1 Year of Ocrevus Not Linked to Higher Risk of Brain Infection PML

One year of Ocrevus (ocrelizumab) treatment does not increase the risk for a rare brain infection — called progressive multifocal leukoencephalopathy (PML) — in people with multiple sclerosis (MS), a study suggests.

The study, “Risk Assessment of Progressive Multifocal Leukoencephalopathy in Multiple Sclerosis Patients during 1 Year of Ocrelizumab Treatment,” was published in the journal Viruses.

MS therapies are designed to suppress the immune system and limit the inflammatory damage to the myelin sheath that surrounds nerve fibers, an underlying cause of MS.

PML is a rare and potentially fatal brain infection caused by the common John Cunningham (JC) virus. It has been associated with the extended use of Tysabri (natalizumab), an MS therapy that suppresses the immune response in the brain by limiting the access of immune cells.

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Ocrevus is a different MS therapy that also suppresses the immune system, but works by depleting antibody-producing B-cells. Although a few cases of PML have been reported in patients treated with Ocrevus, most had been prescribed other immune-suppressing MS therapies. As such, the risk of PML in those treated with Ocrevus remains unclear.

To investigate further, scientists based at the Sapienza University of Rome, in Italy, collected blood and urine samples from 42 relapsing-remitting MS patients (24 females and 18 males) before Ocrevus treatment (baseline) and at various timepoints over one year of treatment to assess PML risk.

The study included 19 patients who had not been treated with any MS therapy (treatment-naive), four who had previously received Tysabri, and 19 who had switched from other MS treatments, such as Gilenya (fingolimod), Aubagio (teriflunomide), and Tecfidera (dimethyl fumarate).

Before Ocrevus initiation, JC viral DNA was detected in urine samples from 34 (81%) patients, but was absent from all blood samples. Viral DNA was found in all patients who received previous MS treatments and in 11 out of the 19 who were treatment-naive. The results were the same after six months of treatment.

After one year of Ocrevus, one additional treatment-naive patient tested positive for JC virus DNA in their urine. Blood samples remained negative except in three patients, all of whom had received prior MS treatment.

The team then conducted a DNA analysis of the VP1 gene from the JC virus, mutations in which have shown predictive value for PML onset.

The analysis showed that all DNA sequences isolated from the patients were 99.9% similar to the JC virus reference strain, which suggested “stability and a similarity across different isolates of the [JC virus],” the scientists wrote. One sample revealed one mutation, which is also found in JC viruses in people of European descent.

The sequence data of another DNA segment called NCCR was associated with a non-virulent form of the JC virus, “frequently found in the urine of healthy individuals, and it is rarely found in the brain of PML patients,” the researchers wrote.

The levels of two types of antibodies — immunoglobulin M (IgM) and IgG — were measured at baseline and after six months and one year. IgM levels significantly decreased during Ocrevus treatment, with mean values dropping from 127.95 to 75.04 after one year, while IgG levels remained constant.

As expected with Ocrevus, the overall levels of B-cells significantly decreased, with complete depletion in 34 participants (81%). The remaining eight had B-cells counts between 0.1% and 0.9% of normal.

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Next, the anti-JC antibody index, a commonly used indicator of PML risk, was compared before and after treatment.

At baseline, the anti-JC index was greater than 1.5 in 26 out of 42 participants — reflecting a high PML risk. The high index was found in four treatment-naive patients, three of those with prior Tysabri exposure, and in all 19 participants treated with other MS therapies.

After six months of Ocrevus, the number of patients with an index above 1.5 remained the same, whereas at one year, one additional Tysabri-treated individual measured above 1.5.

Finally, 15 participants had an anti-JC index of 0.9 or less at baseline and after six months of treatment, indicating a low risk. After one year, 14 of these maintained a low PML risk, all of whom were treatment-naive.

“Our results showed that [Ocrevus] therapy in [JC virus]-positive patients is safe and did not determine PML cases,” the researchers wrote.