538 FcRn blockade with SYNT001 for the treatment of pemphigus

Werth, V.; Culton, Donna A.; Blumberg, Laurence J.; Humphries, James E.; Blumberg, Richard S.; Hall, Russell P.

doi:10.1016/j.jid.2018.03.546

Cited by 14 publications

(15 citation statements)

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“…Interestingly, two clinical trials are currently being conducted to evaluate the safety and efficacy of FcRn inhibitory treatments in patients with other autoimmune skin blistering diseases (NCT03334058) (190). Hence, this may become a treatment option for EBA patients in the not too distant future (167).…”

Section: Circulation and Pathogenicity Of Autoantibodies Against Col7mentioning

confidence: 99%

Epidermolysis Bullosa Acquisita: The 2019 Update

et al. 2019

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Epidermolysis bullosa acquisita (EBA) is an orphan autoimmune disease. Patients with EBA suffer from chronic inflammation as well as blistering and scarring of the skin and mucous membranes. Current treatment options rely on non-specific immunosuppression, which in many cases, does not lead to a remission of treatment. Hence, novel treatment options are urgently needed for the care of EBA patients. During the past decade, decisive clinical observations, and frequent use of pre-clinical model systems have tremendously increased our understanding of EBA pathogenesis. Herein, we review all of the aspects of EBA, starting with a detailed description of epidemiology, clinical presentation, diagnosis, and current treatment options. Of note, pattern analysis via direct immunofluorescence microscopy of a perilesional skin lesion and novel serological test systems have significantly facilitated diagnosis of the disease. Next, a state-of the art review of the current understanding of EBA pathogenesis, emerging treatments and future perspectives is provided. Based on pre-clinical model systems, cytokines and kinases are among the most promising therapeutic targets, whereas high doses of IgG (IVIG) and the anti-CD20 antibody rituximab are among the most promising “established” EBA therapeutics. We also aim to raise awareness of EBA, as well as initiate basic and clinical research in this field, to further improve the already improved but still unsatisfactory conditions for those diagnosed with this condition.

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Section: Circulation and Pathogenicity Of Autoantibodies Against Col7mentioning

confidence: 99%

Epidermolysis Bullosa Acquisita: The 2019 Update

et al. 2019

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“…Headaches have also been reported in clinical studies of other FcRn inhibitors such as efgartigimod 23,24 and orilanolimab. 25,26 The change in rozanolixizumab administration route from IV 7 to subcutaneous infusion reduced both the frequency and severity of headaches. The safety and tolerability of rozanolixizumab was further demonstrated by the absence of any AEs leading to treatment withdrawal or study discontinuation and the small number of patients (n 5 2) experiencing infusion site reactions.…”

Section: Exploratory End Points: Change In Bleeding Score and Adasmentioning

confidence: 99%

Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia

et al. 2020

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Primary immune thrombocytopenia (ITP) is a predominantly immunoglobulin G (IgG)-autoantibody-mediated disease characterized by isolated thrombocytopenia. Rozanolixizumab, a subcutaneously infused humanized monoclonal anti-neonatal Fc receptor (FcRn) antibody, reduced serum IgG in healthy volunteers. In this phase 2, multicenter, open-label study, patients with persistent/chronic primary ITP received 1 to 5 once-weekly subcutaneous infusions of rozanolixizumab (cumulative doses, 15-21 mg/kg). Primary objectives were safety and tolerability, and secondary objectives were clinical efficacy (change in platelet count) and pharmacodynamic effect (change in IgG). In all, 51 (77.3%) of 66 patients reported 1 or more adverse events (AEs), all mild-to-moderate, most commonly headaches (26 [39.4%] of 66), of which 15 were treatment related. Four patients had serious AEs, but none were treatment related. No AEs resulted in discontinuation of the study drug. No serious infections occurred. Platelet counts of ≥50 × 109/L were achieved at least once at any time after multiple infusions (5 × 4, 3 × 7, or 2 × 10 mg/kg: 35.7%, 35.7%, and 45.5% of patients, respectively) or single infusions (15 or 20 mg/kg: 66.7% and 54.5% patients, respectively). Minimum mean IgG levels and maximum mean platelet counts both occurred by day 8 in the higher (15 and 20 mg/kg) single-dose cohorts and maximum platelet count occurred by day 11 onward in the multiple-dose cohorts. No clinically meaningful changes occurred in IgA, IgM, IgE, or albumin levels. In patients with persistent/chronic primary ITP, rozanolixizumab demonstrated a favorable safety profile and rapid, substantial platelet increases concordant with substantial IgG reductions, especially with single doses. By day 8, in the 15 and 20 mg/kg single-dose cohorts, >50% patients achieved clinically relevant platelet responses (≥50 × 109/L), coinciding with the lowest mean IgG levels. These data support phase 3 development of rozanolixizumab in persistent/chronic primary ITP. This trial was registered at www.clinicaltrials.gov as #NCT02718716.

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“…SYNT001a is an IgG4 humanized monoclonal antibody which specifically inhibits FcRn function. Phase 1b demonstrated tolerability and safety and reported promising data that treatment results in lowering of anti‐desmoglein 3 IgG levels and reduction in disease severity by day 30 . SYNT1001a is now in a phase 2 multi‐centre open label clinical trial (NCT03075904).…”

Section: Evolving Therapeutic Targetsmentioning

confidence: 99%

“…Phase 1b demonstrated tolerability and safety and reported promising data that treatment results in lowering of anti-desmoglein 3 IgG levels and reduction in disease severity by day 30. 136,156 SYNT1001a is now in a phase 2 multi-centre open label clinical trial (NCT03075904). SYNT1001a has been designated as an orphan drug in September 2018.…”

Section: Inhibitory Antibodiesmentioning

confidence: 99%

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

Kridin

Kowalski

Kneiber

et al. 2019

Acad Dermatol Venereol

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Autoimmune blistering diseases comprise a group of heterogenous conditions characterized by the loss of tolerance and subsequent development of autoantibodies targeting epidermal and subepidermal adhesion proteins. Blisters and erosions form on the skin and mucous membranes leading to significant morbidity and mortality. Traditional therapies rely on systemic immunosuppression. Advancements in our understanding of the pathophysiology of pemphigus and pemphigoid have led to the development of molecules which target specific pathways involved in induction and perpetuation of disease. In this review, we outline the novel therapeutic strategies including B‐cell depletion, T‐regulatory cell repletion, cell signalling inhibitors and small molecular inhibitors, inhibitory monoclonal antibodies, as well as complement inhibition. We additionally review their current level of clinical evidence. We lastly review therapeutics targets gleaned from the experimental epidermolysis bullosa acquisita mouse model. These emerging treatments offer an exciting progression from basic science discoveries that have the potential to transform the treatment paradigm in autoimmune blistering diseases.

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538 FcRn blockade with SYNT001 for the treatment of pemphigus

Cited by 14 publications

References 0 publications

Epidermolysis Bullosa Acquisita: The 2019 Update

Epidermolysis Bullosa Acquisita: The 2019 Update

Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

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