Hydroxychloroquine Shows Potential to Treat PPMS in Phase 2 Trial
Treatment with hydroxychloroquine, an anti-malaria medication, appeared to help slow disability progression among people with primary-progressive multiple sclerosis (PPMS) in a small, proof-of-concept clinical trial.
Hydroxychloroquine “is a promising treatment candidate for PPMS and should be investigated further in randomized controlled clinical trials,” its researchers wrote.
Results of the study “Hydroxychloroquine for Primary Progressive Multiple Sclerosis,” were published in Annals of Neurology.
In relapsing forms of MS, for which there are numerous approved treatments, disease progression is driven mainly by acute inflammation in the brain. In contrast, disease progression in PPMS (and, possibly, non-active secondary progressive MS) is thought to happen because of chronic neurodegeneration and the abnormal activity of brain immune cells called microglia.
Hydroxychloroquine, or HCQ, has been used for decades to treat malaria; it was first approved for medical use in the U.S. in 1955. HCQ can also reduce the activity of the immune system, and it is regularly used in the management of certain autoimmune diseases, such as lupus and rheumatoid arthritis.
Notably, HCQ is known to get into the brain — indeed, one of the medication’s known side effects, retinopathy (damage to the retina of the eye), occurs specifically because HCQ can enter the brain. Additionally, preclinical research has shown that HCQ can lower the activity of microglia, the immune cells whose chronic activation is thought to drive PPMS.
Based on these preclinical data, a team of researchers in Canada hypothesized that HCQ “may enter the brain and reduce microglial activation in MS,” which could delay the progression of disability in people with progressive MS. The team conducted a small clinical trial to test this idea.
“We chose the generic drug HCQ because it is widely used in [autoimmune] diseases and generally well tolerated,” the researchers wrote.
Their study is called a futility analysis. This type of a study is not designed to test whether a medication is effective — in fact, the exact opposite is true.
The point of a futility analysis is to test whether a medicine does not work. If the analysis fails to prove that the medication is not effective, then there’s a chance that it actually is effective — providing a rationale for future, larger studies to test efficacy.
In the Phase 2 trial (NCT02913157), a group of people with PPMS were treated with 200 mg of oral HCQ twice daily for 18 months. All those enrolled had substantial disability but were able to walk with assistance. Notably, patients with signs of acute inflammation on MRI scans were excluded.
The researchers assessed the number of patients with worsening disability between months six and 18. Disability was assessed based on the time it took a person to walk 25 feet. The six-month run-in period was included because, in other diseases, HCQ is known to reach its maximum potency only after a few months of continuous treatment.
Based on prior clinical data of PPMS patients, researchers calculated that, if fewer than 10 of the first 35 treated patients experienced disease progression over those months, futility would be disproven. In other words, there would be a possibility that the medicine actually is effective.
This goal was reached: Of these 35 trial participants, only eight (23%) experienced significant disability worsening from months six to 18. Among all who completed the trial and were able to walk throughout, nine of 39 (also 23%) experienced worsening disability.
A total of 49 PPMS patients received at least one dose of HCQ in the study, and were analyzed for safety. Among them, about a third (31%) experienced side effects attributed to the medication, which included vivid dreams, nausea, stomach upset, and tinnitus (ringing in the ear).
“Over the 18-month course of this single-arm futility trial, HCQ was generally well tolerated, and meaningfully fewer people than expected experienced clinically significant worsening of disability,” the researchers concluded.
Study results support future trials to explore the efficacy of HCQ in treating PPMS and to further investigate the medication’s biological and pharmacological properties, they said.
“Current treatment options for PPMS are unsatisfactory,” the researchers added.