Sanofi’s Phase III clinical trials of tolebrutinib for multiple sclerosis (MS) and myasthenia gravis have been placed on partial clinical hold by the US Food and Drug Administration (FDA).
With the latest development, new participant enrolment in the US has been halted while the study drug will be suspended for subjects who are part of the trial for less than 60 days.
Furthermore, US subjects who have concluded a minimum of 60 days in the study will continue to receive the treatment.
The partial clinical hold comes after a small number of drug-induced liver injury cases were detected with tolebrutinib exposure in Phase III studies.
Most of the affected subjects were observed to have concurrent complications that are found historically to predispose to drug-induced liver injury.
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Notably, the rise in laboratory values used for tracking liver injury was found to be reversible following discontinuation of the treatment in all cases.
After holding talks with the FDA about these cases, trial protocols were updated in May 2022 to revise the frequency of monitoring and subject enrolment criteria were modified to eliminate pre-existing risk factors for hepatic dysfunction.
Subject enrolment in the clinical programme is progressing with the updated trial protocols and improved safety monitoring in regions outside the US.
To assess the effectiveness of safety measures, the company is also working with independent data monitoring committee members and investigators globally.
The programme in MS has been enrolling subjects since 2019 and comprises over 2000 patients presently receiving tolebrutinib for treatment durations of up to three years.
An investigational brain-penetrant and bioactive Bruton’s tyrosine kinase (BTK) inhibitor, tolebrutinib attains cerebrospinal fluid (CSF) concentrations required for acting on B lymphocytes and microglial cells.
Currently, tolebrutinib is being analysed in Phase III clinical trials to treat relapsing forms of MS (RMS), non-relapsing secondary progressive MS (nrSPMS), primary progressive MS (PPMS) and myasthenia gravis (MG).
The safety and efficacy of the therapy have so far not been assessed by any regulatory agency globally.
In June this year, Sanofi and GSK reported positive data from the trial of their adjuvanted bivalent D614 and Beta (B.1.351) Covid-19 vaccine candidate.