In the Phase IIa study, AP1189 will be tested in a double-blind, placebo-controlled multicentre study as add-on therapy to ACE-inhibitor or Angiotensin-2 receptor antagonists in a once-daily dose regimen for four weeks with the primary purpose to show treatment effect on urinary protein excretion relative to pre-treatment levels and placebo. The patients will be dosed with either 100 mg AP1189 or Placebo in a 2:1 randomization in up to 24 patients. Following approval by the Danish Medicinal Agency (DMA) and the local Ethical Committee the company now announces that the study has been initiated. For details related to the study see www.clinicaltrial.gov.
Nephrotic syndrome (NS) is a relatively rare condition characterized by loss of protein in the urine that is associated with development of edema, hypoalbuminia and elevated plasma lipids, ie development of NS. NS can further develop into chronic kidney disease and is associated with risk for development of hypertension and ischemic cardiovascular disease.
Idiopathic membranous nephropathy (iMN), is one of the most common causes of Nephrotic Syndrome in adults. In most case, iMN is caused by circulating antibodies against the M-type receptor of phospholipase 2 (Anti-PLA2r). These antibodies bind to the PLA2r on a specific cell type in the kidneys called podocytes thereby inducing morphological and functional changes in the kidneys resulting in high levels of protein in the urine.
Podocytes express melanocortin Type 1 receptors (MC1r) and it has been shown that MC1r stimulation preserved the structure of the podocytes and reduce proteinuria in experimental models of NS. In patients compounds such as ACHTAR Gel with the MCr agonist ACTH as active ingredient, have been shown to reduce proteinuria even in difficult to treat patients including patients with glucocorticoid resistant NS.
AP1189 is a biased MC1r and MC3r agonist that in an animal models of NS mimicking iMN and have shown to induce treatment effect comparable to what has been reported for other MCr agonists and in a head to head animal study with ACTH showed superior treatment effect with significantly lower levels of proteinuria following 4 weeks treatment (Patent application no: WO/2019/243625)
First-line treatment of iMN is Angiotensin-converting-enzyme inhibitors or Angiotensin II receptor blockers to control blood pressure and decrease the protein loss in the urine. If continued symptoms follow for more than six months, the patients will be treated with glucocorticoids and immunosuppressives. The first-line treatment options are often associated with treatment-limiting side effects and a fraction of patients will despite treatment continue to have symptoms.
ACTH treatment has been shown to be effective in difficult to treat patients with glucocorticoids resistant proteinuria, pointing to specific melanocortin type 1 receptor (MC1r) mediated effects of the ACTH treatment. However, ACTH treatment is also associated with often treatment limiting side effects that significantly restrict the use of the compound.
- There is therefore a need for new treatment options in NS patients. In addition to the anti-inflammatory and
pro-resolving effects of the AP1189, the compound, similarly to ACTH treatment, also stimulates the MC1r on the podocytes in kidneys. As AP1189 does not induce the treatment limiting side effects seen following ACTH treatment, the AP1189 compound could be a very attractive new treatment option in NS. We therefore consider it a major milestone in the development of the compound that we now have a Phase II clinical study up running in the iMN patients says Thomas Jonassen, CSO in SynAct Pharma.
This information is such information that SynAct Pharma AB is obliged to publish in accordance with the EU Market Abuse Regulation. The information was submitted, through the agency of the below contact person, for publication on June 29, 2020.