In July, SynAct Pharma applied for an amendment of the ongoing phase IIa study with AP1189 in patients with idiopathic membranous nephropathy (iMN). In the new study format, the dosing duration is increased from four weeks to three months and the new AP1189 tablet is used. The protocol amendment has now been approved by the Danish Medicines Agency and is currently being assessed in Sweden and Norwary. BioStock talked to CSO Thomas Jonassen.
SynAct Pharma’s drug developments focused on treating autoimmune and inflammatory diseases by promoting resolution of the inflammation, without suppressing the immune system. The lead indication for the company’s drug candidate AP1189 is rheumatoid arthritis, where positive phase IIa results were presented at the end of 2021 and where the company has initiated further development in clinical phase IIb.
In parallel with the development program in RA, AP1189 is evaluated in patients with idiopathic membranous nephropathy (iMN), the most common cause to primary nephrotic syndrome (NS) which is a kidney condition associated with increased loss of protein into the urine resulting in tissue swelling and edemas. Even though iMN itself is a relatively rare disease, it is estimated that 12 million people only in the US are affected by different diseases causing membranous nephropathy, making room for a novel innovative treatment to control the nephropathy. Consequently, even though that iMN itself is uncommon, the potential of AP1189 within nephrology is big if the compound is effective in the iMN patients.
Study redesign to increase likelihood of a positive outcome
In November 2021, SynAct Pharma decided to redesign the clinical phase IIa study in iMN patients to be able to extend the treatment period to 3 months and use the newly developed AP1189 tablet.
According to the company, the new study design may increase the likelihood to show treatment effects on urinary protein excretion, the main efficacy read-out in the study. Also, it might increase patient compliance as once-daily dosing with a tablet is more convenient than daily intake of the previously used oral suspension that is prepared by the patient itself with AP1189 powder and water.
SynAct-CS003 evaluates safety and efficacy of AP1189 in nephropathy
The purpose of the study, called SynAct-CS003, is to assess safety and efficacy of once-daily dosing of AP1189 tablets vs placebo for 12 weeks as an add-on to treatment with ACE-inhibitors or angiotensin II receptor blockers, which is the first-line treatment of iMN to control blood pressure and decrease the protein loss in the urine.
SynAct aims to enroll 18 patients to the study and expect to report key results during 2023. 12 patients with iMN will be treated with 100 mg AP1189 and 6 patients will be treated with a placebo.
If AP1189 proves to be an efficient and safe treatment in iMN, it could be the first drug specifically approved for this disease. Furthermore, positive read-outs would support the development of AP1189 in other diseases associated with proteinuria and NS such as minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and Systemic Lupus Erythematosus (SLE) and with additional opportunities to treat diabetic patients suffering from nephropathy.
CSO highlights the potential
BioStock contacted SynAct Pharma’s CSO Thomas Jonassen to get to know more about the potential of AP1189 in nephrology and the revision of the SynAct-CS003 study.
First of all, what is the potential of AP1198 in kidney diseases?
– The nephrology program is set up to explore the potential of AP1189 to treat kidney diseases. For years, melanocortin receptor derived therapy has been highlighted as a potential treatment approach for kidney diseases and the clinical effect of melanocortins has been shown by use of ACTH derived therapy in patients with glucocorticoid refract symptoms, not at least in diseases characterized by large amount of protein in the urine.
– Continued loss of protein through the urine is associated with development of nephrotic syndrome (NS). A condition that untreated is associated with development of edemas, hypertension, hypolipidemia, development of chronic kidney disease and a significantly increased risk of severe cardiovascular disease. Several autoimmune diseases, including idiopathic membranous nephropathy (IMN), induce severe proteinuria and eventually NS. Most of these diseases are rare, but proteinuria and NS are also seen secondary to lifestyle diseases such as hypertension and diabetes and systemic inflammatory diseases such as Lupus erythematosus.
»For years, melanocortin receptor derived therapy has been highlighted as a potential treatment approach for kidney diseases«
– From mode of action of AP1189, the compound could be specifically effective in patients with NS, and we therefore decided to initiate a study in patients with iMN and have experienced a high degree of interest for this potential among nephrologists who often need to treat with compounds that due to immunosuppression has unwanted side effects.
Could you tell us a bit about today’s treatment alternatives for these patients?
– Treatment of iMN aims to maintain renal function and achieve reduction of proteinuria. All patients receive supportive care to control blood pressure and minimize protein loss via ACE inhibitors and angiotensin 2 receptor antagonists. A selection of patients may also undergo treatment to reduce the levels of lipids in the blood, typically by use of statins. Patients at high risk of disease progression receive treatment with immunosuppressive drugs consisting of rituximab, a monoclonal antibody, for those patients with stable renal function, or glucocorticoids and cytotoxic drugs for those with impaired renal function.
»In a way, you could say that AP1189 has the same abilities from a treatment perspective as ACTH but without the unwanted side effects«
– As mentioned, a number of patients do not respond to glucocorticoids and here ACTH derived therapy has shown to be effective. This treatment concept was invented in Lund and has found a place in daily clinic in the US by use of ACHTAR gel. Interestingly, ACTH induced its effect in these patients through stimulation of melanocortin receptors. Unfortunalely, the treatment also induce a lot of adverse events as it stimulates glucocorticoid release. In a way, you could say that AP1189 has the same abilities from a treatment perspective as ACTH but without the unwanted side effects.
Why did you decide to revise the phase II study in patients with iMN?
– When we first designed the study, we were limited to four weeks of treatment and administration with oral suspension. Now we can benefit from our new tablet formulation and the possibility to dose for 12 weeks. In consultation with our investigators in Denmark, Norway and Sweden, we have worked to update the protocol to make the study much more clinically relevant.
»In consultation with our investigators in Denmark, Norway and Sweden, we have worked to update the protocol to make the study much more clinically relevant.«
– We further had to await the completion of the bioequivalence study with our new tablet and importantly get the tablets produced in substantial amounts to cover the clinical demand. With the approval from this week we are ready to move on with the study in its new and highly clinically relevant format.