In a phase 3, randomized clinical trial, natalizumab (Tysabri) failed to slow the progression of ambulatory disability unrelated to relapses (primary end point) in patients with secondary progressive multiple sclerosis (MS). Although patients who received natalizumab were less likely to have progression of ambulatory disability than those receiving placebo, the difference was not significant, according to the results presented at the 2016 American Academy of Neurology annual meeting.
Nevertheless, natalizumab was associated with a significant (44%) reduction of upper-extremity disability progression unrelated to relapses, as measured by the 9-Hole Peg Test (9HPT).
“The ASCEND study did not meet the primary end point, as natalizumab treatment did not delay progression of ambulatory disability. However, natalizumab showed significant benefit in slowing sustained progression of upper-extremity disability, as measured by the 9HPT, and the meaningfulness of this finding was confirmed by ABILHAND,” said Deborah Steiner, MD, MS, Medical Director, Biogen, Cambridge, MA.
Despite many clinical trials in progressive MS, no treatment has demonstrated efficacy in reducing disability progression unrelated to relapses in patients with secondary progressive MS.
Natalizumab, a recombinant humanized monoclonal antibody, reduces inflammation by inhibiting the transmigration of leukocytes into the brain, and has been proved more effective than placebo in treating relapsing-remitting MS.
The ASCEND clinical trial was an international, multicenter, double-blind, phase 3 study of patients with secondary progressive MS for at least 2 years. Eligible patients had evidence of disability progression unrelated to clinical relapses in the year before enrollment, and had Expanded Disability Status Scale scores ranging from 3 to 6.5.
Patients were randomized to 300 mg intravenous natalizumab or to placebo every 4 weeks for up to 96 weeks.
The proportion of patients who had progression of ambulatory disability (the study primary end point) was higher in the placebo group (48%) than in the natalizumab group (44%), but this difference was not significant, said Dr Steiner.
Nevertheless, natalizumab was associated with a significant 44% reduction of upper-extremity disability progression unrelated to relapses, as measured by 9HPT, a prespecified component of the primary end point.
The ABILHAND questionnaire, a patient-reported outcome instrument assessing upper-extremity impairment, clearly differentiated patients who had upper-extremity disability progression from patients who did not.
“The upper-extremity finding is notable. If you consider the fact that these patients are using either unilateral or bilateral assistance, may be in wheelchairs, and may soon be confined to bed, being able to preserve upper-extremity function and still use one’s hands is extremely important,” said Dr Steiner.
Other secondary end points did not reach significance at the group level, although point estimates were all in favor of natalizumab, Dr Steiner reported.
In addition, exploratory efficacy end points of inflammatory activity demonstrated strong treatment effects for natalizumab, with a 54.7% relative reduction in the annualized relapse rate. The relative reduction in the number of T1 Gd+ and T2 lesions was 95% and 89%, respectively, compared with placebo.
Finally, natalizumab was well-tolerated. Adverse events, including urinary tract infection, headache, fatigue, and falls, were consistent with the known safety profile of natalizumab, although the use of natalizumab has been linked to progressive multifocal leukoencephalopathy, a rare but potentially lethal adverse reaction, Dr Steiner said.
Preserving upper-extremity mobility in patients with secondary progressive MS may be worthwhile, said Dr Steiner, adding that additional testing to confirm the positive finding for upper-extremity function may be warranted.