Dirucotide
Testing on dirucotide (MBP8298), an intravenous therapy considered as a treatment for secondary progressive MS, was discontinued in 2009 after the therapy did not meet its primary endpoint in the Phase III MAESTRO-01 study. The makers of dirucotide, Eli Lilly and Company and BioMS Medical Corp., have no plans to study the compound further in secondary progressive MS patients. The study outcome and subsequent discontinuation came after dirucotide was granted Fast Track designation in 2008, meant to expedite the FDA approval process.
MAESTRO-01 included 611 patients across Canada and nine countries in Europe with HLA-DR2 or DR4 immune response genes. Study participants intravenously received either dirucotide or placebo every 6 months for two years. The study’s primary endpoint—goal—was to delay disease progression as measured by the Expanded Disability Status Scale (EDSS). In addition to not meeting its endpoint, dirucotide showed no statistical significance compared to placebo on the secondary endpoints either. The treatment was well tolerated and the most common side effect reported was injection site reaction.
Dirucotide is a synthetic peptide made up of 17 amino acids linked in a sequence that is identical to a portion of human myelin basic protein (MBP). Because MS is an autoimmune disease and inappropriately attacks myelin coating on nerves, the thought was that by using a part of one of the proteins in myelin to “re-educate” the immune system, the therapy might provide an effective treatment for MS that suppresses the immune system.
In research done before the MAESTRO-01 study, dirucotide appeared to work in two ways. First, it caused immune cells (presumably autoimmune cells involved in the attack on the brain in MS) to recognize dirucotide and die through a process called programmed death. Secondly, like a vaccine, treatment with dirucotide was thought to induce new immune cells that are regulators of the immune system, which can enter the brain and inhibit the inflammation that characterizes MS. The therapy, however, only displayed clinical benefits in patients with either HLA-DR2 or HLA-DR4 immune response genes, which are found in up to 75% of MS patients. As such, MAESTRO-01 study participants all had those specific immune response genes.
In 2007, results from a Phase II study were published in the European Journal of Neurology (EJN). The two-year study of 32 progressive MS patients compared dirucotide to placebo, which were both intravenously administered every 6 months. Patients with either the HLA-DR2 or DR4 genes demonstrated no disease progression during the 2-year study, whereas over 50% of patients on placebo did. Additionally, during the 5-year follow-up study participants who took dirucotide demonstrated a median time to disease progression of 78 months as opposed to 18 months for those on placebo. Disease progression was measured using the EDSS scale, which measures a patient’s disability level. Dirucotide appeared to provide a more than 6-year delay in disease progression in treated participants. During the course of the Phase II trial, dirucotide appeared to be well tolerated and injection-site redness and burning was the most common side effect.
Results from another Phase II study, this time on relapsing-remitting MS patients, did not achieve its primary endpoint—a reduction in patients’ annualized relapse rates—either. Investigators, however, explained the outcome by saying that dirucotide was developed for progressive MS patients and, as such, the study results were not surprising.