Rituximab fails to eliminate meningeal inflammation in progressive MS

 

Researchers are heading back to the drawing board after a tiny phase 1 trial of intrathecal rituximab in certain patients with progressive multiple sclerosis failed to eliminate inflammation in the meninges.

The study investigators had hoped the treatment would significantly help progressive MS patients with leptomeningeal inflammation, which has been linked to worsening disease. However, “this paradigm seems to have not gotten rid of the meningeal inflammation significantly. We need a better approach,” said Pavan Bhargava, MD, of Johns Hopkins University, Baltimore, who spoke in an interview in advance of presenting the study findings at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

According to Dr. Bhargava, inflammation of the meninges – the lining of the brain – is more common in patients with progressive MS and is thought to be a driver of worsening disease. “People with the presence of the meningeal inflammation seem to have a more severe disease course,” he said, also noting that researchers have found that patients with collections of immune cells in the meninges are more likely to have more nerve cell damage and demyelination, especially along the surface of the brain under the meninges.

The new study aimed to test the value of targeting immune cell follicles with doses of rituximab given intrathecally – straight into the spinal fluid – to greatly boost the penetration of the drug into the meninges. When given intravenously, Dr. Bhargava said, only a minuscule amount of rituximab makes it to the brain.

Dr. Bhargava’s team screened 36 patients with progressive MS with MRI scans and found that 15 showed signs of meningeal inflammation. Of those, 11 agreed to take part in the study, and 8 fit the criteria.

The participants (median age 55.5 years; five were female) received two intrathecal treatments of 25 mg of rituximab 2 weeks apart, were monitored via follow-up clinical evaluations and lab tests at weeks 2, 8, 24, and 48, and received lumbar punctures and MRI scans at weeks 8 and 24.

“The main outcome was safety,” he said. “Most patients tolerated the rituximab, and the only side effect occurred in one patient who had abnormal sensations in the leg for 35-45 minutes. Otherwise, the medication was safe.”

The researchers detected no change in the meningeal inflammatory lesions before and after the treatment at 24 weeks.

But the tiny dose, much smaller than the typical two doses of 1,000 mg of IV rituximab over 2 weeks, completely depleted B cells in the blood of almost all patients, Dr. Bhargava said. “It was likely leaking out into the blood and clearing the B cells.” Peripheral blood B cells decreased from a median of 18.55% at baseline to 0.1% at week 2 and 8 with an increase to 3.6% at 24 weeks.

This effect was not as robust in spinal fluid, he said, where B cells were not fully depleted.

The findings suggest more cycles of treatment may be needed to target types of immune cells other than B cells, he noted. Or perhaps another drug would work better if it has a different mechanism and can penetrate more effectively.

The next step, he said, is to screen alternative drug approaches in animal models with meningeal inflammation that’s similar to that found in humans.

The study was funded by the International Progressive MS Alliance and the Race to Erase MS. Dr. Bhargava reported no relevant disclosures.

SOURCE: Bhargava P et al. ACTRIMS Forum 2018 Abstract P027.

 

Researchers are heading back to the drawing board after a tiny phase 1 trial of intrathecal rituximab in certain patients with progressive multiple sclerosis failed to eliminate inflammation in the meninges.

The study investigators had hoped the treatment would significantly help progressive MS patients with leptomeningeal inflammation, which has been linked to worsening disease. However, “this paradigm seems to have not gotten rid of the meningeal inflammation significantly. We need a better approach,” said Pavan Bhargava, MD, of Johns Hopkins University, Baltimore, who spoke in an interview in advance of presenting the study findings at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

According to Dr. Bhargava, inflammation of the meninges – the lining of the brain – is more common in patients with progressive MS and is thought to be a driver of worsening disease. “People with the presence of the meningeal inflammation seem to have a more severe disease course,” he said, also noting that researchers have found that patients with collections of immune cells in the meninges are more likely to have more nerve cell damage and demyelination, especially along the surface of the brain under the meninges.

The new study aimed to test the value of targeting immune cell follicles with doses of rituximab given intrathecally – straight into the spinal fluid – to greatly boost the penetration of the drug into the meninges. When given intravenously, Dr. Bhargava said, only a minuscule amount of rituximab makes it to the brain.

Dr. Bhargava’s team screened 36 patients with progressive MS with MRI scans and found that 15 showed signs of meningeal inflammation. Of those, 11 agreed to take part in the study, and 8 fit the criteria.

The participants (median age 55.5 years; five were female) received two intrathecal treatments of 25 mg of rituximab 2 weeks apart, were monitored via follow-up clinical evaluations and lab tests at weeks 2, 8, 24, and 48, and received lumbar punctures and MRI scans at weeks 8 and 24.

“The main outcome was safety,” he said. “Most patients tolerated the rituximab, and the only side effect occurred in one patient who had abnormal sensations in the leg for 35-45 minutes. Otherwise, the medication was safe.”

The researchers detected no change in the meningeal inflammatory lesions before and after the treatment at 24 weeks.

But the tiny dose, much smaller than the typical two doses of 1,000 mg of IV rituximab over 2 weeks, completely depleted B cells in the blood of almost all patients, Dr. Bhargava said. “It was likely leaking out into the blood and clearing the B cells.” Peripheral blood B cells decreased from a median of 18.55% at baseline to 0.1% at week 2 and 8 with an increase to 3.6% at 24 weeks.

This effect was not as robust in spinal fluid, he said, where B cells were not fully depleted.

The findings suggest more cycles of treatment may be needed to target types of immune cells other than B cells, he noted. Or perhaps another drug would work better if it has a different mechanism and can penetrate more effectively.

The next step, he said, is to screen alternative drug approaches in animal models with meningeal inflammation that’s similar to that found in humans.

The study was funded by the International Progressive MS Alliance and the Race to Erase MS. Dr. Bhargava reported no relevant disclosures.

SOURCE: Bhargava P et al. ACTRIMS Forum 2018 Abstract P027.

 

Researchers are heading back to the drawing board after a tiny phase 1 trial of intrathecal rituximab in certain patients with progressive multiple sclerosis failed to eliminate inflammation in the meninges.

The study investigators had hoped the treatment would significantly help progressive MS patients with leptomeningeal inflammation, which has been linked to worsening disease. However, “this paradigm seems to have not gotten rid of the meningeal inflammation significantly. We need a better approach,” said Pavan Bhargava, MD, of Johns Hopkins University, Baltimore, who spoke in an interview in advance of presenting the study findings at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

According to Dr. Bhargava, inflammation of the meninges – the lining of the brain – is more common in patients with progressive MS and is thought to be a driver of worsening disease. “People with the presence of the meningeal inflammation seem to have a more severe disease course,” he said, also noting that researchers have found that patients with collections of immune cells in the meninges are more likely to have more nerve cell damage and demyelination, especially along the surface of the brain under the meninges.

The new study aimed to test the value of targeting immune cell follicles with doses of rituximab given intrathecally – straight into the spinal fluid – to greatly boost the penetration of the drug into the meninges. When given intravenously, Dr. Bhargava said, only a minuscule amount of rituximab makes it to the brain.

Dr. Bhargava’s team screened 36 patients with progressive MS with MRI scans and found that 15 showed signs of meningeal inflammation. Of those, 11 agreed to take part in the study, and 8 fit the criteria.

The participants (median age 55.5 years; five were female) received two intrathecal treatments of 25 mg of rituximab 2 weeks apart, were monitored via follow-up clinical evaluations and lab tests at weeks 2, 8, 24, and 48, and received lumbar punctures and MRI scans at weeks 8 and 24.

“The main outcome was safety,” he said. “Most patients tolerated the rituximab, and the only side effect occurred in one patient who had abnormal sensations in the leg for 35-45 minutes. Otherwise, the medication was safe.”

The researchers detected no change in the meningeal inflammatory lesions before and after the treatment at 24 weeks.

But the tiny dose, much smaller than the typical two doses of 1,000 mg of IV rituximab over 2 weeks, completely depleted B cells in the blood of almost all patients, Dr. Bhargava said. “It was likely leaking out into the blood and clearing the B cells.” Peripheral blood B cells decreased from a median of 18.55% at baseline to 0.1% at week 2 and 8 with an increase to 3.6% at 24 weeks.

This effect was not as robust in spinal fluid, he said, where B cells were not fully depleted.

The findings suggest more cycles of treatment may be needed to target types of immune cells other than B cells, he noted. Or perhaps another drug would work better if it has a different mechanism and can penetrate more effectively.

The next step, he said, is to screen alternative drug approaches in animal models with meningeal inflammation that’s similar to that found in humans.

The study was funded by the International Progressive MS Alliance and the Race to Erase MS. Dr. Bhargava reported no relevant disclosures.

SOURCE: Bhargava P et al. ACTRIMS Forum 2018 Abstract P027.