VTX-4
Diabetic Peripheral Artery Disease
Peripheral artery disease (PAD) is a chronic
and progressivevascular disorder with high morbidity
and low quality of life. The worldwide prevalence of
PAD was estimated at 236 million, with 9 million patients
in the United States. Of these, 30% are diabetic,
predisposing this subgroup to the most severe
complications. Additional high-risk populations include
the elderly, African-Americans, veterans,
and low-income populations. The hallmark
characteristic of
PAD is narrowing of the arteries resulting in
reduced blood flow to the limbs. In its early stage,
symptoms include
muscles pain in the legs during walking which limits
mobility (intermittent claudication). Because of reduced
blood flow, the decrease in tissue perfusion promotes chronic limb-threatening ischemia, poor wound healing, and tissue loss including muscle. In its severe manifestation, gangrene may develop and if the limb cannot be salvaged amputation is required. Annual US healthcare costs exceed $62 billion, representing a large burden on healthcare providers. Due to the increase in the aging population and incidence of diabetes, PAD will reach epidemic status by 2026 which will drastically increase overall health spending, primarily for Federal and state insurance agencies.
The Need: Restoration Of Blood Flow To Starved Tissues
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A recent AHA scientific statement includes the observation that the extent and severity of PAD is generally underappreciated by health care professionals and patients. It also mentions that a major gap in its management is the unavailability of efficacious medications. Clinical management for PAD includes exercise, anti-hypertensive drugs, cholesterol lowering agents, anticoagulation therapy and vasodilators. Despite these strategies, many patients will require a revascularization procedure to restore blood flow as the disease progresses. There is also a high rate for the need of a second revascularization procedure as well. Within 30 days of the initial surgery, 16% of patients will need a second procedure and 24% will require one within 1 year. Overall, the current therapeutic status for the treatment of PAD is suboptimal. VTX-4 will be the first therapeutic modality with the ability to restore blood flow.
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Activation Of The RAGE Receptor Prevents New Vessel Growth
The RAGE receptor (receptor for advanced glycation endproducts) plays an important role in the etiology and progression of PAD through multiple pathways. Pathological examination of limbs from patients with PAD reveals increased expression of RAGE. Glucose can be irreversibly crosslinked to proteins forming advanced glycation end products (A.G.E.s) that can activate the RAGE receptor. Under normal circumstances, A.G.E. levels are low and the RAGE receptor is relatively inactive. In diabetes, due to elevated glucose and A.G.E. concentrations, RAGE is highly activated triggering an inflammatory cascade within the vascular wall. The multiple pathways increase reactive oxygen species, increase vascular permeability to activated immune cells and cause the release of pro-inflammatory cytokines. These events lead to atherogenesis, microvascular disease expression, inhibition of the normal capillary angiogenic response to tissue hypoxia and prevents the growth of larger collateral arteries thru arteriogenesis.
VTX-4 Blocks RAGE Activation By A.G.E.s
VTX-4 is a humanized, IgG monoclonal antibody raised against the A.G.E. recognition domain of the RAGE receptor. In preliminary studies, VTX-4 decreased the activation of RAGE by A.G.E.s in vascular smooth muscle cell-based assay by reducing cytokine production and activation of the RAGE-associated kinase signal transduction pathway. Administration to mouse and pig models of Type 1 diabetic peripheral artery disease before and after femoral artery occlusion increased new arteriole sprouting, collateral artery formation, restored blood flow to lower limbs and prevented muscle mass loss. In both the Type 1 PAD pig and a Type 2 mouse model without an occluded artery, an increase in wound healing was observed that correlates with the increase in tissue blood flow and confirming a clinically relevant endpoint has been achieved.
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Effect On Arteriogenesis in Type 1 Model
Effect On Wound Healing In Type 2 Model
