

Neovascular age-related macular degeneration

Also known as OTX-TKI
Manufacturer
Ocular Therapeutix
Last updated
309 sources

Product information and disease descriptionProduct descriptionProduct informationPharmacology

Pharmacodynamics

16 evidence topics · 11 sources

Intracellular kinase inhibition and hydrogel delivery of axitinib: independent review

“Tyrosine kinase inhibitors (TKIs) are small molecules that act at the intracellular level to inhibit receptor tyrosine kinase by preventing tyrosine kinase phosphorylation and the downstream signaling cascade.” (opens the source at this quote in a new tab)

“Notably, TKIs are capable of inhibiting all isoforms of VEGF as well as other receptor tyrosine kinases including fibroblast growth factor receptor and platelet-derived growth factor receptor.” (opens the source at this quote in a new tab)

“Axitinib binds to the intracellular ATP-binding site of VEGFR-1, VEGFR-2, and VEGFR-3, thereby inhibiting receptor phosphorylation” (opens the source at this quote in a new tab)

“Cross-linked polyethylene glycol polymer chains form a hydrogel, allowing diffusion of the micronized molecule.” (opens the source at this quote in a new tab)

Rationale for single-agent dual VEGF and PDGF receptor inhibition in choroidal neovascularization

“Axitinib is a small molecule tyrosine kinase inhibitor mainly targeting VEGFR1-3 and PDGFR.” (opens the source at this quote in a new tab)

“Targeting VEGFR1-3, axitinib offers an anti-VEGF spectrum as broad as aflibercept, but also adds PDGFR and c-Kit inhibition” (opens the source at this quote in a new tab)

“In our hands, axitinib was not only capable of a modulation of VEGF-mediated endothelial cellular function, but also expanded current treatment options by inhibition of pericytes attributable to its impact on PDGF-signaling, as pericytes do not express c-Kit” (opens the source at this quote in a new tab)

“From a future perspective, axitinib as a single substance offering dual anti-VEGF/PDGF inhibition might allow for an easier, better-tolerated application.” (opens the source at this quote in a new tab)

Kinase selectivity and potency: sponsor cell-based and biochemical assays
CompoundVEGFR2 IC50 (nM)PDGFR-β IC50 (nM)FGFR2 IC50 (nM)TIE2 IC50 (nM)
Axitinib“0.032”“1.6”“72”“1500”
Sunitinib“2.900”“11.0”“>10000”“1400”
Vorolanib“3.300”“16.0”“1400”“>10000”

“Kinome profiling demonstrated VEGFR-1, -2, -3 and PDGFR- α, -β are the top 5 axitinib kinase targets exhibiting >85% inhibition.” (opens the source at this quote in a new tab)

“Cellular assay data demonstrated no TIE2 inhibition within physiological drug solubility range at cell ATP levels via the gold standard cell phosphorylation assay.” (opens the source at this quote in a new tab)

TIE2 inhibition: comparative study sponsored by a competitor developer

“HotSpot™ assay and TIE2 IC 50 values showed that only axitinib potently inhibited TIE2 (up to 89%).” (opens the source at this quote in a new tab)

“Of the three TKIs, only axitinib potently inhibited TIE2 which is an undesired trait as TIE2 is essential for vascular stability.” (opens the source at this quote in a new tab)

VEGFR2 potency above IC50: comparative in vivo angiogenesis findings

“This experiment demonstrates that in a VEGF-dependent study, any of the three TKIs when used at the VEGFR2 IC 50 value will achieve the desired efficacy and when levels higher than IC 50 are utilized the result is little to no enhancement in the effect; hence, the higher potency for VEGFR2 inhibition reported for axitinib relative to vorolanib and sunitinib appears to be of no benefit when compounds are present at concentrations at or above the receptor IC 50 value for that particular TKI.” (opens the source at this quote in a new tab)

Melanin binding

“Both vorolanib and axitinib showed little or no binding to melanin, so the K d and B max values of these two TKIs could not be determined” (opens the source at this quote in a new tab)

Vascular leakage in a VEGF challenge rabbit model: 0.45 mg second-generation implant

“OTX-TKI maintained low leakage scores throughout the study period” (opens the source at this quote in a new tab)

“Bevacizumab had a marked reduction in efficacy after day 31” (opens the source at this quote in a new tab)

“At day 73, bevacizumab had similar scores to untreated control” (opens the source at this quote in a new tab)

Endothelial cells and pericytes in vitro

“Axitinib inhibits angiogenesis in endothelial cells and pericytes via VEGFR and PDGFR modulation in vitro.” (opens the source at this quote in a new tab)

Pericyte phenotype with combined VEGF and PDGF receptor inhibition

“Combined anti-VEGF/PDGF inhibition seems to induce a proto-myofibroblast-like phenotype in human pericytes in vitro, but reduce profibrotic cellular mechanisms due to prolonged anti-PDGF inhibition.” (opens the source at this quote in a new tab)

Preclinical ocular tolerability: 6-month GLP toxicology study in non-human primates

“No signs of inflammation or clinically significant changes in IOP were observed following intravitreal injection with OTX-TKI implant” (opens the source at this quote in a new tab)

“OTX-TKI 700 μg dose represents a human equivalent dose of 1400 μg axitinib and 2.3X ocular dose safety margin when normalized to the vitreous volume between humans and monkeys” (opens the source at this quote in a new tab)

Preclinical repeat dosing every 6 months in non-human primates

“Repeated IVT dosing of OTX-TKI in NHPs was generally well tolerated over an 18-month period with no inflammation and no IOP elevations, supporting the favorable safety profile of repeat doses of OTX-TKI every 6 months in NHPs (~8-9 months in humans)” (opens the source at this quote in a new tab)

Exposure-response in humans: clinical activity relative to preclinical tissue concentrations

“This preclinical PK data aligns with the pharmacodynamics data we observed in our U.S. clinical trial, namely the high proportion of rescue-free subjects up to Month 10 and suggests that AXPAXLI may provide continuous VEGF receptor inhibition.” (opens the source at this quote in a new tab)

Onset of anatomic activity: Australian phase 1 trial

“Some subjects showed a decrease in intraretinal or subretinal fluid by two months in cohorts 2 (400 µg) and 3a (600 µg).” (opens the source at this quote in a new tab)

“We observed extended duration of activity of six months or more for over 60% of subjects across all cohorts and for over 80% of subjects in cohort 3a, in which we administered a 600 μg dose.” (opens the source at this quote in a new tab)

Kinase selectivity of axitinib compared with sunitinib: independent review

“In vitro, individual TKIs differ in their VEGFR-binding affinity, receptor selectivity profiles, and off-target inhibition.” (opens the source at this quote in a new tab)

“Axitinib, for example, is a potent and selective inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3 with minimal activity against other kinases, whereas sunitinib has broader activity, also targeting platelet-derived growth factor receptors (PDGFRs), c-Kit, and FLT3.” (opens the source at this quote in a new tab)

“These differences in molecular selectivity may influence not only efficacy and durability but also safety profiles when these agents are applied to ocular tissues via sustained-release platforms.” (opens the source at this quote in a new tab)

Concentration-dependent inhibition of endothelial cell and pericyte proliferation and migration by axitinib in vitro

“Human endothelial cells (HUVEC) and human pericytes (hPC-PL) were treated with axitinib doses ranging from 1.0 ng/ml to 10 μg/ml.” (opens the source at this quote in a new tab)

“In HUVEC, a significant decrease in cellular proliferation compared to untreated controls could be observed from 0.1 to 10 μg/ml axitinib” (opens the source at this quote in a new tab)

“In pericytes, stimulation with 20 ng PDGF-BB resulted in an approximately 6-fold migratory increase” (opens the source at this quote in a new tab)

“On regular Cultrex, treatment with 0.5, 1, and 2.5 μg/ml axitinib showed a significant decrease of vessel-associated area by 48, 50, and 62% respectively” (opens the source at this quote in a new tab)

“IC50 values of antiproliferative activity were generally lower on endothelial cells than on pericytes. This correlates well with the pharmacological profile of axitinib, which offers VEGFR2-inhibition with an IC50 of 0.2 nM versus 1.6 nM for PDGFR” (opens the source at this quote in a new tab)

In vitro tolerability range of axitinib on endothelial cells and pericytes

“In HUVEC, no statistically significant decrease of metabolic activity and cell count compared to controls treated with vehicle could be observed from 1.0 ng/ml to 7.5 μg/ml axitinib” (opens the source at this quote in a new tab)

“In pericytes, no reduction of metabolic activity could be observed within the range of solubility of axitinib up to 10 μg/ml” (opens the source at this quote in a new tab)

“All effects on both cell lines were observed in non-toxic concentrations of axitinib.” (opens the source at this quote in a new tab)