Efficacy and Safety of the Melanocortin Pan-Agonist PL9643 in a Phase 2 Study of Patients with Dry Eye Disease

Abstract

Purpose: The melanocortin receptor pan-agonist PL9643, a potential therapy for ocular diseases, was investigated in a phase 2, 12-week study in patients with dry eye disease (DED). Methods: This was a placebo-controlled study evaluating efficacy and safety of thrice-daily PL9643. Placebo (vehicle) was similar to tears. Primary endpoints were intra-patient changes in inferior corneal fluorescein staining and ocular discomfort after 12 weeks. Secondary endpoints were changes in additional DED signs or symptoms. Multiple secondary endpoints were not adjusted for multiplicity. Patients with moderate or severe DED were analyzed in addition to the overall intent-to-treat (ITT) population. Results: In the ITT population (n = 160) the PL9643 group did not demonstrate significant treatment difference versus placebo at week 12/day 85 for the primary endpoints (P > 0.05). In patients with moderate or severe DED (n = 53), PL9643 treatment demonstrated either nominally significant (P < 0.05) or trending (P < 0.1) improvement over placebo in mean change from baseline at week 12/day 85 in several sign endpoints, including fluorescein staining in inferior, superior, corneal sum, and total sum regions; Lissamine Green staining in temporal, nasal, conjunctival sum, and total sum regions; and tear film breakup time. Conjunctival redness also showed (nonsignificant) improvement at week 12/day 85. There were no drug-related adverse events (AEs) and no drug-related discontinuations. Conclusions: PL9643 showed no significant efficacy for the ITT population; however, efficacy results across several signs and symptoms in the subpopulation of moderate to severe DED patients, the low number of ocular AEs, and no tolerability issues suggest that PL9643 shows promise as a therapeutic for DED. Clinical Trial Registration number: NCT04268069.

Keywords: PL9643; conjunctival staining; dry eye disease; efficacy; melanocortin receptor agonist; tear film breakup time.

FIG. 1.

(A) Study design. (B) Patient disposition. AE, adverse event; CAE, controlled adverse environment; ITT, intent-to-treat.

FIG. 2.

Difference between PL9643 and placebo at weeks 2 and 12 for the population with moderate to severe DED for corneal and conjunctival fluorescein staining (A) and corneal and conjunctival Lissamine Green staining (B). Note: Treatment difference was LS (SE) change from pre-CAE baseline to post-CAE for each treatment LS mean change from baseline. Fluorescein and Lissamine Green staining were measured with the Ora Calibra Corneal and Conjunctival Staining Scale. *Nominal P < 0.05 versus placebo through analysis of covariance. Note: the type I error for secondary endpoints was not adjusted for multiplicity. Therefore, statistical significance for these endpoints should be viewed as hypothesis generating and not as statistical evidence. CAE, controlled adverse environment; DED, dry eye disease; LS, least squares; SE, standard error.

FIG. 3.

Difference between PL9643 and placebo at weeks 2 and 12 for the population with moderate to severe DED for conjunctival redness (A), tear film breakup time (B), and ocular discomfort (C). Treatment difference was LS mean (SE) change from baseline post-CAE for (A, B) and was pre-CAE for (C). Conjunctival redness was measured by the Ora Calibra Conjunctival Redness Scale; ocular discomfort was measured by the Ora Calibra Ocular Discomfort Scale. *Nominal P < 0.05 versus placebo through analysis of covariance. The type I error for secondary endpoints was not adjusted for multiplicity. Therefore, statistical significance for these endpoints should be viewed as hypothesis generating and not as statistical evidence. CAE, controlled adverse environment; DED, dry eye disease; LS, least squares.

FIG. 4.

Difference between PL9643 and placebo at weeks 2 and 12 for the population with moderate to severe DED. Ora Calibra Ocular Discomfort and 4-Symptom Questionnaire (A) and Visual Analog Scale (B). Treatment difference was LS mean (SE) change from pre-CAE baseline. *Nominal P < 0.05 versus placebo through analysis of covariance. Note: the type I error for secondary endpoints was not adjusted for multiplicity. Therefore, statistical significance for these endpoints should be viewed as hypothesis generating and not as statistical evidence. CAE, controlled adverse environment; DED, dry eye disease; LS, least squares.