Release characteristics of different formulations or neat nimodipine were tested different in vitro and in different models [32–34]. More recently, we tested this in Wistar rats at subcutaneous doses of 20 or 200 mg/kg and buffer or plasma nimodipine concentrations, which were measured daily. We found sustained nimodipine release for all doses and formulations, including the neat nimodipine, which was likely because of its high lipid solubility within subcutaneous fat (Fig. 3).

Because nimodipine microparticles in hyaluronic acid have never been injected into the subarachnoid or intraventricular CSF, potential toxicity was investigated in rats and beagles in escalating doses up to threefold times the estimated human dosage (1,200 mg). All animals survived until their sacrifice and there were no EG-1962-related toxicity findings in clinical observations, neurobehavioral evaluations, body weight, food consumption, ophthalmoscopy, hematology, coagulation, clinical chemistry, urinalysis, organ weight, or macroscopic pathology.

We are initiating two clinical trials. The PROMISE (Prolonged Release nimOdipine MIcro particles after Subarachnoid hemorrhage) trial will be designed as an unblinded, non-randomized, single-center, single-dose, dose-escalation safety and tolerability phase 1 study in patients neurosurgically treated for aSAH at the Department of Neurosurgery, Medical Faculty of the Heinrich-Heine University, Düsseldorf, Germany, and will solely investigate the effect of intracisternal EG-1962 administration. The NEWTON (Nimodipine microparticles to Enhance recovery While reducing TOxicity after subarachNoid hemorrhage) trial will be a phase 1/2a multicenter, controlled, randomized, open-label, dose escalation, safety, tolerability, and pharmacokinetic study comparing EG-1962 and nimodipine in patients with aneurysmal SAH treated by neurosurgical clipping or endovascular coiling. In this study, EG-1962 will be administered by intraventricular catheter that would be in place as part of standard of care in eligible patients.

Due to the promising preclinical data, there is a strong rationale to investigate the effects of EG-1962 in patients suffering from high-grade SAH. Therefore, we are initiated two clinical trials on intracisternal and intraventricular EG-1962 application.