May 10 2022

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.”


For further information, please contact: 

vasopharm GmbH
Christian Wandersee, CEO
Tel: +49-931-359099-0

Optimum Strategic Communications
Mary Clark, Hollie Vile, Elakiya Rangarajah
Tel: +44 (0) 203 922 0900



About vasopharm GmbH
vasopharm is a privately held drug development company focused on small molecule therapeutics for the treatment of Traumatic Brain Injury (TBI). vasopharm was founded in July 1998 as a spin-off from the University of Würzburg Medical School by Harald Schmidt, MD, PhD, Professor of Pharmacology and Toxicology, and Ulrich Walter, MD, Professor of Clinical Biochemistry and Pathobiochemistry. For more details please visit

About Traumatic Brain Injury
Traumatic brain injury (TBI) occurs when a sudden external force, such as a road traffic accident or fall, causes damage to the brain. This can impair cognitive, physical, and psychosocial functioning temporarily or permanently. This impairment can lead to disability and loss of independence. TBI is the leading cause of death and disability in young adults in the developed world. Annually, within the US alone, head trauma is the cause of approx. two million emergency room visits, 475,000 hospital admissions, nearly 52,000 deaths and approx. 80,000 cases of severe long-term functional, cognitive, and learning disabilities.

Current approaches are limited to the symptomatic treatment of acute TBI focusing on short term patient mortality (increasing blood pressure and reducing intracranial pressure) with limited impact on reducing long-term physical and cognitive deficits. To date, there is no specific therapy for patients suffering from the consequences of TBI.

Direct costs attributed to the current symptomatic treatment of TBI exceed $10bn p.a. in the US alone. TBI results in more lost working years than cancers, stroke and HIV/AIDS combined. On a global scale, the number of life-years lost due to TBI is four times that of diabetes-related loss. Moderate and severe TBI is associated with a 2.3 and 4.5-fold higher risk of Alzheimer’s disease, respectively. See for more information. 

About Ronopterin
Ronopterin is an analogue of the natural co-factor, tetrahydrobiopterin involved in the generation of nitric oxide by the Nitric Oxide Synthase (NOS) family of enzymes. Ronopterin selectively inhibits the inducible NOS (iNOS) without significantly interfering with the function of other NOS enzymes. iNOS activation with increased release of nitric oxide is significantly involved in the cascade of damaging sequelae following brain injury including increased glutamate release. Ronopterin-mediated inhibition of iNOS is associated with a significant decrease in glutamate, a new facet to the Ronopterin’s mode of action.

Ronopterin has successfully passed phase 1, 2, and 3 trials. Its safety and efficacy profile underscore a positive benefit-risk assessment supporting its use to treat traumatic brain injury (TBI) patients. Ronopterin has pharmacologic effects on renal function that allow its controlled use in patients with risk of kidney dysfunction. Also, it does not interfere with neuronal or endothelial nitric oxide synthases (NOS) which are important for normal brain and body functioning. Beyond TBI, Ronopterin carries a development potential for a broad range of acute and chronic diseases characterized by activation of inflammatory cascades with subsequent activation of iNOS.

About Nostra
NOSTRA (NOSynthase Inhibition in TRAumatic brain injury) (Phase 2a) was an exploratory placebo-controlled, randomised, multi-centre study comparing Ronopterin to placebo, in addition to standard of care. The trial was conducted in six centres in Austria, France, Spain, Switzerland. and United Kingdom. Ronopterin treated patients had a significantly better clinical outcome than patients given placebo, as assessed by the therapy intensity level (at day 6 after TBI) and the extended Glasgow Outcome Score (at 6 and 12 months after TBI). The primary endpoint was eGOS at 6 months for which the median was 6 with Ronopterin vs 4.5 in the placebo arm. The trial results strongly indicate a neuroprotective role of Ronopterin in patients with moderate and severe TBI. Treatment aggressiveness reflected by the Therapy Intensity Level was significantly reduced (p<0.04).

About Nostra III
The NOSTRA III trial entitled “Efficacy of Ronopterin in patients with moderate and severe traumatic brain injury (NOSTRA-III)” (NCT02794168) examined the efficacy and safety of Ronopterin in patients with moderate and severe traumatic brain injury (TBI).

The placebo-controlled, randomised, double-blind, multi-centre NOSTRA III trial was conducted in 38 centers in 5 European countries (Austria, France, Germany, Spain, United Kingdom) and completed as planned. In total 223 patients comprise the Full Analysis Set with 112 patients randomized to the Ronopterin treatment arm and 111 patients in the Placebo treatment arm. As in the NOSTRA trial, Ronopterin was added to the Standard of Care and the primary endpoint was again extended Glasgow Outcomes Scale at 6 months after TBI.

While the primary endpoint was not met, the prespecified analysis revealed significantly higher eGOS levels in the patients aged 18-39 years vs 40-60 years.

During the entire course of the study, an independent Drug Monitoring Committee (DMC) unanimously recommended to continue the study according to the original study protocol.
The DMC concluded that at no time any safety concerns were identified.

By extending the time to infusion from 12 to 18 hours after TBI to facilitate recruitment, the number of patients with infusion start between 6 and 12 hours was unintentionally reduced, reaching 30% in the NOSTRA III compared to 88% in the NOSTRA trial. This obvious difference forms the basis of the detailed post-hoc analysis. The combined analysis of the two trials with start of Ronopterin infusion within 12 hours after TBI shows improved neurologic outcome in all patients 18-60 years of age with significantly increased proportion of patients with Good Recovery (GOS 5) at 6 months (Ronopterin: 39% vs Placebo: 18%, p=0.03). The proportion of patients with low Therapy Intensity Level was significantly decreased (77% vs 67%, p<0.004).