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Lancet 2023 Sep 9;402(10405):859-870. doi: 10.1016/S0140-6736(23)01554-4. Epub 2023 Aug 14.
Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial
Richard Lafayette, Jens Kristensen, Andrew Stone, Jürgen Floege, Vladimir Tesař, Hernán Trimarchi, Hong Zhang, Necmi Eren, Alexander Paliege, Heather N Reich, Brad H Rovin, Jonathan Barratt; NefIgArd trial investigators
PMID : 37591292
Introduction
In a world where IgA is wreaking havoc on kidneys, a storyline describing one hero has been painted. Targeted-release budesonide has been described as a beacon of hope safe from steroidal side effects. Nefecon, is an oral, targeted-release capsule formulation of budesonide, designed for medication release in the distal ileum for maximal exposure of the B-cell-containing Peyer’s patches. Budesonide’s action theoretically aligns with four major hits of IgA Nephropathy (IgAN) as it suppresses the production of abnormal galactose deficient IgA1 antibodies from the Gut associated lymphoid tissue (GALT) (Liao et al, Front Immunol 2023). The supposed cherry on top is the minimal systemic absorption of budesonide due to high first pass hepatic metabolism, theoretically reducing the risk of systemic steroid side effects. In 2023, the NephJC team described the results of the initial part of the ‘Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy’ (NefIgArd trial; NephJC summary). Dear readers, join us as we embark on a journey to critically examine whether this is truly a groundbreaking advance in the treatment of IgAN.
Four hit model and site of action of Budesonide in IgA Nephropathy (Adapted from Pattrapornpisut et al, Am J Kidney Dis)
Systemic steroids have been tested in patients with IgAN. Though the STOP-IgAN (Rauen et al, NEJM 2015) did not show a benefit, the subsequent larger TESTING trial (Lv et al, JAMA 2022) showed a significant reduction in the kidney composite outcome (40% decrease in GFR; kidney failure or renal death) in the steroid group. But this came at a cost - increased risk of serious adverse events, mostly infections. The initial phase 2b NEFIGAN trial (Fellström et al, Lancet 2017, N=199) reported that 9 months of treatment with Nefecon (16 mg/day) led to a significant 27% reduction in the primary endpoint, 24-h urine protein–creatinine ratio (UPCR), compared with placebo (p=0·0003). Nefecon treatment was also associated with a benefit in terms of estimated glomerular filtration rate (eGFR), which was maintained at 12 months, and was well tolerated. The NEFIGAN trial paved the way for the phase 3 NefIgArd trial (Lafayette et al, Lancet 2023) which we will discuss this week. The table below details all the major landmark trials of steroid use in IgA Nephropathy patients.
The Study
NefIgArd was a phase 3, multicenter, international, randomized, double-blind, placebo-controlled trial that included 132 hospitals in 20 countries.
Supplementary Figure S1. Summary of NefIgArd Phase 3 study design from Lafayette et al, Lancet 2023
Interventions
During the initial screening period, RAS blockade was optimized. The intervention was a 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. Participants were instructed to take their masked, randomized study treatment (16 mg/day of Nefecon capsules or matching placebo) orally for a period of 9 months, followed by a 2-week taper. These results were discussed in the earlier NephJC summary. In the subsequent observational follow-up period, no study drug was administered, but optimized supportive care was maintained. The allocation to treatment groups remained blinded to investigators, patients, and all personnel directly involved with patients till the study completion.
Study Population
The eligibility criteria were as shown below
Study eligibility criteria (adapted from Lafayette et al, Lancet 2023)
Study plan
Following randomization, patients completed onsite study visits at baseline and at 3, 6, 9, 12, 18, and 24 months, with additional between-visit telephone follow-ups and unscheduled study visits as needed. Key data (eGFR, proteinuria, albuminuria, adverse events, vital signs, bodyweight, clinical laboratory variables, and physical examination findings) were recorded at these visits.
Outcomes
The patients were stratified at baseline by:
Proteinuria (<2 or >2 gm/24 hr)
eGFR (<60 or ≥60 mL/min per 1·73 m2)
Geographic region (Asia-Pacific, Europe, North America, or South America)
The primary efficacy endpoint was the time-weighted average of eGFR over 2 years, with eGFR calculated by a central laboratory at each timepoint (two separate measures were taken at both baseline and 24 months).
Secondary endpoints
Composite endpoint of time from randomization to confirmed 30% reduction in eGFR (confirmed by two values over ≥4 weeks) or confirmed kidney failure (defined as dialysis for ≥1 month, kidney transplantation, sustained, for ≥1 month, eGFR <15 mL/min per 1·73 m2, or kidney- related death)
Ratios of UPCR and urine albumin– creatinine ratio (UACR) compared with baseline, averaged over time points between 12 and 24 months
Ratio of eGFR compared with baseline averaged over time points between 12 and 24 months
Time from first dose of study drug to receiving rescue medication. Rescue medication was defined as systemic immunosuppressive drugs (including glucocorticoids in some situations), dialysis, and renal transplantation that could impact efficacy.
The proportion of patients receiving rescue treatment
Statistical analysis
With 360 patients, the study had 90% power to detect a statistically significant difference in eGFR at 2 years, with use of a one-sided alpha of 2.5%, assuming a difference in mean eGFR of 2.24 mL/min/ 173 m2 in 2 years. For the primary efficacy endpoint (time-weighted average of eGFR over 2 years), each time point was weighted in proportion to the time elapsed since the previous recording. Time from randomisation to confirmed 30% eGFR reduction or kidney failure was analyzed with inverse probability of censoring weights to estimate the effect of Nefecon in the absence of rescue medication over the 2-year trial period. Data were analyzed using a weighted Cox model with covariates of treatment, log-baseline UPCR, log-baseline eGFR, and geographical region.
Funding
The study steering committee led the trial design, with support from the sponsor (Calliditas Therapeutics). The sponsor managed the trial’s protocol, data collection, and analysis, and assisted with data interpretation and manuscript preparations. One of the authors (JK), who was responsible for the trial’s design, execution, checking the data, and writing is an employee of the sponsor.
Results
The NefIgArd trial recruitment ran from Sept 5, 2018 to Jan 20, 2021 with final follow up visit on Feb 6, 2023. 812 patients were screened and 366 patients randomized in study. 2 patients were randomized incorrectly.
The Full Analysis Set (FAS)
Roughly half the patients failed screening and the remaining half (N=364) were randomized (182 to in each treatment arm). Most pateints (359) randomized patients received at least one dose of the assigned study treatment; 5 patients did not start study treatment. 87% patients from the Nefecon arm and 91% from the placebo arm received 9 months of randomized treatment. 88% patients of the Nefecon arm and 91% of the placebo arm completed the long term follow-up.
Figure S2: Patient distribution for full NefIgArd phase 3 trial from Lafayette et al, Lancet 2023
Patient Demographics
The baseline characteristics can be seen in the table below. About a third of the participants were female, and the mean age was in the early forties. About a quarter of the participants were of Asian ethnicity with White participants making up the bulk. The median GFR was 55 with median proteinuria of ~ 1.25 g/g UPCR. Median time from kidney biopsy to enrollment was about 2.5 years. Roughly half the participants each were on an ACEi or an ARB, with 4% being on dual RAS blockade. Ten patients (5%) in the Nefecon arm and 11 patients (6%) in the placebo arm started treatment with SGLT2 inhibitors during the 2 year study.
Table 1: Patient demographics and baseline characteristics (FAS)
Primary Outcome
Over the 2-year period, Nefecon demonstrated benefits compared with placebo in terms of eGFR. The time-weighted average change from baseline was 5.05 mL/min/1.73 m2 in favor of Nefecon. Specifically, during the 9-month treatment period, the eGFR benefit observed with Nefecon was sustained through the 15-month observational follow-up. After 2 years, the change in eGFR from baseline was -6.11 mL/min/1.73 m2 in the Nefecon group compared to -12.00 mL/min/1.73 m2 in the placebo group. These eGFR treatment benefits corresponded to a 2.95 mL/min/1.73 m2 difference in the 2 year total eGFR slope representing 50% less deterioration of kidney function with Nefecon.
Figure 1 (A): Mean absolute change in eGFR from baseline to 24 months (FAS) from Lafayette et al, Lancet 2023
The eGFR benefit with Nefecon vs placebo was consistent regardless of baseline UPCR.
Figure: 1 (B) Mean absolute change in eGFR from baseline to 24 months (FAS) (patients stratified according to baseline UPCR, <1.5 g/g and ≥1.5 g/g from Lafayette et al, Lancet 2023
The subgroup analysis can be seen below. It is overall quite unremarkable demonstrating consistent effect in all the subgroups.
Figure S4. Subgroups summary of time-weighted average of eGFR over 2 years using robust regression analysis (FAS), from Lafayette et al, Lancet 2023
A post hoc sensitivity analysis was done since the flozin benefits in IgAN were reported after this trial was initiated, Nefecon showed beneficial effects on eGFR independent of flozination.
Supplementary Table S2. Sensitivity and supplementary analyses of the time-weighted average of eGFR over 2 years (mL/min/1·73 m2) from Lafayette et al, Lancet 2023 (MMRM=Mixed-Effects Model for Repeated Measures)
Secondary Endpoints
30% eGFR reduction or kidney failure time to event analysis
The time from randomization to confirmed 30% reduction in eGFR or kidney failure was significantly delayed with Nefecon vs placebo arm, hazard ratio (HR) 0.45 (95% CI, 0.26−0.75) and fewer patients in the Nefecon arm reached a composite of 30% reduction in eGFR or kidney failure (12 versus 21 percent). The eGFR benefit of Nefecon in time-to-event analysis was observed to be independent of proteinuria level,
Table 2: Composite endpoint of time from randomization to confirmed 30% eGFR reduction or kidney failure, overall and by UPCR subgroup (FAS)
Proteinuria changes
Over the 2 years observational period, the Nefecon group demonstrated a similar reduction in UPCR compared to the end of the 9 month treatment period despite Nefecon being stopped. Between 12 and 24 months, there was a 40.9% reduction (95% CI 31.9-48.7) in time-averaged UPCR with Nefecon. Overall, Nefecon reduced time-averaged UPCR from baseline by 40.3%, while in the placebo arm there was a 1% increase. The maximal effect of Nefecon occurred at 12 months (49.7% reduction of UPCR). UACR analysis yielded consistent results: Nefecon showed a 46.3% reduction in time-averaged UACR between 12-24 months.
Figure 2: Mean percentage change in UPCR (g/g) from baseline to 24 months (FAS), from Lafayette et al, Lancet 2023
Lastly, rescue medication use (defined as systemic immunosuppressive drugs (including glucocorticoids in some situations), dialysis, and renal transplantation that could impact efficacy, was required in 15 (8%) patients in the Nefecon group and 20 (11%) in the control (HR 0.68, 95% CI 0.34 - 1.33, p = 0.26).
Safety
Targeted-release budesonide 16 mg/day was well tolerated during the treatment period. Rates of treatment-emergent adverse events (TEAE), including infection, were similar between the arms although the rates of adverse events leading to discontinuation of treatment were higher with Nefecon 17 (9%) vs 3 (2%) in the placebo arm. The most common reported TEAEs during treatment with Nefecon were peripheral edema, hypertension, muscle spasms, acne and headache (most of which would be due to systemic steroid effects). TEAE were generally non-serious adverse events of mild severity and were reversible. The serious TEAEs were twice as common with Nefecon as placebo. In the Nefecon arm, two patients had serious hypertension events and one patient had serious peripheral as well as face edema events while the fourth patient had severe peripheral edema events, which one would presume might be related to systemic steroid effects.
Table 3: Key safety variables (FAS), from Lafayette et al, Lancet 2023
The most commonly reported TEAE during the observational follow-up period was SARS-COV-2 infection though it was similar, being 26 (15%) in the Nefecon arm and 30 (17%) in the placebo arm.
Treatment-emergent serious adverse events (TESAE)
18 (10%) patients in the Nefecon arm versus 9 (5%) patients in the placebo arm had TESAEs. The authors considered them unrelated to study treatment, but it is hard to consider weight gain, insomnia, dyspepsia, and hypertension to be unrelated to systemic steroid effects. During the observational follow-up, the incidence of TEAE and TESAE were similar in both arms - which is understandable as participants were not on active therapy anymore.
Table S8: Summary of TEAEs during treatment period, from Lafayette et al, Lancet 2023.
The incidence of infection related adverse events (35% versus 31%) were similar in both arms.
Although HbA1c concentration remains unaffected with Nefecon, new onset diabetes occurred in seven patients during a 2-year period, who were prediabetic at baseline. Four of these patients who were treated with Nefecon had events of diabetes reported during the 9 month treatment period. Three patients, one treated with Nefecon and two placebo treated patients had diabetes events reported during a 15 month follow up.
The authors claim that there were no clinically relevant differences in body weight or blood pressure between two arms, nor increased risk of fractures found in the Nefecon arm. However the numbers of adverse events clearly demonstrate that weight gain and hypertension were more common with Nefecon than with placebo.
Discussion
In the NefIgArd study, the phase 3 primary endpoint at 2 years was met, demonstrating that 9 months treatment with oral, targeted-relased budesonide (Nefecon), along with optimized standard care, provided statistically significant preservation of eGFR compared with placebo. The eGFR benefit at the end of the 9 month treatment period was maintained during the 15 months observational follow-up with sustained proteinuria effects supporting a disease-modifying effect. Study drug was well tolerated during the treatment period; however, hypertension, edema, muscle spasm, weight gain, dyspepsia, and acne were reported more frequently with Nefecon compared to placebo. These side effects can likely be explained by systemic availability of the drug, approximately 10%, even after high first pass metabolism (European Medicines Agency report).
Strengths
The trial itself was pretty well done in terms of the important aspects: it was a double blind randomized trial with placebo controls. There was an initial RASi optimization (though not clearly described). Flozins were not part of the initial optimization, as the data on their benefit in IgAN were not available at the time of trial planning/initiation. Though the initial results were focused on proteinuria (to obtain expedited FDA approval), the 24 month results described here focus on the kidney function changes in the form of GFR slopes.
Limitations
Patients were not stratified according to Oxford MEST-C score at the time of randomization preventing evaluation of association between histologic features and treatment response. The study had a follow-up duration of only 2 years. The long-term clinical outcomes were measured as surrogate measures which were considered likely to translate into positive treatment effects on longer term clinical outcome measures such as kidney failure, but the trial itself was not powered for those outcomes (e.g. 40% loss of GFR, kidney failure, as was the TESTING trial). It's unclear whether patients with proteinuria levels below the lower limit for enrolment would also benefit with study drugs. A noticeable limitation is the study had enrolled only 23% Asian patients, in whom IgA Nephropathy is otherwise more common than other ethnicities. The hypothesis that targeted-release budesonide exerts its beneficial effects on the course of IgAN specifically via local effects on Peyer patches in the distal ileum remains unproven. The higher rates of adverse events suggests that Nefecon having no systemic steroid effects is a myth. The control group was placebo, not oral steroids which would have made the claims of superior safety profile over steroids easier to swallow.
Nefecon or low dose steroids?
The total cost of treatment per cycle with Nefecon is about $14,160 USD, which works out to be about $150,000 for the 9 month treatment period. An economic analysis from the manufacturer claims for it to be cost effective (Ramjee et al, Clin Outcomes Res 2023), but it relies on optimistic extrapolations presuming decreases in dialysis utilization in the long term. In reality, considering such higher cost and lack of evidence supporting superior efficacy and safety over oral glucocorticoids, it will be difficult to foresee Nefecon being widely used worldwide, particularly in Asia where IgAN prevalence is highest as well as where countries belong to low income or lower middle income groups.
What’s next?
The role of Nefecon in the treatment of IgAN is still not fully defined. Since the NefIgArd trial was started, we now have clear evidence of the benefit of low dose steroids (TESTING trial Lv et al JAMA 2022; NephJC summary), sparsentan (PROTECT trial Rovin et al, Lancet 2023; NephJC summary), and flozins (see webfigure 5 in Baigent et al, Lancet 2022). Other immunological and non immunological strategies seem to be quite promising in phase 3 development (e.g. atrasentan, sibeprenlimab, and iptacopan, among others). Since none of the new options have been compared head:head, one has to decide how and in what sequence one should use these drugs. Some experts would suggest (e.g. listen to this discussion on the Freely Filtered podcast from Sean Barbour) that early on when the disease is active one should use immunological therapy which might provide a longer and lasting ‘remission’. Should that be low dose steroids or Nefecon? We suspect cost will be the deciding factor. Should flozins be added along with RASi as background therapy (before adding steroids or Nefecon)? And where does sparsentan fit in here? We have more questions than answers given the nature of trial designs done so far as incremental evidence accumulates.
Conclusion
The FDA has already approved Nefecon in adults with primary IgA nephropathy who are at risk of disease progression, irrespective of proteinuria levels. Without a head:head comparison (which is quite unlikely to happen) it is difficult to comment on the relative safety/efficacy of Nefecon versus low dose steroids, and it is quite likely access will dictate which option is chosen. Considering the current understanding of pathophysiology of IgA nephropathy, a multitargeted therapy approach is anticipated in coming years as many of the ongoing trials with newer agents get completed.