D-Pharm Ltd, a clinical stage, technology-driven biopharmaceutical company developing proprietary products for treatment of CNS disorders, announced top-line safety results following completion of its phase 2 clinical study of THR-18 in acute ischemic stroke (AIS) patients treated with tissue plasminogen activator (tPA).

THR-18 is novel drug-candidate designed to reduce or neutralize the life-threatening adverse effects of tPA. The study has successfully defined the maximal tolerated and safe dose of THR-18 in AIS patients. Compared to placebo, THR-18 significantly decreased the number of AIS patients with brain edema and intracranial haemorrhage.

tPA is the only FDA approved therapy for treatment of acute stroke patients. Despite this, tPA is underused; it is estimated that less than 5% of patients receive this treatment primarily because of the risk of intra-cerebral hemorrhage (ICH) or failure to arrive within the narrow time window approved for treatment.
 
THR-18 is a novel drug-candidate derived from the natural inhibitor of tPA, PAI-1. This phase 2 clinical study of THR-18 was the first double-blind, placebo-controlled, escalating single-dose, study to assess the safety, pharmacokinetics, and pharmacodynamics of THR-18 (0.18 or 0.54 mg/kg) in thirty AIS patients treated with tPA. The main pre-specified endpoints in the study include the numbers of patients with ICH and brain edema, and clinical stroke outcome assessed by the modified Rankin scale (mRS) and the NIH stroke scale (NIHSS) up to 30 days following stroke.

The data indicate that in contrast to the placebo group, no patients treated with THR-18 had an intracranial haemorrhage, (p=0.02). Similarly, THR-18 reduced by more than twice the occurrence of brain edema (p<0.05). These results correlate well with the interim analysis performed on the first treatment groups that completed the 30 day follow-up period. The interim data show that THR-18 markedly reduces the degree of disability and enhances neurological recovery of stroke patients compared to placebo.

Dr Gilad Rosenberg, D-Pharm’s VP of clinical development commented, “It is certainly encouraging to see the reduced rates of  brain swelling and intracranial bleeding in the tPA-treated stroke patients given THR-18, and I look forward to see whether these findings translate into less disability and better neurological recovery once the clinical endpoint data become available for the full data set.”

Dr Alex Kozak, D-Pharm’s CEO, noted: “In spite of the huge unmet need, the majority of stroke patients do not receive treatment with tPA, the only clot-busting drug approved for this indication. Our data add credence to the idea that THR-18 may antagonize the neurotoxic effect of tPA. Improvement of the safety profile of tPA with THR-18 shall bring a desperately needed treatment to millions more stroke patients.”

THR-18 corresponds to a fragment of plasminogen activator inhibitor-1 (PAI-1), a natural inhibitor of tPA activity. THR-18 uncouples the clot-dissolving properties of tPA from its deleterious non-fibrinolytic effects on the blood vessel wall, including intracranial haemorrhage and brain edema, and leaves tPA’s catalytic activity intact.