Fexagratinib in MS Shows Promise for Human Use

The results from a new study of the multi-kinase inhibitor fexagratinib in mouse models are raising hopes that the therapy may be effective at slowing or reversing disease progression in patients with multiple sclerosis (MS).¹

Fexagratinib’s multi-kinase inhibition is the key to its ability to fight MS, according to corresponding author Martin Berghoff, of the Justus-Liebig-University of Giessen, in Germany, and colleagues. Previous research has highlighted the roles of the FGF, CSF, and VEGF signaling pathways in the pathology of MS.

Neurologic disease concept | image credit: ralwel - stock.adobe.com

“In chronic brain lesions, FGF-1 is expressed in oligodendrocytes, microglia/macrophages and lymphocytes; FGF-2 is mainly found in microglia/macrophages, and FGFR1 is up-regulated in oligodendrocyte precursor cells,” they wrote. “CSFR is increased in lesions in MS and EAE [experimental autoimmune encephalomyelitis].”

A study by Berghoff and colleagues published 4 years ago found FGF receptors in oligodendrocytes were potential therapeutic targets in inflammatory and demyelinating diseases, such as MS.² A year later, they published data showing that cell-specific deletion of FGFR1 in oligodendrocytes had anti-inflammatory and neuroprotective effects in the cerebellum in EAE.³

Fexagratinib, which was previously known as AZD4547, “potently inhibits the tyrosine kinase activity of FGFR1-3, CSFR and VEGFR-2," Berghoff and colleagues noted. Because of that, they wanted to see whether its multi-kinase inhibition might lead to meaningful effects on MS disease course, inflammation, neurodegeneration, and remyelination.

In the new study, which was published in the British Journal of Pharmacology, the investigators tested their hypothesis on female C57BL/6J mice in which EAE was induced. Mice were treated with 1 of 2 different oral doses of fexagratinib or with placebo. Two types of experiments were conducted. In one group, fexagratinib was administered at the time of EAE induction in order to see how well the therapy prevented the disease. In the second group, fexagratinib was not administered until the animals started exhibiting symptoms. In that group, the goal was to see how well the therapy could suppress disease progression.

Berghoff and colleagues said the results of the therapy were significant.

“In the prevention experiment, treatment with 6.25 or 12.5 mg/kg-1 fexagratinib prevented severe first clinical episodes by 66.7% or 84.6% respectively,” they wrote. “Mice treated with 12.5 mg/kg-1 fexagratinib hardly showed any symptoms in the chronic phase of EAE.”

Similarly, the therapy led to long-term reductions of severe symptoms of 91% and 100% for the smaller and larger doses, respectively. The investigators added that inflammation and demyelination were reduced, while axonal density oligodendrocytes, oligodendrocyte precursor cells, and re-myelinated axons all increased in mice who received the therapy.

Berghoff and colleagues noted that there are 13 trials currently registered at the National Library of Medicine in which fexagratinib is being evaluated, including phase 1 and 2 trials. So far, the available safety data from those trials has been generally positive, with mostly mild to moderate adverse events, including gastrointestinal problems and dry mouth and skin.

They said the promising results in mouse models, coupled with the encouraging safety data in trials for other indications, suggest oral fexagratinib might be a meaningful therapy in humans with MS.

“Since the substance targets three receptors involved in pathology of EAE, multi-kinase inhibition by fexagratinib in a well-tolerated dose of 1 mg/kg-1 in humans may be a promising approach to reduce inflammation and neurodegeneration, to slow down disease progression and support remyelination in patients,” they concluded. “Synergetic inhibition of pathways by fexagratinib may lead to a stronger reduction of symptoms and demyelination, and enhanced axonal preservation than selective FGFR inhibition.”

References:

1. Gurski F, Shirvanchi K, Rajendran V, et al. Anti-inflammatory and remyelinating effects of fexagratinib in experimental multiple sclerosis. Br J Pharmacol. Published online October 5, 2024. doi:10.1111/bph.17341
2. Kamali S, Rajendran R, Stadelmann C, et al. Oligodendrocyte-specific deletion of FGFR2 ameliorates MOG35-55 -induced EAE through ERK and Akt signalling. Brain Pathol. 2021;31(2):297-311. doi:10.1111/bpa.12916
3. Rajendran R, Rajendran V, Giraldo-Velasquez M, et al. Oligodendrocyte-specific deletion of FGFR1 reduces cerebellar inflammation and neurodegeneration in MOG35-55-induced EAE. Int J Mol Sci. 2021;22(17):9495. doi:10.3390/ijms22179495