The results of this study show that topical ocular administration of the Tie2 activator razuprotafib, as an adjunct to standard of care latanoprost, was well tolerated and significantly reduced IOP in patients with glaucoma. This confirms and extends results in two consecutive clinical trials assessing subcutaneous administration of razuprotafib for the treatment of diabetic retinopathy, where significant IOP reduction was observed in ocular normotensive patients.
9 In the current trial, adjunctive topical ocular razuprotafib BID dosing was more effective than QD dosing with increasing IOP lowering effect in both the QD and BID group between day 14 and day 28, reaching statistical significance at 28 days in the BID group. Moreover, the adjunctive IOP lowering effect was larger in patients with baseline IOP ≥26 mm Hg. The time- and pressure-dependence of IOP lowering are consistent with razuprotafib's proposed mechanism of action to increase conventional outflow facitlity by targeting Schlemm's canal function and repair.
9
Supporting the proposed mechanism, mouse and human genetic data have established a role for the Tie2 pathway in the development and maintenance of Schlemm's canal.
13–18 Importantly, human genetic studies show that both Tie2 and Angpt1 loss-of-function variants associate with risk of congenital glaucoma, and single-nucleotide polymorphisms in the Angpt1 promoter region significantly associate with ocular hypertension and OAG risk.
18–21 The molecular target of razuprotafib, VE-PTP, is expressed by SC endothelium in mice and humans, and topical ocular administration of razuprotafib in mice increased Tie2 activation, enhanced SC filtration area, and increased outflow facility, resulting in reduced IOP.
9–12 As a genetic correlate to the studies with razuprotafib, the developmental defect of SC size in Tie2
+/− mice could be partially compensated by removing one VE-PTP allele in double hemizygous mice.
16 Importantly, SC luminal area is smaller, and outflow facility is lower in glaucomatous eyes compared to age-matched controls.
22–24 Taken together, these findings further support Tie2 activation with razuprotafib as a potential disease modifying approach to treating OAG mediated by the anatomical remodeling effects on Schlemm's canal. Moreover, because razuprotafib works by increasing conventional outflow, it represents an ideal adjuvant therapy to standard of care prostaglandins that reduce IOP primarily via a secondary outflow route known as the uveoscleral or unconventional outflow pathway.
25
Overall, razuprotafib was well tolerated, with mostly mild hyperemia as the main adverse effect. The hyperemia is likely due to the vasodilator effect of activating endothelial nitric oxide synthase downstream of Tie2 activation.
26,27 The hyperemia was transient, peaked within two hours of dosing, and was not associated with other adverse events such as conjunctival pain or hemorrhage. Other than mild dysgeusia, no clinically significant non-ocular adverse events were noted.
The main limitation of this study was the short duration of treatment. The time dependent trend of IOP lowering after one month of treatment supports the proposed MOA involving increased conventional outflow via the remodeling of Schlemm's canal and suggests that a longer study may have resulted in a larger IOP lowering effect. Another limitation of this study was study entry based on a relatively low post-washout IOP (≥24 mm Hg at 8:00 and ≥22 mm Hg at 10:00, 12:00, and 16:00 hours). A conventional outflow targeted agent would be expected to have a larger IOP lowering effect in patients with higher baseline IOP as illustrated by the larger IOP lowering effect of razuprotafib in patients with baseline IOP ≥ 26 mm Hg. Based on these considerations, a longer study including patients with higher post-washout IOP or basing entry on IOP after a prostaglandin run-in period may have resulted in a larger IOP lowering effect.
Netarsudil, another conventional outflow targeted therapy available as a once-daily fixed-dose combination with latanoprost (Rocklatan), yields a ∼1.5 mm Hg reduction in IOP compared to latanoprost alone.
28,29 However, unlike razuprotafib, the IOP lowering effect of netarsudil appears to be larger in patients with IOP ≤ 25 mm Hg and the IOP lowering effect appears to wane over time. The differences between razuprotafib and netarsudil could be due to the specific component of conventional outflow targeted, Schlemm's canal remodeling versus episcleral venous pressure, respectively. In particular, the reduced performance of netarsudil in patients with highly elevated IOP could be secondary to severe outflow limitation proximal to the episcleral veins (i.e., Schlemm's canal or the trabecular meshwork). Thus combining razuprotafib or possibly Vizulta (latanoprostene bunod), a once daily nitric oxide donating prostaglandin that targets the trabecular meshwork, with netarsudil could be optimal for patients with advanced disease.
30 Nonetheless, continued requirement of BID dosing of razuprotafib would represent a relative disadvantage for patient convenience due to additional dosing frequency and decreased potential of creating a “one bottle” drug. Thus further assessment of both BID and QD dosing over a longer duration in patients with higher baseline IOP will inform the potential for razuprotafib as a Schlemm's canal targeted OHT/OAG therapy.