LYON, France — Treatment with natalizumab (Tysabri, Biogen Idec) reduces inflammation, axonal damage, and demyelination in patients with progressive multiple sclerosis (MS), a new phase 2 study shows.
It also appears to have a favorable effect on clinical outcomes and to raise no new safety concerns when used for both primary progressive MS (PPMS) and secondary progressive MS (SPMS).
"The possible beneficial effects on clinical endpoints should be studied in future placebo-controlled trials of both PPMS and SPMS patients," lead researcher Jeppe Romme Christensen, MD, Research Laboratory for Stereology and Neuroscience, Bispebjerg University Hospital, Copenhagen, Denmark, concluded.
The study results were reported here at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Limited Success
Researchers believe that in MS, immune cells pass into the central nervous system, where they cause inflammation and nerve damage, and that adhesion molecules on the surface of immune cells play an important role in this process.
The monoclonal antibody natalizumab binds to a-4 integrin, an adhesion molecule on the surface of immune cells, blocking the migration of these into the brain. Natalizumab is already used to treat relapsing-remitting MS.
About 60% of patients with MS have progressive disease and many suffer severe disability, Dr. Christensen told delegates. Treatments targeting systemic inflammation have had only limited success in these patients, he said.
The open-label, 60-week Danish proof-of-concept study enrolled 12 patients with PPMS and 12 with SPMS.
Patients had to be aged19 to 55 years; have an Expanded Disability Status Scale (EDSS) score of 6.5 or less, with evidence of progression during the past 2 years; have no relapses in the previous month; and not be receiving immunosuppressive drugs. Seven patients with SPMS and 10 with PPMS completed the study.
The 2 groups were balanced in terms of sex, age, and duration of the progressive phase, but, as expected, they differed in terms of disease duration (14 years for patients with SPMS and 4 for those with PPMS). During the study period, researchers investigated the patients by using cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and clinical tests.
Treatment with intravenous natalizumab resulted in a significant (P = .0004) reduction in CSF osteopontin concentrations, a marker of inflammation and the primary endpoint, and in another CSF marker, chemokine (C-X-C motif) ligand 13 (P = .02). The reduction almost reached significance for a third CSF marker, MMPg, (P = .06).
The significant (P = .03) decrease in markers of axonal damage observed in the study indicate beneficial effects on tissue damage, noted Dr. Christensen.
Affected Tissue Integrity
The agent also affected MRI atrophy from weeks 12 to 60 (P = .0003), and it increased the magnetization transfer ratio, a predictor of future disease progression, said Dr. Christensen. This was seen on measures of both normal-appearing white matter (P = .001) and cortical grey matter volume (P = .004). These results may represent "important effects on tissue integrity," noted Dr. Christensen.
As well, there was a small statistically significant (P = .01) decrease in EDSS score.
The study uncovered 3 serious adverse events in 2 patients (ureteral stone, deep-vein thrombosis, and pneumonia), but none were thought to be related to natalizumab. Progressive multifocal leukoencephalopathy is a known safety issue among patients taking natalizumab but was not seen in this short study.
None of the patients in the study had signs of relapses or progression during treatment, he said.
"To conclude, natalizumab treatment of progressive MS patients may reduce inflammation and tissue damage," said Dr. Christensen. "Systemic inflammation may contribute to intrathecal inflammation and axonal damage in progressive MS."
Asked by a delegate whether natalizumab has a greater effect on primary versus secondary progressive MS or vice versa, Dr. Christensen said he and his research team have not yet analyzed that data, "but my impression is that there is an equal treatment effect."
There is already a study ongoing in SPMS, he noted, "and I hope this will encourage a study in PPMS as well."
Session co-chair Ludwig Kappos, chair, neurology, Department of Biomedicine, University Hospital, Basel, Switzerland, asked whether the study patients are continuing to receive treatment in light of reports that some patients with more progressive disease had unexpected relapses.
Dr. Christensen responded that he sees most of the patients in his clinic and to his knowledge few have been reported to have progressed. He did note that in 1 patient progression started 9 months after treatment cessation.
It will be important to have systematic follow-up of these patients, Dr. Kappos noted.