An agent biologically similar to the humanized monoclonal antibody natalizumab is as effective and safe as the original reference drug for relapsing-remitting multiple sclerosis (RRMS) — and has a similar level of immunogenicity, new research shows.
Investigators note that these phase 3 trial findings are the final stage in the regulatory approval process.
“There will be a biosimilar that with respect to all parameters — efficacy, side effects, immunogenicity — doesn’t differ from the original drug and will probably be an option to consider to reduce treatment costs in MS,” lead investigator Bernhard Hemmer, MD, a professor in the Department of Neurology, sildenafil exercise Technical University of Munich, Germany, told Medscape Medical News.
The findings were published online January 23 in JAMA Neurology.
Potential Cost Savings
Disease-modifying therapies (DMTs), particularly targeted biologics, have revolutionized the treatment of MS, including RRMS. Natalizumab, which was the first targeted biologic therapy approved for RRMS, is very effective and widely used, Hemmer said.
However, this and other DMTs are costly. Biosimilars, which are medicines clinically similar to an already marketed reference biologic medicine, can address this issue. In the areas of rheumatology and oncology, biosimilars have already demonstrated significant cost savings and improved treatment access.
The biosimilar natalizumab (biosim-NTZ), developed by Polpharma Biologics, is the first biosimilar monoclonal antibody therapy to be developed for MS.
Health authorities such as the US Food and Drug Administration require comparative phase 3 studies to confirm there are no clinically relevant differences between a proposed biosimilar and its reference medicine.
The new multicenter phase 3 double-blind randomized trial known as Antelope included 264 adult patients with RRMS at 48 centers in seven Eastern European countries. Most study participants were women (61.4%) and their mean age was 36.7 years.
All were randomly assigned to receive intravenous infusions every 4 weeks of 300 mg of biosim-NTZ or reference natalizumab (ref-NTZ) for a total of 12 infusions.
At week 24, 30 patients were switched from ref-NTZ to biosim-NTZ for the remainder of their infusions. Including such a population is required by regulatory agencies to ensure switching patients from a drug they’ve been taking to a new biosimilar does not introduce any concerns, said Hemmer.
Comparable Efficacy, Safety Profile
The primary efficacy endpoint was the cumulative number of new active brain lesions on MRI.
At baseline, 48.1% of the biosimilar group and 45.9% of the reference drug group had at least one gadolinium-enhancing lesion. In addition, 96.9% of the biosimilar group had more than 15 T2 lesions compared with 96.2% of the reference group.
At week 24, the mean difference between biosim-NTZ and ref-NTZ in the cumulative number of new active lesions was 0.17 (least square means, 0.34 vs 0.45), with a 95% CI of –0.61 to 0.94 and a point estimate within the prespecified margins of ± 2.1.
The annualized relapse rate (ARR) for biosim-NTZ and ref-NTZ was similar at 24 weeks (0.21 vs 0.15), as well as at 48 weeks (0.17 vs 0.13). For Expanded Disability Status Scale scores, which were similar between treatment groups at baseline (mean, 3.4 vs 3.2), change at 24 and 48 weeks was minimal and similar in both groups.
The safety profile was as expected for patients with RRMS receiving natalizumab. There were few adverse events of special interest, with similar proportions across all treatment groups.
The overall adverse event profile for patients who switched from ref-NTZ to biosim-NTZ was similar to patients continuing ref-NTZ treatment and did not indicate any new or increased risks associated with switching.
Rates of treatment-emergent adverse events (TEAEs) were similar, at 64.9% for biosim-NTZ, 68.9% for ref-NTZ, and 73.3% for the switch group. The most-reported TEAEs among all treatment groups were nervous system disorders and infections and infestations.
Progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal demyelinating disease of the central nervous system, is associated with some DMTs — notably ref-NTZ. It is caused by infection with the John Cunningham virus (JCV) (also referred to as human polyomavirus), the researchers note.
As per the study protocol, no participant had a JCV-positive index of more than 1.5 at baseline. Proportions of patients positive for anti-JCV antibodies were similarly distributed between treatment groups throughout the study.
Similar Immunogenicity
There was strong concordance regarding positivity for treatment-emergent anti-drug antibodies between the biosim-NTZ and ref-NTZ groups (79.4% and 74.0%). This was also the case for antinatalizumab-neutralizing antibodies (69.0% and 66.2%).
“There was nothing that indicated immunogenicity is different” between the two agents, said Hemmer.
While this might change “when you look at longer time periods,” antibodies to natalizumab usually develop “very early on,” he added.
Hemmer noted that this comparison of the proposed biosimilar with the reference drug had no real surprises.
“If the immunogenicity is the same, the mode of action is the same, and the dose is the same, you would expect to have a similar clinical effect and also a similar side effect profile, which is indeed the case,” he said.
Hemmer added that he has no insight as to when the drug might be approved but believes developers expect that to occur sometime this year.
Welcome Results
Commenting for Medscape Medical News, Torge Rempe, MD, assistant professor in the department of neurology, University of Florida College of Medicine, and the William T. And Janice M. Neely professor for research in MS, said he welcomes these new results showing the biosimilar matched the reference medication.
“The authors report no significant difference in their primary endpoint of cumulative number of active lesions as well as their secondary clinical endpoints of annualized relapse rate and changes from baseline Expanded Disability Status Scale scores,” said Rempe, who was not involved with the research.
The study also shows the reported adverse events were similar between the biosimilar and reference natalizumab, he noted.
However, although no cases of progressive multifocal leukoencephalopathy were uncovered during the study period, further research is needed to determine long-term safety in this area, Rempe said.
Finally, he agreed that the development of biosimilars such as this one addresses the issue of high annual costs for DMTs, an area of concern in the field of MS.
The study was funded by Polpharma Biologics. Hemmer has reported receiving personal fees from Polpharma and Sandoz during the conduct of the study and personal fees from Novartis, Biocom, and TG Therapeutics outside the submitted work. He has also received a patent for genetic determinants of antibodies against interferon-beta and a patent for KIR4.1 antibodies in MS; served on scientific advisory boards for Novartis; served as a data monitoring and safety committee member for AllergyCare, Polpharma Biologics, Sandoz, and TG Therapeutics; and received speaker honoraria from Desitin, grants from Regeneron for MS research, and funding from the Multiple MS EU consortium, the CLINSPECT-M consortium, and the German Research Foundation. Rempe has reported no relevant financial relationships.
JAMA Neurol. Published online January 23, 2023. Abstract
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