July 12 2022

vasopharm GmbH Announces Brain Lactate Microdialysate Data from Post Hoc Analyses of Clinical Trials in Traumatic Brain Injury

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

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.”

 

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