Laquinimod – new promising treatment of multiple sclerosis
Laquinimod is a compound under development for the treatment of autoimmune diseases including MS, Crohn's disease and Lupus. Active Biotech has signed an agreement with the Israeli pharmaceutical company Teva for the development and commercialization of laquinimod.
Multiple sclerosis
Multiple sclerosis (MS) is a chronic, progressive disease affecting the central nervous system. The disease affects the central nervous system (the brain and spinal cord). The symptoms are caused by the body's own immune system attacking and damaging the myelin sheaths surrounding nerve fibers. This causes inflammation within the central nervous system causing the patient to suffer relapses and disease progression. The etiology of the disease is unknown, but is assumed to depend, like other autoimmune diseases, on both genetic and environmental factors.
There are various forms of MS, the most common is relapsing remitting MS ("RRMS"). It is characterized by unexpected recurring relapses that can last from a few days to a few weeks and are followed by complete or partial remission. In approximately 80 percent of all patients, the disease begins as RRMS but most develop after some ten or so years into secondary progressive MS ("SPMS"), which is characterized by a gradually increasing degree of disability, without the recovery periods.
MS primarily affects young and middle-aged people. The disease often first appears when the patient is between 20 and 50 years old, and the number of women affected is twice as high as the number of men. A total of about two million people throughout the world suffer from MS. The disease is more common in the northern hemisphere. The Nordic region, the British Isles and North America are regarded as high-risk areas.
There are currently three types of drugs for the treatment of MS: interferons, glatiramer acetate and natalizumab. The drugs reduce the number of relapses and are therefore all approved for treatment of MS patients with relapses. The total market for MS pharmaceuticals amounted to USD 10.2 billion in 2009 (Therapeutic Categories Outlook, Cowen & Co, March 2010). Since MS patients must be on medication throughout their lifetime, an oral treatment creates a substantial advantage compared with existing products on the market, all of which must be injected.
Crohn's disease
Crohn's disease is a chronic inflammatory condition that affects the gastrointestinal tract. The symptoms of Crohn's disease can vary significantly among afflicted individuals. The main gastrointestinal symptoms are abdominal pain, diarrhea, vomiting, or weight loss. Crohn's disease can also cause complications outside of the gastrointestinal tract such as skin rashes, arthritis, and inflammation of the eye.
The precise cause of Crohn's disease is not known. The disease occurs when the immune system attacks the gastrointestinal tract and for this reason, Crohn's disease is considered to be an autoimmune disease. This autoimmune activity produces inflammation in the gastrointestinal tract, and therefore Crohn's disease is classified as an inflammatory bowel disease, IBD.
Ongoing research
The global clinical Phase III program has been completed with the results from the second Phase III study, BRAVO. Teva has ongoing clinical Phase II trials for the treatment of Crohn's disease and for the treatment of lupus. All of these diseases are chronic, inflammatory diseases with an underlying autoimmune component.
Further information regarding the clinical trials is found on www.clinicaltrials.gov.
Current results
In December 2010, positive results were reported from the two-year Phase III ALLEGRO study, which demonstrated that relapsing-remitting multiple sclerosis (RRMS) patients treated with 0.6 mg daily oral laquinimod experienced a statistically significant reduction in annualized relapse rate compared to placebo. Additional clinical endpoints, including significant reduction in disability progression, as measured by Expanded Disability Severity Scale (EDSS), were also achieved. The ALLEGRO study also confirmed laquinimod’s highly favorable safety profile.
On August 1, 2011, results from the Phase III BRAVO study, which was designed to evaluate the efficacy, safety and tolerability of oral laquinimod compared to placebo and to provide a benefit-risk assessment comparing oral laquinimod and a reference arm of injectable Interferon β-1a (Avonex®). BRAVO is the second of two pivotal Phase III studies in the clinical development program for laquinimod, an investigational, oral, once-daily therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS). The BRAVO study demonstrated a trend of reducing the annualized relapse rate in laquinimod treated patients compared to placebo, the primary end point of the study, but did not reach statistical significance (p=0.075). The reduction of disability progression measured by EDSS also showed a trend in favor of laquinimod without reaching statistical significance. The reduction of brain atrophy observed in the laquinimod treated patients was significantly reduced compared to the placebo group.
The randomization process for BRAVO was adequately performed and according to the study protocol; however, placebo and treatment study groups showed dissimilarity in two baseline magnetic resonance imaging (MRI) characteristics. According to a standard and pre-specified sensitivity analysis included within the original statistical analysis plan, when this imbalance was corrected laquinimod demonstrated a significant reduction in the annualized relapse rate (21.3 percent, p=0.026), as well as a significant reduction in the risk of disability progression measured by EDSS (33.5 percent, p=0.044). In this analysis laquinimod also demonstrated a significant reduction of brain atrophy (27.5 percent, p<0.0001).
The BRAVO findings support the direct effect of laquinimod in the central nervous system (CNS) and are in line with the results of the first laquinimod Phase III trial, ALLEGRO. Additionally, as in ALLEGRO, the BRAVO study showed that laquinimod has a very favorable safety and tolerability profile.