AS NEW TREATMENT OPTIONS become available for the pharmacologic treatment of presbyopia, it is important to dissect the data and clinical trials to better understand the role that demographics play in patient selection, as we seek to identify the proper patient profile.

Pilocarpine is a cholinergic muscarinic receptor agonist that was first approved, at higher concentrations, for treatment of glaucoma. It acts through cholinergic receptors on the iris sphincter causing pupillary sphincter contraction, resulting in miosis.¹ With regard to presbyopia, miosis is used to increase depth of focus and improve near vision.² It can also have the additional benefits of reducing aberrations.

With near tasks only comprising a certain percentage of a patient’s visual day, an ideal pharmacologic treatment for presbyopia must improve near vision without compromising distance visual acuity. In addition, the medication must be well tolerated, and adverse effects must be minimal if patients are going to utilize this option, as opposed to other current presbyopia correcting options. This scenario is where reformulation can play a critical role in redefining a category.

Qlosi^TM (Orasis Pharmaceuticals) is a low-dose, preservative-free ophthalmic solution of 0.4% pilocarpine HCl, recently approved for the treatment of presbyopia. Its concentration is one-fifth of the most commonly prescribed concentration (2.0%) pilocarpine eyedrops available for glaucoma and one-third of the currently available presbyopia eyedrops (1.25%).

Qlosi’s clinical trials, NEAR-1 and NEAR-2, were identical randomized, double-masked, vehicle-controlled, parallel-group, phase 3 studies. A total of 613 participants 45 to 64 years old with distance-corrected near visual acuity (DCNVA) logMAR ≥0.40 and ≤0.90 were randomized into 2 groups: CSF-1 (n=309) or vehicle (n=304). Participants applied 1 drop of CSF-1 or vehicle 2 times daily in both eyes at an interval of 2-3 hours for 2 weeks.

Ophthalmic assessments were performed at several time points on days 1, 8, and 15. Response was defined as ≥3-line gain in DCNVA without a loss of ≥1 line in corrected distance visual acuity (CDVA) in the study eye under mesopic room lighting conditions. Pupil diameter and change from baseline were measured at all time points on clinic visit days.

In both trials, Qlosi met its primary and key secondary endpoints on day 8, achieving statistically significant 3-line or more gains in DCNVA and no losses of 1 line or more in distance visual acuity. Pooled across the two studies, 40% and 50% of participants demonstrated these gains at 1 hour post-dose 1 and 1 hour post-dose 2, respectively (P<.0001). Qlosi also achieved statistically significant 3-line improvement at all measured time points on days 1 and 15. On day 15, participants achieved statistically significant 3-line or more improvement in DCNVA as early as 20 minutes and for up to 8 hours post-dose 1. In addition, Qlosi demonstrated an excellent tolerability and safety profile, with comparable redness and comfort vs vehicle, validating the preservative-free presentation and proprietary formulation of Qlosi. The most common treatment-related adverse events of headache and instillation site pain occurred in only 6.8% and 5.8% of participants, respectively. Of all Qlosi participants, only 2.6% reported moderate treatment-related adverse events. All other adverse events were mild.

Additional analyses demonstrated that Qlosi produced a consistent pupil reduction across days 1, 8, and 15 at 1 hour post-dose 1 and 1 hour post-dose 2. Consistent with improvement in visual acuity, pupillary constriction was observed as soon as 30 minutes after 1 dose of treatment on day 1 and 20 minutes on day 15, lasting up to 8 hours. Notably, the percentage of 3-line responders increased from day 1 to day 15, without a corresponding change in the average pupil diameter. This gain over time suggests that neuroadaptation may play an important role in near vision improvement (Figure 1).³

In a post-hoc analysis, treatment response in different subgroups of presbyopes treated with Qlosi was analyzed. Treatment response was defined as ≥3-line gain in mesopic DCNVA without loss of ≥1 line in CDVA in the study eye. A generalized estimating equation model with logistic link function and a binary distribution with unstructured covariance matrix was constructed to compare the rate of treatment response across stratifications on day 8. Analysis was based on the following:

• Age: 45-54 vs 55-64 years old;
• Sex: male vs female;
• Iris color: light vs brown;
• Baseline pupil size under mesopic room lighting conditions: >3.5 mm vs ≤3.5 mm;
• Baseline manifest refraction spherical equivalent:
  • - Myopes: -4.5 to <-0.5 D;
  • - Emmetropes: -0.5 to +0.5 D;
  • - Hyperopes: >+0.5 to +2.0 D; and
• Baseline DCNVA: ≤0.50 logMAR (20/63 or better) vs >0.50 logMAR (worse than 20/63) at 40 cm.

Among the different subgroups, baseline DCNVA demonstrated a significant predictive effect in achieving a 3-line gain on day 8. The participants whose baseline DCNVA was worse than 20/63 achieved a significantly better treatment response than those whose baseline was 20/63 or better (Figure 2).

Intuitively, this outcome makes sense because the worse the patient is at baseline, the more likely the patient is to achieve a 3-line gain. Clinically speaking, evaluating baseline DCNVA is our best clinical benchmark for determining whether a patient will achieve a 3-line gain. Despite observing a numerically higher treatment response in younger participants, women, those with a light iris, those with a baseline pupil size ≤3.5 mm, and myopes, the variations within these subgroups were not statistically significant. This outcome indicates that Qlosi treatment was effective across all groups; therefore, clinicians should not rule out patients based on age, gender, iris color, or baseline pupil size.⁴

In summary, Qlosi’s preservative-free, low-dose formulation demonstrated superiority over vehicle in achieving near visual acuity improvement and pupil size reduction. Near visual acuity improved from days 1 to 15 with consistent pupil size reduction, suggesting that neuroadaptation may play a role in adjusting to a new near vision. Last, proper patient selection is crucial for predicting outcomes and managing patient expectations. Baseline DCNVA demonstrated a predictive effect in treatment response on day 8. These results will not only assist with patient selection but also will help with setting expectations regarding how a patient will learn their new near vision. We are eager to prescribe Qlosi once it is available in 1H 2024, as this optimized formulation will provide a break from readers, which so many of our patients are seeking. ■

The Qlosi trademark is owned by Orasis Pharmaceuticals.

References

1. Haghpanah N, Alany R. Pharmacological treatment of presbyopia: a systematic review. Eur J Transl Myol. 2022;32(3):10781.
2. Orman B, Benozzi G. Pharmacological strategies for treating presbyopia. Curr Opin Ophthalmol. 2021;32(4):319-323.
3. Lang JR, Coats J, Gaddie IB. Persistence of near vision improvement and pupil size: Results of the pooled (NEAR) phase 3 studies of CSF-1 (0.4% pilocarpine HCl) for presbyopia. Poster presented at: Annual meeting of the American Academy of Optometry; Oct 11-14, 2023.
4. Coats J, Lighthizer N, Wesley G. Treatment response in different subgroups of presbyopes treated with CSF-1 (0.4% pilocarpine HCl): pooled results of the phase 3 NEAR clinical trials. Poster presented at: Annual meeting of the American Academy of Optometry; Oct 11-14, 2023.

 

Dr. Lang is the lead optometrist at Associated Eye Care in Minnesota and is the director of the practice’s ocular disease residency program. He specializes in cornea and ocular surface diseases, as well as therapeutic contact lenses and surgical comanagement. He is also adjunct clinical faculty at the Illinois College of Optometry, The Ohio State University, and Salus University.

 

Dr. Coats works in a large OD/MD practice in Arkansas. The majority of her clinical practice is dedicated to ocular disease, comprehensive eye care, perioperative care, and contact lenses, with a special interest in the ocular surface and dry eye disease.