Development of Novel Small Molecule Anti-Fibrotic Agent for the Treatment of Systemic Scleroderma - ABSTRACT
The goal of this STTR proposal is to develop a novel anti-fibrotic agent suitable for oral administration which
could be used to safely and effectively treat Systemic Sclerosis (SSc), or Systemic Scleroderma patients. SSc
is one of the most disabling and lethal immune-mediated rheumatic disorders. SSc is a rare disease, affecting
40,000-150,000 people in the United States and conferring a five to eight-fold higher risk for mortality. It is a
heterogeneous, multiorgan disease characterized by vascular endothelial alterations that results in chronic
inflammation and immune responses leading to progressive fibrosis and organ(s) failure. Major impacted organs
are skin, lungs, kidneys, and vasculature system. In SSc patients, vascular endothelial cell injury
characteristically precedes inflammation and autoimmune responses that stimulates the progression into tissue
fibrosis scaring. The leading cause of early death (5 years from diagnosis) is interstitial lung disease (ILD).
Treatment routinely relies on Nintedanib (TK inhibitor) and Tocilizumab (IL-6 mAb), and symptomatic treatments
but these have limited efficacy, and tolerability and/or toxicity issues. As of today, disease fibrosis progression
and mortality rate for SSc remains greater than for any other rheumatic disease; highlighting the clear unmet
medical need for disease modifying therapies that will prevent or reduce the damage to major organs. Targeting
repair and regeneration of the vascular endothelial cell injury via the Apelinergic System (apelin/APJ) signaling
pathway provides a unique and novel opportunity for the treatment of SSc patients (as of today vascular
endothelium repair and regeneration is an under targeted area in SSc drug development). The system is well-
established as an endogenous anti-injury and organ-protective mechanism that is activated post vascular
endothelium injury and is expressed in all SSc disease impacted organs.
APIE Therapeutics, in collaboration with RTI International, has identified a lead anti-fibrotic drug
candidate, apelin agonist APT101, for the treatment of lung fibrosis. First, in a bleomycin-induced lung fibrosis
mouse model therapeutic treatment with APT101 significantly inhibited the production of collagen in the lungs (a
hallmark of lung fibrosis progression), as detected via the Hydroxyproline Assay, and primary end point of the
study. Second, APT101 showed significantly reduced fibrosis in myocardial infarction animal studies (mice and
rats) and significantly reduced biomarker responses in ex-vivo human cell co-culture disease models relevant to
lung, skin, and kidney fibrotic diseases. Taken together, this evidence suggests that activation of the apelinergic
system has the potential to disrupt the pathogenic cascade responsible for progressive fibrosis in SSc. Our aims
for this proposal are obtain preclinical data in validated SSc models: 1) in-vivo efficacy model and, 2) ex-vivo
human tissue model. The results from Aims 1 and 2 will inform a data driven decision regarding APT101 IND
initial indication and subsequent plans for Phases II proposal.
