May/June 2010, Vol 3, No 3 - Pipeline
Alice Goodman
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At the 2010 annual meeting of the American Academy of Neurology (AAN), the largest explosion of new agents in development was for multiple sclerosis (MS), the second most common neurologic disability in young and middle-aged adults.

Oral fingolimod (Galenia), currently under FDA review, is a first-in-class oral agent that represents a new approach to the treatment of MS; it is a sphingosine 1-phosphate receptor (S1P-R) modulator that binds to the S1P-R on circulating lymphocytes, sequestering them in lymph nodes away from the central nervous system. Preliminary evidence suggests that this drug can reduce inflammation and nerve damage, and promote repair of damaged nerve cells.

Two different analyses of data from the large, 2-year, randomized, placebo-controlled, multicenter phase 3 FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis) study showed that oral fingolimid was clinically effective and improved magnetic resonance imaging (MRI) scans of patients with relapsing-remitting MS (RRMS).

FREEDOMS enrolled 1272 patients in 22 countries. Patients were randomized to a low dose of fingolimod (0.5 mg/day), a higher dose of fingolimod (1.25 mg/day), or to placebo and were treated for 2 years. After that, patients could continue on the lower dose of fingolimod for an extension study. Compared with placebo, oral fingolimod significantly reduced annualized relapse rates and slowed progression of disability. In addition, MRI scans of the brain showed evidence of less brain tissue loss and fewer MS-enhancing lesions in the fingolimod group compared with the placebo group.

Because both doses reduced the annualized relapse rate by >50% compared with placebo and prevented disability progression, the manufacturer will seek approval for the lower dose.

Cladribine (Leustatin), the second oral agent in development with a new approach to MS, was effective across a range of clinically important subgroups of patients with RRMS, based on the double-blind, 96- week CLARITY (Cladribine Tablets MS Orally) trial. Reductions in annualized relapse rates of >54% were achieved with 3.5 mg/kg and 5.25 mg/kg of the drug.

An injectable formulation of cladribine is already approved for the treatment of leukemia. The drug is given in short courses over each cycle for a total of 8 to 10 days annually and results in targeted and sustained immunomodulation. Consistent reductions in MS relapse rates were seen in men and women and with no regard to the use of disease-modifying drugs.

Alemtuzumab (Campath), an investigational MS drug, was superior to standard treatment of RRMS with interferon beta-1a (Rebif), according to 4-year results of the phase 2 CAMMS223 study. Patients taking alemtuzumab were free from clinically active MS twice as often as patients taking interferon beta-1a (71% vs 35%, respectively).

“These data may set a new bar for clinical outcomes in MS," said lead investigator Omar Khan, MD, Professor of Neurology, Wayne State University School of Medicine, Detroit, MI.

Alemtuzumab is a humanized monoclonal antibody approved for use in B-cell chronic lymphocytic leukemia. The drug binds to the CD52 protein on cell surfaces and directs the immune system to destroy those cells. The drug has a safety warning regarding cytopenias, infusion reactions, and infections.

Adverse events reported include infusion-related reactions in patients who received alemtuzumab and flulike symptoms in patients treated with standard therapy. Infections were more common in the alemtuzumab-treated group, particularly upper respiratory tract infections, but these were mainly mild to moderate in severity.

T-Cell Immunotherapy (Tovaxin) is an individualized autologous irradiated T-cell vaccine prepared by isolating myelin reactive T-cells from a patient’s own blood and expanding the cells ex vivo to a therapeutic dose. The vaccine has a dual mechanism of action, depleting circulating cells that attack the myelin sheath of nerves and rebalancing the immune system by causing a shift from pathogenic inflammatory T-cells to anti-inflammatory T-cells.

Promising results were seen in the post-hoc analysis of the Tovaxin for Early Relapsing Multiple Sclerosis trial, which included 129 patients who had at least 1 MS relapse during the previous year. Tovaxin reduced the annualized relapse rate by 42% compared with placebo. At week 52, patients treated with the vaccine had less progression of MS-related disability compared with placebo, and MRI results also favored the vaccine cohort.

The only adverse events reported with the vaccine were mild-to-moderate injection-site reactions.

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