Melanocortin derived Therapy

The melaconortin system is an endogen systems where the substances α- and γ- melanocortin stimulating hormone (MSH) as well as Adrenocorticotropic Hormone (ACTH) collectively called melanocortins acts on specific receptors in a number of tissue and organs. The melanocortins are peptides that is released into the blood stream for the from the pituitary gland as well as released in a para- and autocrine (ie local in tissue and organs) fashion to modulate a number of different responses.

A total number of five melanocortin receptors has been identified, where the type 1 receptor originally was described in melanocytes in the skin and induced skin pigmentation upon stimulation with αMSH.

The type 2 receptor is present in the adrenal gland is in central in regulation of the release of glucocorticoids (GC´s). Glucocorticoids are essential for life as they regulate and promote essential mechanisms in the cardiovascular, metabolic, homeostatic and immune system. However, where natural levels of GC´s are essential for life, high levels as seen in Cushing disease and following long term treatment with GC´s is associated with a number of severe side effects.

The Type 3 receptor was originally shown to be present in the brain and to be associated with regulation of the autoimmune nerve system, in regulation of food intake as well as in central regulation of sexual function.

The Type 4 receptor has for more than two decades been target for drug development, as the receptor plays a pivotal role in central regulation of food intake. MC4r agonist are among the most potent compounds to reduce food intake, but has unfortunately unwanted side effects limiting their use in the general population of obese as they induce tachycardia and hypertension through stimulation of the sympathetic nerve system.

The role of the type 5 receptor has for years been unclear, but interestingly recent data indicates that MC5r plays a central role in regulation of T-cell activity, including an ability to induce T-regulatory cells important for regulation of immunologic homeostasis.

Melanocortin induce anti-inflammatory and pro-resolving effects through stimulation of Type 1 and type 3 receptorson a number of cells in the immune system.

In acute inflammation, local levels of melanocortins, as αMSH, is secreted locally within the inflamed tissue or organ by immune active cells, thereby reducing the risk for develop excessive inflammation. αMSH then stimulate MC1r and/or MC3r on cells as neutrophils and macrophages to secure

  1. that infiltration of inflammatory cells and release of proinflammatory mediators are reduced.
  2. that the ability to clear up the inflammatory process is stimulated, ie that melanocotins stimulate resolution of inflammation.

A central pathway in the resolution process is to recruit macrophages and induce a shift in phenotype of macrophages, whereby the cells ability to clear pro-inflammatory cells as neutrophils are stimulated. A process called efferocytosis.

Upon excessive inflammatory processes the endogen stimulation of the melanocortin receptors is not sufficient to promote resolution and it such setting pharmacological intervention with melanocortins has shown to be a very promising approach.

A number of development projects with melanocortin derived therapy has shown very promising effects. The founders of SynAct Pharma developed a peptide agonist AP214 into Phase 2 in high risk patients undergoing cardiac surgery and showed promising effects on the ability to protect against development of impaired kidney function, a severe condition where excessive inflammation both systemic and local plays an importing role for the deleterious consequences of the surgical intervention.

Today only one compound targeting the melanocortin-system is on the market, the ACHTAR gel marketed by Mallinckrodt Pharmaceutical. ACTHAR gel is used for rheumatoid diseases, as Rheumatoid Arthritis, for treatment of relapses in Multiple Sclerosis, for treatment of Nephrotic syndrome and for treatment of infantile Spasms with the current annual revenue above 1 B US$. As ACHTAR-gel not only stimulates the type 1 and type 3 melanocortins receptors, but also the Type 2 receptors, an major challenge associated with the use of ACHTAR- gel is stimulation of glucocorticoid releases and thereby treatment limiting side effects- The use of ACHTAR gel is therefore limited to difficult to treat cases where no other treatment options has shown to effective.

In addition, treatment with ACHTAR gel, other ACTH derived compound as well as traditional peptide agonists to the melanocortin receptors will induce unwanted skin pigmentation though stimulation of MC1r on melanocytes. A mechanism that is specifically related to cAMP mediated pathways within the melanocytes.  Potential treatment limiting side effects as the result is marked hyperpigmentation.

Mode of action of the SynAct compound AP1189 differs from all other compounds developed within the melanocortin field, as the compound as  a biased agonist against the MC1r and MC3r does not active cAMP mediated pathways, which mean that the compound does not stimulate skin pigmentation in melanocytes and it compared to ACHTAR gel does not stimulate the MC2r and thereby not the unwanted release of GC´s.