Abstract
The therapeutic potential of a novel, targeted-release formulation of oral budesonide (Nefecon) for the treatment of IgA nephropathy (IgAN) was first demonstrated by the phase 2b NEFIGAN trial. To verify these findings, the phase 3 NefigArd trial tested the efficacy and safety of nine months of treatment with Nefecon (16 mg/d) versus placebo in adult patients with primary IgAN at risk of progressing to kidney failure (ClinicalTrials.gov: NCT03643965). NefIgArd was a multicenter, randomized, double-blind, placebo-controlled two-part trial. In Part A, 199 patients with IgAN were treated with Nefecon or placebo for nine months and observed for an additional three months. The primary endpoint for Part A was 24-hour urine protein-to-creatinine ratio (UPCR) after nine months. Secondary efficacy outcomes evaluated included estimated glomerular filtration rate (eGFR) at nine and 12 months and the UPCR at 12 months. At nine months, UPCR was 27% lower in the Nefecon group compared with placebo, along with a benefit in eGFR preservation corresponding to a 3.87 ml/min/1.73 m2 difference versus placebo (both significant). Nefecon was well-tolerated, and treatment-emergent adverse events were mostly mild to moderate in severity and reversible. Part B is ongoing and will be reported on later. Thus, NefIgArd is the first phase 3 IgA nephropathy trial to show clinically important improvements in UPCR and eGFR and confirms the findings from the phase 2b NEFIGAN study.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 391-402 |
| Number of pages | 12 |
| Journal | Kidney international |
| Volume | 103 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2023 |
Bibliographical note
Funding Information:JB is a consultant to Calliditas and Chair of the NefIgArd Study Steering Committee, and reports grants and personal fees from Calliditas, outside the submitted work. RL reports receiving personal fees and grants from Alexion, Aurinia, Calliditas, Omeros, Pfizer, Roche, Travere, and Vera, and being an advisory board member for Akahest and Equillium. JK served as Chief Medical Officer for Calliditas until November 30, 2019. AS reports personal fees from Calliditas and has acted as a consultant for Athenex, Biosight, Carrick, Cogent, Cullinan, Deciphera, Dizal, GSK, Guard, Intellia, IO Biotech, Iteos, Jazz, Jounce, Keros, Mina, PsiOxus, Repare, RhoVac, and Urogen in therapeutic areas other than kidney disease. DC reports grants from Alnylam Pharmaceuticals and personal fees from Alexion, outside the submitted work; he is also data monitoring committee chair/member for ChemoCentryx, Novartis, and Vera Therapeutics, as well as a member for the clinical endpoint committee of Aurinia. JF reports personal fees from Calliditas, Chinook, Idorsia, Novartis, Omeros, Travere, and Visterra during the conduct of the study, as well as from Amgen, AstraZeneca, Astellas, Boehringer Ingelheim, Fresenius, and Vifor, outside the submitted work. VT reports personal fees from Calliditas during the conduct of the study, as well as personal fees from Novartis, Omeros, and Travere, outside the submitted work. HT reports personal fees from Calliditas during the conduct of this study, as well as Chinook, Novartis, and Omeros, outside the submitted work. AP reports grants from Calliditas during the conduct of the study, and personal fees from Alexion, AstraZeneca, and Vifor Pharma, outside the submitted work. BHR reports personal fees from AstraZeneca, Aurinia, Bristol Myers Squibb, Calliditas, ChemoCentryx, EMD Serono, Janssen, Novartis, Morphosys, Omeros, and Retrophin; nonfinancial support from Lupus Foundation of America; and grants from the National Institutes of Health (NIH), outside the submitted work. HZ reports personal fees from Calliditas during the conduct of the study, as well as personal fees from Chinook, Novartis, and Omeros, outside the submitted work. The other author declared no competing interests.
Funding Information:
This trial was sponsored and funded by Calliditas Therapeutics AB. A trial steering committee including participating international investigators and representatives of the sponsor oversaw the conduct of the trial in conformation with the approval protocol. All participants provided written informed consent before enrolment. An independent Data and Safety Monitoring Board is in place to monitor the overall conduct of the study and safety data and reviewed the part A analysis. All authors were involved in the development and approval of the manuscript, assume responsibility for the completeness and accuracy of the data, and vouch for the fidelity of the trial to the study protocol. The first author drafted the first version of the manuscript with assistance from 2 medical writers, Fiona Wilson and Chiara Triulzi, funded by the sponsor. All authors submitted revisions and jointly made the decision to submit the manuscript for publication. The sponsor oversaw all study processes. JK is an employee of the sponsor, who contributed to the study design, provided study oversight, participated in data analysis, data interpretation, and writing of the report. Both placebo and Nefecon treatments were provided by the sponsor. Following database lock and unblinding, the sponsor and all investigators had access to analyses performed on trial data. BHR had final responsibility for the decision to submit for publication. JB, RL, BHR, VT, HT, JF, DC, JK, and AS conceived and designed the trial and protocol. JB, RL, VT, HT, JF, HZ, and NE were the principal investigators. JB, RL, BHR, VT, HT, JF, DC, JK, and AS contributed to the trial design and protocol. JB, RL, BHR, VT, HT, JF, HZ, NE, and AP were study site investigators and contributed to implementation of the study and data collection. JK was responsible for execution of the study. AS was responsible for statistical analyses, performed by MedPace (Cincinnati, Ohio, USA). JB, BHR, JK, and AS prepared the first draft of the manuscript. All authors had access to all of the data from the study, and AS and JK verified the raw data. All authors contributed to data analysis, interpretation of study results, and preparation of the report, critically reviewed and edited the manuscript, and approved the final version for submission.
Funding Information:
This trial was sponsored and funded by Calliditas Therapeutics AB. A trial steering committee including participating international investigators and representatives of the sponsor oversaw the conduct of the trial in conformation with the approval protocol. All participants provided written informed consent before enrolment. An independent Data and Safety Monitoring Board is in place to monitor the overall conduct of the study and safety data and reviewed the part A analysis. All authors were involved in the development and approval of the manuscript, assume responsibility for the completeness and accuracy of the data, and vouch for the fidelity of the trial to the study protocol. The first author drafted the first version of the manuscript with assistance from 2 medical writers, Fiona Wilson and Chiara Triulzi, funded by the sponsor. All authors submitted revisions and jointly made the decision to submit the manuscript for publication. The sponsor oversaw all study processes. JK is an employee of the sponsor, who contributed to the study design, provided study oversight, participated in data analysis, data interpretation, and writing of the report. Both placebo and Nefecon treatments were provided by the sponsor. Following database lock and unblinding, the sponsor and all investigators had access to analyses performed on trial data. BHR had final responsibility for the decision to submit for publication.
Publisher Copyright:
© 2022 International Society of Nephrology
Keywords
- IgA nephropathy
- glomerular disease
- glucocorticoids
- gut-associated lymphoid tissue
