A phase II study of ARA 290 as therapeutic strategy in no-option critical limb ischemia patients.

Critical Limb Ischemia (CLI) is the end-stage of lower extremity peripheral
artery disease in which severe obstruction of blood flow results in ischemic
rest pain, ulcers/gangrene and a significant risk for limb loss. CLI is
responsible for an estimated 220,000-240,000 amputations yearly in the United
States and Europe, and is a source of significant mortality, morbidity,
disability and social and economic costs. The annual costs of CLI have recently
been estimated to be > $10 billion for the United States alone. Current
strategies for CLI are revascularization, restoring blood supply to the
ischemic area. Unfortunately, in a substantial proportion of patients (i.e.
patients with diabetes mellitus(1) or patients requiring distal repair in the
absence of an adequate vein graft) the prospects of intervention are notably
poor, and in patients with small vessel disease and occlusion of the tibial
arteries intervention may even be impossible. Prognosis for these patients in
terms of quality of life, life expectancy and costs is poor, and these patients
can only be treated by a below- or above-knee amputation.
Erythropoietin (EPO) is a well-known stimulator of erythrocyte production and
widely used in the treatment of anemia caused by kidney disease, cancer, or
chronic inflammation Over the past decade, it has become evident that
erythropoietin, besides its effect on hematopoiesis, possesses many other
biological activities that can generally be summarized as counteracting the
actions of proinflammatory cytokines and their deleterious effects in tissue
injury). In these nonhematopoietic activities, EPO is locally produced in the
immediate vicinity of the injury.
ARA 290 is an 11-amino acid, linear peptide that is being developed as a tissue
protective peptide. ARA 290 mimics the tissue protective pharmacology of
erythropoietin but is devoid of its haematopoietic effects. In preclinical
models of tissue damage ARA 290 has been shown to exhibit general
anti-inflammatory activities, to promote wound healing in various animal
models of impaired wound healing, and to promote neuroregeneration (including
a profound reduction of neuropathic pain in animal models of this pathology).
These observations suggest that activation of the tissue protective
erythropoietin receptor may promote tissue homeostasis in CLI, thereby limiting
tissue loss and pain.

A proof of concept study to test whether ARA 290 improves wound healing and
reduces neuropathic pain in no-option patients with CLI

A randomized placebo controlled study of ARA 290 or placebo in no option
critical limb ischemia patients

ARA 290 or placebo

The clinical experience with ARA 290 is very limited. Thus far no side effects
have been upserved in phase I studies (multiple doses up to 2 mg per dose).