In chronic debilitating diseases, improved therapeutics are those state-of-the-art drugs that control the devastating symptoms and limit, or prevent disease progression without causing other pathologies through the treatments’ adverse effects.
It looks as if Xoma might have a promising new drug for diabetes that promises to fulfill the above requirements for breakthrough drugs.
In the news, XOMA (XOMA) has used its technological monoclonal capability to correct hyperglycemia in a mouse model of diabetes with a first in kind long-acting XMetA fully-human allosteric monoclonal antibody to the insulin receptor. The study is published in the May issue of the American Diabetes Association's journal Diabetes. Results of a study conducted by XOMA and confirmed by investigators at the University of California, San Francisco demonstrate that XMetA has potential to control blood glucose levels in patients with diabetes.
The study by Bhaskar, et al. demonstrated that XMetA markedly reduced elevated fasting blood glucose levels and normalized glucose tolerance in mice experimentally rendered diabetic. After six weeks of treatment, there was a statistically significant reduction in hemoglobin A1c levels in animals treated with XMetA compared to controls (p < 0.05). In addition, elevated non-HDL cholesterol levels were improved relative to control mice (p < 0.05). Hypoglycemia and weight gain were not observed during this study, nor was proliferation of cell growth.
Ira D. Goldfine, M.D., Professor Emeritus, Department of Medicine and the Diabetes Center, University of California, San Francisco said, "In the treatment of diabetes, novel and improved therapeutic modalities for patients with impaired insulin secretory function are needed." Dr. Goldfine who is currently a XOMA Distinguished Scientific Fellow added, "XMetA has shown potential to deliver a long-acting, glucose-regulating effect without generating hypoglycemia. The characteristics of this molecule may result in an opportunity to leverage this potential therapeutic option earlier in the treatment of diabetes."
Using XOMA's ModulX™ technology lead to new insights into the regulation of signaling pathways. This gained knowledge enabled Xoma to discover three distinct classes of allosteric antibodies that act differentially on the insulin receptor. XMetA, an antibody from one such class, selectively activates pathways leading to glucose lowering while avoiding pathways leading to cellular proliferation. Patrick J. Scannon, M.D., Ph.D., Xoma’s Executive Vice President and Chief Scientific Officer believes that this profile is unique and offers a new approach to treatment of diabetes.
The rationale behind the experimentation with XMetA is that while conventional monoclonal antibodies bind at the ligand-receptor binding site to provide either complete activation or inhibition akin to an on/off switch, XMetA binds to other sites, termed allosteric sites, which function as a dimmer switch to modulate the ligand-receptor interaction. This approach offers expanded potential for the targeted treatment of diabetes.
Using its ModulX™ technology platform XOMA has developed proprietary methods for identifying allosteric modulating monoclonal antibodies. Its first allosteric antibody, gevokizumab, is an allosteric inhibitor of the ligand interleukin-1beta (IL-1β), currently in clinical development for non-infectious uveitis including Behçet’s uveitis, moderate to severe acne, cardiovascular disease and other conditions associated with inflammation. Gevokizumab has been evaluated in Phase 1 and 2 clinical trials involving approximately 500 patients. Development of gevokizumab is being conducted collaboration with the independent pharmaceutical company.Les Laboratoires Servier.
Xoma’s preclinical pipeline includes the XMetA and XMetS programs for the development of antibodies that modulate the insulin receptor for the treatment of diabetes and metabolic syndrome, and additional programs focused on the validated oncology targets TGFβ, FGFR4 and RON. XOMA 3AB, a three-antibody co-formulation drug product candidate designed to treat botulinum toxin (Type A) poisoning, among the most deadly bioterror threats. XOMA 3AB, currently in Phase 1 testing funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.
The firm has two product candidates partnered with Novartis: HCD122 - a monoclonal antibody to CD40 currently in Phase 1/2 clinical trials for the treatment of lymphoma, and LFA102, a monoclonal antibody to the prolactin receptor currently in a Phase 1 clinical trial for certain breast and prostate cancers.
XOMA is pursuing partnerships to maximize the value of XMetA for diabetes and to further develop other antibodies from its technology platforms.