Expert Interpretation--The First Targeted Drug Delays The Decline Of Renal Function By 50%

For a long time, there has been no specific treatment for IgA nephropathy, and countless young and middle-aged patients have prematurely progressed to end-stage renal disease and lost their ability to work due to a lack of effective intervention. Nefecon (budesonide delayed-release capsules, Naifukang), the world's first drug targeting the cause of IgA nephropathy, as the first mucosal immune modulator targeting the intestinal tract, has brought new hope to break through the current treatment dilemma.

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Recently, the results of the Nefecon Phase III clinical study NefIgArd (Part B) revealed that the drug can reduce the decline rate of glomerular filtration rate (eGFR) by 50% in 2 years after 9 months of treatment and 15 months of drug withdrawal, and significantly slow down the rate of renal failure. Functional decline. How should the clinical significance of this result be viewed? What is the future application prospect of Nefecon? Professor Zhang Hong and Professor Lu Jicheng from the Nephrology Department of Peking University First Hospital expounded their views and opinions in the interview.

Q1. The phase III clinical study of Nefecon has reached the primary endpoint. How will this affect the treatment of IgA nephropathy in the future?

Professor Zhang Hong: IgA nephropathy is the most common primary glomerular nephropathy worldwide, and my country is a country with a high incidence of IgA nephropathy. The disease mostly affects young adults and is extremely harmful. About 30% of patients progress to end-stage renal disease, ie uremia, 10 to 20 years after onset. Unfortunately, there has been a lack of specific treatment for IgA nephropathy, and traditional programs including RAS inhibitors, hormones, and immunosuppressants are all non-causal treatments. The emergence of Nefecon is expected to break this situation.

From the perspective of pathogenesis, abnormal intestinal mucosal immune function is involved in the occurrence and development of IgA nephropathy, which is the source and core pathogenic link of IgA nephropathy. Through a special manufacturing process, Nefecon targets and releases budesonide in the terminal ileum, where the Peyer's patches are an important part of the intestinal mucosal immune system and also the pathogenic galactose-deficient IgA1 molecule (Gd-IgA1) main sources of. As the world's first drug for the treatment of IgA nephropathy, Nefecon can reduce the production of pathogenic IgA1 from the source. In Phase IIb/III clinical studies, Nefecon can significantly reduce the levels of Gd-IgA1 and IgA immune complexes in the circulation, confirming The concept of cause-based treatment.

The recently announced Phase III clinical study NefIgArd (Part B) has reached its primary endpoint, confirming that Nefecon can significantly delay the decline of renal function in patients with IgA nephropathy at the end of the 9-month treatment period and follow-up to 15 months after complete drug withdrawal. The results have important clinical significance and provide strong evidence-based support for Nefecon’s renal function protection, which may promote a major change in the treatment pattern of IgA nephropathy in the future.

Professor Lv Jicheng: The NefIgArd study is divided into two parts. The previously published part A results confirmed that Nefecon can reduce proteinuria, and the recently released part B confirmed that it can delay the decline of renal function and delay the decline of eGFR in 2 years in a longer follow-up period. 50%, which is a large clinical benefit. Nefecon is the first drug approved in the world for the specific treatment of IgA nephropathy. For most patients, in the case of traditional treatment options and their limited efficacy, the drug undoubtedly brings new hope and provides more treatment options.

Q2. How do you view the clinical significance of eGFR data? Can Nefecon delay the decline of kidney function?

Prof. Zhang Hong: In the Phase III study, 364 patients with IgA nephropathy diagnosed by renal biopsy were randomized 1:1 to take Nefecon 16mg/d orally or placebo for 9 months based on optimized RAS inhibitor treatment, and then stopped the drug for observation 15 months. During the 2-year study period, the average change in eGFR from baseline in the Nefecon treatment group was -2.47 mL/min/1.73 m2, while that in the placebo group was -7.52 mL/min/1.73 m2. The average eGFR in the Nefecon treatment group was higher than that in the placebo group 5.05 mL/min/1.73 ㎡, the difference was statistically significant (P <0.0001). The 9-month treatment cycle of Nefecon can delay the decline of eGFR by 50% in 2 years. Undoubtedly, such benefits are of great significance to patients. The slowdown of eGFR decline means that the time for patients to progress to end-stage renal disease is prolonged, and the risk of needing dialysis or kidney transplantation is reduced, thus truly improving the prognosis of patients with IgA nephropathy. At present, regardless of the machine concept of the cause of treatment, improvement of biomarkers, and clinical endpoints (including eGFR and proteinuria), it is fully supported that Nefecon is a drug that can fundamentally and effectively improve the prognosis of patients.

Professor Lv Jicheng: In Phase III clinical study, the eGFR benefit of the Nefecon treatment group persisted 15 months after stopping the drug, which may be due to the cause-specific treatment mechanism of the drug. Nefecon acts on the source of the pathogenesis of IgA nephropathy, from the local inhibition of pathogenic IgA1 production in the ileum to the reduction of IgA immune complex deposition in the kidney, and the improvement of renal function indicators. This does require a process. In the Phase III study, the level of circulating Gd-IgA1 decreased significantly by 21.4% at 3 months of Nefecon treatment, and further decreased to 34% at 9 months of treatment; proteinuria began to significantly decrease at about 3 months of treatment, decreased significantly by 27% at 9 months, and a continuous decrease in proteinuria could still be observed after stopping the drug; eGFR did not change significantly during the treatment period, and renal function remained stable. In other words, once the disease progression is fundamentally improved from the source, the delayed effect of renal function protection will be reflected. This also explains the persistent benefit of Nefecon in eGFR and proteinuria after discontinuation. It is hoped that the improvement of renal pathology can be further confirmed by re-examination of renal biopsy in patients in the future.

Q3. What are the potential implications for renal function preservation of Nefecon's durable reduction in proteinuria?

Professor Lu Jicheng: As a surrogate indicator of renal function, proteinuria has played an important role in the research of IgA nephropathy and even the entire field of renal disease, which can greatly shorten the clinical research cycle. There is a good linear relationship between the reduction of proteinuria and the reduction of the risk of future renal failure, which has become an important evaluation index for the approval of new drugs. Based on the results of Part A of the NefIgArd study (with proteinuria as the primary endpoint), Nefecon will receive accelerated approval from the US Food and Drug Administration (FDA) for marketing in 2021, and conditional marketing approval from the European Commission in 2022.

Professor Zhang Hong: We know that IgA nephropathy is an immune-mediated disease. Although RAS inhibitors, as an important means of optimizing supportive treatment, can reduce proteinuria and protect renal function to a certain extent, the proteinuria of many patients continues to progress. For patients with IgA nephropathy at high risk of progression, control of proteinuria is an especially important therapeutic strategy to stabilize renal function. The phase III study included such an IgA nephropathy group. After at least 3 months of optimized treatment with RAS inhibitors, the 24-hour urine protein quantification ≥ 1g or urine protein-to-creatinine ratio (UPCR) ≥ 0.8g/g belonged to the high-risk progression group. The results showed that the decrease in UPCR compared with the baseline at 9 months of Nefecon treatment was significantly better than that of the placebo group (34% vs. 5%), and after 3 months of drug withdrawal, the UPCR was significantly reduced by 48% from the baseline compared with the placebo group, The effect persisted after 15 months of drug withdrawal, and the UPCR in the Nefecon treatment group was significantly reduced by 31% compared with baseline at 2 years, while the placebo group was only reduced by 1%. The results further support that Nefecon can provide long-lasting protection for renal function.

Q4. Is Nefecon also suitable for Chinese patients? Please anticipate the results of the Chinese subgroup of the Phase III study.

Professor Zhang Hong: The NefIgArd study enrolled 60 Chinese patients. China started the phase III study later than the international ones, and the enrollment is relatively lagging. The data of the Chinese subgroup has not yet been released. I think the results of proteinuria and eGFR should be consistent with global results. Generally, compared with foreign populations, Asian populations or Chinese populations have more severe clinical and pathological manifestations of IgA nephropathy and faster progression, so it is speculated that they may benefit better from Nefecon treatment.

Professor Lu Jicheng: The racial difference in the benefits of Nefecon is indeed a problem that should be paid attention to clinically. In addition to the Chinese population, the NefIgArd study also included other Asian populations, and its data can provide a certain reference. Theoretically speaking, regardless of race, the intestinal mucosa is an important source of pathological IgA production, so it is speculated that Nefecon should be suitable for most IgA nephropathy patients, including the Chinese population. I very much look forward to the announcement of the results of the 2-year follow-up of the Chinese subgroup as soon as possible.

Q5 .Please look forward to the future application prospects of Nefecon. What are some good suggestions for the clinical drug regimen of IgA nephropathy?

Professor Zhang Hong: As the world's first targeted cause-specific drug for the treatment of IgA nephropathy, Nefecon is an important milestone. At present, phase III clinical studies have confirmed that it can reduce proteinuria, delay the decline of eGFR, and has a clear protective effect on renal function. It is expected that its clinical application has broad prospects. From the point of view of mechanism and concept, the treatment for all IgA nephropathy patients should be treated as a basic treatment, and for some special types such as crescentic IgA nephropathy, it may also need to be combined with other drug therapy. In the future, there will be more choices of targeted therapy drugs for IgA nephropathy. The clinical drug regimen should optimize the treatment of each target, to maximize the protective effect of renal function while minimizing side effects, taking into account both efficacy and safety.

Professor Lu Jicheng: The treatment options for IgA nephropathy are very limited, especially for patients with persistent proteinuria above 1g/d after adequate supportive treatment including antihypertensive and RAS inhibitor treatment. ~80% will progress to uremia and new intervention methods are urgently needed. Nefecon provides a new and effective means to further delay the progression of IgA nephropathy and also enhances the confidence of doctors and patients in treatment. In the future, as new drugs continue to be launched and there are more and more treatment options, optimizing combination regimens will become a new direction for clinical research.

Professor Zhang Hong:

Chief Physician, Doctoral Supervisor

Graduated from Peking University School of Medicine, Doctor of Medicine, Okayama University, Japan, Visiting Researcher, Department of Genetics, Yale University School of Medicine, USA. Chinese Medical Special Talents, New Century Excellent Talents of the Ministry of Education, Outstanding Youth Winners of the National Natural Science Foundation of China.

Vice Chairman of Beijing Society of Nephrology, Member of International Society of Nephrology (ISN) Continuing Education Advisory Committee (ISN CME Advisory Committee), Member of ISN Clinical Trial Promotion Association (ISN-ACT), Member of ISN Clinical Research Committee (ISN-CRP), Member and Secretary-General of the Expert Committee of the International IgA Nephrology Alliance (IIGANN); Responsible Editorial Board Member of Asia-Pacific Nephrology Nephrology.

Research direction: pathogenesis and diagnosis and treatment strategies of glomerular diseases.

He presided over a number of national and ministerial-level projects and international cooperative research. He is the global leader of the IgA nephropathy international multi-center research TESTING research and the leader of the CREDENCE research in China. Two of the postgraduates supervised won the national excellent doctorate, one was awarded the Beijing excellent doctorate, and three were awarded the excellent doctorate of Peking University. In the past 5 years, he has published more than 200 SCI papers.

Professor Lu Jicheng:

Chief Physician, Doctoral Supervisor

Member of the Research Scientific Committee of the International IgA Nephropathy Alliance (IIgANN)

National Outstanding Youth Fund Winner (2019)

Young and middle-aged scientific and technological innovation leading talents of the Ministry of Science and Technology (2018)

Winner of National Natural Science Foundation of China Outstanding Youth Fund (2013)

New Century Excellent Talents of the Ministry of Education (2012)

Reviewer for Lancet, Circulation, JAMA intern med, Kidney Int, AJKD, and other journals

The main research direction is the pathogenesis and treatment of IgA nephropathy; research on evidence-based medicine of chronic kidney disease

Published more than 100 SCI papers, including Lancet, JAMA, Eur Heart J, JASN, KI, AJKD, and other journals, many of which have influenced the revision of international guidelines in the field of nephritis and hypertension;

Developed a number of transformational achievements including IgA nephropathy class I new drug (first-in-class), non-invasive diagnostic kits, and home renal function testing equipment, with a transformational amount of more than RMB 200 million.

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