Last updated June 30, 2022, by Teresa Carvalho, MS
ā Fact-checked by InĆŖs Martins, PhD
What is laquinimod for MS?
Laquinimod (also known as nerventra or ABR-215062) is an investigational oral therapy that’s been tested in clinical trials for treating multiple sclerosis (MS) andĀ Huntingtonās disease.
However, Active Biotech, the company developing this medication, announced in 2020 that it was discontinuing the development of laquinimod for these two conditions following unsatisfactory results. The company is now exploring the therapy in an inflammatory eye disease called uveitis.
How does laquinimod work in MS?
MS is caused by the immune system mistakenly attacking the myelin sheath, an insulating layer surrounding nerve cells. This inflammatory response causes neuronal damage and impairs the normal transmission of nerve signals, leading to progressive nerve cell death.
Laquinimod is a small molecule that has immunomodulatory abilities. Its exact mechanism of action is not fully understood, but the medication is believed to regulate how the immune system responds to myelin proteins.
In MS patients, the immune system sees myelin as foreign, which results in pro-inflammatory T-cells being produced that contribute to inflammation and damage to nerve cells. Laquinimod shifts that response so that regulatory T-cells (Tregs) are activated instead. Tregs are able to dampen the inflammatory properties of other immune cells, playing a protective role in MS.
The molecule also is thought to stop damaging immune cells from entering the brain and spinal cord, and some studies suggest it increases levels of the brain-derived neuroprotective factor (BDNF) protein, which may help preserve the structure and function of nerve cells.
How was laquinimod administered in MS?
Laquinimod has been tested in multiple sclerosis as a hard capsule, taken by mouth once per day. Clinical trials evaluated doses ranging from 0.1 mg to 1.5 mg a day, but only the doses of 0.6 mg or lower were deemed safe for these patients.
Laquinimod in MS clinical trials
Laquinimod has been investigated in several clinical trials for MS. A total of five Phase 2 and Phase 3 studies looked at its effect in relapsing-remitting multiple sclerosis (RRMS) and a single Phase 2 trial was conducted for primary progressive MS (PPMS).
ALLEGRO trial
A Phase 2b trial (NCT00349193) involving 306 RRMS patients initially showed a 0.6 mg laquinimod dose significantly reduced the number of inflammatory brain lesions after 36 weeks (about eight months) compared with a placebo.
Teva, which developed laquinimod in collaboration with Active Biotech until 2018, then launched a Phase 3 clinical trial called ALLEGRO (NCT00509145) to further investigate that dose. The trial enrolled 1,106 RRMS patients who were randomly assigned to receive 0.6 mg of laquinimod, or a placebo, once daily for two years.
The trial met its primary goal, with laquinimod significantly reducing the mean number of relapses per year from 0.39 to 0.30. This represented a 28% reduction in the risk of relapses compared with a placebo.
The medication also reduced the risk of confirmed disability progression ā defined as a sustained increase in Expanded Disability Status Scale (EDSS) over at least three months ā by 36%, and resulted in a 37% reduction in the number of lesions with active inflammation. The total number of lesions with and without inflammation on MRI scans also was reduced by 30%.
BRAVO trial
BRAVO (NCT00605215)Ā also investigated two years of treatment with the 0.6 mg dose in 1,331 RRMS patients. It was generally similar to ALLEGRO, with the exception that this trial included a third group of patients who received the approved MS treatment Avonex (interferon beta-1a).
In this trial, laquinimod did not significantly reduce relapse rates nor lower the proportion of patients with three-month confirmed disability progression compared with a placebo. The medication significantly reduced the rate of brain shrinkage compared with both a placebo and Avonex, but no other differences between the approved therapy and laquinimod were observed.
CONCERTO trial
Due to the inconsistent results in ALLEGRO and BRAVO, Teva launched a third Phase 3 trial ā dubbed CONCERTO (NCT01707992) ā that tested the 0.6 mg dose as well as a higher, 1.2 mg dose of laquinimod against a placebo in 2199 RRMS patients.
In January 2016, however, the data monitoring committee overseeing this trial recommended the discontinuation of the higher dose due to a greater frequency of cardiovascular events, none of which were fatal. Teva and Active Biotech immediately stopped the higher doseĀ and encouraged participants to continue with follow-up examinations.
Results from the lower-dose group showed no significant delays in confirmed disability progression, failing to meet the trial’s primary goal. The treatment also failed to meet aĀ secondary objective of slowing disease progression at six and nine months.
However, those who received the active treatment experienced significantly smaller changes in brain volume over the two years, had lower relapse rates, and had fewer lesions with active inflammation.
ARPEGGIO trial
The ARPEGGIO Phase 2 trial (NCT02284568) was initially designed to evaluate the effectiveness, safety, and tolerability of two laquinimod doses (0.6 mg or 1.5 mg per day) in 374 PPMS patients. But after the eight cardiovascular events (seven in CONCERTO, one in ARPEGGIO), its higher dose was discontinued upon recommendation from the monitoring committee.
Results showed that nearly one year of treatment with the lower dose failed to reduce brain atrophy compared with a placebo, meaning the trial did not meet its primary goal. Other measures of disease progression, including confirmed disability worsening, and changes in walking function, dexterity, and cognition also were not significantly different between the groups. Only lesions with active inflammation were significantly lower in the active treatment group.
Common side effects of laquinimod
The most common side effects of laquinimod reported in MS clinical trials included:
- diarrhea
- increased liver enzymes
- abdominal and back pain
- cough
- appendicitis
- respiratory tract infections
- headache
- nausea
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