Laquinimod

Laquinimod is an oral, immunomodulatory investigational drug with a novel mechanism of action, preventing neurodegeneration and inflammation in the central nervous system. Laquinimod in development for once-daily treatment of Huntington’s disease (HD), a rare neurodegenerative disease and in July 2018 top line data from a phase 2 study in patients with this diseases was announced. Laquinimod has been granted Orphan Drug Designation for this indication by the FDA, which provides for seven years of market exclusivity in the event of future registration.

Active Biotech entered in 2004 a development and license agreement with Teva Pharmaceutical Industries Ltd for laquinimod. In September 2018, Active Biotech regained the global development and commercialization rights for laquinimod from Teva.

Clinical trials

In July, 2018, Active Biotech provided an update that the Phase 2 LEGATO-HD study, evaluating the safety and efficacy of laquinimod as a treatment in Huntington’s disease (HD), did not meet its primary endpoint slowing disease development. However, the secondary endpoint, reduction of brain atrophy, was met. Laquinimod showed a good safety profile in the study.

The previous clinical development program evaluating laquinimod in multiple sclerosis (MS) includes three completed phase 3 studies, ALLEGRO, BRAVO and CONCERTO in relapsing remitting MS (RRMS) and the completed Phase 2 study, ARPEGGIO in primary progressive MS (PPMS). Development of laquinimod in MS has been discontinued.

Targeting neurodegeneration and inflammation

Phase 2 trial in HD

Ongoing

LEGATO-HD (ClinicalTrial: NCT02215616) is a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 2 study of laquinimod as a potential treatment in patients with HD. The study was designed to evaluate three dose arms (0.5mg, 1.0mg, and 1.5mg daily) versus placebo. The highest dose of 1.5 mg was discontinued in January 2016 as a precautionary measure after cardiovascular safety problems were observed in multiple sclerosis studies with laquinimod of 1.2 mg and 1.5 mg respectively. No similar issues were identified in the LEGATO-HD study. Approximately 350 patients were randomized in the study, mainly within EU and the US. The study was conducted by Teva in collaboration with the Huntington Study Group and European Huntington’s Disease Network.

The primary endpoint evaluating the change from baseline at month 12 of Unified Huntington’s Disease Rating Scale – Total Motor Score (UHDRS-TMS) for the 1.0 mg dose as compared with placebo was not achieved. The secondary endpoint, percent change in brain atrophy (caudate volume) from baseline at 12 months in the 1.0 mg dose as compared to placebo, was met. The safety profile in the study was similar to that expected in the patient population.

The exploratory outcome includes change of (UHDRS-TMS) and percentage change in brain atrophy for the 0.5 mg dose, as well as changes in measured motor function, cognitive function, functional capacity and brain volumes for the 1.0 and 0.5 mg doses individually. The safety measures included adverse event reporting, clinical laboratory tests, vital signs, electrocardiograms, physical examinations and suicidality.

Phase 3 trials in RRMS

Completed

The global clinical development program evaluating laquinimod for treatment of RRMS includes three completed Phase 3 studies, ALLEGRO (Comi et al. N Engl J Med 2012; 366:1000-9), BRAVO (Vollmer et al. J Neurol. 2014; 261(4):773-83) and CONCERTO (ClinicalTrials.gov Identifier: NCT01707992). The ALLEGRO study showed that laquinimod administered once daily reduced the rate of relapse (primary end point) and slowed the progression of disability in patients with RRMS. In the BRAVO study the treatment resulted in statistically nonsignificant reductions in relapse rate (primary end point) and disability progression, but significant reductions in brain atrophy vs. placebo. When a baseline imbalance in MRI characteristics in the BRAVO study was corrected for according to a pre-specified sensitivity analysis included in the statistical analysis plan, laquinimod demonstrated a significant reduction in the annualized relapse rate as well as a significant reduction in the risk of disability progression. In the CONCERTO study, the primary endpoint, three-month confirmed disability progression, was not met. The secondary endpoints (brain atrophy, relapse rate and MRI data) were achieved and in line with previous studies. The excellent clinical safety profile of laquinimod 0.6 mg daily, which has been studied with more than 12,000 patient-years of exposure, was confirmed in the CONCERTO trial. Complete data will be published in a scientific journal. Based on the CONCERTO results, Teva has no plans to pursue further development of laquinimod in RRMS.

Phase 2 trial in PPMS

Completed

In April 2015, the first patient was enrolled in the ARPEGGIO study (ClinicalTrial: NCT02284568 ), a randomized placebo-controlled Phase 2 trial evaluating laquinimod in PPMS. In December 2017, Active Biotech and Teva announced that the primary endpoint, brain atrophy as defined by percentage brain volume change (PBVC) from baseline to week 48, was not met after daily oral doses of 0.6 mg laquinimod. The secondary endpoint, time to confirmed disability progression, was also not met. There was, however, a substantial reduction in new T2 lesions observed in patients treated with laquinimod, indicating an effect on the inflammation in CNS by laquinimod also in PPMS patients.

Key Publications

Legato-HD Study: A Phase 2 Study Assessing The Efficacy And Safety Of LaquinimodAs 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 treatment in the R6/2 mouse model
Ellrichmann G, Blusch A, Fatoba O, Brunner J, Hayardeny L, Hayden M, Sehr D, Winklhofer KF, Saft C, Gold R. Sci Rep. 2017; 7: 4947

Laquinimod rescues striatal, cortical and white matter pathology and results in modest behavioural improvements in the YAC128 model of Huntington disease
Garcia-Miralles M, Hong X, Tan LJ, Caron NS, Huang Y, To XV, Lin RY, Franciosi S, Papapetropoulos S, Hayardeny L, Hayden MR, Chuang KH, Pouladi MA. Sci Rep. 2016; 6:31652

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