Novartis Announces New Phase II Data Showing Sustained Proteinuria Reduction with Oral Iptacopan in IgA Nephropathy Patients Over 6 Months

From February 24-27, 2022, the World Congress of Nephrology (WCN) was held in Kuala Lumpur, the capital of Malaysia. On the 27th, during the Late-breaking Clinical Trials session, Professor Dana V. Rizk from the United States reported the 6-month follow-up results of a randomized, double-blind, placebo-controlled Phase II clinical trial on the use of Iptacopan, an oral complement alternative pathway B factor inhibitor, for patients with IgA nephropathy.

In this Phase II clinical trial (NCT03373461), patients with IgA nephropathy (n=112) were randomized to receive either placebo or different doses of Iptacopan. Preliminary results from 3 months of follow-up were presented as a breakthrough clinical trial at the 58th European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) Congress held from June 5–8, 2021, achieving the primary endpoint [1]. The results showed that at 90 days, Iptacopan demonstrated a statistically significant dose-response effect (p=0.038) in reducing proteinuria (measured by the 24-hour urine protein-to-creatinine ratio [UPCR 24h]) compared to placebo. The highest dose, 200 mg twice daily, reduced proteinuria by 23% at 90 days compared to placebo, while also showing a trend toward stabilizing kidney function.

The results published at this conference were from the 6-month follow-up [2]. During the 6-month period, there was a continuous decrease in proteinuria among patients with IgA nephropathy, with a 40% reduction in proteinuria observed in the Iptacopan 200mg bid dose group. Throughout the 6-month follow-up, sustained suppression of biomarkers reflecting alternative complement pathway activation and urinary sC5b-9 was observed in all iptacopan groups receiving doses above 10mg bid. Additionally, Iptacopan demonstrated good tolerability and safety.

No drugs have been approved yet in China to treat IgA nephropathy, and clinical needs remain unmet.

IgA nephropathy is the most common primary glomerulonephritis, with an annual global incidence of at least 2.5 per 100,000 adults, and is more prevalent among Asians [3]. IgA nephropathy is confirmed by renal biopsy showing predominant deposition of IgA immunoglobulin in the glomeruli, clinically presenting mainly with hematuria and proteinuria. Currently, no drugs have been approved in China for the treatment of IgA nephropathy. Regarding the treatment of IgA nephropathy, the 2021 edition of the KDIGO Clinical Practice Guideline for Glomerular Diseases recommends [4]: All IgA nephropathy patients with proteinuria >0.5g/24h, regardless of whether they have hypertension, should be treated with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), aiming to reduce proteinuria to below 1g/24h and control systolic blood pressure to <120mmHg; For IgA nephropathy patients with a high risk of progression despite optimal supportive care (proteinuria levels still >0.75-1g/24h after 90 days of optimized supportive care), immunosuppressive therapy should be considered, and all patients are recommended to participate in clinical trials.

The guideline also recommends that IgA nephropathy patients who remain at high risk of chronic kidney disease (CKD) progression despite receiving optimal treatment should be considered for a six-month course of glucocorticoid therapy. Prior to treatment, a discussion with the patient regarding the side effects and risks of the therapy is necessary, especially for patients with eGFR <50ml/min/1.73㎡. The clinical benefits of glucocorticoids in IgA nephropathy have not been clearly established. Caution should be exercised when considering their use in patients with eGFR <30ml/min/1.73㎡, diabetes, BMI >30kg/m², infections (tuberculosis), secondary diseases (cirrhosis), active peptic ulcers, psychiatric disorders, and osteoporosis. Clearly, the safety of steroid therapy has always been a concern in clinical practice.

A real-world study was released at this WCN conference, using the American Optum’s deidentified National Electronic Health Records Database (January 2007 to December 2019), evaluating 96 million people across all 50 states in the United States to compare the incidence of infections and other adverse reactions between IgA nephropathy patients receiving hormone therapy and those not receiving hormone therapy. The results showed [5] that the incidence of infections, osteoporosis, hypertension, and diabetes was higher in IgA nephropathy patients receiving hormone therapy than in those not receiving hormone therapy.

Iptacopan Mechanism of Action and Clinical Development Potential

The complement system (CS) is a component of innate immunity that recognizes and targets foreign substances and damaged/abnormal host cells, serving as an important line of defense in the human body. The CS consists of over 50 plasma and cell surface proteins, and complement activation is mainly divided into three pathways: the classical pathway, the lectin pathway, and the alternative pathway. These three pathways share a common terminal, which is the formation of the membrane attack complex (MAC), ultimately leading to cytolysis [6].

Complement is a double-edged sword, and an increasing number of discoveries indicate its involvement in the onset and progression of many diseases. The kidney is one of the organs most susceptible to abnormal complement activation, and abnormal complement activation can be observed in various kidney diseases. Under physiological conditions, the alternative complement pathway is in a state of low-level activation balance. Abnormal activation of the alternative complement pathway participates in the onset and progression of various kidney diseases. Direct consequences of the abnormal activation of the alternative complement pathway include atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). The activation of the complement system also participates in and exacerbates the progression of diseases such as IgA nephropathy and membranous nephropathy (MN) [7-8].

Iptacopan is an oral, selective small-molecule inhibitor of Factor B, which potently inhibits Factor B and MAC induced by the alternative complement pathway, but does not inhibit Factor D or the activation via the classical and lectin pathways [9]. Iptacopan is a leading product in Novartis' renal disease pipeline, targeting the alternative complement pathway, a key driver of complement-mediated kidney diseases (CMKD). Iptacopan is currently in parallel development for multiple renal diseases, including C3G, IgA nephropathy, aHUS, idiopathic membranous nephropathy (iMN), as well as the blood disorder: paroxysmal nocturnal hemoglobinuria (PNH).

On March 10, 2022, the 17th World Kidney Day arrived with the spring. The theme of this year's World Kidney Day is "Kidney Health for All——Bridge the Knowledge Gap to Better Kidney Care." We look forward to the vigorous development of new drugs in nephrology to benefit more patients with kidney diseases.

References:

[1] Barratt J, et al. Late breaking clinical trial presentation at 58th ERA-EDTA Congress, Fully Virtual, June 5–8, 2021.

[2] cm.theisn.org/cmPortal/Searchable/WCN2022/config/normal#!abstractdetails/0000168420.

[3]McGrogan A, Franssen CFM, de Vries CS. The incidence of primaryglomerulonephritis worldwide: a systematic review of the literature.NephrolDial Transplant. 2011;26(2):414–430.

[4]Kidney International (2021) 100,S1–S276.

[5]cm.theisn.org/cmPortal/Searchable/WCN2022/config/normal#!abstractdetails/0000157640.

[6]RicklinD, et al.Nat Rev Nephrol. 2016  ; 12(7): 383–401

[7]Fearn A , et al. World Journal of Nephrology, 2015.

[8]Thurman, Joshua M . Nephrology, dialysis, transplantation: official publicationof the European Dialysis and Transplant Association - European RenalAssociation, 2017.

[9]SchubartA et al., PNAS 2019;116(16):7926–931.

Remarks:

· The purpose of this material is to convey cutting-edge pharmaceutical information and research progress, not for advertising purposes. The information contained in this material is for reference only; please follow the advice or guidance of doctors or other healthcare professionals.

·The drug Iptacopan mentioned in this material has not been approved in mainland China.