Author's response Comments on: Efficacy and safety of pilocarpine hydrochloride ophthalmic solution USP 1.25% w/v (PresVu eye drops) versus placebo ophthalmic solution for the treatment of presbyopia – A multicentric clinical trial

Dear Editor, We appreciate the authors’ interest in pharmacological treatments for presbyopia and their reference to our recent multicentric clinical trial published in the Indian Journal of Ophthalmology.[1] First, we acknowledge the authors’ observation regarding the 30-day follow-up period. We completely agree that longer-term data will be valuable in establishing the sustained efficacy and safety profile of pilocarpine 1.25%. However, the risks mentioned, such as retinal detachment or lens opacity, are speculative and not supported by current evidence. Our study, like the pivotal GEMINI trials, was designed for short-term efficacy and safety. As noted in our paper, retinal events reported in other studies occurred in high myopes or pseudophakic patients, both independent risk factors, making causality with pilocarpine difficult to establish. The absence of long-term data on pilocarpine is a well-recognized limitation in the current body of literature and was clearly acknowledged in our publication. Instead of reiterating known gaps, we would encourage the authors, and others in the community, to consider initiating well-designed, real-world studies with longer follow-up periods that contribute new evidence to address these questions. Second, our study was designed to evaluate the safety and efficacy of pilocarpine 1.25% in emmetropic presbyopes without ocular comorbidities, its intended user group. In patients with glaucoma, cataract, or retinal disease, near vision correction is typically not a therapeutic priority. As stated in our discussion, pilocarpine should not be prescribed in such cases. Therefore, the comment that external validity is “ambiguous” or that safety has not been investigated in these groups is not applicable. Third, subjective patient experience was an integral part of our study. We used the validated Near Vision Presbyopia Task-based Questionnaire (NVPTQ) to assess patient-reported improvements in everyday near tasks,[2] including reading expiry labels and mobile text. As shown in Supplemental Fig. 4, published in the original Study,[1] total NVPTQ scores positively correlated with both satisfaction and near vision gains. We have transparently acknowledged in our discussion the possibility of night vision disturbances due to pilocarpine-induced miosis, while noting that this was not commonly reported in our study cohort. Last, while headaches were reported in a minority of patients, most were transient and typically resolved within a few days. Importantly, no discontinuations due to intolerable side effects were observed in our study or in larger pivotal trials like GEMINI, suggesting that long-term adherence is unlikely to be significantly affected. As for comparisons with surgical options, such as multifocal IOLs, inlays, or LASIK, these are fundamentally different in invasiveness, cost, and patient selection. Pilocarpine eye drops are intended for emmetropic presbyopes seeking a noninvasive, reversible alternative to reading glasses, not for patients already inclined toward surgical correction. In conclusion, we reiterate that pilocarpine 1.25% should be prescribed with caution and only after comprehensive ophthalmic evaluation, including intraocular pressure, angle assessment, and thorough peripheral retinal examination. The drug is intended for use in otherwise healthy, emmetropic presbyopes seeking spectacle independence. It should not be used in patients with coexisting ocular comorbidities such as glaucoma, cataract, or retinal disease as these populations typically do not present with near vision concerns warranting pharmacologic correction. Conducting studies in such subgroups may pose ethical challenges and limited clinical relevance. While cautious exploration of pilocarpine in pseudophakic patients with total posterior vitreous detachment may be reasonable, heightened care is warranted given the known association between presbyopia and increased retinal detachment risk. We believe our trial and accompanying discussion have already acknowledged all the key clinical and safety concerns raised by the authors, including potential side effects, patient-reported outcomes, and limitations of short-term data. No new issues have been brought forward in this letter. Disclosures Dr Sabyasachi Sengupta is a speaker and receives travel support for Novartis, Roche, Lupin and Bayer. Ms. Vidya Ajila is an employee of ENTOD Pharmaceuticals and heads regulatory affairs, Dr Aditi Datta is the founder of the contract research organization (Biosite Research) that carried out this multicentric clinical trial and has been reimbursed for her services. This study was sponsored by ENTOD Pharmaceuticals; however, the sponsor had no role in the study design, execution, data collection, analysis, or interpretation of results. Financial support and sponsorship: Nil. Conflicts of interest: There are no conflicts of interest.