#NephJC Chat
Tuesday Jan, 10th, 2023 at 9 pm Eastern (AEST = Jan 10 th, 11am)
Wednesday Jan 11th, 2023, at 9 pm Indian Standard Time and 3:30 pm GMT (AEST = Jan 12th, 2am)
Kidney Int 2022 Oct 19;S0085-2538(22)00836-5.
doi: 10.1016/j.kint.2022.09.017. Online ahead of print.
Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy
Jonathan Barratt ,Richard Lafayette, Jens Kristensen, Andrew Stone, Daniel Cattran, Jürgen Floege, Vladimir Tesar, Hernán Trimarchi, Hong Zhang , Necmi Eren, Alexander Paliege Brad H Rovin NefIgArd Trial Investigators
PMID: 36270561
Introduction
The mere mention of NefIgArd might bring the reader’s imagination to the elven stronghold in Lord of the Rings (no, that was Nargothrond), or to one of Thor’s nine kingdoms of Norse mythology (no, that was Niflheim), or even to the lawless villains of The Witcher series (no, those were Nilfgaardians). So, dear readers, it may come as a surprise that we are not here to dwell on fictional worlds of fantasy, but rather to discuss the defense of the glomerulus from the ravages of the nefarious IgA nephropathy (IgAN). In fact, we are going to examine a new weapon that has now been forged for the defense of the kidney, Nefecon. [Voice over: But isn’t that just another steroid?] So read on fearless practitioners, and join us for another NephJC adventure if you dare! Perhaps there is even room in the Sci-Fi universe for a story featuring the exploits of Kidney Boy, Super Swap and their merry band of NSMC interns protecting the meek and diligent nephrons from their archenemy Auto-Immunia. [Voice over: But at what cost!?] Back to reality…
Image from NephU: IgAN Pathogenesis
The pathogenesis of IgAN involves deposition of IgA1-containing immune complexes within the glomerular mesangium inducing inflammation and damage. IgA nephropathy is a very heterogeneous entity. Some individuals will have microscopic hematuria and nothing else. Others will have a rip-roaring crescentic IgAN with relentless rapidly progressive glomerulonephritis (RPGN) and kidney failure. In addition, one can find just about everything in between these extremes. Hence, the use of anti-inflammatory drugs does make sense in certain cases with significant proteinuria and declining kidney function. Previous studies by Pozzi et al. and Manno et al. have shown better kidney survival with a 6 month course of corticosteroid in patients with IgAN.
The more recent STOP-IgAN trial showed a reduction in proteinuria with steroids, but no improvement in kidney survival. More importantly, STOP-IgAN showed significantly increased risk of gastrointestinal and respiratory infections in the steroid arm. Next the TESTING trial was designed to evaluate if steroids, along with optimal supportive therapy, could safely prevent chronic kidney disease in patients with IgAN at risk of progression. In TESTING, steroid use reduced the risk of kidney failure by almost 3 times while predisposing to 5 times the increased risk of side-effects including infections. Due to serious adverse events, TESTING was suspended for 14 months, but was then resurrected with new inclusion criteria (eGFR 30 ml/min instead of 20 ml/min as the lower limit for inclusion), lower dose methylprednisolone (0.4 mg/kg/d, maximum 32 mg/d) and PJP prophylaxis. In low-dose TESTING, oral methylprednisolone for 6-9 months significantly reduced the composite outcome of decline in kidney function, kidney failure or death due to kidney disease over a median follow-up of 4.2 years. Serious adverse events were still significantly higher in the methylprednisolone group vs placebo group (37 vs 8 total events that occurred in 10.9% vs 2.8% of patients). There were also 4 deaths (3 with high dose methylprednisolone, and 1 with low dose). So, perhaps steroids are the anti-hero of this story, with a good and a bad side. [Voice over: Come to the dark side. It is the only way you can save your friends.]
Is it then possible to make steroids safer? Can we have the benefits of the steroidal immunosuppression without the accompanying infections and diabetes, weight gain and bone pain? Since IgA is thought to be triggered by the mucosal IgA system, a steroid only having an effect on the gut-derived lymphoid system theoretically achieve this holy grail. In the phase 2 trial (NEFIGAN, Barratt et al, Lancet 2017), this targeted release budesonide system did demonstrate effects on proteinuria and GFR worth pursuing. Leading to the phase 3 trial of Nefecon - whose approval has preceded the publication.
The Study
Methods
Study Design
This was an international, multi-center phase 3 trial (112 sites, 20 countries)
15-35 day screening period
Part A: 9-month treatment period with 16 mg/d oral budesonide, with 3-month follow-up
further 12-month observational period for eGFR
Part B: After 9 months of treatment and after a 2-week tapering period, during which patients will have their blinded treatment reduced from 4 to 2 capsules, patients entered the observational follow-up period (part B), during which no study drug is administered, with only optimized supportive care. The allocation to treatment groups will remain blinded to investigators, patients, and all personnel directly involved with patients and the ongoing conduct of the study until completion of part B. During part B no further blinded treatment (placebo or Nefecon) is given, but the blind is maintained. Part B is still ongoing and will be reported later in 2023.
Interventions
1:1 randomization to Nefecon (targeted release oral budesonide) or placebo within 35 days of enrollment. Blinding was ensured by providing drug and placebo as modified release capsules, carefully matched in appearance, smell, and taste. No cortisol levels were made available because this would have led to unblinding based on expected cortisol reduction with Nefecon treatment.
Study Population
Inclusion Criteria
UPCR > 0.8 g/g (≥90 mg/mmol) or proteinuria > 1 gram/24 hr
eGFR > 35 to < 90 ml/min/1.73 m^2
Maximally tolerated or allowed (country specific) ACEi or ARB for 3 months prior to randomization
Controlled DM type 1 or 2, with A1C < 8%
IgAN on biopsy in last 10 years
Exclusion Criteria
Secondary forms of IgAN
Non-IgAN glomerulonephritis, including HSP
Inadequate blood pressure control > 140/90 mmHg
Kidney transplant
Treatment with systemic glucocorticoids or immunosuppressants in the 12 months prior to enrollment
High risk patients: peptic ulcer disease, moderate osteoporosis, poorly controlled diabetes, chronic infections
Outcomes and Analysis
Primary outcome: reduction in proteinuria, measured by 24 hour collection, at 9 months
Secondary outcomes were
eGFR at 9 months
Urine ACR at 9 months
eGFR at 12 months
Stratified by baseline:
Proteinuria: < 2 gram/24 hr, or > 2 gram/24 hr
eGFR: < 60 ml/min/1.73 m2, or > 60 ml/min/1.73 m2
Geographic region: North America, South America or Asia Pacific
At 9 months, 2-week taper from 4 to 2 capsules then discontinue medication
Based on the phase 2 NEFIGAN trial, 200 participants were needed to have 90% power to demonstrate statistical significance using a 1-sided alpha level of 0.025, assuming a 25% relative reduction in UPCR. Type 1 error was controlled across parts A and B using a predefined testing hierarchy in which the part A primary endpoint was tested at a 1-sided significance level of 0.02. All p values were 1-sided since the trial was designed to establish superiority of Nefecon. UPCR and UACR were log transformed for all analysis and analyzed using a mixed-effect model for repeated measures.
Funding: Calliditas Therapeutics, manufacturer of Nefecon (AKA budesonide/ Tarpeyo/ KINPEYGO) funded the study. Both placebo and Nefecon were provided by the sponsor. The sponsor was on the trial steering committee. The analysis was done by JK (an employee of the sponsor). The first draft of the manuscript was written by the first author with the assistance of two medical writers funded by the sponsor.
Results
Average time from IgAN diagnosis 2.5 years
657 patients screened, 306 randomized and 294 patients received at least 1 dose of study drug
Figure 1 Patient distribution as of Part A cutoff
FAS (full analysis set) = patients who had the opportunity to receive the intended 9 months of treatment, 199 patients
97 Nefecon and 102 placebo patients
¾ of patients received at least 92% of maximum intended dose over 9-month period
Demographics
67.8% male, 85.9% white, 54.2% <45 years old
Median UPCR 1.26 g/g (141 mg/mmol),60% with baseline proteinuria ≧ 2 gram/24 hr, median eGFR 55 ml/min/1.73 m2
65.3% with microhematuria by dipstick at baseline
Higher percentage of patients in Nefecon group had diabetes
Efficacy
At 9-months with optimal RAS blockade:
Proteinuria: 31% reduction in Nefecon group compared with 5% in placebo group
Proteinuria improved in Nefecon patients at 12 months as well (3 months after study drug discontinuation)
Baseline glycosylated hemoglobin had no impact on the primary endpoint
eGFR (at 9-months):
Nefecon decreased -0.17 ml/min/1.73 m2
Placebo decreased -4.04 ml/min/1.73 m2
Difference was maintained at 12-months (p = 0.0111)
Subgroup analysis
The UPCR benefit was seen across all subgroups very clearly. For eGFR, the benefits are more modest, and once the subgroups are sliced, appear even less impressive - though remain overall quite consistent for 9 months.
Figure 3: Subgroup analysis for primary outcome (proteinuria)
Figure S2: Subgroup analysis for eGFR at 9 months
However, for the subgroups slicing at 12 months for eGFR, there seems to be a difference based on the baseline UPCR (1.5g cutoff). From the supplement, the interaction test between the eGFR treatment and baseline UPCR at 9 months within the NefIgArd study did not reach conventional statistical significance at 5% (P = 0.2490). However, in a pre-defined pooled analysis with NEFIGAN, the relationship with baseline UPCR and proteinuria and eGFR treatment effect were highly statistically significant (two-sided P = 0.0046 and P = 0.0012) respectively. A post hoc analysis showed a statistically significant (P = 0.0429) relationship between eGFR treatment effect and baseline UPCR at 12 months within NefIgArd alone. This is represented in figure 4 (benefit in UPCR > 1.5 g) and figure S1 (no benefit in UPCR < 1.5 g).
Figure 4: Benefit in eGFR slope at 12 months based in subgroup with UPCR > 1.5 g
Figure S1: Lack of benefit in eGFR slope at 12 months based in subgroup with UPCR < 1.5 g
Safety
Discontinuation due to TEAE (Treatment Emergent Adverse Events)
9.3% in Nefecon versus 1% in placebo
Hypertension, peripheral edema, muscle spasms, acne
2.5% of TEAEs were severe
4 patients in Nefecon and 1 patient in placebo
Unclear what events were considered “severe”
Infection events similar between groups
39.2% in Nefecon versus 41% in placebo
No severe infections causing hospitalizations and no deaths
Discussion
In STOP-IgAN and Low Dose-TESTING we once again witnessed variable improvement in IgA nephropathy with steroids, both unfortunately marred by serious adverse events, including death. Enter Nefecon, a magical/mythical super steroid that reportedly avoids all the nastiness of methylprednisolone. Targeted release Nefecon is designed to act specifically in the ileocecal region (the Peyer’s patches) of the intestines, with fewer systemic effects. Nefecon is assumed to bind to glucocorticoid receptors in the gastrointestinal mucosa or submucosa and thus suppress the gastrointestinal immune response. It may be beneficial to selectively target the gastrointestinal tract because exposure to antigens in the intestines, and the body’s immune response, may be one of the initial triggers leading to IgAN pathogenesis. As with all glucocorticoids, Nefecon binds glucocorticoid receptors with subsequent upregulation of anti-inflammatory proteins. Of note, glucocorticoid receptors are also present on the podocytes, and a direct interaction with the podocytes by budesonide has not been excluded.
So, is this new medication the Nefe-Con or the Nefe-Hero? Not only did Nefecon decrease proteinuria in all subgroups studied, but it also appeared to preserve eGFR at 12 months in all groups except those with low baseline proteinuria (< 1.5 g/g, figure S1). In addition, there was an unexpected rise in eGFR at 3 months in the Nefecon group (as yet unexplained, but not thought to be due to hemodynamics, figure 4). Also on the plus side, infectious events were similar to placebo over the course of the study, with no serious infections requiring hospitalization and no deaths.
NefIgArd did have several limitations. First, included patients were primarily Caucasian, although there is currently no robust reason to believe that the mechanism of disease varies between races/ethnicity. Other factors, including environmental exposures as triggers for disease initiation may explain the differences in IgAN outcomes globally - and the lack of Asian ethnicity where IgAN is most predominant seems like a glaring limitation. Next, contemporaneous biopsies were not required. This prevented an association being made between histologic features and their response to treatment. It would always be best, especially in such a clinically diverse entity as IgAN, to be comparing apples to apples in determining medication effect. Additionally, although budesonide is being marketed as a “targeted” medication, with fewer systemic effects, the authors report this is “only speculative at this time” as mechanistic studies are currently ongoing. What we did not get in this study was a direct comparison to the standard of care, low dose systemic steroids.
“What we did not get in this study was a direct comparison to the standard of care, low dose systemic steroids. ”
This is significant because while prednisone/methylprednisolone are cheap (pennies per dose), budesonide is several hundred times more expensive. It is similar to voclosporin or finererone: nice, shiny and new, but of limited utility if patients can not afford treatment. Ultimately, without a head-to-head study it remains unclear if there is true superiority to older drugs in the same class. Speaking of shiny and new, EMPAKIDNEY was completed after NefIgArd and had 817 patients with IgAN (check the supplement!) and showed benefits similar to DAPA-CKD, with improvement in proteinuria and slowing eGFR decline. No doubt, most physicians would prefer the side-benefits of SGLT2-inhibitors over the side-effects of steroids. Although we cannot directly compare the patient populations in NefIgArd and the flozin trials, most clinicians would likely opt for both steroid and flozin treatment until there is further data.
Conclusion
Steroids are proving useful in the treatment of IgAN, especially in patients with high risk for CKD progression. Newer “targeted” steroids, like budesonide, may decrease the risk of serious adverse events, while maintaining the benefits of decreasing proteinuria and eGFR preservation. There are still many questions regarding length of treatment, partial responses, repeat treatment for relapses, and use in the post-transplant setting. [Voice over: As a new day dawns in the year 2023…let’s hope for truth, justice and a better tomorrow!]
Brian Rifkin, MD
Hattiesburg Clinic
NSMC Faculty
Reviewed by Jade Teakell and Jamie Willows
Header image from Wellcome Images, Licence: Attribution 4.0 International (CC BY 4.0)
Credit: Mouse kidney. Kevin Mackenzie, University of Aberdeen.
Coming up next we have the TESTING RCT (again), with updated results on methylprednisolone treatment for IgA nephropathy.