Avigen's research programs, aimed at supporting our therapeutic pipeline, are tailored to cater to our strengths and therefore advance projects from a mid-preclinical stage into clinical development.
Neuropathic Pain
The identification of new agents for the treatment of neuropathic pain is proceeding on three fronts. First, Avigen has a focused medicinal chemistry optimization effort around AV411. The primary goals are to identify new chemical entities (NCEs) and to select a clinical development candidate to expand our patent portfolio, to improve physicochemical properties, and to expand even further the margin of safety. Second, we continue research with the Watkins Laboratory at the University of Colorado, Boulder, around IL-10 and related molecules, oriented at selecting a candidate for advancement into IND-enabling studies. Lastly, in animal pharmacology/toxicology studies, Avigen is exploring another set of NCEs involving either clinically validated drug molecules and/or targets.
Opioid-Induced Withdrawal
Opioid (i.e., morphine and related drugs) therapy is well known to be limited or plagued by dependence and tolerance. Often, cessation of chronic therapy is further typified by disabling withdrawal symptoms. These issues surrounding opiate therapies represent a major unmet medical need. Opioid substitution therapy is probably the best treatment; unfortunately, it is inadequate.
Investigators have recently demonstrated that glia (astrocytes, microglia) oppose the actions of morphine. One study demonstrating such a link involved investigation of morphine analgesic tolerance and withdrawal-induced pain enhancement. These studies demonstrated that spinal cord glia become increasingly activated in response to chronic morphine, as measured both by glial activation markers and the production/release of neuroexcitatory substances including pro-inflammatory cytokines. Blockade of spinal cord glial activation or antagonism of spinal pro-inflammatory cytokines suppressed the development of morphine analgesic tolerance and withdrawal-induced pain enhancement. Spinal cord glial activation therefore counteracts morphine analgesia and the development of morphine withdrawal-induced hyperalgesia. Avigen is collaborating with Drs. Linda Watkins and Mark Hutchinson at the University of Colorado, Boulder, to further investigate this phenomenon. We have initiated animal studies to test the hypothesis that AV411 can ameliorate morphine tolerance. With continued success, these studies will provide guidance as to appropriate clinical regimens for AV411 entry into morphine withdrawal trial(s).
Neurodegeneration Drug Discovery
Avigen's approach for treating select neurodegenerative disorders such as Parkinson's disease or Alzheimer's is founded upon our interest and efforts in glial attenuation. Just as the concept of the contribution of astrocyte and microglia activation to neuropathic pain has become better established, the contribution of glial activation to neurodegenerative diseases is also gaining recognition. Hence, we are exploring the potential utility of drug candidates from our glia-attenuating R&D programs described above for extension into this much-needed therapeutic area.
A Unique Treatment for Hemophilia
Avigen is continuing to resource a provocative project involving a unique drug therapy to improve hemostasis in bleeding disorders. The only therapies currently utilized for hemophilias (Hem) A and B involve costly and inconvenient factor replacement. We have conceived and validated on the lab bench and in animals a unique therapeutic approach that is expected to be a safe, low-cost, and effective treatment for multiple bleeding disorders (Hem A, Hem B, severe von Willebrand's). The class of molecules are what we have designated non-anticoagulant sulfated polysaccharides (NASPs), which are heparin-like molecules but which paradoxically improve extrinsic pathway clotting activity. Hence, selected candidates such as AV513 provide a useful pro-coagulant supplement in settings of hemostatic deficiency. Extensive pharmacological studies have been performed in-house and in collaboration with Drs. George Broze at Washington University and David Lillicrap at Queen's University. AV513 treatment of hemophilic mice and dogs reduces bleeding behavior and improves clotting dynamics. Normalization of hemostasis can be achieved in the presence of very low background levels of factor such that single-agent or combination-therapy product profiles can be envisioned. Current studies are aimed at regimen optimization and safety validation for clinical development. In addition, research is in progress for identification of proprietary NCEs.
