RASP inhibition gets high marks in early trial of dry eye disease
The novel reactive aldehyde species (RASP) inhibitor reproxalap delivers rapid and meaningful control of signs and symptoms of dry eye disease (DED), according to the results of a phase IIb trial.
Over 12 weeks treatment, reproxalap was generally superior to vehicle in terms of all symptom scales, nasal region staining, and tear quality assessments, the investigators said. There was a clear dose-response effect, and the 0.25% concentration of reproxalap was selected for the phase III testing.
According to the Tear Film & Ocular Surface Society International Dry Eye Workshop II (TFOS DEWS II) pathophysiology report, DED has to do with hyperosmotic tissue damage, which in part contributes to inflammation that causes tear film instability and potentiates tissue damage as part of a “vicious circle.” [Ocul Surf 2017;15:438-510; Br J Ophthalmol 2016;100:300-306]
“Thus, novel anti-inflammatory approaches have the potential to interrupt the pathophysiological cycle of DED,” the investigators pointed out.
In the case of RASP, the species are known as precytokine systems–based mediators of inflammation. Indeed, the well-characterized RASP malondialdehyde (MDA) has been implicated in inflammatory ocular diseases, including autoimmune diseases, allergic conjunctivitis, and DED. [Exp Eye Res 2008;86:70-80; Immunol Lett 2012;147:29-33; Respir Res 2017;18:36]
DED patients, in particular, show elevated MDA levels in tears than do healthy individuals, with the highest levels seen among those with more severe disease. These data formed the basis for evaluating RASP inhibition as a novel and broad-based treatment approach, according to the investigators. [Br J Ophthalmol 2010;94:1083-1087; J Allergy Clin Immunol 2005;116:836-843; Mol Vis 2010;16:2465-2475; Curr Eye Res 2016;41:1143-1149]
In the current trial, 300 patients (mean age, 63.5 years) were randomized to receive topical reproxalap 0.1% (n=100) or 0.25% (n=100) or vehicle (n=100). Both eyes received treatment four times daily for 12 weeks.
End-of-treatment results showed that relative to vehicle, the study drug produced the largest symptomatic and sign improvements in ocular dryness (0.25 percent; p=0.047) and nasal region fluorescein staining (0.25 percent; p=0.030), respectively. [Am J Ophthalmol 2021;doi:10.1016/j.ajo.2021.01.011]
Significantly more patients receiving 0.25% reproxalap versus vehicle reported dryness scores of 0 (p=0.012). Furthermore, the improvements in combined DED symptoms occurred as early as week 2 (p<0.0001) in patients with baseline scores above median values.
In terms of safety, there were no clinically significant and persistent changes from baseline seen with the study drug with respect to slit lamp biomicroscopy, undilated fundoscopy, visual acuity, or intraocular pressure. A total of 173 ocular treatment-emergent adverse events were documented, most of which were mild in severity.
“The results represent the first vehicle-controlled evidence for the therapeutic potential of RASP inhibition to mitigate the signs and symptoms of DED,” according to the investigators.
“Future testing of reproxalap may also include other methodologies to assess DED signs, such as noninvasive tear film stability, lid margin staining, tear meniscus height, lipid layer interferometry, and expressed meibum quality,” they added.