Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein-kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly subcutaneous administrations of garadacimab as prophylaxis for hereditary angioedema. METHODS: VANGUARD was a pivotal, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial that recruited patients (aged ≥12 years) with type I or type II hereditary angioedema across seven countries (Canada, Germany, Hungary, Israel, Japan, the Netherlands, and the USA). Eligible patients were randomly assigned (3:2) to receive garadacimab or placebo for 6 months (182 days) by an interactive response technology (IRT) system. Randomisation was stratified by age (≤17 years vs >17 years) and baseline attack rate (1 to <3 attacks per month vs ≥3 attacks per month) for the adult group. The randomisation list and code were kept by the IRT provider during the study, with no access by site staff and funding representatives. All patients and investigational site staff, and representatives from the funder (or their delegates) with direct interaction with the study sites or patients, were masked to treatment assignment in a double-blind fashion. Randomly assigned patients received a 400-mg loading dose of subcutaneous garadacimab as two 200-mg injections or volume-matched placebo on day 1 of the treatment period, followed by five additional self-administered (or caregiver-administered) monthly doses of 200-mg subcutaneous garadacimab or volume-matched placebo. The primary endpoint was the investigator-assessed time-normalised number of hereditary angioedema attacks (number of hereditary angioedema attacks per month) during the 6-month treatment period (day 1 to day 182). Safety was evaluated in patients who received at least one dose of garadacimab or placebo. The study is registered with the EU Clinical Trials Register, 2020-000570-25 and ClinicalTrials.gov, NCT04656418. FINDINGS: Between Jan 27, 2021, and June 7, 2022, we screened 80 patients, 76 of whom were eligible to enter the run-in period of the study. Of 65 eligible patients with type I or type II hereditary angioedema, 39 were randomly assigned to garadacimab and 26 to placebo. One patient was randomly assigned in error and did not enter the treatment period (no dose of study drug received), resulting in 39 patients assigned to garadacimab and 25 patients assigned to placebo being included. 38 (59%) of 64 participants were female and 26 (41%) were male. 55 (86%) of 64 participants were White, six (9%) were Asian (Japanese), one (2%) was Black or African American, one (2%) was Native Hawaiian or Other Pacific Islander, and one (2%) was listed as other. During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group (0·27, 95% CI 0·05 to 0·49) than in the placebo group (2·01, 1·44 to 2·57; p<0·0001), corresponding to a percentage difference in means of -87% (95% CI -96 to -58; p<0·0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0·00-0·31) for garadacimab and 1·35 (1·00-3·20) for placebo. The most common treatment-emergent adverse events were upper-respiratory tract infections, nasopharyngitis, and headaches. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events. INTERPRETATION: Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favourable safety profile. Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults. FUNDING: CSL Behring.

Efficacy, pharmacokinetics, and safety of subcutaneous C1-esterase inhibitor as prophylaxis in Japanese patients with hereditary angioedema: Results of a Phase 3 study.

BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by recurrent attacks of angioedema. HAE types I and II result from deficient or dysfunctional C1-esterase inhibitor (C1-INH). This Phase 3 study assessed the efficacy, pharmacokinetics (PK), and safety of subcutaneous (SC) C1-INH in Japanese patients with HAE. METHODS: The prospective, open-label, multicenter, single-arm Phase 3 study recruited patients with HAE types I or II to an initial run-in period, followed by a 16-week treatment period where patients received 60 IU/kg C1-INH (SC) twice weekly. The two primary endpoints were the time-normalized number of HAE attacks per month and C1-INH functional activity at Week 16. RESULTS: Nine patients entered the treatment period and completed the study. Treatment with C1-INH (SC) significantly reduced the mean monthly attack rate from 3.7 during the run-in period to 0.3 during treatment (exploratory p value of within-patient comparison = 0.004). After the last dose of C1-INH (SC) at Week 16, the mean trough concentration of C1-INH was 59.8%, and the mean area under the plasma concentration-time curve to the end of the dosing period and to the last sample were 5317.1 and 13,091.5 h•%, respectively. During the study, there were no deaths, serious adverse events, or adverse events leading to study discontinuation. CONCLUSIONS: C1-INH (SC) (60 IU/kg twice weekly) was efficacious and well tolerated as a prophylaxis against HAE attacks in Japanese patients with HAE types I or II, which was supported by the increased and maintained C1-INH functional activity. EudraCT Number 2019-003921-99; JapicCTI-205273.

Biological Function and Immunotherapy Utilizing Phosphatidylserine-based Nanoparticles.

Phosphatidylserine (PS) is a naturally occurring anionic phospholipid that is primarily located in the inner leaflet of eukaryotic cell membranes. The role of PS during apoptosis is one of the most studied biological functions of PS. Externalization of PS during apoptosis mediates an "eat me" signal for phagocytic uptake, leading to clearance of apoptotic cells and thus maintain self-tolerance by immunological ignorance. However, an emerging view is that PS exposure-mediated cellular uptake is not an immunologically silent event, but rather promoting an active tolerance towards self and foreign proteins. This biological property of PS has been exploited by parasites and viruses in order to evade immune surveillance of the host immune system. Further, this novel immune regulatory property of PS that results in tolerance induction can be harnessed for clinical applications, such as to treat autoimmune conditions and to reduce immunogenicity of therapeutic proteins. This review attempts to provide an overview of the biological functions of PS in the immune response and its potential therapeutic applications.

Pharmacokinetic/pharmacodynamic modeling for dose selection for the first-in-human trial of the activated Factor XII inhibitor garadacimab (CSL312).

Factor XII (FXII) is a serine protease involved in multiple cascades, including the kallikrein-kinin system. It may play a role in diseases in which the downstream cascades are dysregulated, such as hereditary angioedema. Garadacimab (CSL312) is a first-in-class, fully human, monoclonal antibody targeting activated FXII (FXIIa). We describe how translational pharmacokinetic (PK) and pharmacodynamic (PD) modeling enabled dose selection for the phase I, first-in-human trial of garadacimab. The PK/PD data used for modeling were derived from preclinical PK/PD and safety studies. Garadacimab plasma concentrations rose with increasing dose, and clear dose-related PD effects were observed (e.g., a mechanism-based prolongation of activated partial thromboplastin time). The PK/PD profile from cynomolgus monkeys was used to generate minimal physiologically-based pharmacokinetic (mPBPK) models with target-mediated drug disposition (TMDD) for data prediction in cynomolgus monkeys. These models were later adapted for prediction of human data to establish dose selection. Based on the final mPBPK model with TMDD and assuming a weight of 70 kg for an adult human, a minimal inhibition (<10%) of FXIIa with a starting dose of 0.1 mg/kg garadacimab and a near maximal inhibition (>95%) at 10 mg/kg garadacimab were predicted. The phase I study is complete, and data on exposure profiles and inhibition of FXIIa-mediated kallikrein activity observed in the trial support and validate these simulations. This emphasizes the utility and relevance of translational modeling and simulation in drug development.

Systemic IgG exposure and safety in patients with primary immunodeficiency: a randomized crossover study comparing a novel investigational wearable infusor versus the Crono pump.

Aim: A novel, Investigational Wearable Infusor (IWI) was evaluated in a randomized, controlled, crossover, open-label study to determine if its delivery of subcutaneous immunoglobulin (IgPro20) achieved a comparable area under the concentration-time curve (AUC) for immunoglobulin G (IgG) versus the Crono S-PID-50 infusion pump (CP). EudraCT: 2016-003798-16. Materials & methods: Patients with primary immunodeficiency (PID) were randomized to receive IgPro20 in Sequence 1 (CP/IWI) or 2 (IWI/CP). The primary end point was AUC for IgG during the final week of each 4-week period. Results: 23 patients were enrolled. Evaluation of area under the concentration-time curve from time 0 (pre-infusion) to 7 days after infusion (AUC0-7 days) (IWI: 1806 h*g/l; CP: 1829 h*g/l) and geometric mean ratio indicated comparable AUCs for IgG for both devices. Conclusion: Similar IgG exposure, indicated by AUC values, can be achieved with IgPro20 using the IWI or CP in PID.

Patients with primary immunodeficiency (PID) are at a higher risk of developing serious infections than healthy individuals. Immunoglobulin G (IgG) replacement therapy reduces this risk, as it raises a patient's antibody levels to help fight off infections. IgG replacement therapy can be performed as an intravenous or subcutaneous (under the skin) infusion. The subcutaneous route is associated with improved quality of life for patients, as therapy can be carried out at home by the patient, allowing for more flexibility, convenience and autonomy. Wearable drug-delivery systems are devices that stick to the body and automatically deliver doses of a drug to the patient. In this study, we investigated whether a novel Investigational Wearable Infusor device could deliver the subcutaneous IgG replacement therapy, IgPro20, in patients with PID. We show that the new infusion device can deliver IgG replacement therapy and allows for similar levels of IgG to be achieved in patients as a comparator device. This wearable drug delivery device simplifies drug administration and could help address some of the challenges associated with self-injection such as complicated infusion preparation, needle phobia and concerns about pain. Trial Registration Number: 2016-003798-16 (EudraCT).

Rational design of a nanoparticle platform for oral prophylactic immunotherapy to prevent immunogenicity of therapeutic proteins.

The safety and efficacy of several life-saving therapeutic proteins are compromised due to their immunogenicity. Once a sustained immune response against a protein-based therapy is established, clinical options that are safe and cost-effective become limited. Prevention of immunogenicity of therapeutic proteins prior to their initial use is critical as it is often difficult to reverse an established immune response. Here, we discuss a rational design and testing of a phosphatidylserine-containing nanoparticle platform for novel oral prophylactic reverse vaccination approach, i.e., pre-treatment of a therapeutic protein in the presence of nanoparticles to prevent immunogenicity of protein therapies.

Subcutaneous administration of Lyso-phosphatidylserine nanoparticles induces immunological tolerance towards Factor VIII in a Hemophilia A mouse model.

A major complication with enzyme replacement therapy of Factor VIII (FVIII) in Hemophilia A (HA) is the development of anti-drug antibodies. Recently, we have shown that FVIII administration in the presence of heterogeneous phosphatidylserine (PS) nanoparticles derived from a natural source induces tolerance to FVIII, suggesting that PS converts an immunogen to a tolerogen. However, the specific structural features responsible for the immune-regulatory properties of PS is unclear. Identifying a specific PS species that is responsible is critical in order to further develop and optimize this nanoparticle. Further, clinical development of this lipid-based strategy requires optimization of the lipid particle that is homogeneous and synthetic. Here, we investigate the ability of mono-acylated Lyso-PS to induce hypo-responsiveness towards FVIII in HA mice. Administration of both PS and Lyso-PS FVIII significantly reduced anti-FVIII antibody responses despite rechallenge with FVIII. Additionally, the Lyso-PS-mediated effect was shown to be antigen-specific as mice responded normally against a rechallenge with an unrelated antigen, ovalbumin. Furthermore, the hypo-responsiveness observed with Lyso-PS may involve interactions with a specific PS receptor, TIM-4, along with increasing regulatory T-cells. These data indicate that using Lyso-PS allows for a more homogenous formulation in order to induce tolerance towards therapeutic proteins.

Phosphatidylserine Is Not Just a Cleanup Crew but Also a Well-Meaning Teacher.

Phosphatidylserine (PS) exposure during apoptosis leads to silent clearance of cells without adverse immune reactions to self-proteins. Given the biological functions of PS in cellular cleanup and global immunosuppression, we hypothesized that administration of PS-protein complexes would reduce immunogenicity. Here, we report that exposing Pompe disease mice to acid alpha glucosidase (rhGAA) with PS or immunosuppressant dexamethasone resulted in lower anti-rhGAA antibodies than in animals receiving rhGAA alone. However, upon rechallenge with rhGAA, only PS-rhGAA pre-exposed mice displayed a durable hyporesponsiveness even after PS administration was ceased. Thus, pre-exposure of antigens administered together with PS were not silently cleared, but the immune system acquired memory about the antigen that averted mounting of a response during rechallenge. In hemophilia A mice, PS hyporesponsiveness toward Factor VIII was reversed by administration of function-blocking antibody against the PS receptor T-cell immunoglobulin and mucin 4, implicating this receptor in PS's effect. Moreover, pre-exposure of myelin oligodendrocyte glycoprotein peptide with PS delayed the onset and reduced the severity of experimental autoimmune encephalomyelitis. These observations suggest that PS's function in apoptosis is not limited to silent antigen clearance without immune responses toward self-proteins but shows that PS reduces immune response during rechallenge to several antigens that also involves initiation of antigen tolerance.