BTK Inhibitor Clinical Breakthrough, Everest Medicines Strengthens Its Renal Disease Advantage

In the field of kidney disease, where clinical needs remain insufficiently addressed, leading domestic innovative pharmaceutical companies are accelerating their strategies to establish a competitive edge in the global market.

On December 4, Everest Medicines announced that its next-generation covalent reversible Bruton's tyrosine kinase (BTK) inhibitor, EVER001 capsule (also known as XNW1011), has achieved positive results in the phase 1b/2a clinical trial for the treatment of primary membranous nephropathy (pMN). Notably, there are currently no approved drugs for the pMN indication globally, and EVER001 is expected to break through this clinical treatment dilemma.

In the same renal disease field, Everest Medicines' innovative drug, Nefecon? (budesonide enteric capsules), also recently received good news. It was included in the "National Essential Medical Insurance, Work Injury Insurance, and Maternity Insurance Drug List (2024)" jointly issued by the National Medical Insurance Bureau and the Ministry of Human Resources and Social Security. Several clinically essential, safe, and effective new drugs were added to the list, with implementation starting on January 1, 2025. Notably, Nefecon?, which marks its one-year anniversary since launch, is also included in the list.

As the world's first drug targeting the underlying cause of IgA nephropathy (IgAN), Nefecon?'s approval fills the domestic gap in treating IgA nephropathy from its source and provides an innovative treatment option for clinicians and patients. With its inclusion in the new version of the National Medical Insurance Drug List, Nefecon? will better meet the growing clinical treatment demands, allowing more kidney disease patients to access this innovative medication. This will enable earlier initiation of targeted therapy and further promote the implementation of standardized clinical treatments.

Combining Efficacy and Safety Advantages, Potential Best-in-Class Product

Membranous Nephropathy (MN) is one of the most common non-diabetic nephrotic syndromes in adults, which can be divided into idiopathic primary (about 80% of cases) and secondary forms (about 20% of cases). The prevalence of MN is increasing year by year in China, and it has become the second most common primary glomerulonephritis after IgA nephropathy. Currently, there are approximately 2 million patients with primary membranous nephropathy (pMN) in China, a disease burden much higher than in other countries (about 80,000–100,000 patients in the U.S., about 80,000 in Europe, and about 40,000 in Japan).

However, to date, there are no approved drugs for the pMN indication globally. Existing treatment options (such as cyclophosphamide, calcineurin inhibitors, and CD20 monoclonal antibodies) are all used off-label. Statistics show that more than one-third of pMN patients will eventually progress to end-stage kidney disease. Therefore, there is a global urgent need for drugs that can improve remission rates, reduce high relapse rates, and decrease the risk of chronic renal toxicity.

As a new generation of covalent reversible BTK inhibitors, EVER001 capsules may revolutionize this treatment landscape with advantages such as excellent selectivity, potent target binding ability, and minimal off-target toxicity. BTK (Bruton's tyrosine kinase) is a key component of the B-cell receptor signaling pathway, which regulates B-cell survival, activation, proliferation, and differentiation. Using small molecule inhibitors to target BTK is an effective option for treating B-cell lymphoma and autoimmune diseases.

Phase I studies in healthy volunteers conducted by China Antibody Pharmaceutical Company indicated that EVER001 has high selectivity, excellent pharmacokinetics, strong target binding, and good safety profiles, supporting further clinical development. Under an exclusive licensing agreement with Sinovant and China Antibody Pharmaceutical, Everest Medicines holds the global rights to develop, manufacture, and commercialize EVER001 for the treatment of kidney diseases.

The 1b/2a phase clinical trial disclosed in this update was approved by the China National Medical Products Administration (NMPA) in September 2022. It is aimed at evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of EVER001 in Chinese patients with glomerular diseases characterized by proteinuria.

As of the data cutoff date (September 13), the results showed that, among patients who completed 36 weeks of treatment in the low-dose group, 81.8% (9/11) achieved clinical remission, while 85.7% (6/7) of patients in the high-dose group who completed 24 weeks of treatment also achieved clinical remission. Except for one patient in the low-dose group, all other patients who completed 36 weeks of treatment in the low-dose group and all patients who completed 24 weeks in the high-dose group achieved immunological complete remission at 36 and 24 weeks, respectively.

Specifically, the 24-hour urinary protein geometric mean (least squares method) decreased by 78.3% in the low-dose group at 36 weeks, while the high-dose group showed a 73.8% decrease at 24 weeks. Anti-PLA2R autoantibody levels had decreased by nearly 100% at the data cutoff, with a reduction of over 90% observed as early as 24 weeks in the low-dose group and 12 weeks in the high-dose group.

On top of significant efficacy, EVER001 also demonstrated overall good safety and tolerability. No clinically meaningful adverse events, such as bleeding, arrhythmia, serious infections, leukopenia, thrombocytopenia, or severe liver dysfunction, were observed—events commonly associated with irreversible covalent BTK inhibitors. This is attributed to the highly selective inhibitory effect of EVER001 on kinases, particularly EGFR, ITK, and TEC kinase families, which are usually linked to adverse safety events.

Industry experts believe that, compared with irreversible covalent BTK inhibitors, EVER001 is a potential best-in-class product. While maintaining high activity, it offers high selectivity and avoids the toxic side effects of continuous inhibition. This could provide a solution to the significant unmet clinical needs in the global pMN field. Based on market potential and clinical treatment opportunities, EVER001 is expected to become a blockbuster drug.

Currently, Everest Medicines is developing EVER001 globally for the treatment of kidney diseases. In addition to pMN, EVER001 also shows considerable potential for other autoimmune kidney diseases, including IgA nephropathy, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and lupus nephritis (LN). With global rights to EVER001 for kidney disease treatment, CStone is poised to further strengthen its "moat" in the field of nephrology with this product across five indications.

Better Efficacy in Chinese Patients, Establishing First-Line Cornerstone Position

In the field of kidney disease treatment, Everest Medicines has successfully built a top-tier product pipeline consisting of groundbreaking or best-in-class drugs. While EVER001 may take time to become a significantly impactful drug, its marketed product Nefecon? has already helped Everest Medicines pioneer the market in this field, laying a solid foundation for further success.

China has one of the highest incidence rates of primary glomerular diseases globally, with IgA nephropathy (IgAN) accounting for approximately 35%–50% of cases. More than 100,000 new IgAN patients are diagnosed each year. IgA nephropathy is mediated by disease-specific immune factors, primarily the galactose-deficient IgA1 (Gd-IgA1) produced in the Peyer's patches at the terminal ileum. These Gd-IgA1 molecules can stimulate the body to produce autoimmune antibodies and form IgA immune complexes (IgA-IC) in circulation. These immune complexes eventually deposit in the kidneys, triggering immune inflammation and causing kidney damage.

Previously, the treatment options for IgA nephropathy in China primarily focused on supportive therapy using renin-angiotensin system (RAS) inhibitors. Due to the lack of targeted treatments that address the root cause of disease progression, the majority of patients progress to end-stage renal disease (ESRD) within 15 years of diagnosis, relying on dialysis or kidney transplants to sustain life, placing a heavy burden on patients. However, the advent of the innovative drug Nefecon? has significantly changed this treatment landscape.

Nefecon? contains 4 mg of budesonide per capsule and utilizes the TARGIT? patented technology, which allows the active ingredient to pass through the gastrointestinal tract without being absorbed and only release it when it reaches the distal ileum. This "dual innovative technology" enables the targeted release of budesonide in the mucosal B cells of the terminal ileum (including Peyer's patches), making it possible for the drug to act directly at the source of the disease.

While the drug's active ingredients exert their precise effects, Nefecon?'s three-layer microencapsulated coating ensures continuous and stable release of budesonide, achieving high concentrations throughout the target area. This reduces the production of Gd-IgA1, which triggers IgA nephropathy, and intervenes in the upstream stages of the disease mechanism, thereby providing a targeted treatment for IgA nephropathy. Thanks to this outstanding therapeutic mechanism, Nefecon?'s efficacy has been continually verified in ongoing clinical trials, with especially notable results in the Chinese patient population.

Recently, Kidney 360, one of the top global nephrology journals, published the complete 2-year data of the Chinese subgroup from the Phase III global clinical trial (NefIgArd study) of Nefecon?. During the 2 years of treatment and observation, Nefecon? demonstrated better efficacy than the global trial results in terms of kidney protection, reduction of proteinuria, and improvement of microscopic hematuria. Compared to the placebo, Nefecon? showed better preservation of glomerular filtration rate (eGFR) after 9 months of treatment, with the Chinese patients showing greater treatment benefit. Additionally, Nefecon? was well-tolerated, with no new safety concerns observed.

Furthermore, at the 2024 American Society of Nephrology (ASN) Kidney Week, the latest analysis of the Nefecon? Phase III clinical trial (NefIgArd) was presented. The results showed that Nefecon? can specifically modulate the production of pathogenic IgA (Gd-IgA1) without altering overall systemic IgA responses or total serum immunoglobulin (Ig) levels, further confirming that Nefecon? is a well-tolerated, targeted therapy for IgA nephropathy.

Serum immunoglobulins are a key component of the immune system, and their homeostasis determines the body’s resistance to diseases. The latest analysis also showed that, compared to other B-cell therapies under development for IgA nephropathy, Nefecon? does not suppress the body’s overall immune system. It selectively reduces Gd-IgA1 levels while maintaining overall serum immunoglobulin levels.

Clinical experts have pointed out that this update changes the treatment pathway outlined in the 2021 KDIGO guidelines, which primarily recommended maximizing supportive treatments. Nefecon? now provides a clearer, targeted treatment strategy for IgA nephropathy, offering new hope for improving the disease prognosis and quality of life for patients. With its establishment as a first-line cornerstone therapy for IgA nephropathy, Nefecon? is expected to lead and pioneer a new era of standardized treatment. Nefecon? is also expected to be included in China's first IgA nephropathy treatment guidelines, recommended as a first-line treatment for patients at risk of disease progression.

Dual Validation through Research and Clinical Trials Supports Long-Term Medication Benefits for Patients

In China, the patient population for IgA nephropathy (IgAN) is vast, with a relatively younger age of onset and poor prognosis. Research has found that nearly all IgA nephropathy patients are at risk of progressing to end-stage renal disease (ESRD) within their lifetime. Therefore, the clinical goal is to protect kidney function over the long term, delaying the need for dialysis or kidney transplantation as much as possible. As a chronic, long-term, autoimmune-mediated primary glomerular disease, IgA nephropathy still requires safe and effective long-term causal treatment options.

With its significant efficacy and safety data, Nefecon? (budesonide delayed-release capsules) is poised to become the preferred long-term treatment option for IgA nephropathy patients. In April 2023, Nefecon? was introduced in several hospitals in Hainan under China's "trial first" policy. Follow-up data from patients using the drug indicated that it effectively stabilized kidney function, reduced proteinuria and hematuria, and was well tolerated by patients.

At the ASN Kidney Week 2024, new real-world data for Nefecon? was also presented. This study aimed to assess the safety and efficacy of Nefecon? treatment for ≥9 months in Asian American patients with IgA nephropathy. The study included 30 eligible IgA nephropathy patients, with a mean age of 46 years, 57% of whom were male, and 100% Asian American. On average, patients received Nefecon? treatment for 11.7 months and were followed up for an average of 14.6 months since starting treatment.

For the subgroup of patients who were treated for more than 9 months (n=23, mean duration of Nefecon? treatment was 12.5 months), preliminary results showed that Nefecon? continued to protect kidney function without increasing the incidence of serious adverse events. The results indicated that IgA nephropathy patients with mild kidney dysfunction who were treated with Nefecon? for over 9 months experienced reduced kidney function decline, provided kidney protection, and had good tolerability. This further confirms that early use of causal treatment in IgA nephropathy patients can prevent or delay further deterioration of kidney function.

Additionally, the open-label extension (OLE) study of the NefIgArd trial, presented at ASN 2024, provided new evidence supporting the long-term causal treatment strategy with Nefecon? for IgA nephropathy. The results showed that IgA nephropathy patients who underwent a second course of Nefecon? treatment had similar estimated glomerular filtration rate (eGFR) and proteinuria benefits as those in the first treatment course, with good tolerability.

Clinical experts view the OLE study results as confirmation of the efficacy and safety of continuing Nefecon? treatment in IgA nephropathy patients for a second treatment course. This provides robust evidence supporting long-term causal treatment strategies for IgA nephropathy and offers clinicians new insights on treatment. Experts recommend using Nefecon? in periodic treatment cycles or dose-reduction maintenance therapy. A single 9-month treatment course may not produce sustained clinical responses in terms of proteinuria reduction or eGFR stabilization. Many patients may require multiple 9-month treatment cycles or dose-reduced maintenance regimens.

In July 2024, the China National Medical Products Administration (NMPA) officially accepted a supplemental application for the complete clinical trial data for Nefecon?’s final stage. Nefecon? is expected to become the first and only approved causal treatment for IgA nephropathy in China. With full approval likely in the near future, Nefecon? will accelerate its growth as a cornerstone drug for first-line treatment in the field of IgA nephropathy. As it has already been officially included in the National Medical Insurance Drug List, Nefecon? will provide access to more IgA nephropathy patients and better meet the long-term disease management needs of these patients.