Treatment-emergent Anti-drug Antibodies Research Articles

Complex immunogenicity assessment in caplacizumab-treated patients with immune-mediated thrombotic thrombocytopenic purpura who have received plasma exchange

BackgroundISTH guidelines for immune-mediated thrombotic thrombocytopenic purpura (iTTP) treatment recommend concurrent therapeutic plasma exchange (TPE), immunosuppressive therapy (IST), and caplacizumab. TPE can complicate anti-drug antibody (ADA) measurements by transferring pre-existing antibodies (pre-Abs) into patients via donor plasma and/or diluting treatment-emergent (TE) ADAs. ObjectivesTo assess the presence of ADAs in patients with iTTP who received caplacizumab. MethodsImmunogenicity data from patients with iTTP receiving caplacizumab once daily plus TPE/IST in four clinical trials (TITAN, HERCULES, Post-HERCULES, and a trial conducted in Japanese patients) in the clinical development program were analyzed. ADA and modified ADA (mADA) assays differentiated pre-Abs from TE ADAs. A functional neutralizing antibody (NAb) assay and neutralizing epitope characterization assay (NECA) assessed the presence of ADAs with neutralizing potential. The impact of ADAs on efficacy, pharmacokinetics/pharmacodynamics, and safety was evaluated. ResultsAmong 228 patients in four studies, prevalence of pre-Abs ranged from 17.1% (TITAN) to 56.7% (HERCULES), while TE ADA prevalence ranged from 3.1% (HERCULES) to 14.3% (Japanese study). The TE NAb-positive rate ranged from 0% (Japanese study) to 12% (Post-HERCULES) using the functional NAb assay and from 2.7% (Post-Hercules) to 14.3% (Japanese study) using NECA. The presence of these antibodies did not impact treatment efficacy or safety. ConclusionsA complex immunogenicity assay strategy was required to define the pre-Ab/TE ADA status of patients with iTTP treated with caplacizumab in a clinical trial setting. In addition to the wide range of pre-Abs observed, few patients had detectable TE ADAs or NAbs, neither of which impacted on efficacy/safety.

Assessment of mirvetuximab soravtansine immunogenicity in patients with folate receptor alpha-positive ovarian cancer.

Aim: The aim of this research was to evaluate the immunogenicity of mirvetuximab soravtansine (MIRV), an antibody-drug conjugate in patients with folate receptor alpha-positive ovarian cancer across four clinical studies.Materials & methods: An assay was developed and validated for the detection of antidrug antibodies (ADAs) against MIRV. A cell-based method was also developed and validated for the detection of neutralizing anti-MIRV antibodies (NAbs). Both ADAs and NAbs were assessed across four clinical studies in 734 patients.Results: Across studies, MIRV demonstrated low immunogenicity with 7.8% of patients with treatment-emergent ADAs, 7.2% with treatment-unaffected ADAs, and 0.5% with treatment-enhanced ADAs. MIRV trough concentrations were comparable in ADA-negative and ADA-positive individuals. Limited data suggest that MIRV ADAs may be associated with decreased efficacy. Due to the very limited number of NAb-positive individuals, no conclusions could be drawn on the effect of NAb on efficacy.Conclusion: Both the validation tests and the data from the MIRV clinical studies demonstrated that these assays were suitable and reliable for the detection of MIRV ADAs and NAbs. These validated assays will continue to be used to monitor MIRV immunogenicity in future clinical trials.

Novel Relaxin Receptor RXFP1 Agonist AZD3427 in the Treatment of Heart Failure: A Phase 1a/b, First-in-Human, Randomized, Single-Blind, Placebo-Controlled Study.

Heart failure mortality remains high despite recent progress in pharmacological treatment. AZD3427 is a selective long-acting analog of relaxin, a vasodilatory hormone with antifibrotic effects. We assessed the safety, pharmacokinetics, and pharmacodynamics of AZD3427 in healthy volunteers and patients with heart failure on standard-of-care therapy. In this first-in-human, phase 1a/b, randomized, single-blind, placebo-controlled study, healthy volunteers were randomized 6:2 to receive a single dose of AZD3427 or placebo by subcutaneous injection in 5 mixed-ethnicity cohorts (5, 10, 30, 90, or 270 mg) and 1 Japanese-descent cohort (270 mg), or by intravenous injection in 1 cohort (15 mg). After confirming safety and tolerability in healthy volunteers, 3 cohorts of patients with heart failure and left ventricular ejection fraction ≤40% and 3 cohorts with ejection fraction ≥41% were randomized 6:2 to receive 5 weekly doses of AZD3427 (5, 15, or 45 mg) or placebo by subcutaneous injection. In total, 56 healthy volunteers and 48 patients with heart failure were randomized. AZD3427 was well tolerated at all doses. After subcutaneous administration, AZD3427 was absorbed slowly, and exposure was approximately linear across the dose range. In patients with heart failure, AZD3427 terminal half-life was 13 to 14 days and there were numerical increases in stroke volume and estimated glomerular filtration rate. No treatment-emergent antidrug antibodies were detected. AZD3427 had favorable safety and pharmacokinetic profiles. Hemodynamic changes in patients with heart failure were consistent with the anticipated effects of a relaxin analog. These findings support further development of AZD3427 as a novel long-term treatment for patients with heart failure. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04630067.

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Pharmacokinetics, Immunogenicity, Safety, and Tolerability After Subcutaneous Administration of Tozorakimab in Healthy Chinese Participants.

Tozorakimab is a high-affinity human immunoglobulin G1 monoclonal antibody that neutralizes interleukin (IL)-33, an IL-1 family cytokine. This phase 1, single-center, randomized, double-blind, placebo-controlled, single ascending dose study (NCT05070312) evaluated tozorakimab in a healthy Chinese population. Outcomes included the characterization of the pharmacokinetic (PK) profile and immunogenicity of tozorakimab. Safety outcomes included treatment-emergent adverse events (TEAEs) and clinical laboratory, electrocardiogram, and vital sign parameters. Healthy, non-smoking, male, and female Chinese participants aged 18-45 years with a body mass index 19-24kg/m2 were enrolled. In total, 36 participants across 2 cohorts of 18 participants were randomized 2:1 to receive a single subcutaneous dose of tozorakimab (300mg [2mL] or 600mg [4mL]) or matching placebo (2 or 4mL). Tozorakimab showed dose-dependent serum PK concentrations with an approximate monophasic distribution in serum over time and a maximum observed peak concentration of 20.1 and 33.7μg/mL in the 300- and 600-mg cohorts, respectively. No treatment-emergent anti-drug antibodies for tozorakimab were observed in any of the participants. There were no clinically relevant trends in the occurrence of TEAEs across the treatment groups. There were no clinically relevant trends over time in clinical laboratory (hematology, clinical chemistry, and urinalysis), electrocardiogram, or vital sign parameters in any treatment group. Overall, tozorakimab demonstrated dose-dependent systemic exposure in healthy Chinese participants and was well tolerated, with no safety concerns identified in this study.

Immunogenicity of avelumab in patients with metastatic Merkel cell carcinoma or advanced urothelial carcinoma.

Like other monoclonal antibodies, immune checkpoint inhibitors may be immunogenic in some patients, potentially affecting pharmacokinetics (PKs) and clinical outcomes. In post hoc analyses, we characterized antidrug antibody (ADA) development with avelumab monotherapy in patients with metastatic Merkel cell carcinoma (mMCC) from the JAVELIN Merkel 200 trial (first-line [1L; N = 116] and second-line or later [≥2L; N = 88] cohorts) or with advanced urothelial carcinoma (aUC) from the JAVELIN Bladder 100 (1L maintenance [N = 350]) and JAVELIN Solid Tumor (≥2L [N = 249]) trials. Treatment-emergent ADAs developed in a numerically higher proportion of patients with aUC (1L maintenance, 19.1%; ≥2L, 18.1%) versus mMCC (1L, 8.2%; ≥2L, 8.9%); incidences within tumor types were similar by line of therapy. In PK analyses, numerically lower avelumab trough concentration and higher baseline clearance were observed in treatment-emergent ADA+ versus ADA- subgroups; however, differences were not clinically relevant. Numerical differences in overall survival, progression-free survival, or objective response rate by ADA status were observed; however, no clinically meaningful trends were identified. Proportions of patients with treatment-emergent adverse events (TEAEs; any grade or grade 3/4), serious TEAEs, TEAEs leading to treatment discontinuation, or infusion-related reactions were similar, with overlapping 80% confidence intervals between ADA subgroups. Efficacy and safety observations were similar in subgroups defined by early development of ADA+ status during treatment. In conclusion, no meaningful differences in PKs, efficacy, and safety were observed between subgroups of avelumab-treated patients with different ADA status. Overall, these data suggest that ADAs are not relevant for treatment decisions with avelumab.

P1061 TEV-48574, an anti-TL1A antibody in development for use in IBD, is safe and well tolerated following 16 weeks of subcutaneous treatment in adults with severe uncontrolled T2-low/non T2 asthma

Abstract Background TEV-48574 is a human antibody that targets tumor necrosis factor (TNF)-like ligand 1A, also known as TNF superfamily member 15 (TNFSF15). It is in clinical development as a potential treatment for ulcerative colitis (UC) and Crohn’s disease (CD). TL1A signalling is believed to amplify immune-mediated inflammation in asthma and inflammatory bowel disease (IBD); thus, targeting TL1A may mitigate over-activation of immune responses. A proof-of-concept phase 2A study evaluated safety, tolerability and efficacy of TEV-48574 as treatment for adults with severe uncontrolled asthma (Clinicaltrials.gov NCT04545385). Although the study terminated (after meeting pre-specified criteria for futility at a preplanned interim analysis) the drug demonstrated favourable safety, tolerability and immunogenicity data, supporting the potential use of anti-TL1A treatment in patients with UC and CD. Methods TEV-48574 was administered as a loading dose followed by 7 maintenance doses given subcutaneously (sc) every 2 weeks for 16 weeks in adult patients (n = 65) with severe T2-low asthma with no/low inflammation at baseline. The primary efficacy endpoint was reduction in patients who experience loss of asthma control (LoAC). Patients were monitored for LoAC at bi-weekly visits and daily by use of a handheld spirometer/e-diary. Safety was assessed throughout the study. Results Of 65 randomized patients, 64 received at least one dose of study drug and were included in the safety analysis (33 active drug; 31 placebo). There were no severe AEs, treatment related SAEs, deaths, or withdrawals due to adverse events, and no medical device-related issues. There were no clinically meaningful changes in lab parameters, vital signs or ECGs. Furthermore, there was no evidence of immune suppression, opportunistic infections, or malignancies. Mild treatment-related adverse reactions occurred in both treatment groups (erythema and pruritus in two placebo patients; erythema in one TEV-48574 treated patient). Mild injection site reactions occurred more frequently (not statistically different) in the TEV-48574 group. Treatment-emergent anti-drug antibodies were reported in patients taking TEV-48574 (3 patients; 9.09%), with no anaphylactic or severe systemic reactions. Conclusion Overall, TEV-48574 administered every 2 weeks over 16 weeks demonstrated a favourable safety and tolerability profile with no emerging safety signals or evidence of immunosuppression. This is consistent with TL1A being an amplifier of inflammation. Treatment with TEV-48574 may dampen excessive inflammation without inducing a state of immunodeficiency in patients with conditions such as UC or CD, supporting further development in these indications.

Pharmacokinetics (PK) of Tiragolumab in First-in-Human Study in Patients with Mixed Solid Tumors (GO30103).

Tiragolumab is a first-in-class, fully human IgG1/kappa anti-TIGIT monoclonal antibody that blocks the binding of TIGIT to CD155 (the poliovirus receptor). We summarize the pharmacokinetics (PK) data from the phase1a/1b GO30103 study of Q3W (every 3weeks) sequential dosing of tiragolumab (2, 8, 30, 100, 400, 600, or 1200mg) followed by atezolizumab (1200mg), Q4W (every 4weeks) sequential dosing (tiragolumab 840mg followed by atezolizumab 1680mg), and Q4W co-infusion (tiragolumab 840mg plus atezolizumab 1680mg). Serum samples were collected at multiple time points following tiragolumab and atezolizumab intravenous infusion in patients with solid tumors for PK and immunogenicity assessment. The serum PK profile of tiragolumab appeared to be biphasic, with a rapid distribution phase followed by a slower elimination phase when administered alone or in combination with atezolizumab. In phase1a, across doses of tiragolumab ranging from 2 to 1200mg (cycle1), the geometric mean (GM), coefficient of variation (CV%), serum tiragolumab Cmax ranged from 0.682 to 270µg/mL (18.6% to 36.5%) and Cmin ranged from 0.0125 to 75.3µg/mL (0.0% to 24.2%). The GM systemic exposure (area under the plasma drug concentration-time curve, AUC0-21) ranged from 310 to 2670µgday/mL (20.5% to 27.0%); interindividual variability in AUC0-21 ranged from 20.5% to 43.9%. Tiragolumab exposure increased in an approximately dose-proportional manner when administered alone or with atezolizumab at doses ≥100mg. Postbaseline, 4/207 patients (1.9%) were positive for treatment-emergent antidrug antibodies (ADA) against tiragolumab, each at a single time point. Tiragolumab combined with atezolizumab demonstrated desirable PK properties, with no drug-drug interactions or immunogenicity liability. There were no meaningful differences in tiragolumab or atezolizumab exposure between the Q4W co-infusion and sequential dosing cohorts. ClinicalTrials.gov: NCT02794571 (date of registration June 6, 2016).

Systemic exposure to aflibercept after intravitreal injection in premature neonates with retinopathy of prematurity: results from the FIREFLEYE randomized phase 3 study

BackgroundThere are no data on pharmacokinetics, pharmacodynamics, and immunogenicity of intravitreal aflibercept in preterm infants with retinopathy of prematurity (ROP). FIREFLEYE compared aflibercept 0.4 mg/eye and laser photocoagulation in infants with acute-phase ROP requiring treatment.MethodsInfants (gestational age ≤32 weeks or birthweight ≤1500 g) with treatment-requiring ROP in ≥1 eye were randomized 2:1 to receive aflibercept 0.4 mg or laser photocoagulation at baseline in this 24-week, randomized, open-label, noninferiority, phase 3 study. Endpoints include concentrations of free and adjusted bound aflibercept in plasma, pharmacokinetic/pharmacodynamic exploration of systemic anti-vascular endothelial growth factor effects, and immunogenicity.ResultsOf 113 treated infants, 75 received aflibercept 0.4 mg per eye at baseline (mean chronological age: 10.4 weeks), mostly bilaterally (71 infants), and with 1 injection/eye (120/146 eyes). Concentrations of free aflibercept were highly variable, with maximum concentration at day 1, declining thereafter. Plasma concentrations of adjusted bound (pharmacologically inactive) aflibercept increased from day 1 to week 4, decreasing up to week 24. Six infants experienced treatment-emergent serious adverse events within 30 days of treatment; aflibercept concentrations were within the range observed in other infants. There was no pattern between free and adjusted bound aflibercept concentrations and blood pressure changes up to week 4. A low-titer (1:30), non-neutralizing, treatment-emergent anti-drug antibody response was reported in 1 infant, though was not clinically relevant.Conclusions24-week data suggest intravitreal aflibercept for treatment of acute-phase ROP is not associated with clinically relevant effects on blood pressure, further systemic adverse events, or immunogenicity.ClinicalTrials.gov IdentifierNCT04004208.

Treatment-emergent antidrug antibodies related to PD-1, PD-L1, or CTLA-4 inhibitors across tumor types: a systematic review

BackgroundIncreased understanding of how the immune system regulates tumor growth has innovated the use of immunotherapeutics to treat various cancers. The impact of such therapies, including programmed cell death protein...

Safety, Tolerability, and Pharmacokinetics of Nirsevimab for the Prevention of RSV Disease in Immunocompromised Children Aged ≤24 Months: Music, an Open Label, Phase 2 Trial

Background Immunocompromised children are at increased risk for severe respiratory syncytial virus (RSV)-associated lower respiratory tract infections (LRTIs), which can lead to poor outcomes, including death. Nirsevimab, an extended half-life monoclonal antibody that targets the RSV prefusion F protein, is approved in Canada, the EU, Great Britain, and the US for the prevention of RSV lower respiratory tract disease in neonates and infants during their first RSV season. In Canada and the US, approval extends to the second season for children remaining at higher risk for severe RSV disease. Here, we present the full analysis of the MUSIC trial (NCT04484935), a 12-month, Phase 2, open-label, uncontrolled, single-dose study of nirsevimab, designed to evaluate the safety, pharmacokinetics (PK), and emergence of antidrug antibodies (ADA) in immunocompromised children ≤24 months of age. Methods Children aged ≤24 months with ≥1 immunocompromising condition received a single intramuscular injection of nirsevimab 50 mg (if weight <5 kg) or 100 mg (if weight ≥5 kg) prior to their first RSV season or 200 mg if entering their second RSV season (Table 1). Safety, ADA, and PK were evaluated to Day 361 (final database lock April 18, 2023). Adverse events of special interest (AESIs) included immediate hypersensitivity (including anaphylaxis), immune complex disease, or thrombocytopenia. Results One hundred children (first RSV season n=46, second RSV season n=54) were enrolled from 8 countries (Table 1). Immunocompromising conditions included primary immunodeficiency (n=33), systemic high-dose corticosteroid therapy, (n=29), immunosuppressive chemotherapy, (n=20), history of organ or bone marrow transplantation (n=16), other immunosuppressive therapy (n=15), and human immunodeficiency virus infection (n=8; children may have had more than one condition). Six children experienced 8 treatment-related adverse events (AEs; pyrexia n=4, abdominal pain n=1, erythema n=1, rash n=2); all were Grade 1 severity , except 1 event of Grade 2 pyrexia, and occurred within 7 days of dosing. No treatment-related serious AEs or new onset chronic diseases were observed. Six AESIs were reported in 5 children; all were Grade 1 hypersensitivity events limited to cutaneous findings (food allergy n=2, contrast media allergy n=1, urticaria n=2, erythema n=1), with 1 considered treatment-related (erythema). Three deaths occurred (LRTI, septic shock, and suspected tumor hemorrhage); all were determined to be unrelated to treatment. Eleven children developed treatment-emergent ADAs (median titer 200.0; Day 31 n=1, Day 151 n=1, and Day 361 n=9); none experienced a treatment-related serious AE, AESI, or skin hypersensitivity reaction. Of the children who were ADA-positive on Day 361, 1 experienced a treatment-related AE (Grade 1 pyrexia within 60 minutes of dosing), and 1 experienced a Grade 1 rash on Day 104, determined to be unrelated to treatment. Children who were ADA-positive on Day 361 were more likely to have nirsevimab levels below the limit of detection versus ADA-negative children, suggesting an influence of ADA on PK between Days 151 and 361. Nirsevimab serum exposures at Day 151 were similar to levels demonstrated to be effective in preventing medically attended RSV LRTI in healthy children enrolled in the Phase 3 MELODY trial (Figure 1). Fourteen children demonstrated a rapid decline in serum concentrations through Day 151 compared with the rest of the children; a review of their medical histories revealed evidence for protein-losing conditions, including graft versus host disease, chronic liver disease, and nephrotic syndrome, in 9 of the 14 children. Although none met protocol-defined case criteria for medically attended RSV LRTI, 3 children had an RSV-positive LRTI (central or local test) requiring medical attendance (in an inpatient or outpatient setting; all after Day 151), of whom 1 was hospitalized. Conclusions In immunocompromised children aged ≤24 months, a single dose of nirsevimab was well tolerated and no safety concerns arose over 361 days. Levels of ADA were low, with minimal effects on PK and no apparent impact on safety outcomes. Nirsevimab serum exposure was consistent with previous studies in healthy children and supportive of efficacy in this population at risk of severe RSV disease. Some children with underlying protein-losing conditions had a rapid decline in nirsevimab serum concentrations.

Efficacy and Safety of Subcutaneous Ravulizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Who Received Prior Intravenous Eculizumab: 2-Year Follow-up

Background : Subcutaneous (SUBQ) ravulizumab, administered weekly via an on-body delivery system, showed pharmacokinetic (PK) non-inferiority to intravenous (IV) ravulizumab over 71 days in adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who were clinically stable on prior IV eculizumab treatment (NCT03748823). This analysis reports results through 2 years of SUBQ ravulizumab treatment during the extension period of a phase 3 randomized trial. The reporting period started at day 15 for patients who continued SUBQ ravulizumab during the extension period (SUBQ/SUBQ) and day 71 for patients who switched from IV ravulizumab to SUBQ ravulizumab (IV/SUBQ). Objectives: To evaluate the PK, pharmacodynamics (PD), efficacy, and safety of SUBQ ravulizumab through 2 years (day 743) of treatment in adult patients with PNH previously treated with IV eculizumab. Methods: Patients (≥ 18 years) who received IV eculizumab (once every 2 weeks) for at least 3 months prior to study entry with clinically stable PNH (lactate dehydrogenase [LDH] levels ≤ 1.5 × upper limit of normal [246 U/L]) were enrolled in the study, which consisted of a screening period (day −1 to day −30), a 10-week randomized treatment period, and an extension period of up to 172 weeks. During the randomized treatment period, patients were assigned (2:1) to receive either SUBQ ravulizumab (weekly) or IV ravulizumab (once every 8 weeks); all patients received SUBQ ravulizumab during the extension period. PK/PD endpoints through 2 years of treatment included serum ravulizumab and free C5 concentrations. Efficacy endpoints included change in LDH from baseline, incidence of breakthrough intravascular hemolysis (BTH), maintenance of transfusion avoidance, and maintenance of stabilized hemoglobin (avoidance of a ≥ 2 g/dL decrease in hemoglobin in the absence of transfusion). Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue subscale questionnaire. Safety outcomes, including adverse events (AEs), serious AEs (SAEs), and adverse device effects (ADEs), were also assessed up to the 2-year data cut-off. Results: In total, 128 patients received SUBQ ravulizumab (SUBQ/SUBQ: n = 84; IV/SUBQ: n = 44; mean [range] duration of SUBQ treatment: 839.4 [37 - 1108] days). During 2 years of SUBQ treatment, serum ravulizumab concentrations were maintained ≥ 175 μg/mL and serum free C5 concentrations < 0.5 μg/mL, the previously defined thresholds for achieving and sustaining complete terminal complement inhibition ( Figure). Efficacy endpoints remained consistent over time. Mean (standard deviation [SD]) percentage change in LDH from baseline to day 743 was +2.3% (21.6%; n = 108). BTH events were infrequent: 5/128 patients (3.9%). Transfusion avoidance was maintained in 74.2% of patients (n = 95/128) and 69.1% (n = 85/123) achieved stabilized hemoglobin. Mean (SD) change in FACIT-Fatigue subscale score from baseline to day 743 was +1.3 (9.09; n = 68). The most common AEs (excluding ADEs related to device product issues) during SUBQ treatment were COVID-19 (25.0%), headache (18.8%), and pyrexia (18.0%). Treatment-emergent SAEs were experienced by 29.7% of patients. No treatment-emergent anti-drug antibodies were observed. ADEs not related to a medical device issue were reported by 25.0% of patients. The most frequently reported ADEs unrelated to a medical device issue were injection site reaction (4.7%), medical device site erythema (4.7%), and injection site erythema (3.1%). Among 30,221 devices used in the study, full volume per device was delivered by 98.6% of devices. Complaints were reported in 1.6% of devices used: 0.1% had a confirmed technical defect, 0.8% had a use error, and 0.7% had other/unknown defects. Conclusions: The efficacy of ravulizumab was maintained following the switch from IV to SUBQ ravulizumab and no new safety signals were identified through 2 years of treatment in patients with PNH. SUBQ ravulizumab demonstrated a favorable benefit-risk profile and the types and incidences of AEs were comparable with those reported for IV eculizumab and IV ravulizumab in previous studies, except for local site reactions. The SUBQ method of administration provides an additional treatment choice for patients with PNH receiving ravulizumab treatment.

Immunogenicity of Cemiplimab: Low Incidence of Antidrug Antibodies and Cut-Point Suitability Across Tumor Types.

The immunogenicity of cemiplimab, a fully human immunoglobulin G4 monoclonal antibody directed against programmed cell death1, was assessed in patients across multiple tumor types. The development of antidrug antibodies (ADAs) against cemiplimab was monitored using a validated bridging immunoassay. To identify ADA-positive samples in the assay, statistically determined cut points were established by analyzing baseline clinical study samples from a mixed population of different tumor types, and this validation cut point was used to assess immunogenicity in all subsequent studies. Regulatory guidance requires that ADA assay cut points be verified for appropriateness in different patient populations. Thus, for the cemiplimab ADA assay, we evaluated whether each new oncology population was comparable with the validation population used to set the cut point. Assay responses from 2393 individual serum samples from 8 different tumor types were compared with the validation population, using established statistical methods for cut-point determination and comparison, with no significant differences observed. Across tumor types, the immunogenicity of cemiplimab was low, with an overall treatment-emergent ADA incidence rate of 1.9% and 2.5% at intravenous dose regimens of 3mg/kg every 2weeks and 350mg every 3weeks, respectively. Moreover, no neutralizing antibodies to cemiplimab were detected in patients with ADA-positive samples, and there was no observed impact of cemiplimab ADAs on pharmacokinetics. Study-specific cut points may be required in some diseases, such as immune and inflammatory diseases; however, based on this analysis, in-study cut points are not required for each new oncology disease indication for cemiplimab.

Tirzepatide Immunogenicity on Pharmacokinetics, Efficacy, and Safety: Analysis of Data From Phase 3 Studies.

Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy. This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety. ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). Samples for ADA characterization were collected at SURPASS trial sites. Participants included ADA-evaluable TZP-treated patients with type 2 diabetes (N = 5025). Interventions included TZP 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1. TE ADA developed in 51.1% of tirzepatide-treated patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81 920 among TE ADA+ patients. Neutralizing antibodies (NAb) against TZP activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of patients, respectively. Less than 1.0% of patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb status had no effect on the pharmacokinetics or efficacy of TZP. More TE ADA+ patients experienced hypersensitivity reactions or injection site reactions than TE ADA- patients. The majority of hypersensitivity and injection site reactions were nonserious and nonsevere, and most events occurred and/or resolved irrespective of TE ADA status or titer. Immunogenicity did not affect TZP pharmacokinetics or efficacy. The majority of hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity.

Secukinumab in Pediatric Patients with Plaque Psoriasis: Pooled Safety Analysis from Two Phase 3 Randomized Clinical Trials.

Plaque psoriasis affects ~ 1% of the pediatric population, negatively impacting quality of life. The efficacy and safety of secukinumab in pediatric patients with moderate to severe or severe chronic plaque psoriasis have been established in two pivotal phase 3 trials (open-label, NCT03668613; double-blind, NCT02471144). The aims were to report the pooled safety of secukinumab up to 52 weeks from two studies in subgroups of pediatric patients stratified by age and bodyweight, and to present, alongside the pediatric data, the pooled safety data from four pivotal adult secukinumab trials. The safety of secukinumab was evaluated in subgroups of pediatric patients defined by age (6 to <12 and 12 to <18 years) and bodyweight (<25 kg, 25 to <50 kg, and ≥50 kg) in the pooled population. Patients received secukinumab low dose (LD; 75/75/150 mg), secukinumab high dose (HD; 75/150/300 mg), placebo, or etanercept (0.8 mg/kg). For safety analyses, data were pooled from the pediatric studies NCT03668613 and NCT02471144, and presented alongside the pooled data from four adult pivotal studies (NCT01365455, NCT01636687, NCT01358578, NCT01555125). A total of 198 pediatric patients (overall exposure: 184.6 patient-years [PY]) and 1989 adult patients (1749.5 PY) receiving secukinumab up to week 52 were included in this analysis. At week 52, the incidence of adverse events (AEs) was lower in the lower age and bodyweight subgroups. The AEs reported within these subgroups were consistent with the overall AEs reported in this analysis. Overall, exposure-adjusted incidence rates for treatment-emergent AEs were lower in the secukinumab-treated pediatric pool (198.8/100 PY) compared with the etanercept (266.3/100 PY) and adult pools (256.1/100 PY). Up to 52 weeks, the incidence rates of the AEs in the secukinumab-treated patients in the 6 to <12 years subgroup and 12 to <18 years subgroup were 167.7/100 PY and 214.7/100 PY, respectively. Similarly, incidence rates of the AEs in the secukinumab-treated patients in the <25 kg, 25 kg to <50 kg, and ≥50 kg subgroups were 177.3/100 PY, 192.5/100 PY, and 206.8/100 PY, respectively. Nasopharyngitis was the most frequently reported AE in secukinumab-treated pediatric patients across age (<12 years: 11.8/100 PY; ≥12 years: 42.4/100 PY) and bodyweight (<25 kg: 22.8/100 PY; 25 kg to <50 kg: 19.0/100 PY; ≥50 kg: 43.0/100 PY). Of the 198 secukinumab-treated pediatric patients, one reported nail Candida, one reported skin Candida, and two reported vulvovaginal Candida. Transient and mostly mild events of neutropenia were observed with secukinumab, none leading to study treatment discontinuation. No incidence of treatment-emergent anti-drug antibodies was reported in pediatric patients treated with secukinumab. Secukinumab was well tolerated in pediatric patients with moderate to severe and severe plaque psoriasis across age and bodyweight subgroups. The overall safety profile of secukinumab in pediatric patients was consistent with that of adult patients. NCT03668613 (Novartis Study Code CAIN457A2311, referred to as A2311), actual study start date: August 29, 2018; actual primary completion date: September 19, 2019; estimated study completion date: September 14, 2023. NCT02471144 (Novartis Study Code CAIN457A2310, referred to as A2310), study start date: September 29, 2015; primary completion date: December 13, 2018; estimated study completion date: March 31, 2023.

Pharmacokinetic analysis of vilobelimab, anaphylatoxin C5a and antidrug antibodies in PANAMO: a phase 3 study in critically ill, invasively mechanically ventilated COVID-19 patients

BackgroundVilobelimab, a complement 5a (C5a)-specific monoclonal antibody, reduced mortality in critically ill COVID-19 patients in a phase 3 multicentre, randomized, double-blind, placebo-controlled study. As part of the study, vilobelimab concentrations and C5a levels as well as antidrug antibodies (ADAs) to vilobelimab were analysed.ResultsFrom Oct 1, 2020 to Oct 4, 2021, 368 invasively mechanically ventilated COVID-19 patients were randomized: 177 patients were randomly assigned to receive vilobelimab while 191 patients received placebo. Pharmacokinetic sampling was only performed at sites in Western Europe. Blood samples for vilobelimab measurements were available for 93 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. On day 8, after three infusions, mean vilobelimab (trough) concentrations ranged from 21,799.3 to 302,972.1 ng/mL (geometric mean 137,881.3 ng/mL). Blood samples for C5a measurements were available for 94 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. At screening, C5a levels were highly elevated and comparable between groups. In the vilobelimab group, median C5a levels were 118.3 ng/mL [IQR 71.2–168.2 ng/mL] and in the placebo group, median C5a levels were 104.6 ng/mL [IQR 77.5–156.6 ng/mL]. By day 8, median C5a levels were reduced by 87% in the vilobelimab group (median 14.5 ng/mL [IQR 9.5–21.0 ng/mL], p < 0.001) versus an 11% increase in the placebo group (median 119.2 ng/mL [IQR 85.9–152.1 ng/mL]). Beyond day 8, though plasma sampling was sparse, C5a levels did not reach screening levels in the vilobelimab group while C5a levels remained elevated in the placebo group. Treatment-emergent ADAs were observed in one patient in the vilobelimab group at hospital discharge on day 40 and in one patient in the placebo group at hospital discharge on day 25.ConclusionsThis analysis shows that vilobelimab efficiently inhibits C5a in critically ill COVID-19 patients. There was no evidence of immunogenicity associated with vilobelimab treatment.Trialregistration ClinicalTrials.gov, NCT04333420. Registered 3 April 2020, https://clinicaltrials.gov/ct2/show/NCT04333420

Anti-drug antibodies related to CTLA-4, PD-1, or PD-L1 inhibitors across tumour types: A systematic review.

e14600 Background: Treatment-emergent anti-drug antibodies (ADAs) are postulated to reduce the efficacy of immune checkpoint inhibitors. A systematic review (SR) was conducted to evaluate the incidence of treatment-emergent ADAs with programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and their impact on treatment outcomes in patients with cancer. Methods: Electronic databases MEDLINE, EMBASE and Cochrane Library were searched in February 2022 for studies reporting incidence of ADAs and the impact of immunogenicity on treatment efficacy in oncology patients treated with PD-1, PD-L1, or CTLA-4 checkpoint inhibitors. Results: Of the 4,612 articles identified, 34 publications reporting on 68 trials were included. An additional 41 and 32 records were identified from clinicaltrials.gov and packaging inserts respectively. In total, 141 trials of 15 checkpoint inhibitors and 16 tumour types were included. There was considerable variability in the reporting of ADAs, and comparisons between trials were challenging due to intra-study heterogeneity. The incidence of ADAs ranged from 0 to 74%. Across trials, in analyses with the largest sample sizes, atezolizumab was associated with the highest incidence of ADAs (29.6%), then nivolumab (12.2%), followed by the remaining treatments (0-4.4%). The incidence of neutralising antibodies (nAbs) mirrored ADA distribution, being highest for atezolizumab (4.3–27.5%) vs other treatments. Only 17 trials reported on ADA impact on treatment outcomes. Of 11 trials examining efficacy, two reported a negative effect of ADAs, eight reported no measurable effect and another had insufficient patient numbers. The impact of ADAs on treatment safety, and pharmacokinetics was also inconclusive. Conclusions: Treatment-emerging ADAs are inconsistently reported across trials and documented in up to 30% of subjects treated with checkpoint inhibitors across indications. Emergence of nAbs follows but does not perfectly mirror ADA titers, raising questions around the functional meaning of different ADAs. Standardised reporting of ADAs and nAbs should be advocated to facilitate more conclusive immunologic and clinical insight as to the relationship with ADAs and response. [Table: see text]

Statistical Approaches for Establishing Appropriate Immunogenicity Assay Cut Points: Impact of Sample Distribution, Sample Size, and Outlier Removal

The statistical assessments needed to establish anti-drug antibody (ADA) assay cut points (CPs) can be challenging for bioanalytical scientists. Poorly established CPs that are too high could potentially miss treatment emergent ADA or, when set too low, result in detection of responses that may have no clinical relevance. We evaluated 16 validation CP datasets generated with ADA assays at Regeneron’s bioanalytical laboratory and compared results obtained from different CP calculation tools. We systematically evaluated the impact of various factors on CP determination including biological and analytical variability, number of samples for capturing biological variability, outlier removal methods, and the use of parametric vs. non-parametric CP determination. In every study, biological factors were the major component of assay response variability, far outweighing the contribution from analytical variability. Non-parametric CP estimations resulted in screening positivity in drug-naïve samples closer to the targeted rate (5%) and were less impacted by skewness. Outlier removal using the boxplot method with an interquartile range (IQR) factor of 3.0 resulted in screening positivity close to the 5% targeted rate when applied to entire drug-naïve dataset. In silico analysis of CPs calculated using different sample sizes showed that using larger numbers of individuals resulted in CP estimates closer to the CP of the entire population, indicating a larger sample size (~ 150) for CP determination better represents the diversity of the study population. Finally, simpler CP calculations, such as the boxplot method performed in Excel, resulted in CPs similar to those determined using complex methods, such as random-effects ANOVA.Graphical

Ravulizumab pharmacokinetics and pharmacodynamics in patients with generalized myasthenia gravis

IntroductionThe terminal complement C5 inhibitor ravulizumab has a long elimination half-life, allowing maintenance dosing every 8 weeks. In the 26-week, double-blind, randomized, placebo-controlled period (RCP) of the CHAMPION MG study, ravulizumab provided rapid and sustained efficacy and was well tolerated in adults with anti-acetylcholine receptor antibody-positive (AChR Ab+) generalized myasthenia gravis (gMG). This analysis evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and potential immunogenicity of ravulizumab in adults with AChR Ab+ gMG.MethodsData were analyzed from 86 patients who received ravulizumab in the CHAMPION MG RCP. Ravulizumab dosing was weight-based: initial loading dose of 2400/2700/3000 mg on Day 1 and maintenance doses of 3000/3300/3600 mg on Day 15 and then every 8 weeks. PK parameters were estimated from serum ravulizumab concentrations determined pre- and post-dose; PD effects of ravulizumab on serum free C5 concentrations were measured; and immunogenicity was assessed using anti-drug antibody and neutralizing-antibody assays.ResultsTarget serum ravulizumab concentrations (> 175 µg/mL) were achieved immediately after the first ravulizumab dose (within 30 min of infusion completion) and maintained throughout the 26-week treatment period irrespective of patient body weight. Following the final maintenance dose, mean Cmax was 1548 µg/mL and Ctrough 587 µg/mL; no meaningful differences were noted among body-weight categories. Inhibition of serum free C5 was immediate, complete (< 0.5 μg/mL), and sustained throughout treatment in all patients. No treatment-emergent anti-drug antibodies were observed.ConclusionsPK/PD evidence supports the use of ravulizumab every 8 weeks for immediate, complete, and sustained inhibition of terminal complement C5 in adults with AChR Ab+ gMG.Trial registrationClinicalTrials.gov ID: NCT03920293 (April 18, 2019).

Presence and impact of antidrug antibodies (ADAs) to tremelimumab (T) or durvalumab (D) in the phase 3 HIMALAYA study of unresectable hepatocellular carcinoma (uHCC).

551 Background: ADAs to immune checkpoint inhibitors may decrease antitumor activity in HCC. Reported rates of treatment-emergent ADAs (TE-ADAs) vary from 1.5% for pembrolizumab and 8.6% for nivolumab to 54.1% for atezolizumab across indications (Enrico et al. Clin Cancer Res 2020). In the global, Phase 3 HIMALAYA study (NCT03298451) in uHCC, the STRIDE regimen (Single T Regular Interval D) significantly improved overall survival vs sorafenib (S); D monotherapy was noninferior to S (Abou-Alfa et al. NEJM Evid 2022). Here, we analyzed ADAs to T and D in HIMALAYA. Methods: Prespecified secondary analyses assessed the presence of ADAs to D and T before the first study dose (baseline), once during treatment and once after treatment discontinuation. For participants (pts) who were ADA-positive at any visit (ADA+), presence of neutralizing antibodies (nAbs) was also assessed. TE-ADA+ was defined as pts with a positive post-baseline sample only or pts with an ADA titer that increased ≥4-fold following treatment. ADA negative (ADA-) was defined as pts with no positive sample at any visit, at baseline or post-baseline. Objective response rate (ORR; RECIST v1.1, inc. unconfirmed), overall survival (OS) and treatment-related adverse events (TRAEs) were evaluated in ADA subgroups. Results: The frequency of ADAs to D was similar in the STRIDE (T+D) and D arms: 8.2% (24/294) and 7.1% (20/282) of pts, respectively, were ADA+ to D; 3.1% (9/294) and 2.8% (8/282) of pts, respectively, were TE-ADA+ to D; and 1.7% (5/294) and 0.7% (2/282) of pts, respectively, had nAbs to D. In the STRIDE arm, 15.9% (29/182) of pts were ADA+ to T, 11.0% (20/182) of pts were TE-ADA+ to T, and 4.4% (8/182) of pts had nAbs to T. Although the number of pts was small, in the STRIDE arm, ORR was 11.1% (1/9) in pts TE-ADA+ to D, 35.0% (7/20) in pts TE-ADA+ to T and 23.9% (94/393) in the full analysis set (FAS). In the D arm, ORR was 25.0% (2/8) in pts TE-ADA+ to D and 18.5% (72/389) in the FAS. OS for pts TE-ADA+/nAb+ to D or T in the D and STRIDE arms was consistent with the FAS. In both arms, TRAE and Grade 3/4 TRAE rates were not increased in the ADA+ vs ADA- groups (Table) and were generally consistent with the overall population. Conclusions: In HIMALAYA, the rates of TE-ADAs and nAbs to D and T were low (≤11%). The presence of ADAs did not appear to impact clinical efficacy or safety of STRIDE or D monotherapy in the small number of ADA+ pts. These results support a low risk of ADAs for STRIDE or D in uHCC. Clinical trial information: NCT03298451 . [Table: see text]

Anti-brolucizumab immune response as one prerequisite for rare retinal vasculitis/retinal vascular occlusion adverse events.

In October 2019, Novartis launched brolucizumab, a single-chain variable fragment molecule targeting vascular endothelial growth factor A, for the treatment of neovascular age-related macular degeneration. In 2020, rare cases of retinal vasculitis and/or retinal vascular occlusion (RV/RO) were reported, often during the first few months after treatment initiation, consistent with a possible immunologic pathobiology. This finding was inconsistent with preclinical studies in cynomolgus monkeys that demonstrated no drug-related intraocular inflammation, or RV/RO, despite the presence of preexisting and treatment-emergent antidrug antibodies (ADAs) in some animals. In this study, the immune response against brolucizumab in humans was assessed using samples from clinical trials and clinical practice. In the brolucizumab-naïve population, anti-brolucizumab ADA responses were detected before any treatment, which was supported by the finding that healthy donors can harbor brolucizumab-specific B cells. This suggested prior exposure of the immune system to proteins with structural similarity. Experiments on samples showed that naïve and brolucizumab-treated ADA-positive patients developed a class-switched, high-affinity immune response, with several linear epitopes being recognized by ADAs. Only patients with RV/RO showed a meaningful T cell response upon recall with brolucizumab. Further studies in cynomolgus monkeys preimmunized against brolucizumab with adjuvant followed by intravitreal brolucizumab challenge demonstrated that high ADA titers were required to generate ocular inflammation and vasculitis/vascular thrombosis, comparable to RV/RO in humans. Immunogenicity therefore seems to be a prerequisite to develop RV/RO. However, because only 2.1% of patients with ADA develop RV/RO, additional factors must play a role in the development of RV/RO.