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  MAC
  Membrane Active Chelators buffer metal ions across membranes preserving homeostasis for cell survival.

Metal ions (e.g. calcium, iron, zinc, copper) are
crucial to every living organism and their tissue distribution is strictly controlled. In healthy tissue, tight regulation of metal ions within and across cell membranes is critical to maintaining homeostasis and cell viability.

In many pathological conditions the ability of the membrane to control ion flux is disrupted, resulting in the loss of metal ion homeostasis. This can be due to a variety of causes such as oxygen deprivation or chemical stress and can significantly impair cell or organ function and eventually lead to cell death. Disrupted metal ion homeostasis is symptomatic of numerous diseases, ranging from cardiac arrhythmia, myocardial infarction and acute stroke to chronic neurodegeneration (e.g., Alzheimer’s and Parkinson’s diseases).

Current approaches to treat metal ion imbalance address abnormal distribution of metal ions by suppressing ion flow across cell membranes, for example, by blocking calcium channels. Such approaches have proven to be successful in cardiovascular disease but have limited success, in treating central nervous system (CNS) disorders. Drug development efforts to modulate metal ion balance have so far concentrated on altering metal ion distribution in the body fluids such as the blood plasma.

D-Pharm’s breakthrough was to recognize that many critical processes, involving metal ions, occur within the unique environment of the cell membrane itself, rather than in the surrounding body fluids. D-Pharm identified that metal ions within cell membranes represent a novel and extremely promising target for drug development. In particular, we acknowledge that control of metal ion homeostasis within and in the vicinity of cell membranes holds significant therapeutic potential for development of novel, safe and efficient drugs for treatment of seriously disabling CNS disorders.

D-Pharm’s platform technology, Membrane Active Chelators (MAC), was developed to seize this opportunity. We are developing a new class of drugs, interacting with metal ions selectively within or in the vicinity of cell membranes.

MAC is based on lipid modification of metal ion chelators. MAC drugs are designed to buffer metal ions such as copper, zinc, calcium and iron in lipid membrane environments. Known chelators, sequester metal ions in all aqueous environments, with potential toxic effects. In contrast, MAC drugs bind metal ions selectively, only within the lipid environment of cell membranes, rendering them safe. MAC drugs restore the membrane balance by a dynamic process of redistributing metal ions within membranes, promoting cell survival.

MAC drugs’ novel mechanism enables the development of highly safe and potent therapeutics to treat a range of metal ion associated pathologies. We believe that MAC drugs have the potential to safely treat neurodegeneration in its acute form (stroke) as well as chronic forms (Alzheimer’s and Parkinson’s diseases).

D-Pharm's most advanced MAC drug candidate, DP-b99, has been studied for efficacy and safety in acute stroke patients. A Phase IIb study was completed and 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.  A Phase III trial with DP-b99 will commence in 2009.   

DP-460 is a preclinical MAC candidate under development for chronic neurodegenerative disease.  DP-460 is efficacious both in vitro and vivo, inhibiting amyloid-beta deposition in models of Alzheimer's disease and reducing cortical p-TAU levels.