This is a Phase 2, randomized, multicenter, double masked, vehicle controlled, parallel group study to evaluate the efficacy and safety of DFL24498 topical ophthalmic solution versus vehicle in participants with dry eye disease. Approximately 417 participants aged 18 years or older who meet all eligibility criteria will be enrolled at study sites in the US. The study duration will be up to 16 weeks and will consist of three periods.

Key Inclusion Criteria:

• A diagnosis of DED at least 6 months before enrollment (current use or recommended use of artificial tears for the treatment of dry eye).

• The global score of the SANDE questionnaire ≥ 30

• DED in at least one eye which is characterized by the following clinical features:

  1. Schirmer I test without anesthesia < 10 mm/5 minutes, and
  2. Total CFS grade ≥ 4 assessed by the NEI grading system, and
  3. Fluorescein tear film break-up time (TFBUT) < 10 seconds.

• Best corrected visual acuity (BCVA) score on early treatment of diabetic retinopathy study (ETDRS) chart of ≥ 35 letters (corresponding to ≥ 0.1 Snellen decimal units or ≤ 1.0 Logarithm of the Minimum Angle of Resolution (Chart) [LogMAR]) in each eye at the time of study enrollment.

• Only participants who satisfy all informed consent requirements will be included in the study.

Key Exclusion Criteria:

• Inability to speak and understand the local language sufficiently to understand the nature of the study, to provide written informed consent, and to allow the completion of all study assessments.
• Evidence of an active ocular infection in either eye.
• Anticipated need for ocular surgery during the study period, or any prior ocular surgery for 6 months prior to screening.
• Intraocular inflammation defined as anterior chamber cell or flare > 0 by Standardization of Uveitis Nomenclature (SUN) grading in either eye.
• Known or suspected ocular malignancy (ocular surface, intraocular, ocular adnexa) in either eye.

Note: Additional protocol defined Inclusion/Exclusion criteria apply.