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WEST PALM BEACH, Fla. -- Tolebrutinib, an investigational brain-penetrant Bruton's tyrosine kinase (BTK) inhibitor, failed to eliminate paramagnetic rim lesions (PRLs) in people with multiple sclerosis (MS), a small showed.

The primary endpoint -- the per-patient proportion of lesions in which the paramagnetic rim disappeared at the end of 48 weeks of tolebrutinib treatment -- was negative, according to Maria Gaitan, MD, of the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland.

The study would have been considered positive if at least one PRL disappeared in at least two of the seven tolebrutinib-treated participants. But of 107 PRLs reviewed in the tolebrutinib group, none disappeared at 48 weeks, Gaitan said at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum.

Through 96 weeks, patients treated with tolebrutinib did not develop new T2 lesions or experience clinical relapses, she added, and B-cell repopulation was slow.

The trial was conducted separately from a previous phase II study, which showed that tolebrutinib reduced new gadolinium-enhancing brain lesions in people with relapsing MS.

"We were looking at the drug's efficacy in an entirely different patient population from the original phase II study," said co-investigator Daniel Reich, MD, PhD, also of NINDS.

"The latter was done in early patients with relapsing-remitting disease. Our trial was a small study in patients without active disease who were treated with effective disease-modifying therapy at baseline," he told MedPage Today. "Our hypothesis was that the therapy they were on would not adequately control inflammation in the brain, but that BTK inhibitors might."

PRLs are a type of chronic active MS lesion that contain iron within the immune cells at their rim, making them detectable on MRI. They are associated with an aggressive disease course and cognitive decline.

Current disease-modifying therapies target peripheral inflammatory mechanisms that underlie relapses or new lesions, Gaitan noted. B cell-depleting drugs do not resolve chronic active MS lesions, she explained.

In their non-randomized study, Gaitan and colleagues evaluated 12 MS patients with PRLs on 7-T MRI. Seven patients were treated with tolebrutinib, and five patients in a reference group were not.

The tolebrutinib group -- four men and three women -- had no inflammatory activity, including no relapses and no new or enhancing lesions, in the past 6 months. They had been on anti-CD20 monoclonal antibody treatment for more than 6 months, and they were within 6 months of their last dose. They agreed to forgo further therapy for the 96-week trial. Mean baseline age was about 48 and median baseline PRLs were 9.

All seven participants received tolebrutinib 60 mg daily for 48 weeks. For the next 48 weeks after that, four patients received 120 mg daily, and three patients remained on 60 mg.

"Tolebrutinib treatment after B-cell depletion showed no safety signals through week 96," Gaitan noted. There were no safety-related discontinuations in the trial and no deaths were reported.

The reference group -- one man and four women -- had the same inclusion criteria but chose to stay on anti-CD20 therapy. Mean baseline age was 42 and median baseline PRLs were 4.5. Over 48 weeks, one infratentorial new lesion was observed in this group and no PRLs disappeared.

The failure to achieve the primary endpoint might have been because the tolebrutinib treatment period was too short, Gaitan suggested. The 60 mg/day dose could have been too low, she added, and 120 mg/day might have been better.

"PRL disappearance may be too high a bar," she observed. The researchers are now conducting a quantitative assessment of minor PRL changes, she said.

"Because this agent has the potential to cross the blood-brain barrier, it is possible that additional study may prove beneficial," noted Natasha Hameed, MD, of Northwell Health Long Island Jewish Hospital, who wasn't involved with the study. "There is still hope for this drug," she told MedPage Today.

It's possible that combination therapy may slow B-cell repopulation, prolonging efficacy against new lesion formation, Gaitan pointed out. "Sequencing of B-cell depletion followed by BTK inhibition may be a promising approach," she said.

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