#ECTRIMS2019 – 6 Years of Ocrevus Use Tied to Low Rates of Serious Infections

#ECTRIMS2019 – 6 Years of Ocrevus Use Tied to Low Rates of Serious Infections

Treatment for more than six years with Ocrevus (ocrelizumab) is linked to lower levels of blood antibodies among people with primary progressive multiple sclerosis (PPMS) and relapsing MS, but rates of serious infections also remain low, an analysis of data from three Phase 3 trials show.

Dropping below a certain threshold in one class of antibodies, called IgG, showed an apparent association with higher rates of serious infections, but again the overall incidence is low.

Tobias Derfuss with University Hospital Basel, Switzerland, presented the data in the talk “Serum immunoglobulin levels and risk of serious infections in the pivotal Phase III trials of ocrelizumab in multiple sclerosis and their open-label extensions,” at the 35th congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), running through Friday in Stockholm.

“Patients with MS have a higher risk of infections, and of hospital admission rates for infection, compared with the general population,” Derfuss said.

Treatment with B-cell targeted therapies like Genentech’s Ocrevus include a risk of decreasing the levels of antibodies (also known as immunoglobulins or Ig), important blood proteins in the immune system that are produced by a type of white blood cell called B-cells. This decrease in antibodies could increase a person’s risk of serious infections.

Ocrevus is an anti-CD20 monoclonal antibody that targets CD20-positive B-cells — cells believed to target axons and the myelin sheaths of healthy neurons, initiating a cascade of immune reactions that leads to MS and disability in patients.

In MS trials assessing Ocrevus, “infections were one of the most frequently reported adverse events,” Derfuss said.

“Do lower immunoglobulin levels due to B-cell depletion [for instance, through Ocrevus use] really translate into greater risk of infection in MS patients?” Derfuss asked.

To answer this question, researchers assessed the levels of three different immunoglobulins — called IgG, IgM, and IgA — in the blood of MS patients enrolled in three pivotal Phase 3 trials: ORATORIO (NCT01194570), OPERA I (NCT01247324), and OPERA II (NCT01412333). The first of these trials evaluated Ocrevus in people with PPMS, the other two in those with relapsing MS.

Patients received Ocrevus for more than six years (288 weeks, data up to January 2019), and levels of the different antibodies were measured at least every 24 weeks. The lower limit of the normal (LLN) value for IgG was set as 5.65 g/L, while IgA was set at 0.70 g/L, and IgM as 0.40 g/L.

Researchers then compared rates of serious infections when antibody levels were below their LLN, to rates when the levels exceeded their LLN.

Analysis revealed that over the six-year period, the decrease in IgM antibody levels among relapsing MS patients was 55.4% (mean reduction of 0.78 g/L), and 53.7% (mean reduction of 0.77 g/L) among PPMS patients.

For IgG, Ocrevus treatment was found to reduce levels of this antibody “at an average rate of -0.32 g/L per year (minus 3% per year),” Derfuss said, resulting in a total reduction of about 18% over the six years.

According to the researcher, IgA results were similar to those of IgG.

Overall, “for the majority of the patients, with either relapsing MS or PPMS, serum immunoglobulin levels remain above LLN at approximately six years,” Derfuss said.

Specifically, at the end of this treatment period, IgG levels in about 7.1% of the patients dropped below the LLN, IgA levels in around 6% of these people, and IgM levels fell below LLN in about 30.8% of patients.

“There was no really difference in the OPERA [relapsing MS patients] and ORATORIO [PPMS patients] cohorts in relation to IgM,” Derfuss noted. Drops here were 7% in the relapsing MS group, and 7.2% in the PPMS group.

Changes in IgG levels related most strongly to serious infections. “There was a more dramatic increase in infections for those patients who dropped below the lower limit of normal [LLN] for IgG,” Derfuss said.

Fourteen serious infections occurred during periods when IgG levels dropped below its established LLN threshold, compared to periods when IgG levels were above the LNN limit (about 208 infections). This corresponded to a rate of serious infections per 100 patient-years of 5.48 in those below LLN, and 2.14 in those above LLN.

During the drop of IgA levels were below the LLN, seven serious infections were detected compared to 215 infections when levels were above LLN: a rate of serious infections per 100 patient-years of 2.74 in those below LLN, and 2.21 in those above LLN.

A drop of IgM below LLN was linked with 71 infections, compared to 151 infections when levels were above LLN: a rate of serious infections per 100 patient-years of 3.54 in those below LLN, and 1.89 in those above LLN.

“Urinary tract infections, cellulitis, and pneumonia were the most common serious infections associated with Ig levels below LLN,” Derfuss said. “No fatal outcomes or opportunistic infections were observed.”

Importantly, most infections resolved with standard of care; and in most cases, patients remained on treatment with Ocrevus.

Overall, at about six years of Ocrevus treatment, “rates of serious infections remain low, and consistent with rates of infection-related hospitalizations in real-world MS cohorts,” Derfuss concluded.

“There is an apparent association between decreased levels of IgG [less so for IgM or IgA] and serious infections, but overall incidence is low,” he added.

Of note, this study was sponsored by Roche, which owns Genentech, Ocrevus’ developer.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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