Carla Nester, MD, Professor of Pediatrics-Nephrology at the University of Iowa, discusses one-year phase 3 data of Empaveli (pegcetacoplan) for treatment of C3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN).

C3G and IC-MPGN are rare kidney diseases characterized by damage to the glomeruli in the kidney. It is believed to be caused by the accumulation of proteins in the kidney due to abnormal activation of the complement system due to genetic mutations or the absence of regulatory proteins. Common signs and symptoms include hematuria, proteinuria, reduced glomerular filtration rate and increased creatinine levels, fatigue, and edema of the hands, feet, and ankles.

One-year phase 3 data was recently presented at the American Society of Nephrology (ASN) Kidney Week 2025 that reinforces the robust and sustained efficacy of pegcetacoplan for C3G and IC-MPGN. Pegcetacoplan is a targeted C3 therapy designed to regulate the excessive activation of the complement cascade. It was approved by the U.S. Food and Drug Administration (FDA) in July 2025 for the treatment of patients ages 12 years and older with C3G or primary IC-MPGN.

Data from the phase 3 study showed maintained proteinuria reduction of 68% achieved at week 26, regardless of immunosuppressant use or baseline proteinuria levels. Complete proteinuria remission was achieved in one-third of patients and sustained through one year, compared to 3% for placebo at week 26. Additionally, pegcetacoplan continued to stabilize kidney function as manifested by estimated glomerular filtration rate (eGFR) and its safety profile remained well-tolerated and consistent.

Dr. Nester also noted that, two anchored indirect treatment comparisons showed pegcetacoplan was superior to iptacopan in patients with C3G in reducing proteinuria and achieving the composite renal endpoint, which combines proteinuria reduction and stabilization of eGFR. A significantly greater proportion of pegcetacoplan-treated patients achieved urine protein creatinine ratio (UPCR) reduction to less than 1 g/g, at least a 50% reduction in UPCR, and the composite renal endpoint.

Chapters:
Introduction 00:00
C3G and IC-MPGN Overview 00:49
Current Management 2:45
Empaveli Overview 4:02
Phase 3 Data 5:04
Take Home Message 9:02

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Jonathan Barratt, Mayer Professor of Renal Medicine at the University of Leicester, discusses interim results from a study testingf mezagitamab for the treatment of immunoglobulin A (IgA) nephropathy.

IgA nephropathy is a kidney disorder that occurs when IgA protein settles in the kidneys. In the early stages, IgA nephropathy has no symptoms. The first sign of this condition may be blood in the urine. End-stage kidney disease may develop. In most instances, the cause of this condition is unknown; however, certain disorders have been linked with IgA nephropathy, such as cirrhosis of the liver, celiac disease, and HIV infection.

Mezagitamab (TAK-079) is an investigational fully human, anti-CD38 monoclonal antibody. The compound is designed to decrease formation of immune complexes, reduce inflammation and resulting proteinuria, and prevent further kidney injury and promote stabilization of kidney function.

Mezagitamab is currently being evaluated as an add-on to stable background therapy for IgAN in a phase 1b, open-label, single-arm, multicenter clinical trial (NCT05174221). Interim data from this proof-of-concept study was recently presented at the American Society of Nephrology (ASN) Kidney Week 2025.

Through week 96, mezagitamab stabilized kidney function with a 55.2% sustained mean reduction in proteinuria as measured by a urine protein-creatinine ratio (UPCR). A sustained reduction of 50.1% in Gd-IgA1 and complete recovery toward baseline IgG were also observed. Additionally, hematuria was resolved in 60% of patients.

Mezagitamab was generally well tolerated with no new safety concerns identified. No serious adverse events, discontinuations due to adverse events, or infections greater than grade 3 were reported.

Chapters:
Introduction 00:00
IgA Nephropathy Overview 00:44
Current Management 2:10
Mezagitamab Overview 3:24
Clinical Trial Design and Results 4:25
Next Steps 6:41

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Kim Moran, Head of U.S. Rare Diseases at UCB, discusses the approval of Kygevvi (doxecitine and doxribtimine) for patients with thymidine kinase 2 deficiency (TK2d).

TK2d is a rare genetic disease characterized by progressive and severe muscle weakness. It is often fatal, with those experiencing initial symptoms on or before the age of 12 years facing a high risk of premature death (often occurring within 3 years after symptom onset). Other common symptoms include breathing difficulties, weakness in the eye muscles, and trouble chewing and swallowing. TK2d is caused by genetic mutations in the TK2 gene.

Kygevvi is a combination of two pyrimidine nucleosides, doxecitine and doxribtimine, that target and restore mitochondrial DNA in the skeletal muscle. It is the first and only treatment, approved by the U.S. Food and Drug Administration (FDA) in November 2025, for patients with TK2d. The approval is based on safety and efficacy data showing Kygevvi reduced the overall risk of death from the start of treatment by 86%.

As Dr. Moran explains, there are only 110 patients diagnosed with TK2d in the United States. To address this unique population, the clinical development program was designed by taking data from chart reviews and a retrospective study and creating a natural history. This natural history data was used as the control group and compared with a single-arm, open-label cohort.

Dr. Moran notes how this approval not only gives physicians a better treatment option for their patients, but also gives the TK2d community hope for better disease management and better treatment options to come.

Chapters:
Introduction 00:00
TK2d Overview 00:25
Kygevvi Overview 1:17
Clinical Development Program 2:06
Take Home Message 2:55

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Michelle Rheault, MD, Pediatric Nephrologist at the University of Minnesota, discusses data from the DUPLEX study testing sparsentan to treat patients with focal segmental glomerulosclerosis (FSGS).

FSGS is a rare kidney disorder characterized by progressive scarring of the glomeruli. FSGS may cause non-specific signs and symptoms, including proteinuria, elevated levels of creatinine, and swelling. The condition often leads to kidney failure. In many cases the cause of FSGS can not be determined. Some cases may be associated with congenital kidney defects, urine backing up into the kidneys, obesity, obstructive sleep apnea, sickle cell anemia, or viruses.

At the American Society of Nephrology 2025 Kidney Week, new data was announced from the DUPLEX (NCT03493685) clinical trial. This study is a phase 3, randomized, multicenter, double-blind, parallel, active-control trial comparing sparsentan to an angiotensin receptor blocker (irbesartan) in patients with FSGS. Sparsentan is a dual endothelin and angiotensin II receptor antagonist that reduces kidney inflammation and proteinuria.

A previous study determined that urine protein-to-creatinine ratio (UPCR) below 0.7 g/g was a clinically meaningful proteinuria target in FSGS. The new data showed that 37.5% of sparsentan-treated patients achieved proteinuria below 0.7 g/g compared with 21.4% of those treated with irbesartan. Regardless of treatment type, patients who achieved UPCR below 0.7 g/g were less likely to reach kidney failure.

In a U.K. based cohort of the study [(U.K. National Registry of Rare Kidney Disease (RaDaR)] achieving UPCR below 0.7 g/g at 24-months was associated with lower risk of kidney failure over an additional 60-months of follow up. Similar results were observed for those who achieved UPCR below 0.7 g/g at any time over 24-months.

Long term use of sparsentan also showed promise. After five years of treatment, the DUPLEX Study demonstrated that treatment with sparsentan resulted in a clinically meaningful and durable reduction in proteinuria, with FSGS patients achieving a 50% reduction from baseline UPCR, compared to a 32% reduction with the maximum labeled dose of irbesartan. This translates to a 26% relative reduction in UPCR for sparsentan-treated patients compared to the maximum labeled dose of irbesartan at 24 months.

Within the RaDaR cohort, robust reductions in the risk of kidney failure were observed for patients achieving complete remission (UPCR below 0.3 g/g) and proteinuria below 0.7 g/g at 24 months. All reductions in UPCR correlated to a reduction in risk of kidney failure events at 5 years. When applied to the DUPLEX Study, the 26% relative reduction in UPCR for patients treated with sparsentan compared to irbesartan, correlates to a significant and clinically meaningful reduction in 5-year risk of kidney failure of 24%.

Chapters:
Introduction 00:00
FSGS Overview 00:33
Current Management 1:27
DUPLEX Clinical Trial 2:26
Take Home Message 4:26

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Ghaith Noaiseh, MD, Associate Professor of Allergy, Clinical Immunology, and Rheumatology at The University of Kansas Medical Center, discusses the development of nipocalimab for the treatment of Sjögren’s disease (SjD).

SjD is an autoimmune disorder in which immune cells attack and destroy the glands that produce tears and saliva. SjD is also associated with rheumatic disorders such as rheumatoid arthritis or systemic lupus erythematosus. The hallmark symptoms of SjD are dry mouth and dry eyes. In addition, SjD may cause skin, nose, and vaginal dryness. It also may affect other organs of the body including the kidneys, blood vessels, lungs, liver, pancreas, and brain.

Nipocalimab is a monoclonal antibody, designed to block FcRn and reduce levels of circulating IgG antibodies. It is currently approved for the treatment of generalized myasthenia gravis in adults and pediatric patients 12 years of age and older who are AChR or MuSK antibody positive. Nipocalimab is continuing to be investigated across three key segments including rare autoantibody diseases, maternal fetal diseases mediated by maternal alloantibodies, and rheumatic diseases.

The phase 2 DAHLIAS clinical trial (NCT04968912) is a multicenter, randomized, placebo-controlled, double-blind, dose-ranging study evaluating the efficacy of nipocalimab in participants with moderate to severe active primary SjD who are anti-Ro60 and/or anti-Ro52 IgG antibody seropositive. Results were recently published in The Lancet.

The study met its primary endpoint with a statistically significant improvement in ClinESSDAI score at week 24 in the nipocalimab mg/kg Q2W group compared to placebo. Reductions in disease activity were supported by changes in key biomarkers such as lower levels of rheumatoid factor, fewer circulating immune complexes, and decreased inflammatory markers.

Patients receiving nipocalimab also reported a decrease in symptoms, with numerical improvements observed in dryness of mouth, eyes, and/or vagina, fatigue, and joint pain. An improvement in objective salivary flow of at least 50% increase from baseline was observed in 32.7% of patients versus 16% in the placebo group at week 24.

Additionally, no new safety signals were observed and immune function was preserved. The overall safety profile is consistent with the known safety profile of nipocalimab in myasthenia gravis.

Chapters:
Introduction 00:00
Sjögren’s Disease Overview 00:53
Current Management 1:56
Nipocalimab in Autoimmune Diseases 4:10
DAHLIAS Clinical Trial 7:57
Take Home Message 11:15
Next Steps 13:41

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Richard Lafayette, MD, Professor of Medicine at Stanford University, discusses the ORIGIN clinical trial evaluating atacicept in adults with IgA nephropathy (IgAN).

IgAN is a kidney disorder that occurs when IgA (immunoglobulin A) protein settles in the kidneys. In the early stages, IgA nephropathy has no symptoms. The first sign of this condition may be blood in the urine. End-stage kidney disease may develop. In most instances, the cause of this condition is unknown; however, certain disorders have been linked with IgA nephropathy, such as cirrhosis of the liver, celiac disease, and HIV infection.

Atacicept is an investigational recombinant fusion protein that contains the soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) receptor that binds to the cytokines B-cell activating factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL). The treatment is designed to promote B-cell survival and autoantibody production associated with IgAN, lupus nephritis, and other autoimmune kidney diseases.

The ORIGIN 3 clinical trial (NCT0471623) is a mult-part study comprising the origin phase 2b study as well as a separate pivotal phase 3 study evaluating the safety and efficacy of atacicept in adults with IgAN (N=431). Data was recently presented at the American Society of Nephrology (ASN) Kidney Week 2025 and published in the New England Journal of Medicine.

Atacicept met the primary endpoint of reduction in proteinuria at week 36 with atacicept-treated patients achieving a 46% reduction from baseline and 42% reduction compared to placebo. Proteinuria efficacy was consistent across prespecified subgroups of age, sex, race, region, baseline proteinuria, baseline estimated glomerular filtration rate, and baseline SGLT2i use. Improvements were also observed in secondary endpoints such as a 68% reduction in Gd-IgA1 and a resolvement of hematuria in 81% of participants with baseline hematuria.

The safety profile of atacicept appears favorable across the ORIGIN clinical program compared to placebo. In the ORIGIN 3 full analysis, fewer serious adverse events were reported with atacicept than placebo, and there were no safety signals indicating immunosuppression.

A submission of a Biologics License Application (BLA) through the Accelerated Approval Program to the U.S. Food and Drug Administration (FDA) is expected in quarter 4 of 2025. Additionally, the ORIGIN 3 trial will continue, with two-year results expected in 2027.

Chapters:
Introduction 00:00
IgA Nephropathy Overview 00:29
Current Management 1:11
Atacicept Overview 3:02
ORIGIN Clinical Trial 4:16
Take Home Message 8:32

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Jonathan Strober, MD, pediatric neurologist and neuromuscular specialist at the University of California at San Francisco, discusses the use of nipocalimab in adolescent patients with generalized myasthenia gravis (gMG).

gMG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. Common symptoms include weakness of the muscles that control the eye and eyelid, facial expressions, chewing, talking, and swallowing. The condition results from a defect in the transmission of nerve impulses to muscles, which is due to the presence of antibodies against acetylcholine. The exact reason this occurs is not known.

Nipocalimab is a fully human IgG monoclonal antibody that binds to the neonatal Fc receptor (FcRn) with high specificity and affinity, blocking its interaction with IgG. The treatment is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of both adult and adolescent patients 12 years and older with gMG.

The objective of the study is to evaluate the safety and efficacy of nipocalimab in adolescents aged 12 to 18 years with gMG who exhibit an insufficient clinical response to standard-of-care therapy. Vibrance-mg (NCT05265273) is a phase 2/3 global, multicenter, open-label study evaluating nipocalimab plus standard of care in adolescents and children with gMG.

In adolescents with gMG, nipocalimab demonstrated a rapid, substantial and sustained reduction in total serum IgG levels over 24 weeks, with effects maintained through week 72 in the long term extension. Clinically meaningful improvements in MG Activities of Daily Living and Quantitative MG scores were achieved over 24 weeks and sustained in most participants through week 72. Treatment was well-tolerated in adolescents with gMG, with a favorable safety profile observed throughout the study.

Chapters:
Introduction 00:00
Myasthenia Gravis Overview 00:25
Data Presented at MGFA 2025 1:57
Next Steps 3:19

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Michael A. Levine, MD, ML, Children’s Hospital of Philadelphia, discusses positive topline results from the CALIBRATE trial of encaleret in patients with autosomal dominant hypocalcemia type 1 (ADH1).

ADH1 is a rare form of hypoparathyroidism caused by variants of the calcium‐sensing receptor gene (CASR). Inherited variants of CASR alter the set point for extracellular calcium, resulting in inadequate parathyroid hormone (PTH) secretion and inappropriate renal calcium excretion leading to hypocalcemia and hypercalciuria. The most common symptoms of ADH1 include muscle spasms in the hands and feet, muscle cramping, prickling or tingling sensations, and twitching of the nerves and muscles in various parts of the body.

Positive topline results from the CALIBRATE clinical trial were recently announced. CALIBRATE is a global phase 3 study evaluating the safety and efficacy of encaleret in patients with ADH1. The trial enrolled 70 adults with ADH1 and randomized 67 participants to encaleret and standard of care. Encaleret is an investigational, orally administered small molecule designed to selectively negatively modulate the calcium sensing receptor, targeting the underlying cause of ADH1.

The study met its primary endpoint, defined as the proportion of participants randomized to receive encaleret achieving both serum calcium and urine calcium levels in the respective target ranges. This was achieved by 76% of encaleret-treated participants compared to 4% for these same participants while on conventional therapy. The pre-specified key secondary analyses comparing encaleret to standard of care included a between group comparison on the proportion of participants achieving both target albumin-corrected serum and urine calcium, and comparisons of intact PTH above the lower limit of the reference range.

Additionally, by day 3 after randomization, 71% of participants assigned to encaleret had an albumin-corrected serum calcium within the reference range. At the end of the titration period at week 20, 98% of participants receiving encaleret had an albumin-corrected serum calcium in the target range, compared with 33% of participants on conventional therapy. Among encaleret responders at week 24, none required conventional therapy during Period 3. Encaleret achieved a mean increase in change from baseline of corrected calcium by 0.82 mg/dL from week 4 to week 24.

Encaleret achieved a mean reduction in change from baseline of 200 mg/day in 24-hour urine calcium from week 4 to week 24. Encaleret was well-tolerated with safety findings generally consistent with known ADH1 biology or related to the mechanism of action of encaleret.

There are plans to submit a New Drug Application (NDA) for encaleret to the U.S. Food and Drug Administration (FDA) in the first half of 2026. Future plans also include the initiation of a registrational trial of encaleret in pediatric patients with ADH1 in quarter 1 of 2026 and a phase 3 study of encaleret in adults with chronic hypoparathyroidism in 2026.

Chapters:
Introduction 00:00
ADH1 Overview 1:14
Current Management 4:21
Encaleret Overview 7:32
CALIBRATE Clinical Trial 9:42
Next Steps 14:03

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Nolan Campbell, PhD, U.S. Medical Director at Johnson & Johnson, discusses the EPIC clinical trial design that will evaluate the efficacy of nipocalimab versus efgartigimod in patients with generalized myasthenia gravis (gMG).

gMG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles due to antibodies attacking the acetylcholine receptors in the neuromuscular junction. Common symptoms include weakness of the muscles that control the eye and eyelid, facial expressions, chewing, talking, and swallowing. Weakness tends to increase during periods of activity and improve after periods of rest. The condition results from a defect in the transmission of nerve impulses to muscles, which is due to the presence of antibodies against acetylcholine. The exact reason this occurs is not known. Some cases have been linked to tumors in the thymus gland. Some cases may go into remission temporarily, and muscle weakness may disappear so that medications can be discontinued.

Nipocalimab is a fully human neonatal FcRn inhibitor that enables the reduction of circulating IgG levels. It was approved earlier this year for the treatment of gMG following positive data from the Vibrance-MG clinical trial.

New data addressing unmet medical needs within the indication of nipocalimab was recently presented at the 2025 American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) meeting and the Myasthenia Gravis Foundation of America (MGFA) Scientific Session.

EPIC Clinical Trial Design

Efgartigimod is another FDA-approved FcRn-targeting treatment for gMG with differing molecular structures, binding affinities, and dosing to nipocalimab. EPIC (NCT07217587) is a phase 3b, multicenter, randomized, open-label, active-controlled interventional study with parallel-group design including treatment switching in adult participants with gMG.

The objective of EPIC aims to evaluate the efficacy of nipocalimab versus efgartigimod in participants initiating FcRn targeted therapy for gMG and to evaluate efficacy and safety of nipocalimab in participants switching from efgartigimod to nipocalimab. The study will consist of a screening phase of up to 32 days, a 12-week randomized open-label head-to-head phase (Arms 1 and 2) or an up to 12-week run-in phase and a 12-week open-label treatment switch phase (Arm 3), and an 8-week safety follow-up phase.

The study’s key primary and secondary endpoints are change from baseline in total immunoglobulin G (IgG) levels and sustained disease control measured by MG Activities of Daily Living and Quantitative MG scores 8-12 weeks post-initiation of treatment, respectively.

Insights and Challenges From Mapping Out the Patient Journey of gMG

Another study discussed at AANEM 2025 looked at the patient journey and further characterized the experience of living with gMG using key patient and caregiver insights from a pre-session survey and focus group discussions. There was a total of 16 participants, with 12 being patients and 4 caregivers.

Common challenges participants faced in the gMG patient journey included misdiagnosis or delayed diagnosis, insurance barriers, and the trial-and-error nature of finding effective treatments. Most participants described gMG as an emotionally challenging disease, due in part to self-doubt caused by HCPs not believing them, grief for lost abilities, and the emotional toll on caregivers of patients with gMG. Implementing self-care practices, finding support groups, and learning to identify limitations and triggers and express them to others were strategies participants utilized to improve their patient journey and protect their mental health. Leveraging these insights may help to improve gMG management and patient outcomes, as US patients with gMG continue to experience substantial disease instability despite currently available treatment options.

Chapters:
Introduction 00:00
Nipocalimab Overview 1:01
MGFA Poster Presentations 2:00
EPIC Clinical Trial 5:01
MG Patient Journey 7:00
Take Home Message 9:32

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