Symposium 0.1 – Late Breaking Clinical Trials

Symposium Summary

Written by Jasna Trbojevic-Stankovic
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Orally administered C5AR inhibitor Avacopan in a randomized, double-blind, placebo-controlled study (ACCOLADE) for treatment of C3 glomerulopathy

Andrew Bomback, United States of America

Complement 3 glomerulopathy (C3G) is a rare kidney disorder comprising C3 glomerulonephritis and dense deposit disease. The complement system plays a significant role within the pathological process of C3 glomerulopathy. The dysregulation of the alternative complement pathway leads to increased levels of terminal fragments of the C5 pathway including C5a, which exhibits a proinflammatory effect attracting and activating myeloid cells. Patients with C3G can present with proteinuria, haematuria, renal failure, and/or hypertension, and generally progress to end-stage renal disease (ESRD) within ten years after diagnosis. Avacopan is an orally administered highly potent antagonist of C5aR which selectively blocks C5a-induced cell activation and leaves the rest of the complement system intact and functioning, providing anti-inflammatory benefits while avoiding broad immunosuppression. It has already presented impressive results in the treatment of ANCA-associated vasculitis.

The Orally Administered C5aR Inhibitor Avacopan in a Randomized, Double-Blind, Placebo-Controlled (ACCOLADE) study aimed to evaluate the safety and efficacy of avacopan in patients with C3G. The study initially enrolled 22 patients with biopsy-proven C3G and C5b-9 level >244ng/mL to receive avacopan 30mg BID and a matching placebo cohort of 22, but later added another 22 biopsy-proven cases with C3G and C5b-9 level ≤244ng/mL as the second stratum in the intervention group and a matching placebo cohort of the same size.

The avacopan therapy led to significant improvement of renal function measured by eGFR and a beneficial difference in the C3 histological index (C3HI) of disease activity after 26 weeks of follow-up. Improvement in GFR correlated with C3HI for disease chronicity which measures the progression of fibrosis and is currently accepted as the best predictor of time to ESRD. Furthermore, the urinary protein to creatinine ratio exhibited a significantly larger decline in patients treated with avacopan after 16 weeks of follow-up. No significant difference was observed in the incidence of adverse events between the groups and no drug-related safety signal has been identified so far.

Figure 1. The effects of avacopan on renal function in patients with IgAN

The current data suggest that avacopan is effective in stabilizing the activity and preventing the progression of chronicity of the C3G disease with a favourable safety profile.

Interim analysis of a phase 2 dose-ranging study to investigate the efficacy and safety of Iptacopan in primary IgA nephropathy

Jonathan Barratt, United Kingdom

IgA nephropathy (IgAN), also known as Berger’s disease, is one of the most common causes of glomerulonephritis in the world. Pathologically, a spectrum of glomerular lesions can be seen, but the deposition of IgA-containing immune complexes in the glomerular mesangium is observed in almost all biopsies. The disease most often affects young adults and up to 50% of the patients eventually develop end-stage renal disease. There are currently no effective targeted therapies approved for IgAN that slow or prevent renal function decline. The current mainstay of treatment remains and optimized goal-directed supportive care with RAS acting agents.

This adaptive seamless randomized, double-blind, placebo-controlled, dose-ranging study, aimed to investigate the safety and efficacy of iptacopan, an attractive therapeutic to halt the progression of IgAN. Iptacopan is an oral, highly potent, safe, and well-tolerated selective inhibitor of factor B (FB) that binds to FB and its catalytically active fragment Bb to suppress the activity of the AP C3 convertase and activation of the amplification loop, and prevent a downstream generation of the alternative pathway (AP) C5 convertase complex.

Forty-six patients with IgAN were initially randomized to receive three different doses of iptacopan or placebo for 90 days treatment period in Period 1. Guided by the Part 1 interim analysis (IA 1) results, an additional 66 patients were then randomized to four doses of iptacopan or placebo in Part 2 for a 180 days treatment period. The patients had an eGFR ≥ 30mL/min, and proteinuria ≥0.75 g/24h at screening and at the end of the run period, and were receiving RAS-acting agents, antihypertensive therapy, or diuretics, but not immunosuppressive therapy ≥90 days before study treatment. Treatment groups were mostly balanced in terms of demographics and baseline characteristics.

Figure 2. The design of the study investigating efficacy and safety of iptacopan in primary IgAN

As expected, iptacopan treatment resulted in inhibition of the AP with a marked decrease of the plasma levels of the Bb fragment. Near-complete inhibition of AP activation was observed with the dose of 200mg BID. Clinically, the iptacopan treatment resulted in a dose-dependent reduction in 24-hour proteinuria. Furthermore, treatment with all doses of iptacopan was associated with a trend towards stabilization of eGFR over the 90 days treatment period compared with a decline in eGFR observed in the placebo group. Lastly, and perhaps most pertinent to a kidney-specific effect of iptacopan in IgAN, a reduction in urinary soluble C5b-9, reflective of terminal pathway activation and formation of membrane attack complexes, was observed. There were no treatment-related serious adverse events or deaths, and no serious infections reported during the study, thus suggesting a favourable safety profile of this drug.

Effects of Dapagliflozin on major adverse kidney events in patients with focal segmental glomerulosclerosis: a prespecified analysis of the DAPA-CKD trial

David C. Wheeler, United Kingdom

Focal segmental glomerulosclerosis (FSGS) is an important cause of nephrotic syndrome progressing to ESRD in about two-thirds of the cases. Current therapeutic approaches to FSGS include RAS blockade and immunosuppression, although there is limited evidence to support these approaches. Recent evidence suggesting that sodium-glucose co-transporter-2 (SGLT2) inhibitors demonstrate nephroprotective effects in type 2 diabetes independent of blood glucose levels inspired the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial which assessed the effects this SGLT2 inhibitors in CKD patients with and without diabetes. Participants who were required to have an eGFR between 25 and 75 mL/min/1.73m2, a urine albumin to creatinine ratio between 200 and 5000 mg/g, and who were receiving a stable dose of RAS acting agents, were randomized to receive dapagliflozin or placebo. Compared to placebo, dapagliflozin reduced the risk of kidney and cardiovascular outcomes and prolonged survival regardless of diabetes status.

Further analysis of a subgroup of 115 participants with FSGS participating in the DAPA-CKD trial Fifty three of these participants were randomized to Dapagliflozin and 62 to placebo. The groups were balanced in terms of demographic and clinical characteristics, except for the prevalence of diabetic patients which was higher in the placebo group.

Figure 3. The effect of dapagliflozin vs placebo on eGFR in patients with FSGS

Dapagliflozin reduced the risk of major kidney and cardiovascular events in FSGS patients by approximately 50% and although the difference between the intervention and the placebo group was not statistically significant, it was consistent with the overall results from the DAPA-CKD trial,. Furthermore, dapagliflozin tended to attenuated the decline in eGFR and reduced proteinuria during the two-year follow-up. The drug was well tolerated with no unexpected side effects in the FSGS subpopulation.

A lung ultrasound-guided treatment strategy (LUST) in end-stage kidney disease patients at high cardiovascular risk: a randomized multicentre trial

Claudia Torino, Italy

Volume overload is a powerful risk factor for all-cause and cardiovascular mortality in End Stage Kidney Disease patients, especially in those with heart failure. There are several techniques for measuring extracellular volume, but they do not provide an insight into heart function parameters responsible for individual tolerance to volume excess and response to ultrafiltration. Extravascular lung water can be assessed by lung ultrasound (US) and quantified by the number of the recorded hyperechoic B-lines. B-lines have been associated with left ventricular filling pressure in patients with heart failure and are a powerful predictor of adverse clinical outcomes in haemodialysis (HD) patients. This technique reliably reflects lung congestion in these patients, thus suggesting its potential to guide volume removal in this population.

The LUST study aimed to investigate whether a lung-US-guided treatment strategy improves survival and decreases the risk of death, decompensated heart failure and myocardial infarction compared to usual care in HD patients at high cardiovascular risk. It involved 363 HD patients with previous myocardial infarction, angina, coronary syndrome, or Heart Failure from 18 European nephrology centres. These patients were randomized to lung-US-guided ultrafiltration regimen or standard care with UF guided by clinical signs and symptoms. A cut-off of 15 B-lines was used to guide intensification of ultrafiltration by longer or additional dialyses in the active arm. The lung US was performed weekly, until the treatment target (<15 US-B lines) was achieved and once a month thereafter. The study arms were well balanced in terms of demographic and clinical characteristics.

During the follow-up period of 24 months, the average number of B-lines decreased from 15 to 9 in the active arm but increased from 16 to 30 in the control arm. Thus, a significantly higher number of patients achieved the targeted number of B-lines <15 in the active than in the control group. Also, the incidence rate of the adjustments of antihypertensive drug therapy was significantly higher in the active arm.

Fig. 4. Trend of the US-BL in the study arms.

Importantly, the intervention was safe because the incidence of dialysis hypotension across the trial was less in the active than in the control arm. No statistically significant difference was found in the combined outcome, all-cause hospitalizations, cardiovascular hospitalizations, or left ventricular ultrasonographic parameters between the groups. Nevertheless, a secondary post hoc analysis showed a higher incidence of recurrent episodes of decompensated heart failure and recurrent cardiovascular events in the usual care group.

In conclusion, the treatment strategy guided by lung-US safely and effectively reduced lung congestion, a risk factor for pulmonary oedema, but was not superior to the usual care strategy in improving a composite endpoint including mortality, myocardial infarction and decompensated heart failure. A post-hoc analysis suggested that a lung US-guided treatment police may reduce the risk for decompensated heart failure. This hypothesis generating finding sets the stage for further studies focusing on prevention of decompensated heart failure in the haemodialysis population.

Further reading

Caravaca-Fontán F, Trujillo H, Alonso M; C3G Study Group of the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Validation of a Histologic Scoring Index for C3 Glomerulopathy. Am J Kidney Dis. 2021;77(5):684-695.e1. doi: 10.1053/j.ajkd.2020.11.011.

Medjeral-Thomas NR, O’Shaughnessy MM. Complement in IgA Nephropathy: The Role of Complement in the Pathogenesis, Diagnosis, and Future Management of IgA Nephropathy. Adv Chronic Kidney Dis. 2020;27(2):111-119. doi: 10.1053/j.ackd.2019.12.004.

Wheeler DC, Stefansson BV, Batiushin M, et al. The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics. Nephrol Dial Transplant. 2020;35(10):1700-1711. doi: 10.1093/ndt/gfaa234.

Heerspink HJL, Stefánsson BV, Correa-Rotter R; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. doi: 10.1056/NEJMoa2024816.

Wheeler DC, Stefánsson BV, Jongs N; DAPA-CKD Trial Committees and Investigators. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9(1):22-31. doi: 10.1016/S2213-8587(20)30369-7.

Zoccali C, Torino C, Tripepi R; Lung US in CKD Working Group. Pulmonary congestion predicts cardiac events and mortality in ESRD. J Am Soc Nephrol. 2013;24(4):639-46. doi: 10.1681/ASN.2012100990.

Rivas-Lasarte M, Álvarez-García J, Fernández-Martínez J, et al. Lung ultrasound-guided treatment in ambulatory patients with heart failure: a randomized controlled clinical trial (LUS-HF study). Eur J Heart Fail. 2019;21(12):1605-1613. doi: 10.1002/ejhf.1604.

Marini C, Fragasso G, Italia L, et al. Lung ultrasound-guided therapy reduces acute decompensation events in chronic heart failure. Heart. 2020;106(24):1934-1939. doi: 10.1136/heartjnl-2019-316429.