Study Establishes XMetA as the First Allosteric Insulin Receptor-Activating Antibody to Improve Glycemic Control In Vivo

XOMA Corporation recently announced its study of XMetA, the company’s fully human allosteric monoclonal antibody to the insulin receptor, is available online and will be published in the May issue of the American Diabetes Association’s journal Diabetes.

XMetA is the first antibody specific for the insulin receptor shown to correct hyperglycemia in a mouse model of diabetes. Results of a study conducted by XOMA and confirmed by investigators at the University of California, San Francisco, demonstrate that XMetA has the potential to be a novel, long-acting agent for the control of 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 6 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.

“In the treatment of diabetes, novel and improved therapeutic modalities for patients with impaired insulin secretory function are needed,” said Ira D. Goldfine, MD, Professor Emeritus, Department of Medicine and the Diabetes Center, University of California, San Francisco. “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.”

“Through insights into the regulation of signaling pathways gained using XOMA’s ModulX technology, we have discovered 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. We believe this profile is unique and offers a new approach to treatment of diabetes,” said Patrick J. Scannon, MD, PhD, Executive Vice President and Chief Scientific Officer at XOMA.

Conventional monoclonal antibodies bind at the ligand-receptor binding site to provide either complete activation or inhibition akin to an on/off switch. However, many receptors also have sites, termed allosteric sites, which function as a dimmer switch to modulate the ligand-receptor interaction. XOMA’s XMet antibodies bind to these allosteric sites, offering expanded potential for the targeted treatment of diabetes.

XOMA has developed proprietary methods for identifying allosteric modulating monoclonal antibodies using its ModulX technology platform and is focusing its research efforts toward the discovery of these types of antibodies. Its first allosteric antibody, gevokizumab, is an allosteric inhibitor of the ligand interleukin-1beta (IL-1β), currently in clinical development. XOMA is pursuing development partnerships to maximize the value of XMetA and other antibodies from its technology platforms.

XOMA discovers and develops innovative antibody therapeutics. Its lead drug candidate is gevokizumab (XOMA 052), a humanized antibody that modulates the inflammatory cytokine interleukin-1 beta, or IL-1 beta. In collaboration with the company’s partner, Les Laboratoires Servier (Servier), XOMA is expected to initiate global Phase III clinical development of gevokizumab to treat non-infectious uveitis, including the subset of patients with Behçet’s uveitis, in 2012.

Separately XOMA has launched a Phase II proof-of-concept program for gevokizumab to evaluate additional indications for further development, including moderate-to-severe inflammatory acne.

In order to retain the value of XOMA’s discoveries and its future revenue potential, XOMA made a strategic decision to establish a commercial capability. To implement this strategy, the company established its US commercial operations through the acquisition of US rights to Servier’s ACEON (perindopril erbumine), a marketed angiotensin converting enzyme (ACE) inhibitor. The agreement with Servier includes a portfolio of fixed-dose combination product candidates where perindopril is combined with other active ingredients to treat hypertension. XOMA has the right to develop and commercialize these products for the US market.

Through its unique discovery platform, the company is focused on discovering and developing allosteric modulating antibodies that combine the beneficial pharmacology of small molecule drugs with the target specificity of antibodies. Among these novel discoveries are new classes of fully human antibodies exemplified by XMetA, which partially activates the insulin receptor, and XMetS, which sensitizes the insulin receptor. These two programs represent distinct and potentially breakthrough therapeutic approaches to the treatment of patients with diabetes. For more information, visit www.xoma.com.