Medicine & Research

RX Update - MS Pipeline

By Ellen Whipple, Pharm. D

The currently approved disease-modifying treatments are generally reliable in decreasing the number of relapses in patients with multiple sclerosis; however, they have only limited efficacy in treating patients having more progressive disease courses. According to Dr. Ben Thrower, medical director of the Multiple Sclerosis Institute at Shepherd Center, “Of all of the currently approved DMTs, only ocrelizumab is approved for patients with primary-progressive multiple sclerosis. There is a clear unmet need for additional products for the treatment of patients with progressive forms of multiple sclerosis.”
Several new DMTs are currently being investigated for the treatment of MS patients. Laquinimod, ozanimod, ponesimod, and siponimod all have a similar mechanism of action to fingolimod (Gilenya), as they work on the sphingosine-1-phosphate (S1P) receptor. Ofatumumab is a CD20-positive B-cell-targeting monoclonal antibody and masitinib is a mast-cell inhibitor. Phase III trial results for some of these pipeline products are expected to conclude within the next 12 months. If results are positive, manufacturers are expected to apply for U.S. Food and Drug Administration approval soon thereafter.

Regulating Immune Response
The goal of disease-modifying treatment for MS is to regulate your immune system. Different treatments approach this complex task in different ways. Among these potential new treatments, some seek to target immune cells (T- and B-cells) directly. Others affect the immune system components (S1P and tyrosine kinase) that control how and when those cells respond.
Laquinimod is an orally-administered DMT. It is being investigated for patients with either relapsing-remitting or secondary-progressive MS. The exact mechanism of action of laquinimod is not understood. It appears that laquinimod shifts the production of “bad” T-cells to “good” T-cells. The “bad” T-cells, known as TH1 cells, are proinflammatory and cause inflammation; whereas, the “good” T-cells, known as TH2 cells, are anti-inflammatory and decrease inflammation. Previously reported phase III trials have had mixed results. In one trial, annualized relapse rates, disability progression, and the number of gadolinium-enhancing lesions were significantly improved with laquinimod compared with placebo. However, in another trial, annualized release rates were not significantly reduced with laquinimod compared with placebo. The most commonly reported adverse events in these trials were elevated liver function tests, abdominal pain, back pain, and cough. The phase III CONCERTO trial in patients with relapsing-remitting MS has not reported results.
Ozanimod is an orally-administered, selective S1P product. It is being studied in patients with relapsing-remitting MS. While preliminary data suggests that ozanimod may have a preferred safety profile to fingolimod (Gilenya), the currently approved S1P agent, and possibly some of the other pipeline S1P products, Dr. Thrower cautions against making any conclusions until more data are available. In one trial, the mean number of gadolinium (Gd)-enhancing lesions and new/enlarging T2 lesions were significantly decreased with ozanimod compared with placebo. The most commonly reported adverse events in this trial included common cold symptoms, headache, and urinary-tract infections. Electrocardiograms and 24-hour Holter monitoring showed no increased incidence of atrioventricular block or sinus pause with ozanimod. The phase III SUNBEAM trial has not reported results.
Ponesimod is also an orally-administered, selective S1P that is being studied in patients with relapsing-remitting MS. In a phase II trial, the mean cumulative number of new T1 Gd-enhancing lesions was significantly reduced with ponesimod compared with placebo. Additionally, mean annualized relapse rates were lower with ponesimod 40 mg compared with placebo. The most commonly reported adverse events with ponesimod included anxiety, dizziness, breathing difficulty, increased liver enzymes, influenza, insomnia, and peripheral edema. Phase III OPTIMUM trial has not reported results.
Siponimod is another orally-administered S1P. It is being studied in patients with both relapsing-remitting and secondary progressive MS. In a phase II trial in relapsing-remitting MS, there were reductions in unique active lesions at three months compared with placebo. Common adverse events included headache, abnormal heartbeat, dizziness, and infections of the nose and throat. In a phase III trial in patients with secondary-progressive MS, siponimod significantly reduced confirmed disability progression vs. placebo. Common adverse events included headache, common cold symptoms, urinary tract infections, falls, and hypertension.
Ofatumumab is a subcutaneously-administered DMT being investigated in patients with relapsing-remitting MS. It works by depleting B-cells. (Among other functions, B-cells activate the T-cells that cause damage to myelin). In a phase II trial, significantly fewer T1 Gd-enhancing lesions, total number of T1 Gd-enhancing lesions, and new or enlarging T2 lesions were observed with ofatumumab compared with placebo. No unexpected safety signals emerged in this study. Infusion-related reactions were common on infusion Day 1, but not observed on infusion Day 2. Neither the phase II MIRROR, trial, nor the phase III ASCLEPIOS trials have reported results.
Masitinib is an orally-administered tyrosine kinase inhibitor that targets mast cells and inhibits several biochemical processes. This DMT is being studied in patients with both primary-progressive and secondary-progressive MS. In one early study, masitinib appeared to have a positive effect on MS-related impairment in patients with primary-progressive and relapse-free secondary-progressive MS. The most commonly reported adverse events were weakness, rash, nausea, edema, and diarrhea. A phase III trial in patients with either primary-progressive or relapse-free secondary-progressive MS has not reported results.