Ronopterin significantly reduces lactate levels in brain microdialysate from TBI patients reflecting energetic stability and neuroprotection during the early vulnerable phase
The combined inhibition of nitric oxide synthesis and reduced lactate levels adds further insight into the mode of action of Ronopterin linked to improved outcome
Low lactate levels add to the previously reported decreased glutamate release, lower treatment aggressiveness, and improved eGOS in Ronopterin treated patients after moderate and severe TBI
The lactate-reducing potential of Ronopterin makes this iNOS inhibitor an interesting drug for acute and chronic neurologic diseases with NO-driven energetic impairment
New patent filed for Ronopterin-mediated lactate reduction
WÜRZBURG, Germany, July 12, 2022 /PRNewswire/ -- vasopharm GmbH, a privately-held biopharmaceutical company focusing on novel therapeutics to treat cerebrovascular diseases, today announces the results of significantly reduced brain microdialysate lactate 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). These analyses expand on the improved clinical outcome, reduced aggressiveness of underlying treatment, and reduced brain microdialysate glutamate levels in patients with moderate and severe TBI with early infusion of Ronopterin after TBI. This reduction in lactate reflects biochemical protection from energetic impairment and cell damage caused by the inducible nitric oxide synthase (iNOS)-mediated increase in peroxynitrite and glutamate levels. Ronopterin has the potential to be the first successful drug therapy for TBI with meaningful signs of biochemical neuroprotection and improvements in neurologic outcome.
Lactate is an important marker of underlying energetic impairment and impaired mitochondrial oxygen use. Within the pathophysiological cascades of brain injury, lactate is tightly linked to glutamate and iNOS. Glutamate activates neurons as part of our normal brain function. Any excessive release of glutamate from cells damaged, e.g. by nitric oxide radicals, as a consequence of increased activation of iNOS induces further cell damage from glutamate-mediated excessive activation of neurons and astrocytes. Glutamate can also activate iNOS, thereby creating a vicious cycle between glutamate and nitric oxide. A crucial consequence of this is evolving mitochondrial damage from the glutamate-driven and iNOS-mediated increase in oxygen and nitrate radicals. This mitochondrial damage in conjunction with radical-induced inhibition of important enzymes results in increased production of lactate.
A decrease in lactate in the context of iNOS inhibition is a beneficial finding.
With early infusion ≤ 12 hours, Ronopterin significantly decreased brain microdialysate lactate levels with a lower proportion of lactate levels ≥ 2.5 mmol/L (70% vs 76%, OR 0.7, 95% CI 0.6-0.9, p=0.001). This significant reduction was predominant during the actual 2 day infusion phase (63% vs 76%, OR 0.5, 0.4-0.7, p<0.0001) and on the first day after the infusion phase (65% vs 84%, OR 0.3, 0.2-0.6, p<0.0001).
The combination of increased brain microdialysate levels of glutamate ≥ 10 μmol/L and lactate ≥ 2.5 mmol/L, reflecting biochemical impairment from glutamate-induced lactate production, was significantly reduced in the Ronopterin-treated patients (40% vs 79%, OR 0.02, 95% CI 0.01-0.04, p<0.0001).
Dr. Stefan Wolf, Department of Neurosurgery Charité Berlin, Germany said:
"As part of our bedside monitoring we closely follow any increases in lactate levels to identify signs of energetic impairment following TBI. This is important to initiate appropriate counter measures to prevent evolving structural and functional damage from impaired perfusion or insufficient oxygenation. A reduction in lactate is a very important sign of protection from secondary brain injury and preserved energetic stability. The combination of reduced lactate and glutamate levels suggests that lactate reflects glutamate-driven lactate production. This profile of biochemical neuroprotection suggests that iNOS inhibition with Ronopterin is paramount for us to consider in our treatment concept."
Professor John Stover, Chief Medical Officer of vasopharm noted:
"We are very excited to see that Ronopterin aimed at improving the neurologic outcome in TBI patients significantly reduces lactate levels under clinical conditions during the early vulnerable phase. To date, this has only been shown in vitro with acetamidine based iNOS inhibitors and in patients in need of barbiturates, a very aggressive treatment option to reduce otherwise uncontrollably increased intracranial pressure. The combined decrease in glutamate and lactate guides our decision making for the use of Ronopterin and forms a strong basis for us to expand our Clinical development plan for Ronopterin."
Professor John Stover will be attending and presenting at the 15th International Neurotrauma Symposium, 17-20 July, in Berlin, Germany.
Presentation details:
16:00-17:30 (CET), 19th July 2022. In Plenary Session 4 on "Recent clinical trials and global challenges in neurotrauma" Prof. Stover will present an Abstract Lecture on "NOSTRA III- early inhibition of iNOS improves outcome following moderate and severe TBI."
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 and lactate release. Ronopterin-mediated inhibition of iNOS is associated with a significant decrease in glutamate and in lactate levels, a new facet to 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, randomized, 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 (67% vs 77%, p<0.004).
SOURCE vasopharm
