Laquinimod

Laquinimod is a first-in-class immunomodulator with a novel mode of action for the treatment of severe inflammatory eye diseases such as uveitis.

This is laquinimod

It has been shown in experimental models of autoimmune/inflammatory diseases that laquinimod targets the aryl hydrocarbon receptor (AhR) that is present in antigen-presenting cells and involved in the regulation of these cells. By targeting the AhR, antigen presenting cells are re-programmed to become tolerogenic, so that instead of activating pro-inflammatory T cells, regulatory T cells with anti-inflammatory properties are activated leading to dampening of the inflammation in the eye.

Uveitis

Uveitis is the inflammation of the uveal tract (iris, ciliary body, and choroid), but can also lead to inflammation of nearby tissues, such as the retina, the optic nerve, and the vitreous humor. The uvea is crucial for the delivery of oxygen and nutrients to the eye tissues, and inflammation of the uvea can cause serious tissue damage to the eye, with symptoms including general vision problems and a risk of blindness. Furthermore, floater spots in the eye, eye pain and redness, photophobia, headache, small pupils, and alteration of iris color are common symptoms. If left untreated, uveitis can lead to severe eye problems, including blindness, cataracts, glaucoma, damage to the optic nerve, and detachment of the retina.

The market

The treatment options for patients with non-infectious uveitis have not advanced substantially for a long period of time. The drug of choice for most patients remains long term high dose corticosteroid therapy. Still, about 40 percent of patients fail in achieving disease control, or cannot continue with high dose corticosteroids due to side effects (Rosenbaum JT. Uveitis: treatment. In: Post TW, ed. UpToDate. Waltham (MA): UpToDate; 2021).

Recently, intra ocular corticosteroid injections have been introduced with benefit for some patients and may limit the systemic corticosteroid-related side effects. However, the procedure of injecting a sustained release depot directly in the eye is not without risks.

Approximately 1.6 million people in the nine major markets were diagnosed with uveitis 2019, whereof approx. 600,000 patients received treatment. Of these about 240,000 will fail corticosteroids and are candidates for the 2nd line of treatment (Global Data Report 2021, Uveitis – Global Drug Forecast and Market Analysis to 2029).

The global sales of drugs for uveitis totaled approx. USD 300 million in 2019 and sales are expected to reach approximately USD 0.8 billion by 2029 (Global Data Report 2021, Uveitis – Global Drug Forecast and Market Analysis to 2029). Laquinimod will be developed as a new treatment for non-infectious uveitis and has the potential to be used in the 1st line of treatment as an add on to corticosteroids as well as in the 2nd line of treatment for patients that have failed corticosteroid treatment.

Non-infectious non-anterior Uveitis – addressable opportunity as an orphan indication

Presented data is based on forecast from Global Data Report (June 2021) for 2029 for the 9 largest markets (US, EU5, Japan, Canada and Australia).

Current treatments

The current standard treatment for patients with non-infectious uveitis is high-dose oral corticosteroids or injections of corticosteroids in or around the eye. Immunosuppressants, such as methotrexate or cyclosporin, are used in 2nd line of treatment, whereas anti-TNF antibodies (Humira) are used as a 2nd or 3rd line of treatment.

There is a high unmet medical need for new effective and safe therapies for non-infectious uveitis:

  • approximately 35 percent of patients suffer from severe visual impairment with the risk of blindness
  • approximately 40 percent of patients fail on corticosteroids therapy
  • long-term treatment of corticosteroids in high doses is associated with severe side effects
  • currently no topical treatment options are available

Therefore, there is a need for new treatments with additive effects to corticosteroids to limit failures in the 1st line of treatment. Furthermore, there is a need for safer therapies that can reduce or replace long-term use of steroids and a treatment that could be administered topically and reach to the back of the eye to minimize systemic adverse effects and to reduce injection-related risks.

Laquinimod in uveitis

Laquinimod will be developed as a new treatment for non-infectious uveitis and has the potential to be used in the 1st line of treatment as an add on to corticosteroids as well as in the 2nd line of treatment for patients that have failed corticosteroid treatment.

Clinical development

An eye drop formulation of laquinimod has been developed and a preclinical safety and toxicity bridging program for topical treatment has been completed.

In parallel, planning is ongoing for a phase II clinical study of oral and eye drop formulations of laquinimod in patients with uveitis.

More information about the study can be found in the box below.

Previous clinical experience with laquinimod

During its years of advanced product development, clinical efficacy and safety data on laquinimod, oral formulation, was established in more than 5,000 patients, primarily in multiple sclerosis (MS) patients, representing more than 14,000 patient-years of exposure. Extensive datasets have also been generated, including regulatory package of preclinical and clinical safety and full commercial scale CMC documentation.

Unique immunomodulatory properties

Phase I Study of Laquinimod Eye-drops in Healthy Subjects

Ongoing

A phase I study of laquinimod eye drops in healthy subjects started in December 2021. The study will include up to 56 subjects treated in part 1 with an increasing dose of laquinimod eye drops and in part 2 with repeated doses of laquinimod eye drops.

The primary objective of the study is safety and tolerability to laquinimod eye drops and the secondary readouts include ocular toxicity, pharmacokinetics and exposure. More information about the study design is available at clinicaltrials.gov (NCT05187403). The single-ascending dose part of the study and the first multiple dose cohort are completed. The eye drop formulation of laquinimod was well tolerated, without serious side effects that can be linked to laquinimod at dose levels where we expect to achieve therapeutic concentrations. The multiple- dose part of the study is ongoing.

Publications

Laquinimod arrests development of experimental autoimmune uveitis (EAU) and inhibits related immune processes, in the context of altered gut microbiota. Biying Xu, Xiuzhi Jia, Jihong Tang, Rachel R Caspi and Igal Gery,. J Immunol May 1, 2020, 204 (1 Supplement) 150.18. Read the abstract here.

A phase II study of laquinimod in Crohn’s disease
D’Haens G, Sandborn WJ, Colombel JF, Rutgeerts P, Brown K, Barkay H, Sakov A, Haviv A, Feagan BG. Gut. 2015 Aug;64(8):1227-35

Magnetic Resonance Spectroscopy Evaluation of Neuronal Integrity and Astrocytosis in a Phase 2 Study of Laquinimod as a Treatment for Huntington Disease (LEGATO-HD). Blair R. Leavitt, Ralf Reilmann, Mark Forrest Gordon, Karen E. Anderson, Andrew Feigin, Sarah J. Tabrizi, Julie C. Stout, Paola Piccini, Bretta Russell-Schulz, Alex L. Mackay, Beth Borowsky, Gail Rynkowski, Rita Volkinshtein, Juha-Matti Savola, Michael R. Hayden. Presented at the International congress of Parkinson’s disease and movement disorders, 2019. Read the abstract here and the poster here.

Brain MRI Volume Changes after 12 months laquinimod treatment of Huntington disease (LEGATO-HD). Ralf Reilmann, Mark Forrest Gordon, Karen E. Anderson, Andrew Feigin, Sarah J. Tabrizi5, Blair R. Leavitt, Julie C. Stout, Paola Piccini, Nicola Hobbs, Richard Manber, Beth Borowsky, Gail Rynkowski, Rita Volkinshtein, Juha-Matti Savola and Michael Hayden. Presented at the International congress of Parkinson’s disease and movement disorders, 2019. Read the abstract here and the poster here.

Quantitative Motor (Q-Motor) Assessments Suggest a Beneficial Central Effect of Laquinimod in a Phase II Study in Huntington Disease (LEGATO-HD). Ralf Reilmann, Mark Forrest Gordon, Robin Schubert, Karen E. Anderson, Andrew Feigin, Sarah J. Tabrizi, Blair R. Leavitt, Julie C. Stout, Paola Piccini, Beth Borowsky, Gail Rynkowski, Rita Volkinshtein, Juha-Matti Savola, Michael R. Hayden. Presented at the International congress of Parkinson’s disease and movement disorders, 2019. Read the abstract here and the poster here.

Legato-HD Study: A Phase 2 Study Assessing the Efficacy and Safety of Laquinimod as a Treatment for Huntington Disease. Ralf Reilmann, Mark Forrest Gordon, Karen E. Anderson, Andrew Feigin, Sarah J. Tabrizi, Blair R. Leavitt, Julie C. Stout, Paola Piccini, Beth Borowsky, Gail Rynkowski, Rita Volkinshtein, Juha-Matti Savola and Michael Hayden. Poster presentation at the annual Huntington Study Group conference, HSG 2018, in Houston, Texas November 8-10, 2018. View the complete poster here.

Legato-HD Study: A Phase 2 Study Assessing the Efficacy and Safety of Laquinimod as a Treatment for Huntington Disease. Ralf Reilmann, Mark Forrest Gordon, Karen E. Anderson, Andrew Feigin, Sarah Tabrizi, Blair R. Leavitt, Julie C. Stout, Paola Piccini, Beth Borowsky, Gail Rynkowski, Rita Volkinshtein, Juha Savola and Michael Hayden. Poster presentation at European Huntingtons Disease Network (EHDN) plenary meeting 2018. View the complete poster here.

Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS. Ziemssen T, Tumani H, Sehr T, Thomas K, Paul F, Richter N, Samara E, Spiegelstein O, Sorani E, Bar-Ilan O, Mimrod D, Hayardeny L. J Neuroinflammation. 2017; 14: 172

Laquinimod dampens hyperactive cytokine production in Huntington’s disease patient myeloid cells
Dobson L, Träger U, Farmer R, Hayardeny L, Loupe P, Hayden MR, Tabrizi SJ. J Neurochem. 2016; 137(5): 782-94

Immune parameters of patients treated with laquinimod, a novel oral therapy for the treatment of multiple sclerosis: results from a double-blind placebo-controlled study. Stasiolek M, Linker RA, Hayardeny L, Bar Ilan O, Gold R. Immun Inflamm Dis. 2015; 3(2): 45-55

A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. Vollmer T. L, Sorensen P.S, Selmaj K, Zipp F, Havrdova E, Cohen J. A, Sasson N, Gilgun-Sherki Y, Arnold D. L. J Neurol. 2014; 261(4): 773-83

Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. Filippi M, Rocca MA, Pagani E, De Stefano N, Jeffery D, Kappos L, Montalban X, Boyko AN, Comi G; on behalf of the ALLEGRO Study Group. J Neurol Neurosurg Psychiatry. 2014; 85(8): 851-8

Assessment of changes in immune measures of multiple sclerosis patients treated with laquinimod. Lund BT, Kelland EE, Hayardeny L, Barilan O, Gilmore W, Weiner LP. J Neuroimmunol. 2013; 263(1-2): 108-15

Placebo-Controlled Trial of Oral Laquinimod for Multiple Sclerosis. Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, M.D., Filippi M, for the ALLEGRO Study Group. N Engl J Med. 2012; 366: 1000-9

Effect of Laquinimod on MRI-monitored disease activity in patients with RRMS: a multicenter, randomized, double-blind, placebo-controlled phase IIb study. Comi G, Pulizzi A, Rovaris M, Abramsky O, Arbizu T, Boiko A, Gold R, Havrdova E, Komoly S, Selmaj KW, Sharrack B, Filippi M. The Lancet 2008; 371(9630): 2085-92

Treatment with laquinimod reduces development of active MRI lesions in relapsing multiple sclerosis. Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O & Nederman T. Neurology. 2005; 64(6): 987-91