Multiple Supratherapeutic Doses of Iptacopan 400 Mg Twice Daily Are Well Tolerated in Healthy Participants: Safety Findings from a Randomized, Participant-Blinded, Placebo-Controlled, Phase I Study

Background: Iptacopan, the first oral proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway of the complement system, is approved as a monotherapy for adults with paroxysmal nocturnal hemoglobinuria and is being investigated in diseases such as immunoglobulin A nephropathy, C3 glomerulopathy and atypical hemolytic uremic syndrome. Iptacopan is administered at a therapeutic dose of 200 mg twice daily (bid). A Phase I, randomized, participant-blinded, placebo-controlled study (A2109) is being conducted to assess the safety, pharmacokinetics and pharmacodynamics of multiple supratherapeutic oral doses of iptacopan (400 mg and 800 mg bid) in healthy volunteers.

Aim: To report the safety findings from the completed Cohort 1 of the ongoing A2109 study, in which healthy participants received multiple 400 mg bid supratherapeutic doses of iptacopan or placebo.

Methods: Healthy individuals aged between 18 and 55 years were enrolled into Cohort 1 and were randomized 2:1 to receive iptacopan 400 mg bid or matching placebo. There was a 28-day screening period, a 14-day treatment period and a 5-day post-treatment washout period. The primary endpoint was safety, including adverse event (AE) reportings, vital signs, electrocardiogram (ECG) assessments and safety laboratory evaluations. Pre-dose safety data were collected at screening and baseline. On treatment, safety laboratory evaluations were performed on Days 2, 3, 7, 10, 14, 15, 16, 18 and 19; vital signs were measured daily; and ECG assessments were done on Days 1, 4, 7, 10, 14 and 19.

Results: Twelve healthy volunteers were enrolled into Cohort 1; 8 received iptacopan 400 mg bid and 4 received placebo.Two participants in the iptacopan arm had AEs during the treatment period; 1 had moderate headache and the other had a mild AE of elevated amylase levels. These 2 AEs were considered related to iptacopan; however, both resolved without the need for additional treatment. No participants discontinued iptacopan. One individual receiving placebo had 5 mild AEs during the treatment period (chills, bilateral hand pain, sensation of feeling flushed, headache and bilateral sclera erythema), which resolved without the need to discontinue treatment. The other 3 participants who received placebo had no AEs. During iptacopan treatment, there was no evidence of an effect on any laboratory parameter (including red or white blood cell count), ECG parameter or vital sign (including heart rate and blood pressure), and there was no adverse impact on liver, kidney or thyroid function.

Conclusions: Multiple supratherapeutic doses of iptacopan 400 mg bid for 14 days were well tolerated in healthy individuals. Based on these results, the study will progress to assess iptacopan 800 mg bid in Cohort 2.

Schmouder:Novartis: Current Employment. Hackling:Novartis: Current Employment. Shah:Novartis: Current Employment. Bellibas:Novartis: Current Employment, Current equity holder in publicly-traded company; Avadel Pharmaceuticals plc.: Current equity holder in publicly-traded company; Ardelyx Inc.: Current equity holder in publicly-traded company; Arrowhead Pharmaceuticals: Current equity holder in publicly-traded company; BioNTech SE: Current equity holder in publicly-traded company; Caribou Biosciences Inc.: Current equity holder in publicly-traded company; Silence Therapeutics Inc.: Current equity holder in publicly-traded company. Kulmatycki:Novartis: Current Employment.

Iptacopan 200 mg bid is approved for patients with PNH. This abstract reports the safety findings of supratherapeutic doses (400 mg bid) of iptacopan in healthy participants