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A lipophilic chelator of calcium, zinc and copper ions, DP-b99 sequesters metal
ions only within, and in, the proximity of cell membranes. The ability of DP-b99 to bind
pathological levels of metal ions is useful for the suppression of cell damage in stroke patients. DP-b99 is a multi-target drug addressing a range of facilitators of cell damage in stroke. Some of the damaging processes last for a few hours, and some for days or weeks. The data suggest that DP-b99 can attenuate both early and late damaging processes in the cascade of events that follow stroke onset and therefore, has potential for useful treatment over a wide therapeutic window. Stroke is associated with insufficient or disrupted blood circulation in the affected areas of the brain. Current data suggest that the lipophilic nature of DP-b99 enables it to effectively penetrate the brain region suffering insufficient blood circulation providing an important attribute for an effective stroke medication. In addition to stroke D-Pharm also intends to investigate DP-b99’s potential in the treatment of traumatic brain injury, and for prophylactic treatment of neurological damage associated with coronary artery bypass grafting. DP-b99 Clinical Trials Two Phase I clinical trials of DP-b99 involved treatment of 70 volunteers over 4 or 6 consecutive days. The drug exhibited good tolerability both in single and multiple dosing. The only major side effect observed was reversible local irritation at the site of injection. The pilot Phase II study was performed on 34 patients with acute ischemic stroke. The study was designed to assess the safety profile, pharmacokinetics and drug interaction in stroke victims. DP-b99 was administered within the first 12 hours after stroke onset. In addition the patients received a second dose of the drug 24 hours after admission. The pilot Phase II trial confirmed that DP-b99 is generally safe medicine. The study was not powered to assess the efficacy of the treatment. However, despite the relatively small number of patients (26 DP-b99 and 8 placebo), the data demonstrated a strong trend for improvement in neurological stroke outcome (NIH stroke scale, NIHSS) in drug treated patients over placebo. The difference reached statistical significance (P < 0.05) in the first, second and seventh days after the stroke.
A Phase IIb study was recently completed in acute stroke patients. The efficacy of DP-b99 was assessed and the data-base of safety and pharmacokinetics of DP-b99 enlarged. A significantly higher recovery rate after stroke was found in the DP-b99 treatment group compared to the placebo group. The study also confirmed the excellent safety and tolerability profile of DP-b99. The wide therapeutic treatment window for DP-b99 was confirmed since there was no difference in response to DP-b99 treatment between those patients treated within six hours or within six to nine hours following stroke onset. This double blind, placebo controlled, multi-center trial enrolled 150 patients with ischemic stroke with a baseline NIH Stroke Scale (NIHSS) score of 7 to 20. Patients were recruited in 27 centers in Germany, Israel and South Africa. DP-b99 was administered intravenously, up to 9 hours following stroke onset. The patient group in the study was stratified into those treated within six hours or within six to nine hours following stroke onset. The efficacy of the treatment was primarily evaluated using the change in NIHSS, a measure of neurological improvement, from baseline to day 90, and the rate of complete recovery according to the Modified Rankin scale, a measure of global disability, and NIHSS (score of 0 or 1 on day 90 after stroke on either scale). The change in NIHSS, from day 0 to day 90 was found to be significantly higher in the DP-b99 treatment group with moderate to severe stroke at baseline (NIHSS 10-16). When all patients were analyzed together, the change of NIHSS was apparent but did not reach statistical significance. There was a significant two-fold increase in the number of patients achieving complete recovery from stroke (Modified Rankin scale) in the DP-b99 treated group compared to placebo (p=0.05). A similar result was also found concerning recovery as judged by the NIHSS. When recovery includes either the Rankin or NIHSS definition, the significance of this result is even greater (p=0.02). Results from this trial confirm the excellent safety and tolerability profile of DP-b99. An independent Drug Safety Monitoring Board (DSMB) met regularly throughout the trial to review the safety data and found no significant differences in the number of serious adverse events, death cases or death causes between the DP-b99 and placebo groups. The safety profile in the current study is in line with D-Pharm's previous clinical experience from the Phase I and IIa studies. In addition to confirming safety and efficacy, this study has better defined the optimal patient population and therapeutic window for DP-b99.
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