Full results from a randomized controlled trial (RCT) suggest that the over-the-counter (OTC) antihistamine clemastine fumarate is safe and effective for treating chronic demyelinating injury in multiple sclerosis (MS)֫ — even in patients who have had symptoms of myelin degeneration for years.
Although preliminary results were presented at the annual American Academy of Neurology meeting last year, full data from the ReBUILD trial were published online October 10 in the Lancet.
The phase 2 ReBUILD crossover study included 50 patients with relapsing MS, a mean disease duration of 5 years, and chronic demyelinating optic neuropathy. The first group received oral clemastine fumarate twice daily for 3 months and then placebo for 2 months, while the second group received the placebo for 3 months and the active treatment for 2 months.
Results showed that during the active treatment phase, latency delay on visual-evoked potentials (VEPs) was reduced from baseline by a significant 1.7 milliseconds per eye, the primary endpoint. In addition, this outcome remained significant throughout the study in the group that started with active treatment and then switched to placebo.
Although there were more reports of fatigue when the participants were taking clemastine fumarate than placebo, no one reported any treatment-related serious adverse events. There were also no dropouts during the study.
The investigators, led by Ari J Green, MD, chief of the Division of Neuroinflammation and Glial Biology and professor at University of California, San Francisco (UCSF), note that this is the first RCT to show efficacy by a remyelinating drug for this type of treatment.
Dr Ari J. Green
“Our findings suggest that myelin repair can be achieved even following prolonged damage,” they write.
Dr Green pointed out that the study’s purpose was to demonstrate that this type of repair is possible. “And to me, that was what was most encouraging,” he told Medscape Medical News.
Possibility of Repair
While current MS treatments block target tissue access for immune cells or suppress inflammatory injury, none fully prevent neuroaxonal degeneration — and there have been no treatments available to remyelinate injury, note the investigators.
Myelin in the central nervous system “is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells [OPCs] in vitro, in animal models, and in human cells,” they write.
The US Food and Drug Administration (FDA) first approved the drug, which crosses the blood-brain barrier, in 1977 for treating allergies. While a generic form has been available OTC in the United States since 1992, the FDA granted an Investigational New Drug exemption for investigating its use in treating MS in 2013.
“We realize that even to get a diagnosis of MS, there has to be pre-existing injury. But the key part that has never been addressed is regeneration and repair of the damage that occurs, particularly to the oligodendrocyte,” said Dr Green.
“The large goal for our program was to work on developing treatments that can help with that whole repair process. We really wanted to prove the concept that repair might be possible, and that was the hope for this trial,” he added.
In the 150-day ReBUILD study, 50 patients with long-standing MS were enrolled at UCSF between January 2014 and April 2015. At screening, baseline, and months 1, 3, and 5, electrodes were placed on participants’ scalps over the occipital lobe. VEPs then recorded cortical responses to an alternating pattern of repetitive visual images.
“Nearly all patients with [MS] ultimately exhibit demyelinating damage to the anterior visual pathway and detection of prolongation of VEP latency has been used as supportive evidence to help confirm a clinical diagnosis,” write the investigators.
The primary outcome measure was shortening of P100 latency delay on full-field, pattern-reversal VEPs from baseline. All of the patients had VEP P100 latency of 118 milliseconds in at least one eye, showing pre-existing deficits in neural transmission.
VEP Improvement
The first treatment group (n = 25; 76% women; mean age, 40.2 years) received clemastine fumarate 5.36 mg twice daily for 90 days and then 60 days of matching placebo. The second group (n = 25; 52% women; mean age, 40.0 years) started with placebo for 90 days and then switched to the active treatment for 60 days.
“The differing length of the two epochs was intended to help determine if any difference in efficacy was based upon variation in exposure time,” explain the researchers.
Combined, the groups met the primary outcome while taking clemastine fumarate, reducing latency delay by 1.7 milliseconds per eye (95% confidence interval [CI], 0.5 – 2.9; P = .005).
Post hoc analysis using a delayed-treatment model showed a reduction in VEP latency delay of 3.2 milliseconds per eye (95% CI, 1.8 – 4.7; P = .0001).
In addition, a latency improvement greater than 6 milliseconds was shown in 16% of group 1 and 26% of group 2 during the active treatment phase vs 3% and 6% of each group, respectively, during the placebo phase.
Low-contrast letter acuity (LCLA) was the principal functional secondary outcome measure. Although patients showed improvement of 0.9 letters per eye while taking clemastine fumarate, this was not statistically significant (P = .085). In post hoc, delayed-treatment analysis, the suggested improvement was a significant 1.6 letters per eye (P = .02).
No MRI measure, including new and enlarging T2 lesions, showed improvement or worsening with the active treatment during the crossover or ad hoc analyses. Nor were there any significant changes on the Expanded Disability Status Scale, timed 25-foot walk, or 6-minute walk test.
No serious adverse event occurred, but fatigue significantly worsened, as measured on the multidimensional assessment of fatigue scale, on vs off active treatment (P = .02).
A First Step?
“To the best of our knowledge, this is the first time a therapy has been able to reverse deficits caused by MS,” said Dr Green in a press release. “It’s not a cure, but it’s a first step towards restoring brain function to the millions who are affected by this chronic, debilitating disease.”
Senior author, Jonah Chan, PhD, professor of neurology and vice chief of the Division of Neuroinflammation and Glial Biology at UCSF, first identified clemastine fumarate as a possible MS treatment back in 2013. Still, “people thought we were absolutely crazy” to launch the current trial, he said in the same release.
“They thought that only in newly diagnosed cases could a drug like this be effective. Intuitively, if myelin damage is new, the change of repair is strong,” said Dr Chan. “In the patients in our trial the disease had gone on for years, but we still saw strong evidence of repair.”
Dr Chan added that the disappointing MRI results actually highlight that MRI is a weak tool for this type of measure. “We still don’t have imaging methods that have been proven to be able to detect remyelination in humans,” he said.
Overall, “we were not only able to see an effect on our principal outcome but there was, even if modest, some evidence of functional recovery on the part of patients. That tells us that the repair process may have functional benefit for patients,” Dr Green told Medscape Medical News.
That said, questions remain as to how long the window can stay open for repair. “Damage that is a decade old or more may be not be as amenable to repair. What we hope we’ve added is a sense that the time window is at least longer than immediate,” said Dr Green.
“I’d say the main takeaway for clinicians is: the era of medically induced brain repair may be upon us.”
He cautioned, though, that the study treatment is not a miracle drug and was associated with fatigue, which is already a problem in MS. And even though it’s available OTC, “it should only be taken with the advice and guidance of a medical professional or within clinical trials.”
Not Clinically Meaningful…Yet
In an accompanying editorial, Jeffrey A. Cohen, MD, Neurologic Institute at Cleveland Clinic, Ohio, and Paul J. Tesar, PhD, Department of Genetics and Genome Sciences at Case Western Reserve University School of Medicine, Cleveland, Ohio, note that the study’s positive results were noteworthy.
“However, the average improvements detected by VEP and LCLA in this short trial were modest and probably not of a clinically meaningful magnitude,” they write.
In addition to the trial’s short duration, they note that the dose was higher than what is commonly used to treat allergic symptoms in clinical practice.
However, testing the treatment for a longer period or at higher doses “might be difficult due to side-effects resulting from clemastine fumarate’s interaction with a variety of G-protein-coupled receptors,” write Dr Cohen and Dr Tesar.
“The scarce mechanistic data in human OPCs and the inability of many potent M1 muscarinic receptor antagonists to stimulate OPC differentiation in vitro suggest some continued uncertainty around [the drug’s] mechanism of action to promote remyelination and the need for further studies,” they add.
In summary, “although clemastine fumarate probably is not the final answer to the search for repair-promoting drugs to treat multiple sclerosis, the ReBUILD trial represents a watershed milestone in that quest.”
The study was supported by the University of California, San Francisco and by the Rachleff Family. Dr Green reports having received grants from the National MS Society and the US National Institutes of Health, other support from MedImmune, and grants and other support from Inception Biosciences. He also reports receiving other support outside the submitted work from Mylan, Sandoz, Dr Reddy, Amneal, Momenta, Synthon, JAMA Neurology, and Bionure. A full list of disclosures for the other study authors are in the original article. Dr Cohen has received consulting fees from Adamas and Celgene “for the development of symptomatic and disease therapies” for MS and as coeditor of Multiple Sclerosis Journal – Experimental, Translational and Clinical. Dr Tesar reports equity as a co-founder of Convelo Therapeutics and developing screening strategies to identify remyelinating compounds.
Lancet. Published online October 10, 2017. Full article, Editorial
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