Discussion
ocular pain, redness, stinging, tearing, inflammation, acute pain, pain, lens, sciatic nerve injury, conjunctival hyperemia, NRS
OCULAR HYPEREMIA, INFLAMMATION, CORNEA, DRUG EFFECT, LENS
This phase 2 PoC study demonstrated that administration of topical SAF312 2.5% four times daily for 3 days was effective in reducing ocular pain in the immediate postoperative period after PRK surgery. Both study primary efficacy endpoints achieved statistical significance favoring SAF312 over vehicle, with a clinically meaningful reduction in mean VAS pain severity scores at the time points of (a) 6 hours after one drop of SAF312 at the end of surgery and (b) average VAS scores over 0 to 12 hours postoperatively after two eye drops (one immediately after surgery and one 6 hours later). These findings are clinically significant considering that acute pain after PRK begins shortly after the procedure and lasts until reepithelization is complete; intense pain is typically experienced within the first 12 hours of surgery, with the peak occurring around 4 to 6 hours after surgery.The efficacy of SAF312 versus vehicle as measured with VAS pain scores throughout 72 hours after the PRK was also assessed as the primary endpoints were set only for the first 12 hours. No significant differences in pain intensity between SAF312 and vehicle group were observed from 36 to 72 hours post-PRK. It is important to reduce both the maximum and overall pain that participants experience during the immediate postoperative period. The difference in VAS pain scores at 6 hours and averaging over 0 to 12 hours for SAF312-treated eyes was 11.1 (34.63 vs. 45.76) points and 8.56 (30.90 vs. 39.46) points lower than for vehicle-treated eyes, respectively. It has been reported that analgesic interventions following surgery that provide a change of 10 out of the 100-mm pain VAS score signifies a minimal clinically important difference, and a VAS ≤33 indicates acceptable pain control.The reduction in pain provided by topical ocular SAF312 is comparable to previous reports for NSAID eye drops and oral opioids. In a study that evaluated diclofenac 0.1% and ketorolac 0.5% applied 2 hours before PRK and continued every 6 hours for 2 days, the VAS pain score (0–10 scale) at 24 hours post-PRK was 4.94 and 6.59 points, respectively.Consistent with the primary outcomes, participants with SAF312 treatment reported lower ORM use at all time points, and a higher proportion of participants on SAF312 had adequate pain control and did not require ORM during the first 24 hours postoperatively. SAF312, like topical NSAIDs, reduced the need for ORM and may be opioid sparing for optimal management of post-PRK pain.Topical ocular SAF312 2.5% treatment after PRK demonstrated a safety profile comparable with vehicle, with no serious or drug-related AEs and no delay in cornea reepithelization. There were no clinically relevant changes observed for visual acuity, blink rate, tear production, or corneal staining after SAF312 administration compared with vehicle. OPAS results also support the well-tolerated safety profile of SAF312, with participants reporting symptoms of redness, burning, sensitivity to light, and tearing to be slightly lower or comparable with vehicle treatment. Fewer SAF312-treated eyes showed severe conjunctival hyperemia on day 2. In contrast, ocular hyperemia and stinging are common AEs associated with topical ophthalmic NSAID treatment.TRPV1 channel antagonists, such as SAF312, offer advantages over other pain management strategies as they prevent ocular pain by blocking a receptor where pain is generated, as opposed to traditional analgesic drugs that either inhibit pain transmission (e.g., opiates) or suppress inflammation (e.g., NSAIDs). The study also confirmed that topical ocular administration of SAF312 2.5% led to a quick but very low level of systematic exposure, consistent with the findings of the FIH study.Owing to the low systemic exposure and the chemical properties of the SAF312 molecule, there seems to be a low risk on the CNS or other systemic side effects.A different TRPV1 antagonist, AMG-517, promoted peripheral neuronal regeneration in rats after unilateral sciatic nerve injury by attenuation of TRPV1 activation. However, the role of SAF312 on the neuronal regeneration is yet to be explored.The strength of the study is its unique bilateral crossover PRK study design, where participants received either SAF312 2.5% or vehicle in the first treated eye and later switched study drug after PRK in the second eye, thereby acting as their own controls. Further, in this study, VAS and ORM use details were captured using a real-time electronic app, adding to its strength as written diaries are prone to error and fabrication. Thus, the results obtained using the ePRO device are more robust.Study limitations include a relatively small sample size. In this study, pain after PRK was primarily assessed using electronic VAS on a 100-mm scale. Literature on a similar topic assessed pain after PRK using various methods besides VAS, including the NRS,In addition, participants in this study had the option of using ORM at any time during the study, which had the potential to confound the VAS pain severity efficacy results. To decouple the effect of ORM on VAS primary efficacy endpoints, any prespecified VAS reading taken within 4 hours of any ORM use was replaced with the VAS value recorded at the time the ORM was taken. Additional sensitivity analyses, including VAS scores after ORM use as missing and ignoring ORM use, were performed to examine the use of ORM on the study conclusions; all sensitivity analyses produced similar results and confirmed the robustness of the findings on drug effect (data not shown). Although bandage contact lens and corticosteroids are routinely used as postoperative standard of care (SOC), it serves as an additional confounding factor in the assessment of the effects of SAF312. This may have created some variability to the number of patients experiencing pain and the severity of their pain.Thus, in this phase 2 clinical trial, topical ocular SAF312 2.5% (dosed four times daily for 3 days) showed efficacy in decreasing the severity of ocular pain associated with corneal epithelial defect after PRK surgery, no delay in wound healing, and a well-tolerated safety profile. The results of the study highlight that SAF312 can be a promising therapeutic option for patients with ocular pain after PRK. Further studies with additional patient-reported outcomes, such as quality of life, will provide better insights into the potential uses of topical SAF312 for ocular pain management.