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Early-Phase Results Promising for BTK Inhibitor in Multiple Sclerosis Therapy

David Bai
A phase 1 trial evaluating the safety and tolerability of PRN2246, a Bruton's tyrosine kinase inhibitor, found the drug having no serious medication-related adverse events in healthy volunteers while also being able to reach the brain.
A phase 1 trial evaluating the safety and tolerability of PRN2246, a Bruton's tyrosine kinase (BTK) inhibitor, found the drug having no serious medication-related adverse events in healthy volunteers while also being able to reach the brain.

Multiple sclerosis (MS) is a neurodegenerative disease in which a person’s immune system functions abnormally, causing inflammation and damage to myelin, which in turn prevents normal signaling by nerve cells and can result in motor disorders and disability.

With a lack of treatments that reverse or prevent disease progression/relapses, MS continues to be a debilitating disease in many patients around the world. Several drug companies are invested in finding alternative therapies that patients with MS and their physicians can use. One major issue with these drugs is that they must be formulated to be able to cross the blood-brain barrier (BBB) to be effective, which makes drug development a challenge.

The purpose of this phase 1 trial was to determine if the BTK inhibitor PRN2246, developed by Principia Biopharma in collaboration with Sanofi, is safe profile in healthy volunteers and can penetrate the BBB. BTK inhibitors work by inhibiting the B-cell signaling pathway and limiting B-cell maturation. If PRN2246 can successfully penetrate through the BBB, the hope is that the drug will be able to modulate the activity of immune B-cells in the central nervous system (CNS) and delay further progression or relapses of the disease.

Eighty healthy individuals were enrolled in this trial to determine the safety profile of PRN2246, the optimal dose that will be used in future trials, and whether the drug can pass the BBB. Preliminary findings from this trial reported PRN2246 was well tolerated and safe with no treatment-related adverse events in these healthy volunteers. In a dedicated arm, investigators affirmed that PRN2246 was found in the cerebral spinal fluid of the participants, demonstrating the drug’s ability to successfully pass the BBB. Doses that were used in this trial ranged between 7.5 mg and 120 mg daily. The presumed dose to be used in future studies is still being determined.

“Confirmation that PRN2246 crosses the blood-brain barrier in humans and achieves therapeutic levels in the CSF [cerebrospinal fluid] is an important milestone for this program and our collaboration with Sanofi,” said Martin Babler, chief executive officer of Principia Biopharma. “We now look forward to evaluating the potential additional benefit of modulating B-cells directly in both the periphery and the CNS in MS patients.”

MS is a disease with a gap of care that has yet to be fully addressed. Results from phase 1 trial of PRN2246 have substantiated that PRN2246 may be worth further investigating. Future observations of PRN2246 as it proceeds through more clinical trials will determine whether this drug may help serve as an alternative treatment for patients with MS.


1. Australian New Zealand Clinical Trials Registry. A Phase I, Randomized, Double-Blind, Placebo-Controlled, Ascending Dose Study to Assess the Safety, Tolerability and Pharmacokinetics of Orally Administered PRN2246 in Healthy Volunteers. Published July 10, 2017. Updated August 6, 2018. Accessed August 8, 2018.

2. Melao A. Potential B-cell targeting oral MS treatment, PRN2246, shows ability to reach brain in phase 1 study. Multiple Sclerosis News Today. Published August 2, 2018. Accessed August 8, 2018.

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