Laquinimod (also known as nerventra or ABR-215062) is an investigational therapy being developed by Active Biotech to treat neurodegenerative diseases, including primary progressive multiple sclerosis (PPMS), relapsing-remitting MS (RRMS), and Huntington’s disease.
Laquinimod was previously being jointly developed by Active Biotech and Teva Pharmaceuticals, following an agreement in 2004. As of Sept. 5, 2018, Active Biotech regained sole rights to develop and commercialize laquinimod.
How laquinimod works
Multiple sclerosis (MS) is a condition caused by the immune system mistakenly attacking the myelin sheath, the insulating layer of protein surrounding nerve cells, in the brain and spinal cord. This causes inflammation and damage, impairing the transmission of nerve signals as well as nerve cell death.
Laquinimod is thought to alter the immune response and may protect nerve cells. It is not fully understood how laquinimod works, but it is thought to act as an aryl hydrocarbon receptor (AHR) agonist. AHR is a protein produced by several immune cells. It can be activated by molecules obtained from food or the environment, and is involved in the regulation of the immune response. By binding to and activating AHR, laquinimod may influence the immune response.
Laquinimod is thought to stop damaging immune cells from entering the brain and spinal cord. Furthermore, it may reduce levels of inflammation by promoting anti-inflammatory cytokines (immune proteins) and decrease levels of inflammatory ones. This may prevent or decrease damage to myelin in the brain.
Some studies also suggest that laquinimod increases levels of a protein called brain-derived neuroprotective factor (BDNF), which may help preserve the structure and function of nerve cells.
Laquinimod in clinical trials
Laquinimod has been investigated in several clinical trials for MS. Three Phase 3 studies looked at its effect in RRMS, and a single Phase 2 trial was conducted for PPMS.
ALLEGRO (NCT00509145) was a two-year, randomized, double-blind, placebo-controlled Phase 3 trial in 1,106 RRMS patients. Results, published in the New England Journal of Medicine, showed that daily laquinimod reduced relapse rates by 23% and disability progression by 36% compared with placebo. Magnetic resonance imaging (MRI) data, published in the Journal of Neurology, Neurosurgery, and Psychiatry, suggested that laquinimod slowed the progression of nerve cell death compared with placebo.
The BRAVO (NCT00605215) study compared the effects of 0.6 mg of laquinimod to that of Avonex (interferon beta-1a) or placebo in 1,331 RRMS patients. Results, published in the Journal of Neurology, revealed that laquinimod did not significantly reduce relapse rates compared with placebo, but did significantly reduce the rates of brain shrinkage and the progression of disability. Avonex also significantly reduced relapse rates, but unlike laquinimod, it did not have any effect on nerve cell death compared with placebo.
Based on the results of these trials, the company began testing laquinimod for RRMS at a high or low dose in a randomized, double-blind, parallel-group, placebo-controlled Phase 3 trial (NCT01707992) called CONCERTO at sites in North America, Europe, and Asia.
A Phase 2 study called ARPEGGIO (NCT02284568) was also launched to test the effectiveness, safety, and tolerability of two doses of the treatment (0.6 mg or 1.5 mg per day) in PPMS patients.
However, in January 2016, the Data Monitoring Committee of the U.S. Food and Drug Administration called for the immediate discontinuation of the higher laquinimod dose in the ARPEGGIO and CONCERTO trials after cardiovascular events were reported in eight participants (seven in the CONCERTO study and one in the ARPEGGIO study). Teva and Active Biotech stopped higher doses immediately in both trials and encouraged participants to continue with follow-up examinations.
The lower dose of laquinimod failed to meet CONCERTO’s primary objective of slowing disease progression after three months of treatment. The treatment also failed to meet a secondary objective of slowing disease progression at six and nine months.
Laquinimod did, however, show positive results in reducing the loss of patients’ brain volume by 40% (a measure of disability progression) at 15 months of treatment compared with a placebo. The number of gadolinium-enhancing T1 lesions in the brain (a measure of inflammation) was also reduced by 30% in treated patients over the same time period, and 28% of patients saw their risk of relapse lowered.
The CONCERTO trial also confirmed the safety of laquinimod (at 0.6 mg per day), with participants reporting only minor side effects, such as headaches, nasopharyngitis, back pain, and joint pain. The results were presented in 2017 at the joint European and American Committee for Treatment and Research in Multiple Sclerosis meeting.
The ARPEGGIO trial demonstrated similar results in PPMS; the lower dose of laquinimod failed to slow disease progression after three months but did reduce the occurrence of new T2 lesions in the brain.
Following the results of CONCERTO, Teva opted to halt further development of laquinimod for RRMS. However, based on the potential of the previous Phase 3 studies, Active Biotech is continuing to support the RRMS program.
Laquinimod is a derivative of the discontinued treatment Linomide (roquinimex).
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