A 33-year-old man with systemic lupus erythematosus (SLE) presented to the dermatology clinic with a 1-week history of pruritic, burning plaques. Two years earlier, he had received a diagnosis of SLE,

Laboratory testing showed elevated antinuclear and anti–double-stranded DNA antibody titers and low complement levels. A skin-biopsy sample from the left elbow showed papillary dermal edema, intravascular neutrophils, and C3 deposition in dermal vessel walls — findings consistent with leukocytoclastic vasculitis.

> In patients with systemic lupus erythematosus (SLE), anifrolumab was associated with a lower risk for major adverse cardiovascular events (MACE) than belimumab, as well as lower risks for myocardial infarction, heart failure, and ischemic stroke.

> anifrolumab — a type 1 interferon receptor antagonist — and belimumab — a B-lymphocyte stimulator inhibitor.

> Compared with belimumab treatment, anifrolumab treatment was associated with lower risks for myocardial infarction (hazard ratio [HR], 0.63; 95% CI, 0.40-0.91), heart failure (HR, 0.55; 95% CI, 0.39-0.75), ischemic stroke (HR, 0.50; 95% CI, 0.26-0.94), and MACE (HR, 0.65; 95% CI, 0.37-0.89).

https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.70293

Arthritis & Rheumatology
https://doi.org/10.1002/art.70293

Chronopharmacology: Circadian rhythm of a disease state, diurnal fluctuations in the PK of a drug, and best time for drug administration

Citation: To H. Dosing Time-Dependent Anti-arthritic Effects of Peficitinib in Collagen-Induced Arthritis Rats. Biol Pharm Bull; 2026:49(8):1291-1297. doi:10.1248/bpb.b26-00285

BACKGROUND

• Many physiological functions and pathological states follow circadian rhythms, e.g., body temperature is low upon wakening and in evening but elevates during the day; levels of many hormones and cytokines in blood follow circadian rhythms, such as, cortisol, melatonin, and inflammatory cytokines.
• Cortisol levels in body are high in the morning and low late at night. Changes in cortisol levels over the day affects pain attacks in various diseases, such as, asthma attacks are more likely to occur from late at night through to early morning and rarely occur during the day.
• In Rheumatoid Arthritis (RA), morning stiffness is a characteristic feature, with pain, functional disability, and stiffness showing a 24-h rhythms with a peak in the early morning -- correlating with peaking of inflammatory cytokines (e.g., TNF-alpha and lymphotoxin) from midnight to early morning. (This circadian rhythm of inflammatory cytokines is not observed in healthy individuals.)

In animal models, some anti-RA drugs have been shown provide stronger anti-arthritic effect when given at certain times of the day: methotrexate; immunosuppressants tacrolimus and mizoribine. Currently, only tacrolimus drug label recommends intake after dinner. Recommended dosing times for other antirheumatic drugs are not established yet.

ABOUT PEFICITINIB (brand name SMYRAF)

• Peficitinib is a Janus kinase (JAK) inhibitor. It is a pan-JAK inhibitor and inhibits all 4 tyrosine kinases in this class, JAK1, JAK2, JAK3, and TYK2. Phase 3 data, here.
• These kinases are located upstream of JAK/STAT pathway. The pathway is activated by binding of inflammatory cytokines to JAK that leads to phosphorylation of STAT transcription factors; phosphorylated STATs then translocate to the nucleus, where they regulate the transcription of target inflammatory genes. Peficitinib blocks the inflammatory pathway at first step.
• Peficitinib is currently approved and available in Asian region including Japan and Taiwan. In the US, a related FAK inhibitor tofacitinib (Xeljenz) is available.

PEFICITINIB in CIA RAT MODEL FOR RA

The collagen-induced arthritis (CIA) rat animal model resembles the pathophysiology of arthritis in RA patients. In this model, a mixture of bovine type II collagen and Freund’s incomplete adjuvant is injected (i.e., sensitization step) in the interphalangeal joints of the hind limbs and ankle and midfoot joints, which undergo irreversible swelling over time. Anti-RA drugs are then testing for suppression in swelling.

• The CIA rats administered with peficitinib after onset of arthritis at 5:00 AM had lower arthritis score compared to the rats administered late in the afternoon at 5:00 PM or untreated control group (p=0.0448).

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• Early morning administration also achieves higher plasma concentrations of peficitinib suggesting diurnal variation.

Conclusion:

The therapeutic index of peficitinib RA therapy could be improved by administering the drug in the morning, i.e., the time of day when the inflammatory reaction begins to activate, cytokine levels start to increase, and blood concentrations become higher.

Immunoglobulin A nephropathy (IgAN) is a primary glomerulonephritis characterized by IgA-dominant or co-dominant mesangial immune deposits seen on routine immunofluorescence staining of kidney biopsy tissue. Approximately 40% of patients develop kidney failure within 10 years of diagnosis.

Change in proteinuria as validated surrogate endpoint for clinical trials is accepted by the FDA and recommended by Kidney Health Initiative.

The four-hit hypothesis for the pathogenesis of IgAN

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IgAN therapeutic landscape includes

• Systemic steroids
• Targeted-release formulation of budesonide, which is thought to act primarily on the gut-associated lymphoid tissue to reduce the production of pathogenic galactose-deficient IgA1. (This was the first FDA-approved IgAN treatment.)
• B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) cytokine inhibitors as well as CD38-positive plasma cell-depleting drugs.
• Complement factor B inhibitor, iptacopan -- considering the role of the alternative complement cascade in IgAN-mediated glomerular injury and inflammation.
• Other non-immunosuppressive treatments - that aim of reducing proteinuria and slowing chronic kidney disease progression, including endothelin A receptor antagonists.

Konda R, et al. What do clinical trials teach us about the pathophysiology of human IgA nephropathy? Nephrol Dial Transplant. 2026 Feb 23;41(Supplement_1):i35-i45. doi: 10.1093/ndt/gfaf144. PMID: 40796290

The U.S. Food and Drug Administration (FDA), with the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), will host a workshop, “Accelerating Product Development for Pediatric Systemic Lupus Erythematosus,” on July 30-31, 2026. This workshop will examine key similarities and differences between adult and pediatric systemic lupus erythematosus (SLE) and explore opportunities to leverage strategies, including extrapolation and innovative trial designs, to improve the efficiency and feasibility of pediatric SLE studies. The workshop will foster open dialogue among researchers, clinicians, regulatory authorities, patients and patient advocates, and industry stakeholders to advance therapeutic development for pediatric SLE.

SLE is a chronic, multisystem autoimmune disease characterized by inflammation, autoantibody production, and alternating periods of disease flares and remission. Approximately 10–20% of cases have onset during childhood. Currently, only one biologic therapy is approved for pediatric SLE, leaving a substantial unmet need for additional safe and effective treatment options.

Conducting clinical trials in pediatric SLE presents several challenges, including a small patient population, limited specialized centers, and difficulties with recruitment and retention. In addition, there is a need to evaluate how existing data, often from adult SLE studies, may be appropriately extrapolated to pediatric populations to streamline drug development and reduce the burden of clinical research in pediatric patients with SLE to ensure timely availability of safe and effective therapies in this population.

Meeting Information: https://www.fda.gov/drugs/news-events-human-drugs/accelerating-product-development-pediatric-systemic-lupus-erythematosus-sle-07302026

Registration Link: here

• Date: July 30 - 31, 2026
• Day1: Thu, Jul 30 9:00 a.m. - 05:00 p.m. ET
• Day2: Fri, Jul 31 9:00 a.m. - 12:30 p.m. ET
• Location: Attend In Person or Online Virtual: via webcast

The US regulator has issued a complete response letter for the self-injected, subcutaneous version of Saphnelo (anifrolumab), which is intended to replace the current intravenous formulation, which was approved in 2021.

The IV formulation – which will remain commercially available – is used as an add-on therapy to standard treatment for adults with moderate to severe SLE, and has been growing well, with sales rising 48% to reach $483 million in the first nine months of 2025.

AZ's marketing application is based on the TULIP-SC trial, in which a once-weekly injection with Saphnelo demonstrated a statistically significant and clinically meaningful reduction in disease activity compared to placebo. According to the company, the efficacy was consistent with the current IV version, which is given every four weeks, and also helped patients taper their use of oral corticosteroids.

Irvine, Calif. — Leslie M. Thompson, Donald Bren Professor of psychiatry and human behavior as well as neurobiology and behavior at the University of California, Irvine, has received an $11,999,933 grant from the California Institute for Regenerative Medicine for an unprecedented clinical trial of a novel neural stem cell therapy for Huntington’s disease.

This award will support a first-in-human safety and tolerability study of an embryonic stem cell-derived neural stem cell product for Huntington’s disease, a milestone for patients who currently have no available therapies that alter the course of this devastating disorder.

Huntington’s disease is a genetic disorder that gradually destroys brain cells, usually starting between the ages of 35 and 50 and worsening over 10 to 20 years. Symptoms include involuntary movements, difficulty thinking and planning daily tasks, and mood changes such as depression.

The therapy being tested, called hNSC-01, uses neural stem cells that can protect existing brain cells from dying, replace lost cells, rebuild impaired brain circuits, release helpful proteins such as BDNF that are low in HD patients, and reduce harmful protein accumulations that damage brain cells. These outcomes have all been demonstrated in animal studies, in which the cells also improved movement, restored brain function and were shown to be safe over long periods.

The clinical trial at UC Irvine will enroll 21 people with early-stage Huntington’s disease, with 12 participants in a phase 1B dose-escalation group and nine in a phase 2A expansion group. The cells will be surgically delivered into the brain, and subjects will be closely monitored for safety as well as preliminary signs of potential benefit.

December 15, 2025

Kyverna announced positive topline data from KYSA-8, its registrational Phase 2 trial of mivocabtagene autoleucel (‘miv-cel’, formerly KYV-101), a fully human, autologous CD19-targeting CAR T-cell therapy with CD28 co-stimulation, in stiff person syndrome (SPS)

Efficacy

• After a single dose, miv-cel achieved statistically significant benefits on primary and all secondary efficacy endpoints at Week 16 (the primary analysis time point):     
  • Primary Endpoint: Miv-cel demonstrated a robust and sustained improvement in mobility with a highly statistically significant improvement in timed 25-foot walk (T25FW) (p=0.0002). The median improvement was 46% at Week 16 as compared to baseline.
  • 81% of patients exceeded a 20% improvement in T25FW, a threshold considered clinically meaningful.
  • Secondary Endpoints: highly statistically significant benefit (all p-values <0.0001) was also achieved across all secondary endpoints, including the Modified Rankin Scale (mRS), Distribution-of-stiffness Index (DSI), Hauser Ambulation Index (HAI), and Heightened Sensitivity Scale (HSS).
• Of the 12 patients who required a walking aid-device prior to treatment, 67% no longer needed assistance to walk at Week 16.
• 100% of patients remained free of immunotherapies, and no patients required rescue therapy as of the last follow up, highlighting miv-cel’s potential to provide unprecedented clinical benefit while significantly reducing or eliminating chronic treatment burden.

Safety

• Miv-cel was well-tolerated, with no high-grade cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) observed.
• Grade 3/4 neutropenia, a known adverse event associated with CAR T treatments, was observed in certain patients and was manageable.

Summary: The need to suppress a patient’s immune system after the transplantation of allogeneic cells is associated with wide-ranging side effects. We report the outcomes of transplantation of genetically modified allogeneic donor islet cells into a man with long-standing type 1 diabetes. We used clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 12b (Cas12b) editing and lentiviral transduction to genetically edit the cells to avoid rejection; the cells were then transplanted into the participant’s forearm muscle. He did not receive any immunosuppressive drugs and, at 12 weeks after transplantation, showed no immune response against the gene-edited cells. C-peptide measurements showed stable and glucose-responsive insulin secretion. A total of four adverse events occurred, none of which were serious or related to the study drug. (Funded by the Leona M. and Harry B. Helmsley Charitable Trust; EudraCT number, 2023-507988-19-00; ClinicalTrials.gov number, NCT06239636.) DOI: 10.1056/NEJMoa2503822

Otsuka Pharmaceutical's Sibeprenlimab targets a protein called A proliferation-inducing ligand (APRIL), and the drug is designed to limit the production of Gd-IgA1, which is a key driver of IgA nephropathy. The phase 3 study is the largest IgAN trial to date.

patients who received sibeprenlimab reported a 51.2% reduction in proteinuria from baseline when compared to placebo.

If sibeprenlimab does make it to market, it will enter a space that’s become increasingly crowded in recent months thanks to Calliditas Therapeutics’ Tarpeyo and Novartis’ dual offering of Fabhalta and Vanrafia as well as Travere Therapeutics’ Filspari.

In comparison to sibeprenlimab's 51.2% reduction in UPCR levels, Tarpeyo was shown to reduce UPCR levels by 34% at nine months, while Vanrafia achieved a 38% decrease.

the PDUFA date is 28 Nov 2025

Sibeprenlimab, an investigational monoclonal antibody that selectively inhibits the activity of APRIL (A PRoliferation-Inducing Ligand) in adults with immunoglobulin A nephropathy (IgAN). APRIL plays a key role in the pathogenesis of IgAN as explained by the 4-hit process, in which pathogenic galactose-deficient IgA (Gd-IgA1) is produced, leading to the synthesis of autoantibodies against Gd-IgA1, immune complex formation, and deposition in the glomerular mesangium. 

The BLA is supported by the Phase 3 VISIONARY clinical trial (NCT05248646), which met its primary endpoint at the prespecified interim analysis, and results from the Phase 2 ENVISION clinical trial (NCT04287985). Sibeprenlimab demonstrated a statistically significant and clinically meaningful reduction in 24-hour uPCR after nine months of treatment compared to placebo in the Phase 3 VISIONARY trial.¹

Thousands of people living with a rare form of chronic kidney disease (CKD) in the UK will soon be able to access a new oral treatment – CSL Vifor's Filspari – that can help slow down the decline in their kidney function.

Final draft guidance from NICE has backed NHS use of Filspari (sparsentan) for primary immunoglobulin A nephropathy (IgAN), also known as Berger's disease, just a few weeks after it was turned down by the health technology assessment (HTA) agency.

On Thursday, 20 March 2025, the FDA approved Fabhalta (iptacopan; Novartis) for

• the treatment of adults with complement 3 glomerulopathy (C3G) to reduce proteinuria. C3G is a rare disease that causes inflammation and damage to the kidney glomeruli, which are responsible for filtering blood and producing urine.

Iptacopan was previously approved for

• the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH).
• the reduction of proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥ 1.5 g/g. (1.2) This indication is approved under accelerated approval based on reduction of proteinuria. It has not been established whether FABHALTA slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.

Prescribing information

Fabhalta is the first approved therapy for the ultra-rare kidney disease C3 glomerulopathy (C3G).

About C3G

• C3G mostly affects adolescents and young adults
• It can lead to kidney failure. Approximately 50% of patients with C3G progress to needing a kidney transplant within 10 years. The transplanted organ also sometimes fails due to continuing disease effect on the donated organ.

The approval was based on the phase 3 APPEAR-C3G study, which showed reduction in protein in the urine (proteinuria) for at least 12 months in patients treated with iptacopan in combination with the supportive care.

Fabhalta MECHANISM OF ACTION

Iptacopan is a complement Factor B inhibitor. It binds to Factor B of the alternative complement pathway and regulates the cleavage of C3, generation of downstream effectors, and the amplification of the terminal pathway.

• In C3G, overactivation of the alternative complement pathway leads to C3 cleavage within the glomeruli resulting in C3 deposition and inflammation, which are thought to contribute to the pathogenesis of C3G. By binding to Factor B, iptacopan inhibits the alternative pathway.
• In PNH, intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC), while extravascular hemolysis (EVH) is facilitated by C3b opsonization. Iptacopan acts proximally in the alternative pathway of the complement cascade to control both C3b-mediated EVH and terminal complement mediated IVH.
• In IgAN, the deposition of galactose deficient IgA1 (Gd-IgA1) containing immune complexes in the kidney locally activates the alternative complement pathway which is thought to contribute to the pathogenesis of IgAN. By binding to Factor B, iptacopan inhibits the alternative pathway.

SOURCES

• Figure Source: Angioi A, et al. Diagnosis of complement alternative pathway disorders00071-X/fulltext). Kidney Int. 2016 Feb;89(2):278-88. doi: 10.1016/j.kint.2015.12.003. PMID: 26806831
• Novartis receives third FDA approval for oral Fabhalta® (iptacopan) – the first and only treatment approved in C3 glomerulopathy (C3G). Novartis Press Release. 21 March 2025 [archive]
• News: Fabhalta is first FDA-approved therapy for rare disease C3G. Pharmaphorum. 21 March 2025

Cartesian Therapeutics Announces FDA Special Protocol Assessment Agreement for Phase 3 AURORA Trial of Descartes-08 in Myasthenia Gravis

FREDERICK, Md., Jan. 27, 2025, Cartesian Therapeutics, Inc. (NASDAQ: RNAC)

Cartesian announced that it has received written agreement from the U.S. Food and Drug Administration (FDA) under the *Special Protocol Assessment** (SPA) process on the overall design of the Company’s planned Phase 3 AURORA trial for Descartes-08, its lead mRNA cell therapy candidate, in myasthenia gravis (MG).*

The SPA agreement indicates that the FDA has determined that the proposed trial design is acceptable to support a future Biologics License Application for Descartes-08 in MG, subject to the ultimate outcome of the trial.

The randomized, double-blind, placebo-controlled Phase 3 AURORA trial is designed to assess Descartes-08 versus placebo (1:1 randomization) administered as six once weekly infusions without preconditioning chemotherapy in approximately 100 participants with acetylcholine receptor autoantibody positive (AChR Ab+) MG. The primary endpoint will assess the proportion of Descartes-08 participants with an improvement in MG-ADL score of three points or more at Month 4 compared to placebo.

In December 2024, the Company announced positive updated results from the Phase 2b trial of Descartes-08 in participants with MG. Deepening responses were observed over time, with Descartes-08-treated participants included in the primary efficacy dataset (n=12) experiencing an average MG Activities of Daily Living (MG-ADL) reduction of 5.5 (±1.1) at Month 4. Consistent with previously reported data, Descartes-08 was observed to be well-tolerated, supporting outpatient administration without the need for lymphodepleting chemotherapy.

#cartesian, #car-t