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Amunix is developing Glucagon-XTEN as a combination product for the treatment of obesity and as a standalone product for hypoglycemia. In addition, Amunix has established a 50%-owned, product-focused spin-off company, Versartis, to clinically develop three novel therapeutic products using the XTEN technology.

Research is underway to create a pipeline of additional products to be developed by Amunix or a partner.

Amunix’ lead product is AMX-808, a modified glucagon construct for improving glycemic control without increasing baseline blood glucose as a monotherapy or combination with exenatide.

Glucagon plays a major regulatory role in controlling blood glucose in vivo, but its short half-life prevents its therapeutic use for non-acute applications.  Through application of the XTEN technology, we report the construction of a glucagon fusion protein with an extended exposure profile (AMX-808).  Prophylactic administration of AMX-808 to dogs confers resistance to a hypoglycemic challenge without affecting baseline blood glucose levels.  Importantly, the solubility and stability of the glucagon peptide are also significantly improved.  Further, continuous administration of AMX-808 for 28 days in diet-induced obese mice resulted in significant reduction in weight gain over the course of the study with no increase in blood glucose levels relative to placebo.  Combination therapy with exenatide in the same diet-induced obese mouse model resulted in significant weight loss and reduction in fasting blood glucose relative to exenatide alone.  The XTEN domain of AMX-808 is non-immunogenic, biodegradable, and enables nightly to weekly dosing or longer depending on the clinical indication.  AMX-808 may have all the attributes required to provide optimal convenience, safety and efficacy for applications in either Type I or Type II diabetes.

Current diabetes treatment paradigms encourage aggressive insulin regimens to minimize blood glucose and HbA1c levels.  Several studies have shown that patient outcomes would be further improved by even more aggressive insulin dosing, but hypoglycemic episodes represent a limiting adverse effect.  While current treatment methods focus almost exclusively on reducing blood glucose levels, normal glucose homeostasis requires the action of multiple hormones with complementary activities in order to maintain blood glucose in a relatively constant range.  Therefore, it is likely that treatment with multiple regulatory hormones may provide a better overall patient outcome by stabilizing blood glucose within a normal range.  Such an approach may help to reduce the incidence of adverse effects such as hypoglycemia.  Further, the actions of glucagon and GLP-1 peptides have been shown to be synergistic with regard to treatment of Type II diabetes. 

The XTEN sequence confers several additional improvements to its payload peptide beyond extended pharmacokinetics.  Addition of the XTEN sequence allows the fusion protein to be expressed recombinantly in E. coli at high yield.  This is expected to result in significant reduction in the manufacturing costs of XTEN fusions relative to synthetic peptides.  Further, the addition of XTEN can improve the solubility of its payload, in the case of glucagon by at least 60-fold.  Our data also show that AMX-808 is stable in liquid formulation for extended periods, with no sign of aggregation typically observed for hydrophobic peptides.  These observations suggest that AMX-808 constructs will be amenable to real-time monitoring and pump approaches.  Such methods are difficult to implement with the unmodified peptide, due to the need for a lyophilized formulation.  Although in vitro cell-based data imply that XTEN can reduce biological activity, the AMX-808 in vivo data show comparable or better glucose mobilization on a molar dose basis relative to unmodified glucagon.  This discrepancy is likely due to the increased exposure of AMX-808 in vivo, suggesting that reduced specific activity is not likely to strongly affect overall efficacy of a fusion construct.  For payloads where peak dose toxicity is a concern, lower specific activity of the XTEN fusion may help to reduce the occurrence of adverse drug effects.

In addition to the above effects, a significant feature of the AMX-808 molecule is the achievement of efficacy without an associated increase in blood glucose levels.  While this result appears initially paradoxical, glucagon is a key signaling hormone component in the glucose counterregulatory system.  Similarly counter-intuitive synergistic effects have been observed with a molecule capable of agonizing the glucagon and GLP-1 receptors simultaneously.  Sustained AMX-808 levels may therefore impact a variety of signaling pathways that modulate insulin sensitivity (among other factors) leading to the observed effects.  The ability to modulate the pharmacokinetic and pharmacodynamic profiles of glucagon through addition of various XTEN constructs provides a unique opportunity to characterize this poorly studied aspect of normal glucose metabolism and regulation.

While further work will be required to elucidate the precise mechanism at play, the observed efficacy without increasing baseline blood glucose levels may be highly significant in enabling novel therapies.  By increasing the size of the attached XTEN sequence, achievement of up to monthly dosing intervals in humans is expected.  Therefore, it may be possible to create an XTEN fusion capable of conferring long-term resistance to hypoglycemia in diabetic patients without increasing long-term blood glucose levels.  Such a construct could also be combined with long-acting exenatide constructs such as exenatide-LAR or VRS-859 to better characterize the recently reported synergy between these two payload activities.  Finally, a long-acting molecule capable of preventing low blood glucose levels (and associated hunger) without significant adverse effects may represent an ideal treatment for obesity in otherwise healthy individuals.