Our Lead Program: Resomelagon (AP1189)
SynAct Pharma’s drug candidate, resomelagon (AP1189), is a once-daily oral biased melanocortin receptor type 1 and 3 (MC1r and MC3r) agonist. The pharmacological effects of the compound are mediated by its ability to balance ongoing inflammation and bringing the immune system in a given inflamed tissue, organ, or circulation to a new homeostatic state with less proinflammatory activity and activation of pro-resolving pathways. This effect is distinct from suppression of the immune system, which may cause unwanted side effects, such as increased risk of infections and other side effects. The mode of action is specifically interesting to apply in active inflammation, including early active states of chronic inflammatory/autoimmune diseases and in hyperinflammatory states of infectious diseases where the benefit of applying immunosuppressive drugs is outweighed by the risk of use.
The selectivity of resomelagon (AP1189) to MC1r and MC3r means that MC2r mediated glucocorticoid release from the adrenal gland is avoided. Thus, the compound induces its pharmacological effects in a steroid-free manner without the significant safety, tolerability, and side effect issues associated with adrenocorticotropic hormone (ACTH) based therapies. Further to that, the compound stimulates the MC1r through biased agonism, activating an alternative pathway, so the compound can be given without the unwanted side effect of skin hyperpigmentation that classical MC1r agonists will induce though cAMP activation in melanocytes.
SynAct Pharma is evaluating resomelagon (AP1189) in two development paths
1. Early intervention in autoimmune/chronic inflammatory diseases
As a novel treatment option in inflammatory/autoimmune diseases with ongoing clinical Phase 2 studies in Rheumatoid Arthritis (RA) and Idiopathic Membranous Nephropathy (iMN). SynAct Pharma´s lead program with development in resomelagon in newly diagnosed treatment naïve RA patients with poor prognosis parameters, ie high disease activity and sign of systemic inflammation, is currently in Phase 2b with active dosing the ADVANCE study. The aim is to position the compound as a new patient-friendly and safe treatment option with once daily oral dosing to induce disease control in a glucocorticoid sparing fashion, with the further potential to reduce and/or delay the introduction of second line treatments. This treatment approach is far from limited to be applied in RA, and the company is therefore working with clinicians and pharmacologists to expand the clinical development beyond RA. In addition to the lead track in RA, the company is also conducting a exploratory study in iMN, a relatively rare autoimmune disease associated with proteinuria and development of nephrotic syndrome. The kidney affection in iMN involves dysregulation of specific cells called podocytes that express MC1r and the hypothesis is that resomelagon through stimulation of the MC1r will be able to improve the functionality of the cells and thereby reduce the proteinuria.
2. Host-directed therapy in viral infections
As a novel treatment option in hyper-inflammatory states of viral infections. The clinical proof of concept was generated in a Phase 2 study conducted in COVID-19 infected patients with severe respiratory insufficiency, and is being further substantiated by clinical development in Dengue viral infection. Dengue is a so-called arbo-viral infection, ie mosquito born disease, that in some of patients can develop to severe dengue, often referred to as dengue hemorrhagic fever or dengue shock syndrome, a life-treatening condition associated with hemoconcentration, thrombocytemia with further risk of hypotension (shock), internal bleeding, organ failure and death. Experimental data supports that resomelagon could be a treatment option to reduce the risk for development of severe Dengue. This hypothesis is tested in the ongoing RESOVIR-2 study as an exploratory phase 2 study. The study is an investigator initiated study as part of the scientific RESOVIR (resolution in viral infection) collaboration with key scientific centers focusing of the potential of resolution therapy a novel host-directed treatment approach in viral infections.