Laquinimod Eye Drops for Uveitis

(LION Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Quan Dong Nguyen

Must not be taking: Cyclosporine, Corticosteroids, CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Infectious disease, Surgery history, Hepatic impairment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

12 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop using certain medications before and during the study. Specifically, you must not use any topical cyclosporine, corticosteroid, or other specified eye medications in the study eye within 14 days of enrollment. Additionally, you must avoid medications that are strong or moderate inhibitors or inducers of CYP3A4 within 2 weeks of the baseline visit and during the study.

Is Laquinimod generally safe for humans?

Laquinimod has been studied for multiple sclerosis and was found to be safe and well-tolerated in early human trials, with a better side effect profile compared to a similar drug, roquinimex. ^{1 2 3 4 5}

How is the drug Laquinimod different from other treatments for uveitis?

Laquinimod eye drops for uveitis are unique because they offer a non-steroidal, potentially less invasive treatment option compared to traditional therapies like corticosteroids or immunosuppressive agents, which often have significant side effects. Unlike systemic treatments, Laquinimod is administered directly to the eye, which may reduce systemic exposure and associated risks. ^{6 7 8 9 10}

What is the purpose of this trial?

The LION Study is a prospective, single-center phase 1 clinical trial to evaluate the safety, tolerability, and distribution of Laquinimod administered as topical eye drops for two weeks in human participants.

Eligibility Criteria

The LION Study is for adults over 18 who can follow study instructions and consent to participate. It's suitable for non-pregnant, non-lactating women who are post-menopausal or sterilized. Participants must be scheduled for specific eye surgeries (PPV or diagnostic vitrectomy) and have normal intraocular pressure.

Inclusion Criteria

Participants who are capable and willing to provide informed consent and follow study instructions

I am scheduled for a specific eye surgery called pars plana vitrectomy.

Participants with intraocular pressure (IOP) ≥ 5 mmHg and ≤22 mmHg in study eye

Exclusion Criteria

I have received eye injections within the last 3 months.

I have HIV or another immune system disorder.

I have an active eye infection causing inflammation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stage One - Open label dose escalation

Up to three subsequent dose-escalation groups will receive Laquinimod eye drops for 2 weeks and samples will be assayed for Laquinimod concentration in aqueous humor, vitreous and plasma.

2 weeks

Daily administration

Stage Two - Randomized, Controlled Comparison

2 Laquinimod doses will be selected for a randomized comparison. The doses in stage 2 will not exceed those studied in stage 1.

2 weeks

Daily administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events assessment at Post operative Day 1 and Day 8.

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Laquinimod

Trial Overview This trial tests Laquinimod eye drops' safety and how well they're tolerated when used daily for two weeks. Researchers also want to see how the drug spreads in the eyes of participants undergoing certain eye surgeries.

Participant Groups

Group I: Stage 2 Comparison Group B Experimental Treatment 1 Intervention

(3 to 6 participants): Participants will receive a dose of Laquinimod as 2 drops in the study eye for 14 days before the surgery. Frequency to be decided at the end of stage 1.

Group II: Stage 2 Comparison Group A Experimental Treatment 1 Intervention

(3 to 6 participants): Participants will receive a dose of Laquinimod eye drops in the study eye for 14 days before the surgery. Frequency to be decided at the end of stage 1.

Group III: Group 3 Experimental Treatment 1 Intervention

(3 to 6 participants): Participants will receive a dose of Laquinimod as 2 drops three times a day(1.8 mg per day) for 14 days before the surgery.

Group IV: Group 2 Experimental Treatment 1 Intervention

(3 to 6 participants): Participants will receive a dose of Laquinimod as 2 drops twice a day (1.2mg per day) in the study eye for 14 days before the surgery

Group V: Group 1 Experimental Treatment 1 Intervention

(3 to 6 participants): Participants will receive a dose of Laquinimod as 2 drops once a day (0.6mg per day) in the study eye for 14 days before the surgery.

Who Is Running the Clinical Trial?

Quan Dong Nguyen

Lead Sponsor

Trials

3

Recruited

70+

Global Ophthalmic Research Center (GORC)

Collaborator

Trials

2

Recruited

40+

Findings from Research

In a study of 188 multiple sclerosis patients on fingolimod (0.5 mg), none developed uveitis, indicating a lower incidence than typically expected in this population.

Only 2.13% of patients experienced macular edema without inflammation, suggesting that while monitoring for eye issues is necessary, fingolimod may not significantly increase the risk of uveitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence of uveitis and macular edema among patients taking fingolimod 0.5 mg for multiple sclerosis. Sonne, SJ., Smith, BT.[2020]

Laquinimod demonstrated neuroprotective and anti-inflammatory effects on the optic nerve and retina in a mouse model of multiple sclerosis, significantly reducing neurological symptoms and improving neuronal function when administered before clinical signs appeared.

The treatment with laquinimod led to a decrease in cellular infiltration and demyelination in the optic nerve, as well as preservation of retinal ganglion cells, suggesting its potential as a therapeutic option for protecting the visual system in MS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Laquinimod protects the optic nerve and retina in an experimental autoimmune encephalomyelitis model. Wilmes, AT., Reinehr, S., Kühn, S., et al.[2019]

In a study involving 2615 patients with relapsing-remitting multiple sclerosis, fingolimod (Gilenya) was associated with a low incidence of macular edema (ME), with only 19 confirmed cases observed, primarily in those receiving the higher dose of 1.25 mg.

Patients with a history of uveitis were found to be at a higher risk for developing ME, highlighting the importance of pre-treatment ophthalmic evaluations and ongoing eye monitoring during fingolimod therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Zarbin, MA., Jampol, LM., Jager, RD., et al.[2022]

Laquinimod is an oral immunomodulatory agent for relapsing multiple sclerosis that has shown a favorable safety profile compared to its predecessor, roquinimex, which had significant side effects.

Clinical trials (Phase I, II, and III) indicate that laquinimod has a moderate effect on reducing relapse rates and new lesions in MS patients, while also demonstrating stronger effects on sustained progression and brain atrophy, suggesting its potential as a valuable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Laquinimod (ABR-215062) for the treatment of relapsing multiple sclerosis. Constantinescu, SE., Constantinescu, CS.[2015]

Methotrexate (MTX) is currently the most effective DMARD for treating juvenile idiopathic arthritis (JIA) and associated uveitis, but controlled studies specifically for uveitis are lacking, limiting the evidence to expert opinions and descriptive studies.

Other treatments like Mycophenolate mofetil (MMF) and cyclosporin A (CsA) show limited or inconsistent efficacy for JIA uveitis, highlighting the need for more controlled studies to determine the best therapies for children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[EBM analysis: classic DMARDs (disease-modifying antirheumatic drugs) and immunosuppressants in arthritis and uveitis]. Niehues, T., Winterhalter, S., Zierhut, M., et al.[2015]

Adalimumab significantly improved inflammation in patients with early onset, chronic anterior uveitis associated with juvenile idiopathic arthritis, showing a 30% reduction in inflammation at month 2 compared to placebo (9 out of 16 responders vs. 3 out of 15, P=0.038).

The treatment was generally safe, with no serious adverse events linked to adalimumab, suggesting it is a viable option for patients who do not respond adequately to topical steroids and methotrexate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ADJUVITE: a double-blind, randomised, placebo-controlled trial of adalimumab in early onset, chronic, juvenile idiopathic arthritis-associated anterior uveitis. Quartier, P., Baptiste, A., Despert, V., et al.[2019]

The 0.19 mg fluocinolone acetonide implant was successfully used in a 20-year-old woman with juvenile idiopathic arthritis (JIA) and chronic uveitis, showing significant improvements in visual acuity and reduction in central retinal thickness over a 12-month follow-up period.

This case suggests that the fluocinolone implant can be a safe and effective long-term treatment option for JIA-associated uveitis, particularly for patients who do not respond well to traditional corticosteroids or have compliance issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bilateral 0.19 mg Fluocinolone Acetonide Intravitreal Implant in the Successful Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis and Secondary Macular Oedema: A Case Report and Review of Intravitreal Therapies. Ansari, AS., Amir, Z., Williams, GS.[2021]

In a study of 19 patients with recurrent idiopathic acute anterior uveitis (RIAAU), methotrexate (MTX) at a target dose of 25 mg/week was found to be highly effective, with 84% of patients remaining flare-free over an average follow-up of 3.3 years.

The frequency of uveitis flares significantly decreased from 2.12 to 0.11 per patient-year, indicating that MTX not only reduces flare-ups but also allows for the tapering off of systemic corticosteroids in all patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High Efficacy of Methotrexate in Patients with Recurrent Idiopathic Acute Anterior Uveitis: a Prospective Study. Bachta, A., Kisiel, B., Tłustochowicz, M., et al.[2017]

In a study of 38 eyes from 27 patients with uveitis treated with dexamethasone implants, significant improvements in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were observed, indicating effective long-term management of ocular inflammation.

The treatment was generally safe, with minimal ocular complications; only 7 instances of increased intraocular pressure were noted, all manageable with medication, and no surgeries were required for complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment with repeat dexamethasone implants results in long-term disease control in eyes with noninfectious uveitis. Tomkins-Netzer, O., Taylor, SR., Bar, A., et al.[2022]

Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) for treating childhood uveitis associated with juvenile idiopathic arthritis (JIA), but controlled studies specifically for uveitis are lacking, limiting its evidence level to III.

Tumor necrosis factor-alpha (TNFalpha) blocking agents show a better evidence level (II-III) for treating uveitis in JIA, indicating they may be more effective, but further controlled studies comparing MTX with these new biological treatments are necessary for optimal therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TNFalpha-blocking agents or conventional immunosuppressive drugs in the therapy of children with uveitis? - an evidence based approach. Winterhalter, S., Niehues, T.[2013]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Incidence of uveitis and macular edema among patients taking fingolimod 0.5 mg for multiple sclerosis. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Laquinimod protects the optic nerve and retina in an experimental autoimmune encephalomyelitis model. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Laquinimod (ABR-215062) for the treatment of relapsing multiple sclerosis. [2015]

5. Germany pubmed.ncbi.nlm.nih.gov

[EBM analysis: classic DMARDs (disease-modifying antirheumatic drugs) and immunosuppressants in arthritis and uveitis]. [2015]

6. England pubmed.ncbi.nlm.nih.gov

ADJUVITE: a double-blind, randomised, placebo-controlled trial of adalimumab in early onset, chronic, juvenile idiopathic arthritis-associated anterior uveitis. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Bilateral 0.19 mg Fluocinolone Acetonide Intravitreal Implant in the Successful Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis and Secondary Macular Oedema: A Case Report and Review of Intravitreal Therapies. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

High Efficacy of Methotrexate in Patients with Recurrent Idiopathic Acute Anterior Uveitis: a Prospective Study. [2017]

9. United States pubmed.ncbi.nlm.nih.gov

Treatment with repeat dexamethasone implants results in long-term disease control in eyes with noninfectious uveitis. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

TNFalpha-blocking agents or conventional immunosuppressive drugs in the therapy of children with uveitis? - an evidence based approach. [2013]