Abigail Brooks is an assistant editor for 

She joined MJH Life Sciences in August 2023 shortly after graduating from Monmouth University where she earned her BA in Communication with a concentration in Public Relations/Journalism and later an MA in Interactive Digital Media. She enjoys traveling, running, and reading books. She can be reached at abrooks@mjhlifesciences.com.

Abigail Brooks, MA

Findings from a phase 2b trial of atacicept in patients with 

 at high risk of disease progression despite being on a renin-angiotensin-aldosterone system inhibitor (RAASi) suggest the dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein may significantly reduce galactose-deficient IgA1 (Gd-IgA1) and stabilize kidney function.

Results from the randomized, double-blind, placebo-controlled trial showed a 35% reduction in proteinuria and stabilization of estimated glomerular filtration rate (eGFR) at week 36 following treatment with atacicept in addition to current standard of care, supporting its advancement to the phase 3 ORIGIN 3 study powered to evaluate the benefit of atacicept 150 mg on UPCR and the rate of change in eGFR over 2 years.

“Atacicept targets 2 key cytokines that are essential for B cell and plasma cell survival and for the secretion of IgA, and those are BAFF and APRIL,” Jonathan Barratt, MD, Mayer Professor of Renal Medicine at the University of Leicester, explained in an interview with 

. He noted that although the class of drugs is not currently available in IgAN, this pathway looks to be “very exciting” in terms of targeting the pathway that drives the production of pathogenic IgA.

Barratt explained findings from ORIGIN trial of atacicept and how it compares to current standard therapies in IgAN and other agents in the pipeline.

Jonathan Barratt, MD: Atacicept Could ‘Transform How We Think About Treating IgA Nephropathy’

An ongoing, randomized, international, multicenter, double-blind, placebo-controlled, phase 2b trial, ORIGIN enrolled participants from 65 centers in 13 countries to receive blinded treatment with atacicept or placebo, self-administered at home once per week for 36 weeks. For inclusion, participants were required to have biopsy-proven IgAN within 10 years before screening, 24-hour urine protein >0.75 g per day, or urine protein-creatinine ratio (UPCR) >0.75 g/g despite at least 12 weeks on a maximally tolerated, stable dose of RAASi, and eGFR ≥30 ml/min per 1.73 m2.

Participants were randomly assigned in a 2:2:1:2 ratio to receive either atacicept 150 (n = 33), 75 (n = 33), or 25 mg (n = 16), or a placebo containing the excipients used in atacicept formulation (n = 34). The primary outcome was the change from baseline in 24-hour UPCR at week 24 in the combined atacicept 150- and 75-mg group compared with placebo. The secondary outcome was the change in UPCR at week 36 in the combined atacicept 150- and 75-mg group as well as in individual atacicept doses versus placebo. Other prespecified endpoints of interest included change in UPCR at week 12, Gd-IgA1 levels, and change in eGFR at weeks 12, 24, and 36.

Results showed mean UPCR decreased 31% from baseline in the combined atacicept 150- and 75-mg group compared with 8% in the placebo group, resulting in a 25% reduction versus placebo at 24 weeks (95% CI, 1.74%–43.01%; 

 = .037). At week 36, mean UPCR decreased by 34% in the combined atacicept 150- and 75-mg group compared with a 2% increase in the placebo group from baseline, resulting in a 35% reduction with atacicept versus placebo (95% CI, 13.03%–51.53%; 

Mean eGFR increased from baseline by 1% in the combined atacicept 150- and 75-mg group at week 36 compared with an 8% reduction from baseline in the placebo group, resulting in an 11% difference (

 = .022), something Barratt noted was a “key” finding, especially through 72 weeks in the open-label extension portion of the trial.

Additionally, compared with a mean 7% decrease from baseline in Gd-IgA1 with placebo at week 36, a 63% decrease was achieved in the combined atacicept 150- and 75-mg group, resulting in a 60% decrease from baseline with atacicept versus placebo (

 <.0001). Atacicept was well tolerated through a median exposure of 36 weeks, with similar proportions of participants with treatment-emergent adverse events between the all-atacicept and placebo groups (73% vs 79%, respectively).

“In terms of the data we have available, it is outstanding. But we have to always remember it is a phase 2 study,” Barratt said. “It's not small in the grand scheme of things, but it is a small group of patients compared to a phase 3. But the data is outstanding.”

Lafayette R, Barbour S, Israni R, et al. A phase 2b, randomized, double-blind, placebo-controlled, clinical trial of atacicept for treatment of IgA nephropathy. 

. Published online March 27, 2024. doi:10.1016/j.kint.2024.03.012

Campbell, P. 72-Week Phase 2B ORIGIN Data Highlight Potential Benefit of Atacicept in IgA Nephropathy. 

https://www.hcplive.com/view/72-week-phase-2b-origin-data-highlight-potential-benefit-of-atacicept-in-iga-nephropathy

Videos

Barratt explained findings from the phase 2b ORIGIN trial of atacicept and how it compares to current standard therapies in IgAN and other agents in the pipeline.

A new tool for predicting patients’ risk of kidney failure and all-cause death may offer a promising alternative to the current benchmark risk prediction model for 

, consistently outperforming the kidney failure risk equation in external testing.

The predictive algorithm and digital dashboard, known as KDpredict, was designed to simultaneously predict kidney failure and death over 1-5 year time horizons and support holistic decision-making for patients with moderate to severe CKD while addressing shortcomings of the kidney failure risk equation.

“We’ve been able to show that KDpredict is consistently more accurate in predicting the risks of kidney failure and death in adults with moderate-to-severe chronic kidney disease than the risk prediction model currently in use,” Pietro Ravani, MD, PhD, professor and clinician scientist in the department of medicine and institute of public health at the University of Calgary, said in a press release.

Acknowledging the shortcomings of the current kidney failure risk equation, investigators sought to build a tool to provide risk predictions for both kidney failure, accounting for the competing risk of death, and all-cause death in adults with newly documented moderate to severe CKD. Of note, the study proposes a strategy for prediction modeling to adapt to local settings rather than a one-size-fits-all model.

The multinational, longitudinal, population-based cohort study included individuals with newly recorded chronic kidney disease stage G3b-G4, defined as estimated glomerular filtration rate (eGFR) 15-44 mL/min/1.73 m2. Population-based health data were linked to form 3 cohorts in Alberta, Denmark, and Scotland, with the Alberta data used to train KDpredict and tested against data from Denmark and Scotland.

The super learner algorithm selected the best-performing regression models or machine learning algorithms based on their ability to predict kidney failure and mortality with minimized cross-validated prediction error based on the Brier score. Prespecified learners, including age, sex, eGFR, albuminuria, presence of diabetes, and cardiovascular disease, were ranked and combined in an ensemble or the learner with the lowest cross-validated prediction error was selected.

The index of prediction accuracy, a measure of calibration and discrimination calculated from the Brier score, was used to compare KDpredict with the kidney failure risk equation. Outcomes included all-cause death and kidney failure, defined as maintenance kidney replacement treatment or eGFR of 10 mL/min/1.73 m2 sustained for more than 90 days, whichever came first.

In total, 67,942 patients from Canada, 17,528 patients from Denmark, and 7740 patients from Scotland were included. Among the cohort, the median age was 77-80 years and the median eGFR was 39 mL/min/1.73 m2.

Median follow-up times were 5-6 years in all cohorts. Kidney failure rates ranged from 0.8-1.1 per 100 person-years and death rates ranged from 10-12 per 100 person-years. Investigators noted KDpredict was more accurate than the kidney failure risk equation in predicting kidney failure risk. Specifically, the 5-year index of prediction accuracy was 27.8% (95% CI, 25.2% to 30.6%) for KDpredict versus 18.1% (95% CI, 15.7% to 20.4%) for the kidney failure risk equation in Denmark and 30.5% (95% CI, 27.8% to 33.5%) for KDpredict versus 14.2% (95% CI, 12.0% to 16.5%) for the kidney failure risk equation in Scotland.

In hypothetical clinical scenarios, investigators pointed out predictions from the kidney failure risk equation and KDpredict differed substantially, potentially leading to diverging treatment decisions. In one example, an 80-year-old man with an eGFR of 30 mL/min/1.73 m2 and an albumin-to-creatinine ratio of 100 mg/g would receive a 5-year kidney failure risk prediction of 10% from the kidney failure risk equation but would receive a 5-year risk prediction of 2% for kidney failure and 57% for mortality from KDpredict.

Investigators also noted individual risk predictions from KDpredict were accurate for both outcomes with 4 or 6 variables. Additionally, models retrained using older data provided accurate predictions when tested in temporally distinct, more recent data.

Investigators highlighted several potential limitations to these findings, some of which include the use of data from 3 countries with predominantly White populations, the use of albuminuria measurements limited to albumin-to-creatinine ratio or protein-to-creatinine ratio in the external testing cohorts, the static nature of the prediction tool, and the need for testing in a randomized trial to validate its usefulness.

“KDpredict is unique in its ability to provide accurate predictions of risk for both clinical outcomes in adults with this severity of CKD at the point of first onset, when a timely discussion should occur,” investigators concluded.

 “By presenting risk predictions of both kidney failure and death, KDpredict supports patient-centered care and holistic decision making.”

Liu P, Sawhney S, Heide-Jørgensen U, et al. Predicting the risks of kidney failure and death in adults with moderate to severe chronic kidney disease: multinational, longitudinal, population based, cohort study. 

University of Calgary. UCalgary researchers can predict kidney failure more accurately. EurekAlert! April 23, 2024. Accessed April 26, 2024. 

https://www.eurekalert.org/news-releases/1042246

Articles

KDpredict uses age, sex, eGFR, and albuminuria to calculate 1-5 year risk of kidney failure and death in chronic kidney disease, outperforming the kidney failure risk equation.

Digital Algorithm Outperforms Current Prediction Model for Kidney Failure, Death Risk in CKD

-glycosylation status plays in the pathophysiology of 

, findings from a recent study suggest the role of galactose-deficient IgA1 (Gd-IgA1) as a biomarker for risk of disease progression may merit further research.

Results of the systematic review and meta-analysis were published in 

 and showed serum Gd-IgA1 levels were not associated with validated prognostic risk factors but were negatively correlated with kidney function based on estimated glomerular filtration rate (eGFR).

A chronic kidney disease that progresses over time and can eventually lead to end-stage renal disease, IgAN is caused by deposits of IgA in the glomeruli and often goes unnoticed in its earlier stages. Its clinical course varies from patient to patient, underscoring the importance of Identifying patients at greatest risk of progressive kidney failure. Accordingly, there is a need for new biomarkers in IgAN to improve prognostication, treatment selection, and monitoring response to treatment.

“The utility of Gd-IgA1 levels to predict prognosis is unclear with a number of conflicting studies,” Pedro Alves Soares Vaz de Castro, a medical student at the Federal University of Minas Gerais, and colleagues wrote.

To examine the value of serum Gd-IgA1 as a biomarker in IgAN, investigators assessed its association with clinical, laboratory, and histopathological features of IgAN through a systematic review and meta-analysis. A literature search was conducted in PubMed, Web of Science, Cochrane, and Scopus using the keywords “IgA Nephropathy”, “Berger’s Disease”, “Immunoglobulin A nephropathy” and similar entry terms. Observational studies, including case-control, cohort, and cross-sectional studies, as well as clinical trials were included.

For inclusion, studies were also required to enroll participants with a kidney biopsy-confirmed diagnosis of primary IgAN in whom Gd-IgA1 levels had been measured. Articles published in English, Spanish, French, and Portuguese were eligible for inclusion. Investigators excluded studies investigating kidney diseases other than IgAN and recurrent IgAN after kidney transplant.

The initial search yielded 1986 studies, of which 47 were selected for full-text reading after screening the title and abstract and 1938 were excluded due to duplication or not including the study question. A total of 29 studies conducted between 2005 and 2022 ultimately met the eligibility criteria and were included in the systematic review.

Of the included studies, 4 (13.7%) were case-control, 14 (48.2%) were cohort, and 11 (37.9%) were cross-sectional. The studies were from 10 different countries, including China (31.0%), Japan (31.0%), and the United States (17.2%). Investigators noted all studies measured Gd-IgA1 levels using an enzyme-linked immunosorbent assay, although the technique varied among studies. Additionally, they pointed out a single study measured Gd-IgA1 levels with liquid chromatography-mass spectrometry.

Upon analysis, there was no significant difference in serum Gd-IgA1 levels between male and female patients with IgAN. Although 3 studies reported a positive correlation between age and Gd-IgA1 levels, the meta-analysis found no such association.

Investigators noted the association between Gd-IgA1 levels and hypertension, hematuria, and proteinuria were inconsistent. However, despite not being associated with several validated prognostic factors, they called attention to a notable negative correlation between serum Gd-IgA1 and eGFR (r = -0.19; 

Investigators were also careful to note several potential limitations to these findings, including the comparison of studies employing different methods of measuring serum levels of Gd-IgA1 and questionable quality of studies, especially in terms of comparability between groups, that may have led to biases that contributed to the variability of the results.

Nonetheless, investigators concluded that “Serum Gd-IgA1 levels were inconsistently associated with the risk of progressive loss of kidney function, however, there are sufficient data to justify continued evaluation of Gd-IgA1 as a prognostic biomarker in IgAN.”

Vaz de Castro PAS, Amaral AA, Almeida MG, et al. Examining the association between serum galactose-deficient IgA1 and primary IgA nephropathy: a systematic review and meta-analysis. 

https://doi.org/10.1007/s40620-023-01874-8

Johns Hopkins Medicine. Immunoglobulin A (IgA) Nephropathy. Conditions and Diseases. Accessed April 26, 2024. 

https://www.hopkinsmedicine.org/health/conditions-and-diseases/immunoglobulin-a-iga-nephropathy

Results showed a negative correlation between serum Gd-IgA1 and kidney function but found no association with several validated IgAN prognostic risk factors.

Study Highlights Serum Gd-IgA1 as Potential Prognostic Biomarker for IgA Nephropathy

Findings from a recent study are highlighting the safety and efficacy of tenofovir disoproxil fumarate for preventing mother-to-child transmission of 

 in female patients with a high viral load during the second or third trimester of pregnancy.

 also call attention to an increased risk of hepatitis flares during the postpartum period after nucleos(t)ide analog discontinuation, with 5 out of 7 participants experiencing a flare within 6 months of stopping tenofovir disoproxil fumarate.

According to the World Health Organization, an estimated 254 million people were living with chronic HBV infection in 2022. In highly endemic areas, it is most commonly spread from mother to child at birth, with infection in infancy and early childhood leading to chronic infection in about 95% of cases. Although transmission can be prevented with antiviral medication, the risk of postpartum hepatitis flares after treatment discontinuation may pose a health risk to infected mothers.

“In particular, in cases where nucleos(t)ide analog administration is discontinued after delivery, hepatitis flares due to termination of HBV suppression are an important concern,” Hayato Kawamura, of the department of gastroenterology and metabolism at Nagoya City University Graduate School of Medical Sciences in Japan, and colleagues wrote.

 “However, the association between antiviral therapy and hepatitis flares in women after the discontinuation of nucleos(t)ide analog for mother-to-child transmission prevention has not been elucidated.”

To examine the efficacy of nucleos(t)ide analog administration for the prevention of mother-to-child transmission of HBV and evaluate the risk of postpartum hepatitis flares after nucleos(t)ide analog discontinuation, investigators recruited pregnant women with HBV DNA ≥5.3 log IU/mL between September 2014 and March 2022 who received 300 mg tenofovir disoproxil fumarate orally once a day at approximately 28 weeks of gestation and discontinued treatment at 4–10 weeks after delivery. In total, investigators assessed the virological and biochemical parameters in 9 mothers after discontinuation, defining a hepatitis flare as an alanine transaminase (ALT) level ≥60 U/L.

HBeAg was positive in 8 cases with high levels of HBV DNA (7.7 to >8.2 log IU/mL), and negative in 1 case with 6.5logIU/mL of HBV DNA. The median time of tenofovir disoproxil fumarate initiation was 28 (interquartile range [IQR], 28–32) weeks of gestation. Tenofovir disoproxil fumarate was discontinued at 4 weeks postpartum in 6 cases, 5 weeks postpartum in 2 cases, and 10 weeks postpartum in 1 case.

Investigators noted a pair of cases were lost to follow-up after tenofovir disoproxil fumarate discontinuation. Of the remaining 7 patients, 5 experienced hepatitis flares within 6 months of tenofovir disoproxil fumarate discontinuation at a median of 11 (IQR, 9-17) weeks postpartum. Among these cases, the median peak ALT level was 165 (IQR, 108-262) U/L. In 3 of the 5 cases with hepatitis flares after treatment discontinuation, nucleos(t)ide analog was reintroduced.

Of note, none of the infants developed any congenital anomaly or acquired HBV infection during infancy. Accordingly, investigators suggested nucleos(t)ide analog administration appeared to be effective against mother-to-child transmission of HBV in pregnant women with high HBV DNA levels. However, they were also careful to outline potential limitations to these findings, including the limited number of cases included in the study and the fact that all included patients were treated with tenofovir disoproxil fumarate.

Nonetheless, they concluded that “the use of nucleos(t)ide analog in HBV-infected mothers with a high viral load during the second or third trimester of pregnancy was highly safe and effective against mother-to-child transmission. However, hepatitis flares were observed frequently in the postpartum period after nucleos(t)ide analog discontinuation.”

Kawamura H, Matsuura K, Ito K, et al. Efficacy of antiviral therapy for the prevention of mother-to-child transmission of hepatitis B virus and the risk of postpartum hepatitis flare after discontinuation of antiviral therapy. 

World Health Organization. Hepatitis B. Newsroom. April 9, 2024. Accessed April 24, 2024. 

https://www.who.int/news-room/fact-sheets/detail/hepatitis-b

Tenofovir disoproxil fumarate was safe and effective for preventing mother-to-child transmission of HBV, but discontinuation was linked to postpartum hepatitis flares. 