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.
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 (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 Dr. Linda Watkins 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).
Next-Generation Glial Attenuators
Through rational medicinal chemistry optimation, Avigen has discovered and preclinically advanced two “generations” of orally active New Molecular Entities (NMEs). The first generation represents a limited departure from the AV411 (ibudilast) structure but which retains glial-attenuating activity in the CNS, affords composition-of-matter IP potential, and is anticipated to enable neurological conditions better wherein AV411 is not being deployed. A development candidate, AV1013, has been selected and advanced through most preclinical- and process-development stages including preliminary toxicology and is awaiting only formal GLP tox and safety pharmacology to enable IND filing.
The second generation of NME represents a more dramatic medicinal chemistry optimization effort wherein glial attenuation has been retained, but oriented within a dual PDE inhibition and kinase inhibition mechanistic modality. Aside from composition-of-matter attributes, these “2nd Gen” compounds have been shown to possess relatively selective target action and in vivo efficacy. The most advanced lead in this class is AV1173, which is being advanced in preclinical studies. Chronic neurological conditions wherein this class of drug may be developed include neurodegenerative diseases like Alzheimer’s or Parkinson’s as well as neuropathic pain.
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.
IL-10 portfolio with University of Colorado, Boulder
A long-standing research collaboration and exclusive license with Linda Watkins and colleagues at CU has yielded two drug candidates for neuropathic pain (and potentially other neurological conditions). AV333 is plasmid IL-10 formulated for intrathecal administration. It has been shown in animal models to yield dramatic attenuation of chronic pain for over 2 months following single administration. Pegylated IL-10 protein is the second drug candidate and is still in drug substance optimization stages, but has already been shown to be effective in vitro and in vivo and to display improved duration of efficacy and CNS tissue distribution.