vasopharm GmbH Announces Brain Glutamate Microdialysate Data from Post Hoc Analyses of Clinical Trials in Traumatic Brain Injury
Ronopterin significantly reduces glutamate levels measured in brain microdialysate from TBI patients, an important and long sought indicator of biochemical neuroprotection
Combined inhibition of nitric oxide synthesis and glutamate increase expands our understanding of Ronopterin’s mode of action and its association with improved outcome in TBI
Decreasing glutamate adds to the previously reported reduction in aggressive therapeutic interventions and improved eGOS after moderate and severe TBI
The glutamate-lowering potential of Ronopterin makes it an interesting candidate for other acute and chronic neurologic diseases involving activated inflammation and iNOS-driven glutamate increase
New patent filed for Ronopterin-mediated glutamate reduction
vasopharm GmbH, a privately-held biopharmaceutical company focusing on novel therapeutics to treat cerebrovascular diseases, today announces the finding of statistically significantly reduced brain microdialysate glutamate levels in the phase 2 (NOSTRA) and phase 3 clinical trials (NOSTRA III) of Ronopterin (formerly VAS203) for the treatment of traumatic brain injury (TBI). This reduction in glutamate is of high importance as increased glutamate levels are associated with evolving cell damage and poor prognosis. These results expand on the reduced treatment aggressiveness and improved clinical outcome in patients with moderate and severe TBI with early infusion of Ronopterin after the injury. Ronopterin has the potential to be the first drug therapy for TBI with clinically meaningful improvements in biochemical changes and neurologic outcome.
Within the pathophysiologic cascades of acute and chronic brain injuries with local inflammatory reactions, the increased activation of inducible nitric oxide synthase (iNOS) is positively correlated with the enhanced release and inhibited uptake of glutamate. Glutamate and nitric oxide are crucial mediators of progressive secondary brain damage. Excessively activated and upregulated iNOS increases the production of nitric oxide and harmful nitrate and oxygen radicals resulting in cellular and mitochondrial damage. Such cellular injury leads to release of glutamate and reduced uptake of glutamate. Increased glutamate is known to result in excitotoxic damage to neurons, glia, and endothelial cells, and increases nitric oxide synthesis, thereby completing the vicious circle between iNOS and glutamate. Ronopterin is a highly selective inhibitor of iNOS without significantly interfering with the action of other NOS enzymes important for normal brain and body function.
Overall, Ronopterin significantly decreased brain microdialysate glutamate levels, with a higher proportion of glutamate levels ≤ 10 μmol/L in patients treated with Ronopterin compared to patients on placebo plus standard of care (74% vs 59%, OR 1.9, 95% CI 1.7-3.6, p<0.0001). This decrease was more apparent with early time to infusion ≤ 12 hours (OR 5.8, 4.6-7.4, p<0.0001).
While the reduction in brain glutamate was already significant during the drug infusion phase with early time to infusion ≤ 12 hours (OR 2.5, 1.7-3.7, p<0.0001), this effect was most pronounced on days 3-5 following the early drug infusion phase (OR 9.6, 6.9-13.3, p<0.0001). This pattern reflects the pharmacokinetic profile of Ronopterin’s first active metabolite and unmasks Ronopterin’s progressively evolving pharmacologic effect.
Professor Andreas Unterberg, University Hospital Heidelberg, Germany, and Lead Investigator for the NOSTRA III trial in Germany said:
“These are the first results obtained as part of a registration trial showing important pharmacodynamic effects of iNOS inhibition on glutamate levels. This significant reduction of glutamate in TBI patients is impressive, especially in view of the long-standing attempts to reduce elevated glutamate levels where other compounds have failed due to unacceptable side effects or lack of efficacy. It appears that the dual effects of reducing iNOS activity and glutamate release are Ronopterin’s very promising mode of action.”
Professor Carl-Henrik Nordström, Department of Neurosurgery, Odense University Hospital, Odense, Denmark, former DMC member for the NOSTRA trial stated:
“It is remarkable to see a repetition in the NOSTRA III study of the reduction in brain microdialysate glutamate levels already observed during the phase 2 trial (NOSTRA). This confirmation conveys confidence in the Ronopterin-mediated reduction in brain microdialysate glutamate levels and may contribute to the observed clinical improvement.”
Professor John Stover, Chief Medical Officer of vasopharm noted:
“We are very intrigued by Ronopterin’s ability to significantly reduce brain microdialysate glutamate levels. This important pharmacodynamic effect forms a strong basis for us to expand our Clinical Development Plan with Ronopterin.”