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FormalPara Lotilaner ophthalmic solution 0.25% (XDEMVY™): Key Points

A GABA-Cl inhibitor selective for mites being developed by Tarsus for the treatment of Demodex blepharitis and Demodex-induced meibomianitis.

Received its first approval on 24 July 2023 in the USA.

Approved for the treatment of Demodex blepharitis.

1 Introduction

Lotilaner ophthalmic solution 0.25% (hereafter referred to as lotilaner 0.25%) [XDEMVY™] is a gamma-aminobutyric acid-gated chloride (GABA-Cl) channel inhibitor selective for mites that is being developed by Tarsus Pharmaceuticals for the treatment of Demodex blepharitis and meibomian gland dysfunction in patients with Demodex lid infestation (Demodex-induced meibomianitis). Demodex blepharitis is a common, underdiagnosed and undertreated eye condition caused by two species of Demodex mites that infest the eyelash follicles and the meibomian glands [1, 2]. While ocular itching is the most common symptom of Demodex blepharitis, it can also present with a range of other symptoms like dryness, discharge, eye redness, burning, tearing, foreign body sensation, pain and blurred vision [2]. The pathognomonic clinical sign of Demodex infestation is the presence of collarettes, which are cylindrical dandruff debris structures that extrude out of the base of the eyelashes and consist of mite waste products and eggs [3]. The main objective in treating Demodex blepharitis is to eliminate or significantly reduce the presence of collarettes [3]. This condition was typically managed with over-the-counter remedies mainly consisting of products based on tea tree oil that are irritating and are toxic to the meibomian glands, with treatment often ineffective [2, 3].

On 24 July 2023, lotilaner 0.25% received its first approval in the USA for the treatment of Demodex blepharitis [4]. The product is available as a multidose eye drop solution bottle [5]. The recommended dosage is one drop into each eye twice daily (≈ 12 hours apart) for 6 weeks. If multiple topical ophthalmic drugs are being used, they should be administered with a minimum of 5 minutes between each application [5]. Lotilaner 0.25% is also currently in phase 3 development for Demodex blepharitis in China and phase 2 development for Demodex-induced meibomianitis in the USA.

figure a

2 Scientific Summary

2.1 Pharmacodynamics

Lotilaner is an isooxazoline class ectoparasiticide used in veterinary [6, 7] and now human medicine. Blocking of GABA-Cl channels by lotilaner results in spastic paralysis and eventual death of the target organisms [5, 6]. In vitro, lotilaner does not inhibit mammalian GABA-Cl channels at concentrations up to 30 μM (≈ 1100 times the recommended human ophthalmic dose) [5, 6]. Ex vivo, lotilaner 0.25% kills > 95% of Demodex mites within 24 h (as cited in [8]).

2.2 Pharmacokinetics

The systemic pharmacokinetic properties of lotilaner 0.25% were assessed in healthy volunteers following single and multiple ophthalmic applications [5]. The peak concentration of lotilaner in whole blood occurred 2 h after a single application on the first day, and 1 h after the final application on day 42. Among 138 patients with Demodex blepharitis who received lotilaner 0.25% twice daily for 42 days, the mean systemic exposure to lotilaner at the end of treatment was 12.0 ng/mL. Lotilaner exhibits high plasma protein binding (> 99.9%) in human plasma, with ≈ 10% partitioning to human blood cells. Lotilaner is not metabolized by cytochrome P450 (CYP) enzymes. Based on the accumulation ratio over the dosing interval of 12 h, the effective half-life of lotilaner is 11 days [5].

2.3 Therapeutic Trials

Where reported, the efficacy assessment of lotilaner 0.25% in Demodex blepharitis in clinical trials [8,9,10,11,12,13,14] was based on the following criteria. Collarette grading scale score ranged from 0 to 4, based on the number/proportion of lashes with collarette per eyelid: 0 to 2 (grade 0), 3 to 10 (grade 1), > 10 to < 1/3 (≈ 50) [grade 2], ≥ 1/3 to < 2/3 (≈ 100) [grade 3]; ≥ 2/3 (≈ 150) [grade 4]. A reduction to ≤ 10 collarettes was considered clinically meaningful in a post hoc analysis [14]. Lid margin erythema grading scale score ranged from 0 to 3 (0 = none; 3 = severe); erythema cure rate was defined as the proportion of patients who achieved grade 0 erythema. Composite cure rate was defined as the proportion of patients who achieved grade 0 collarette and grade 0 erythema. Mite eradication rate was defined as the proportion of patients who achieved a Demodex density of 0 per lash in the analysis eye.

figure b

Features and properties of lotilaner ophthalmic solution 0.25%

Alternative names

TP-03, XDEMVY™

Class

Amides; Amines; Anti-inflammatories; Antibacterials; Antimalarials; Antiparasitics; Azoles; Chlorinated hydrocarbons; Chlorobenzenes; Eye disorder therapies; Fluorinated hydrocarbons; Oxazoles; Skin disorder therapies; Small molecules; Thiophenes

Mechanism of action

Gamma-aminobutyric acid (GABA)-Cl receptor antagonists specific for mites

Route of administration

Ophthalmic

Pharmacodynamics

Inhibits GABA-gated chloride channels; causes spastic paralysis and death of Demodex mites

Pharmacokinetics

Time to Cmax in whole blood 1–2 h; plasma protein binding > 99.9%; not metabolized by CYP enzymes; effective half-life 11 days

Most frequent adverse reaction

Instillation site stinging and burning (10%)

ATC codes

 

 WHO ATC code

S01 (Ophthalmologicals), S01A (Antiinfectives)

 EphMRA ATC code

S1A (Ophthalmological Anti-Infectives)

Chemical name

3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl]thiophene-2-carboxamide

2.3.1 Phase 3 and 2b/3 trials

2.3.1.1 Saturn-2

Lotilaner 0.25% was effective in the treatment of Demodex blepharitis in the randomized, double-masked, vehicle-controlled, multicentre, phase 3, Saturn-2 trial (NCT04784091) [13]. Eligible patients were adults (age ≥ 18 years) with Demodex blepharitis who had all of the following signs in the same eye: > 10 lashes with grade ≥ 2 collarettes on the upper lid; at least mild erythema of the upper eyelid margin; and mite density of ≥ 1.5 mites per lash in the upper and lower eyelids combined. At screening stage, patients were required to exhibit a corrected distance visual acuity of ≥ 0.7 logarithm of the minimum angle of resolution, as assessed by the Early Treatment of Diabetic Retinopathy Study scale in each eye at screening. Exclusion criteria included use of prescription treatment (antibacterial, antiparasitic, anti-inflammatory) or non-prescription products (e.g., tea tree oil, hypochlorous acid) within 14 days, as well as topical prostaglandin analog use within 30 days. Patients were randomized to receive lotilaner 0.25% (n = 203) or the formulation without lotilaner (vehicle control) [n = 209] one drop in each eye twice daily (morning and evening) for 6 weeks. The Demodex life cycle has been estimated to be ≈ 3 weeks, and the 6-week treatment period was intended to provide acaricidal dosing across two full life cycles of Demodex [13].

Significantly more lotilaner 0.25% than vehicle control recipients achieved the primary endpoint of ≤ 2 collarettes in the upper eyelid of the analysis eye on day 43 (56.0% vs 12.5%; p < 0.0001) [13]. This finding was supported by the proportion of patients with a collarette reduction to ≤ 10 collarettes (89.1% vs 33.0%), mite eradication rate (51.8% vs 14.6%), erythema cure rate (31.1% vs 9.0%) and the composite cure rate (19.2% vs 4.0%) on day 43 (p < 0.0001 for all). On day 43, 90.7% of lotilaner 0.25% recipients and 88.5% of vehicle control recipients found the drop to be neutral to very comfortable. The mean dosing compliance was 98.7% in the lotilaner 0.25% group [13].

2.3.1.2 Saturn-1

Lotilaner 0.25% was effective in the treatment of Demodex blepharitis in the randomized, double-masked, vehicle-controlled, multicentre, phase 2b/3, Saturn-1 trial (NCT04475432) [12]. This trial was similar to Saturn-2 with respect to inclusion/exclusion criteria, randomized treatments (n = 212 for lotilaner 0.25% and 209 vehicle control) and treatment duration (6 weeks). Significantly more lotilaner 0.25% than vehicle control recipients achieved the primary endpoint of ≤ 2 collarettes in the upper eyelid of the analysis eye on day 43 (44.0% vs 7.4%; p < 0.0001). This finding was supported by the proportion of patients with a collarette reduction to ≤ 10 collarettes (81.3% vs 23.0%), mite eradication rate (67.9% vs 17.6%), erythema cure rate (19.1% vs 6.9%) and the composite cure rate (13.9% vs 1.0%) on day 43 (p ≤ 0.0001 for all) [12].

2.3.2 Phase 2 Trials

2.3.2.1 Europa

Lotilaner 0.25% was effective in the treatment of Demodex blepharitis in the randomized, double-masked, vehicle-controlled, multicentre, phase 2b, Europa trial (ACTRN12620000320954) [11]. Eligible patients were adults (aged ≥ 18 years) diagnosed with Demodex blepharitis, meeting the following criteria in at least one eye: over 10 collarettes on the upper eyelid, upper eyelid margin erythema of at least mild intensity and an average mite density of ≥ 1.5 mites per lash. Patients were randomized to receive lotilaner 0.25% (n = 27) or vehicle control (n = 27) one drop in each eye twice daily for 42 days. At day 42, significantly more lotilaner 0.25% than vehicle control recipients achieved the primary endpoint of ≤ 2 collarettes in the upper eyelid of the analysis eye (80.0% vs 15.8%; p < 0.001), with similar results seen for mite eradication rate (73.3% vs 21.1%; p = 0.003) and composite cure rate (73.3% vs 10.5%; p < 0.001) [11].

2.3.2.2 Io

Lotilaner 0.25% was effective in the treatment of Demodex blepharitis in the single-arm, open-label, phase 2a, Io trial (ISRCTN 24398865) [9]. The eligibility criteria in this trial were similar to those in the Europa trial. In Io, 18 patients received lotilaner 0.25% one drop in each eye twice daily for 42 days. At day 42, 72.2% of patients achieved ≤ 2 collarettes in the upper eyelid of the analysis eye and the mite eradication rate was 77.8% [9].

2.3.2.3 Jupiter

A pilot formulation of lotilaner 0.25% was effective in the treatment of Demodex blepharitis in the randomized, double-masked, vehicle-controlled, phase 2b Jupiter trial (ISRCTN12449602) [10]. The eligibility criteria in this trial were similar to those in the Europa trial. Patients were randomized to receive lotilaner 0.25% (n = 30) or vehicle control (n = 30) one drop in each eye twice daily for 28 days. Lotilaner 0.25% treatment was associated with a significant (p ≤ 0.003) decrease in collarette grade versus vehicle control beginning at day 14 and this difference continued through day 90. At day 28, significantly more lotilaner 0.25% than vehicle control recipients achieved a collarette reduction to ≤ 10 collarettes (87.5% vs 22.2%; p < 0.001) and mite eradication (66.7% vs 25.9%; p = 0.005) [10].

2.3.2.4 Mars

A pilot formulation of lotilaner 0.25% showed promising efficacy in the treatment of Demodex blepharitis in the first-in-human, single-arm, open-label phase 2a Mars trial [8]. This study enrolled adult (≥ 18 years) patients with Demodex blepharitis, defined as > 10 collarettes on the upper lid, lid margin erythema and Demodex density of ≥ 1.5 mites per lash. Patients received lotilaner 0.25% one drop in each eye twice daily for 28 days. In 15 evaluable patients, lotilaner 0.25% treatment was associated with significant (p < 0.05) improvements in mean collarette grade and mean mite density at day 14 and these improvements were sustained through day 90. The mite eradication rate was 57.1% at day 28 [8].

Key clinical trials of lotilaner ophthalmic solution 0.25% (Tarsus Pharmaceuticals, unless stated otherwise)

Drug(s)a

Indication

Phase

Status

Location(s)

Identifier

Lotilaner 0.25%, vehicle

Demodex blepharitis

3

Completed

USA

NCT04784091, TRS-010, Saturn-2

Lotilaner 0.25%, vehicle

Demodex blepharitis

2b/3

Completed

USA

NCT04475432, TRS-009, Saturn-1

Lotilaner 0.25%, vehicle

Demodex blepharitis

3

Active, not recruiting

China

NCT05629390, CTR20220726, LIBRAb

Lotilaner 0.25%, vehicle

Demodex blepharitis

2b

Completed

Mexico

ACTRN12620000320954, TRS-006, Europa

Lotilaner 0.25%

Demodex blepharitis

2a

Completed

Mexico

ISRCTN24398865, TRS-005, Io

Lotilaner 0.25%, vehicle

Demodex blepharitis

2b

Completed

Mexico

ISRCTN12449602, TRS-004, Jupiter

Lotilaner 0.25%

Demodex blepharitis

2a

Completed

Mexico

Mars

Lotilaner 0.25%, vehicle

Demodex-induced meibomianitis

2

Active, not recruiting

USA

NCT05454956, TRS-008, Ersa

  1. aA pilot formulation for Mars and Jupiter studies, and the currently approved formulation for all other studies
  2. bSponsored by LianBio

2.4 Adverse Events

Lotilaner 0.25% was well tolerated in patients with Demodex blepharitis in clinical trials [8,9,10,11,12,13]. In a combined analysis of Saturn-2 and Saturn-1 (n = 833), the most common ocular adverse reaction to lotilaner 0.25% was instillation site stinging and burning (incidence 10%) [5]. Other ocular adverse reactions that occurred in < 2% of patients were chalazion/hordeolum and punctate keratitis [5].

In Saturn-2, treatment-related ocular adverse events (AEs) occurred in 19.2% and 12.4% of patients in the lotilaner 0.25% and vehicle control groups, respectively, with the most common being instillation site pain (7.9% vs 6.7%) [13]. Other treatment-related ocular AEs that occurred in ≥ 1% of patients in either lotilaner 0.25% or vehicle control groups were dry eye (1.5% vs 0.5%), reduced visual acuity (0.5% vs 1.4%), chalazion (1.0% vs 0%), conjunctival hyperaemia (1.0% vs 0%), eyelid pruritus (1.0% vs 0%), photophobia (1.0% vs 0%), visual impairment (0.0% vs 1.0%), instillation site irritation (1.0% vs 0%) and vital dye staining of the cornea present (1.0% vs. 0%). There were no treatment-related serious AEs in the Saturn-2 trial [13].

The AE profile of lotilaner 0.25% in Saturn-1 was generally similar to that seen in Saturn-2 [12]. Patients completing the 6-week treatment period in Saturn-1 were observed for 365 days in an extension study to assess the long-term safety of lotilaner 0.25% [15]. Ocular AEs that occurred in > 1% of patients in either lotilaner 0.25% or vehicle control groups in the extension study were reduced visual acuity (3.9% vs 3.6%), visual impairment (1.6% vs 0.9%), vitreous detachment (0.8% vs 1.8%), chalazion (0% vs 1.8%) and hordeolum (1.6% vs 0%). There were no treatment-related serious AEs in the extension study [15].

2.5 Ongoing Clinical Trials

A randomized, double-blind, vehicle-controlled phase 3 trial (LIBRA; NCT05629390) is evaluating the efficacy and safety of lotilaner 0.25% in Chinese patients with Demodex blepharitis. A randomized, double-blind, vehicle-controlled, pilot, phase 2 trial (Ersa; NCT05454956) is comparing twice-daily and thrice-daily dosage regimens of lotilaner 0.25% for the treatment of Demodex-induced meibomianitis.

3 Current Status

Lotilaner 0.25% received its first approval on 24 July 2023 for the treatment of Demodex blepharitis in the USA [4].