SIG990 is an isoprenylcysteine (IPC) analog that modulates toll-like receptor (TLR) and G-protein signaling demonstrating promising results in several in vitro cell based assays and efficacy in in vivo topical inflammatory animal models. SIG990 is a safe topical treatment that potentially addresses both erythema and inflammatory lesions and thus would be a significant and potentially better therapeutic option for rosacea patients then what is currently on the market. Its Investigational New Drug (IND) Application to evaluate SIG990 in rosacea has been cleared by the FDA. Instrumental in the pre-clinical development of SIG990 was funding from the National Institute of Allergy and Infectious Diseases (NIAID) via SBIR support. We have currently out-licesed this molecule to Dermata Therapeutics to move this drug candidate into human clinical testing.
PROPOSED METHOD OF ACTION
The precise etiology of rosacea is unknown. Multiple factors such as genetic predisposition, heredity, systemic inflammatory conditions, microbes, microcirculatory disturbances are believed to be involved. Besides a probable genetic contribution several environmental triggers including heat, cold and ultraviolet radiation have been identified (Figure 1). Many of these are sensed directly or indirectly by toll-like receptors (TLRs) in skin cells which are known to be up-regulated in rosacea patients. TLR signaling induces cathelicidin (LL-37) and pro-inflammatory cytokine/chemokine expression. Once produced, LL-37 and several cytokines act as ligands for G-protein-coupled receptors (GPCRs) activating further inflammatory signaling. Together, these effector molecules elicit vascular changes, neutrophil recruitment, lymphocyte infiltration and ROS production which contribute to the pathogenesis of the disease.
The peptide LL-37 is formed in the skin through cleavage of a cathelicidin protein hCAP-18 by the serine protease enzyme cathepsin G or kallikrein 5 . In addition to its antimicrobial properties, LL-37 has been shown to be a vasodilator  and a chemoattractant for human blood peripheral monocytes, neutophils and T cells acting thorough the G-protein coupled receptor FPRL-1 . The pioneering work of Dr. Richard Gallo on the role of LL-37 in rosacea  has led to heightened interest in the role that antimicrobial peptides play in the pathogenesis of rosacea, especially with respect to TLRs which are known be over-expressed in the skin of rosacea subjects .
The systems biology approach taken by Signum to identify candidates that will have an action on erythema and inflammatory lesions in rosacea is based on a panel of in-house tests which have been calibrated using agents which a have a proven effect in different presentations of the disease. The action of SIG990 on erythema is evidenced by comparison, in our models, with the α-adrenergic agonists, oxymetazoline (Allergan) and brimonidine (Galderma) (TPA mouse ear inflammatory assay), and in addition by the demonstrated anti-redness action of the cosmetic ingredient Arazine™ (licensed to Elizabeth Arden and Rohto Pharmaceuticals) to which it is chemically related. Favorable comparison in Signum’s in vitro LL-37-endothelial cell-IL-6 model with azaleic acid (Finacea®, Intendis), metronidazole (Metrogel, Galderma) and doxycycline (Oracea, Galderma), agents approved for treatment of lesions, lends credence to the hypothesis that SIG990 will be effective versus erythema and lesions.
As further support to our mechanistic hypothesis, Dr. Gallo recently reported that azelaic acid and doxycycline target cathelicidin, improving rosacea symptoms [6, 7]. He also showed azelaic acid and doxycycline may help decrease levels of the protease kallikrein-5, one of the main problems for rosacea-affected skin [6, 7]. We have shown that SIG990 acts on downstream inflammatory mediators by inhibiting production of cytokines via TLRs and G-protein coupled receptors (LL-37-FPRL-1). Furthermore, in a rosacea clinical trial with Oracea, the sponsor planned to measure outcomes in lesions as well as inflammatory markers such as protease expression and LL-37, implying that the primary mode of action on lesions of this agent is not antimicrobial effect at the doses used (40 mg po). SIG990 has been shown to modulate several epidermal differentiation markers (Keratin-1, Filaggrin) and block neutrophil infiltration, both suggested to play a role in the formation of inflammatory lesions. Lastly, recent findings point towards a potential role for IL-17 in the initiation of pustular lesions seen in rosacea patients  and SIG990 has been shown using T-cell receptor activated PBMCs to inhibit IL-17 cytokine production.
- “Preclinical anti-inflammatory and safety assessment of SIG990, a novel topical small molecule for the treatment of rosacea”. Poster presented at the 2011 Society of Investigative Dermatology conference.
- Yamasaki, K. and R.L. Gallo, The molecular pathology of rosacea. J Dermatol Sci, 2009. 55(2): p. 77-81.
- Yamasaki, K., et al., Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin. FASEB J, 2006. 20(12): p. 2068-80.
- De, Y., et al., LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med, 2000. 192(7): p. 1069-74.
- Yamasaki, K., et al., Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nature Medicine, 2007. 13(8): p. 975-80.
- Yamasaki, K., et al., TLR2 Expression Is Increased in Rosacea and Stimulates Enhanced Serine Protease Production by Keratinocytes. J Invest Dermatol.
- Kanada, K.N., T. Nakatsuji, and R.L. Gallo, Doxycycline indirectly inhibits proteolytic activation of tryptic kallikrein-related peptidases and activation of cathelicidin. J Invest Dermatol. 132(5): p. 1435-42.
- Coda, A.B., et al., Cathelicidin, kallikrein 5, and serine protease activity is inhibited during treatment of rosacea with azelaic acid 15% gel. J Am Acad Dermatol. 69(4): p. 570-7.
- Gerber, P.A., et al., Rosacea: The cytokine and chemokine network. J Investig Dermatol Symp Proc. 15(1): p. 40-7.