Incidence Of Anti-drug Antibodies Research Articles

Pharmacokinetics, pharmacodynamics, safety, and tolerability of BION-1301 in adults with relapsed or refractory multiple myeloma.

8022 Background: APRIL (“a proliferation-inducing ligand”) levels are elevated in the serum of patients diagnosed with multiple myeloma (MM) and is correlated to promotion of malignancy, chemo- and immune-resistance. BION-1301 (BION) is a recombinant, humanized monoclonal antibody against APRIL. We report on the initial pharmacokinetic/ pharmacodynamic (PK-PD) profile, safety, and tolerability of BION in adults with relapsed or refractory MM. Methods: Adults with MM and disease progression after ≥3 systemic therapies were recruited for the study. BION was administered every 14 days through intravenous infusion. This ongoing Phase 1/2, open-label, multicenter study is evaluating 6 cohorts with increasing BION dose levels of 50, 150, 450, 1350, and 2700 mg administered Q2W intravenously (cohort 6 - 1350 mg dose given QW and Q2W). Serum was analyzed for BION, anti-drug antibodies (ADA), and free APRIL (fAPRIL) at baseline and upon treatment, and evaluated by PK-PD modeling. Results: As of 7Dec2018 reporting through the first 4 cohorts, 15 patients were enrolled in the study (N = 3-4 per cohort). BION has been well-tolerated to date. While exposure increased dose-proportionally from 50 to 1350 mg, half-life and clearance did not significantly differ between 50 and 1350 mg. APRIL serum levels decreased with increasing BION doses. To date no DLT was observed. Non-neutralizing ADA were detected in 1 of the 15 patients. BION transiently reduced fAPRIL levels starting at a dose of 50 mg. A prolonged reduction was seen at higher doses, and at 450 mg, reduction was maintained in 2 patients on treatment for 6 cycles (5.5 months). The area under the normalized fAPRIL curve (Days 1-15) decreased 5-fold from 50 to 1350 mg. Data fit well in an exploratory PK-PD model, with kinetic binding of BION and fAPRIL according to in vitro parameters, and peripheral compartments for both entities. While at 450 mg, 95% target engagement (TG) was achieved around peak exposure levels, at 1350 mg this 95% TG was maintained throughout the dosing interval of 3 doses. Conclusions: BION dose-dependently inhibits serum levels of fAPRIL between 50 to 1350 mg dose levels. Exposure was approximately dose-linear over the dose range evaluated, with a low incidence of ADA. Promising TG was obtained at prolonged dosing of 450 mg Q2W. A favorable safety profile supports continued dose escalation and more frequent dosing regimens based on PK-PD modeling. The study is ongoing with subjects exposed to higher and/or more frequent doses anticipated to result in accelerated and sustained APRIL TG. Clinical trial information: NCT03340883.

Immunogenicity of Sarilumab Monotherapy in Patients with Rheumatoid Arthritis Who Were Inadequate Responders or Intolerant to Disease-Modifying Antirheumatic Drugs.

IntroductionThis open-label study evaluated the immunogenicity, safety, and efficacy of sarilumab monotherapy in patients with active, moderate-to-severe rheumatoid arthritis (RA) and inadequate response or intolerance to prior conventional synthetic disease-modifying antirheumatic drugs.MethodsAdults with RA (n = 132) were randomized to receive subcutaneous sarilumab (150 [n = 65] or 200 mg [n = 67]) every 2 weeks (q2w) for 24 weeks. Endpoints included incidence of antidrug antibodies (ADAs) at week 24, safety, and efficacy.ResultsPersistent ADAs occurred in eight patients (12.3%) receiving sarilumab 150 mg q2w, seven of whom (10.8%) had neutralizing antibodies (NAbs), and in four patients (6.1%) receiving sarilumab 200 mg q2w, two of whom (3.0%) had NAbs; all exhibited low antibody titers. Infections and neutropenia were the most common adverse events (AEs). There were three serious AEs, no reports of anaphylaxis, and few hypersensitivity reactions (e.g., rash) with no notable differences in hypersensitivity reactions in ADA-positive patients relative to ADA-negative patients. Changes in absolute neutrophil count, alanine aminotransferase level, and platelet count were consistent with interleukin-6 signaling blockade and in agreement with previous observations. At week 24, overall American College of Rheumatology 20%/50%/70% improvement criteria responses were 73.8%/53.8%/29.2%, respectively, with sarilumab 150 mg q2w and 71.6%/50.7%/29.9% with sarilumab 200 mg q2w. No patients with an ADA-positive response showed loss of efficacy.ConclusionsADA titers were low and persistent ADAs and NAbs occurred relatively infrequently in both sarilumab dose groups. ADA did not meaningfully impact the safety or efficacy of either dose of sarilumab over 24 weeks.Trial RegistrationClinicalTrials.gov, identifier NCT02121210.FundingSanofi Genzyme and Regeneron Pharmaceuticals, Inc.Plain Language SummaryPlain language summary available for this article.Electronic Supplementary MaterialThe online version of this article (10.1007/s40744-019-0157-3) contains supplementary material, which is available to authorized users.

LA-EP2006: A Pegfilgrastim Biosimilar.

LA-EP2006 (Ziextenzo®) is the fifth biosimilar of pegfilgrastim, a pegylated recombinant granulocyte colony-stimulating factor, to be approved in the EU. It is approved for use in adults treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes) to reduce the duration of neutropenia and the incidence of febrile neutropenia. LA-EP2006 matched reference pegfilgrastim in terms of physicochemical characteristics and functional properties, and the pharmacodynamic and pharmacokinetic similarity of the medicines has been shown in healthy volunteers. LA-EP2006 demonstrated clinical efficacy equivalent to that of EU-sourced reference pegfilgrastim in adult women with breast cancer receiving chemotherapy. The tolerability and safety profile of and the incidence of anti-drug antibodies with LA-EP2006 were similar to those of EU-sourced reference pegfilgrastim in this patient population. The role of reference pegfilgrastim in the management of chemotherapy-induced neutropenia is well established and LA-EP2006 provides an effective biosimilar alternative for patients requiring pegfilgrastim therapy.

Reporting a phase II, open-label study assessing the safety and efficacy of MS1819-SD, a recombinant lipase, for the treatment of exocrine pancreatic insufficiency

Background: Chronic pancreatitis is the most common cause of exocrine pancreatic insufficiency (EPI) in adults. EPI is a deficiency in exocrine pancreatic enzymes resulting in an inability to maintain normal digestion. This inadequate digestion, especially fat malabsorption, occurs when intraduodenal levels of lipase fall below 5–10% of normal enzyme output. Furthermore, in EPI due to chronic pancreatitis, decreased bicarbonate output leads to impairment of micelle formation of fats. Fat maldigestion is compounded by decreased pancreatic secretion of lipase and colipase, further dampening hydrolysis of intraluminal fat. Methods: A multicenter, Phase II, open-label, non-randomized study was conducted to investigate the safety of escalating doses (280 mg/day, 560 mg/day, 1120 mg/day and 2240 mg/day) of MS1819 Spray Dried (MS1819-SD, a lipase produced by the LIP2 gene of Yarrowia lipolytica using recombinant DNA technology) in patients with chronic pancreatitis (NCT03481803) and decreased fecal pancreatic elastase-1 (FE-1). Patients ‘washed-out’ their standard of care treatment for EPI establishing a baseline. Each patient subsequently received escalating doses of MS1819-SD in 2-week increments. The total treatment phase ranged from 48 to 60 days. Safety was assessed by adverse event (AE) incidence, including clinical or laboratory abnormalities, and efficacy was determined using Coefficient of Fat Absorption (CFA) change from baseline. Systemic exposure and immunogenicity potential of MS1819 were investigated in patients’ serum. Results: A total of 11 patients (9 males, 2 females) were enrolled in France, Australia and New Zealand. The study mean age was 59.2 years (11.19 standard deviation [SD]) and mean weight was 70.6 kg (12.84 SD). Disease etiology was alcoholism in 4 patients, idiopathic in 3 patients, genetic in 2 patients, auto-immune in 1 patient and gallstone induced pancreatitis for 1 patient. In the highest dose group (2240 mg/day) 4/10 patients reported an AE. One serious AE occurred at this dose but it was not considered to be treatment related (pre-planned removal of stent). A drug-related AE was reported at the 1120 mg dose (slight hepatic cytolysis, mild in nature). No circulating MS1819 was detected hence the mechanism of this adverse event cannot be explained or related to systemic exposure. MS1819 immunogenicity was observed in some patients with post-treatment anti-drug antibodies (ADAs) detected. However, some pre-existing ADAs were also detected and the incidence of ADAs was mild (3/10 patients) with moderate ADA titers. Increases in CFA were reported with all doses of MS1819-SD, these increases were particularly high in patients with baseline CFA <40%. Comparing CFA with FE-1 (24 patients with both recorded at screening) a positive spearman rank correlation of 0.64 (p < 0.001) was obtained. Although the study was not powered to detect a difference in efficacy parameters, the least square mean increase in CFA was 21.8% with MS1819-SD 2240 mg (p = 0.002; per protocol analysis). Conclusion: In general, a favorable safety profile was reported at all doses of MS1819-SD included in the study. Statistically significant and clinically meaningful increases in CFA compared to baseline were recorded. Although the efficacy analysis was pre-planned, the study was not powered to demonstrate differences in the groups and only a small number of patients were included. Favorable trends were also observed on other evaluated endpoints, including the Bristol stool scale, number of daily evacuations and stool weight. Additional studies are warranted to further evaluate the use of MS1819-SD to treat EPI in patients with chronic pancreatitis or cystic fibrosis.

Abstract P6-18-31: PROCLAIM-CX-072: Monotherapy for advanced triple negative breast cancer with skin metastases in a phase 1-2 trial of the PD-L1 probody therapeutic CX-072

Abstract Background: Probody™ therapeutics are novel, fully recombinant antibody prodrugs designed to remain relatively inactive in healthy tissue and to be specifically activated by proteases in the tumor microenvironment. In this way, Probody therapeutics may broaden the therapeutic window for effective but potentially toxic anticancer agents. CX-072 is a Probody therapeutic directed against programmed death-ligand 1 (PD-L1) for the treatment of cancer patients. In a first-in-human, open-label, multicenter, dose-escalation, 3+3 design, phase 1-2 study, PROCLAIM-CX-072 (PRObody CLinical Assessment In Man) (NCT03013491), 22 patients were enrolled in the phase 1 dose escalation portion. Twenty patients were evaluable per RECIST v1.1. Three patients had confirmed partial response (15%), including a 39-year-old woman with stage IV triple negative breast cancer (TNBC) treated with 10 mg/kg CX-072 monotherapy whose disease had progressed on one previous line of chemotherapy for metastatic disease. Metastatic sites included extensive nodal disease and skin/chest wall lesions. The tumor was negative for PD-L1 expression, was microsatellite stable, and had a low tumor mutational burden (4 mutations/megabase). Positive results from the phase 1 study suggest that additional exploration of treatment with CX-072 monotherapy in the TNBC patient population is warranted. Dose expansion trial design: The phase 2 dose expansion part of the PROCLAIM-CX-072 study will include enrollment of TNBC patients with skin metastases. Key inclusion criteria for patients in the TNBC cohort are as follows: naive to immunotherapy (PD-1/PD-L1 and CTLA-4 inhibitors), approved immune checkpoint inhibitor agents not available, histologically confirmed triple negative (estrogen receptor–, progesterone receptor–, and human epidermal growth factor receptor-2–negative cancer per ASCO-CAP guidelines), previously treated with 1 to 3 systemic chemotherapy regimens, and locally advanced and recurrent skin or subcutaneous metastases not suitable for surgical resection or radiotherapy. Patients will receive doses of 10 mg/kg CX-072 intravenously every 2 weeks. Efficacy will be evaluated using RECIST v1.1 and immune-related RECIST criteria. Safety and tolerability will be assessed based on the incidence and severity of adverse events (categorized by NCI CTCAE criteria, v4.03) and relationship to study drug. Other analyses will include pharmacokinetics, incidence of anti-drug antibodies against CX-072, exploratory analysis for immune response, and CX-072 activation in the tumor. PROBODY is a trademark of CytomX Therapeutics, Inc. Citation Format: Adams S, Hamilton E, Ott PA, Cho D, Kalinsky K, LoRusso P, Will M, Huels V, Benson B, Murias C, Arkenau H-T. PROCLAIM-CX-072: Monotherapy for advanced triple negative breast cancer with skin metastases in a phase 1-2 trial of the PD-L1 probody therapeutic CX-072 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-31.

A phase I, randomized, observer-blinded, single and multiple ascending-dose study to investigate the safety, pharmacokinetics, and immunogenicity of BITS7201A, a bispecific antibody targeting IL-13 and IL-17, in healthy volunteers

BackgroundInhibition of interleukin (IL)-13, a Type 2 inflammatory mediator in asthma, improves lung function and reduces exacerbations; however, more effective therapies are needed. A subset of asthma patients also exhibits elevated IL-17, which is associated with greater disease severity, neutrophilic inflammation, and steroid resistance. BITS7201A is a novel, humanized bispecific antibody that binds and neutralizes both IL-13 and IL-17.MethodsSafety, pharmacokinetics, and immunogenicity of BITS7201A were evaluated in a phase 1 study. Part A was a single ascending-dose design with 5 cohorts: 30-, 90-, and 300-mg subcutaneous (SC), and 300- and 750-mg intravenous (IV). Part B was a multiple ascending-dose design with 3 cohorts: 150-, 300-, and 600-mg SC every 4 weeks × 3 doses. Both parts enrolled approximately 8 healthy volunteers into each cohort (6 active: 2 placebo). Part B included an additional cohort of patients with mild asthma (600-mg SC).ResultsForty-one subjects (31 active, 10 placebo) and 26 subjects (20 active, 6 placebo) were enrolled into Parts A and B, respectively. The cohort with mild asthma patients was terminated after enrollment of a single patient. No deaths, serious adverse events, or dose-limiting adverse events occurred. In Part A, 12 active (39%) and 5 placebo subjects (50%), and in Part B, 6 active (30%) and 3 placebo subjects (50%) experienced at least 1 treatment-emergent adverse event (TEAE). The most common AEs were fatigue (n = 3) and influenza-like illness (n = 2). One injection-site reaction was reported. Two subjects with elevated blood eosinophil counts at baseline had transient elevations in blood eosinophils (≥Grade 2, > 1500 cells/μL). In Parts A and B, 16 of 30 (53%) and 16 of 17 (94%) active subjects, respectively, tested positive for anti-drug antibodies (ADAs). No anaphylaxis or hypersensitivity events occurred. BITS7201A exhibited single- and multiple-dose pharmacokinetic characteristics consistent with an IgG monoclonal antibody; exposure generally increased dose-proportionally. Postdose elevations of the serum pharmacodynamic biomarkers, IL-17AA and IL-17FF, occurred, confirming target engagement.ConclusionsBITS7201A was well tolerated, but was associated with a high incidence of ADA formation.Trial registrationClinicalTrials.gov, NCT02748642; registered April 6, 2016 (retrospectively registered).

Preclinical pharmacokinetics of a novel anti-c-Met antibody–drug conjugate, SHR-A1403, in rodents and non-human primates

1. The in vivo pharmacokinetics (PK) profiles of a novel c-Met antibody–drug conjugate (ADC), SHR-A1403, were investigated and characterized in mice, rats and monkeys.2. Serum concentrations of ADC and total antibody were detected using validated ELISA methods. The results showed low systemic clearance of both ADC and total antibody in all three species as reflected by gradual decrease in serum concentrations. Half-life (t1/2) of ADC ranged from 4.6 to 11.3 days in the three species.3. Tissue distribution study in tumor-bearing mice showed high accumulation of 125I-SHR-A1403 in tumor tissues over the other organs/tissues, indicating the favorable safety of SHR-A1403 and characteristics of an ADC drug.4. Relatively low grade of anti-drug antibody (ADA) in monkeys had no impact on PK profile of the ADC.5. During discovery stage, undesirable exposure and/or ADA incidence were observed for SHR-A1403 with high or low drug-antibody ratio (DAR), which was DAR = 5 to 6 and DAR = 1, respectively, and therefore prompted selection of an appropriate DAR value (DAR = 2) for SHR-A1403 used in preclinical development and clinical trials.6. In conclusion, our work demonstrated favorable PK characterization of SHR-A1403, and supported for investigational new drug application (IND) and the ongoing first-in-human trial in the US.

Immunogenicity of golimumab and its clinical relevance in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

Golimumab immunogenicity was extensively studied during clinical development. As anti-drug antibody (ADA) detection with the standard bridging EIA (original-EIA) can yield false-negative results or underestimate ADA incidence and titres due to drug interference, a more sensitive assay was needed to determine clinical impact. A highly sensitive drug-tolerant EIA (DT-EIA) was developed and cross-validated against the original-EIA. Samples from phase-3 subcutaneous golimumab rheumatological trials (GO-FORWARD-rheumatoid arthritis, GO-REVEAL-psoriatic arthritis, GO-RAISE-ankylosing spondylitis) were then retested. Associations between ADAs and golimumab pharmacokinetics, efficacy and safety were assessed. The DT-EIA was more sensitive than the original-EIA and capable of detecting ADAs amid golimumab concentrations far exceeding those in immunogenicity test samples. Consequently, an 8-fold increase in the incidence of ADAs was observed with the DT-EIA (31.7%) vs original-EIA (4.1%) in the studies. Most ADA-positive patients identified by the DT-EIA had lower antibody titres, while most with higher titres were previously identified as ADA-positive by the original-EIA. With the DT-EIA, ADA-positive patients generally had lower trough serum golimumab concentrations than ADA-negative patients; however, ADA impact on serum golimumab concentrations was more notable at higher ADA titres (⩾100). No impact of ADAs on clinical efficacy or injection-site reactions was evident. ADA incidence was expectedly higher using the DT-EIA vs original-EIA; newly detected ADAs were characterized mostly by low titres, with no impact on clinical efficacy or injection-site reactions, consistent with previously observed original-EIA results. Golimumab immunogenicity with the DT-EIA is consistent with existing knowledge regarding the clinical relevance of ADAs detected with the original-EIA in patients with rheumatological disorders. NCT00264550, NCT00265096, NCT00265083.

Incidence and risk factors for adalimumab and infliximab anti-drug antibodies in rheumatoid arthritis: A European retrospective multicohort analysis

ObjectivesTo evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients. MethodsThe study combined retrospective cohorts from the ABIRISK project totaling 366 RA patients treated with adalimumab (n = 240) or infliximab (n = 126), 92.4% of them anti-TNF naive (n = 328/355) and 96.6% of them co-treated with methotrexate (n = 341/353) with up to 18 months follow-up. ADA positivity was measured by enzyme‐linked immunosorbent assay. The cumulative incidence of ADA was estimated, and potential bio-clinical factors were investigated using a Cox regression model on interval-censored data. ResultsADAs were detected within 18 months in 19.2% (n = 46) of the adalimumab-treated patients and 29.4% (n = 37) of the infliximab-treated patients. The cumulative incidence of ADA increased over time. In the adalimumab and infliximab groups, respectively, the incidence was 15.4% (5.2–20.2) and 0% (0–5.9) at 3 months, 17.6% (11.4–26.4) and 0% (0–25.9) at 6 months, 17.7% (12.6–37.5) and 34.1% (11.4–46.3) at 12 months, 50.0% (25.9–87.5) and 37.5% (25.9–77.4) at 15 months and 50.0% (25.9–87.5) and 66.7% (37.7–100) at 18 months. Factors associated with a higher risk of ADA development were: longer disease duration (1–3 vs. < 1 year; adalimumab: HR 3.0, 95% CI 1.0–8.7; infliximab: HR 2.7, 95% CI 1.1–6.8), moderate disease activity (DAS28 3.2–5.1 vs. < 3.2; adalimumab: HR 6.6, 95% CI 1.3–33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2–6.3). ConclusionsThe current study focusing on patients co-treated with methotrexate for more than 95% of them found a late occurrence of ADAs not previously observed, whereby the risk continued to increase over 18 months. Disease duration, DAS28 and lifetime smoking are clinical predictors of ADA development.

A comparative clinical study of PF-06410293, a candidate adalimumab biosimilar, and adalimumab reference product (Humira\xae) in the treatment of active rheumatoid arthritis

BackgroundThis double-blind, randomized, 78-week study evaluated the efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics of PF-06410293, a candidate adalimumab biosimilar, versus adalimumab reference product (Humira®) sourced from the EU (adalimumab-EU) in biologic-naïve patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) (10–25 mg/week). We report results for the first 26 weeks of treatment.MethodsPatients with active RA (N = 597) were randomly assigned (1:1) to PF-06410293 or adalimumab-EU, while continuing with MTX treatment. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 12. Therapeutic equivalence was concluded if the two-sided 95% confidence interval (CI) for the ACR20 difference between the two arms was entirely contained within the symmetric equivalence margin (±14%). Additionally, a two-sided 90% CI was calculated by using an asymmetric equivalence margin (−12%, 15%). Secondary efficacy endpoints to week 26 included ACR20/50/70, change from baseline Disease Activity Score based on high-sensitivity C-reactive protein [DAS28–4(CRP)], European League Against Rheumatism (EULAR) response, DAS28–4(CRP) of less than 2.6, and ACR/EULAR remission. QuantiFERON-TB testing was performed at screening and week 26.ResultsPatients (78.7% of whom were female and whose mean age was 52.5 years) had a mean baseline RA duration of 6.8 years. The mean baseline DAS28–4(CRP) values were 5.9 (PF-06410293) and 6.1 (adalimumab-EU). The observed week-12 ACR20 values were 68.7% (PF-06410293) and 72.7% (adalimumab-EU) in the intention-to-treat population. With non-responder imputation, the treatment difference in week-12 ACR20 was −2.98% and corresponding CIs—95% CI (−10.38%, 4.44%) and 90% CI (−9.25%, 3.28%)—were entirely contained within the equivalence margins (symmetric and asymmetric, respectively). The secondary efficacy endpoints were similar between arms. Over 26 weeks, injection-site reactions occurred in 1.7% versus 2.0%, hypersensitivity events in 4.4% versus 8.4%, pneumonia in 0.7% versus 2.0%, and opportunistic infections in 2.4% versus 1.7% in the PF-06410293 and adalimumab-EU arms, respectively. One death due to myocardial infarction occurred (adalimumab-EU arm). Rates of anti-drug antibody incidence were 44.4% (PF-06410293) and 50.5% (adalimumab-EU).ConclusionsThe study results demonstrate that efficacy, safety, and immunogenicity of PF-06410293 and adalimumab-EU were similar during the first 26 weeks of treatment in patients with active RA on background MTX.Trial registrationClinicalTrials.gov Identifier: NCT02480153. First posted on June 24, 2015; EU Clinical Trials Register EudraCT number: 2014-000352-29. Start date: October 27, 2014.

Efpeglenatide, a Long-Acting Glucagon-Like Peptide-1 Receptor Agonist—Immunogenicity Profile Based on Preclinical and Clinical Studies

Once-weekly (QW), subcutaneous efpeglenatide (efpeg) is a long-acting glucagon-like peptide 1 receptor agonist, with glucose- and weight-lowering effects, in development for type 2 diabetes (T2D). Efpeg is based on a single amino acid-modified exendin analog coupled to a fragment crystallizable (Fc) fragment of the human immunoglobulin G molecule for slow clearance that permits QW dosing. As immunogenicity may hamper pharmacological effects, the incidence of anti-drug antibodies (ADAs) was assessed in efpeg studies. In a cynomolgus monkey study, no primate developed ADAs (Table). In clinical dose-finding studies (efpeg exposure &amp;lt;3 months), no treatment-emergent ADAs (TE ADAs) or in vitro neutralizing antibodies (nAbs) were detected. Primary and immunogenicity endpoints from efpeg QW clinical studies (&amp;gt;3 months) are shown (Table). In patients with T2D or obesity, efpeg QW led to significant reductions in glycated hemoglobin and body weight, respectively, with low immunogenicity (&amp;lt;20% of patients with TE ADAs) and no nAbs. Analysis of individual patient data suggest that presence of ADAs did not impact efficacy and no serious or severe immunogenicity events were reported. Overall, the modification of exendin and Fc conjugation in efpeg were associated with low development of ADAs, with no apparent immunogenicity effects on pharmacological action. Disclosure S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. J. Kang: Employee; Self; Hanmi Pharmaceutical. M.E. Trautmann: Consultant; Self; ProSciento. Stock/Shareholder; Self; Eli Lilly and Company. Consultant; Self; Hanmi Pharmaceutical, CeQur Corporation, Intarcia Therapeutics, Inc., Servier. K. Yoon: None. C.H. Sorli: Employee; Self; Sanofi.

Incidence of Antidrug Antibodies in Rheumatoid Arthritis Patients From Argentina Treated With Adalimumab, Etanercept, or Infliximab in a Real-World Setting.

Biologic agents may induce immune responses that could impact drug action. The aims of this study were to assess antidrug antibodies (ADAs) in patients with rheumatoid arthritis (RA) from Argentina treated with etanercept, adalimumab, or infliximab at a single visit and correlate it with efficacy outcomes. In this subset analysis of a noninterventional, multinational, cross-sectional study (NCT01981473), adult patients with RA treated continuously for 6 to 24 months with etanercept, adalimumab, or infliximab were evaluated for ADAs and trough drug concentrations of 2 days or less prior to the next scheduled dose. Efficacy measurements included Disease Activity Score based on a 28-joint count-erythrocyte sedimentation rate, low disease activity, and Health Assessment Questionnaire-Disability Index. Targeted medical history of injection site/infusion reactions, serum sickness, and thromboembolic events were reported. Baseline demographics, disease characteristics, and duration of treatment of the 119 patients (etanercept: n = 54, adalimumab: n = 52, infliximab: n = 13) were similar across all groups. No etanercept-treated patient tested positive for ADAs compared with 19 (36.5%) of 52 patients and 4 (30.8%) of 13 patients treated with adalimumab and infliximab, respectively. In adalimumab- and infliximab-treated patients, ADA presence correlated negatively with trough drug levels. A greater proportion of ADA-negative patients achieved Health Assessment Questionnaire-Disability Index of 0.5 or less and had better composite efficacy measures compared with ADA-positive patients. The rate of targeted medical events reported was low. In this subset analysis, RA patients from Argentina treated with adalimumab or infliximab, but not etanercept, tested positive for ADAs. Antidrug antibody-negative patients showed a tendency toward better clinical outcomes compared with ADA-positive patients.

Immunoassay methods used in clinical studies for the detection of anti-drug antibodies to adalimumab and infliximab.

SummaryWe examined the assay formats used to detect anti‐drug antibodies (ADA) in clinical studies of the anti‐tumour necrosis factor (TNF) monoclonal antibodies adalimumab and infliximab in chronic inflammatory disease and their potential impact on pharmacokinetic and clinical outcomes. Using findings of a recent systematic literature review of the immunogenicity of 11 biological/biosimilar agents, we conducted an ancillary qualitative review of a subset of randomized controlled trials and observational studies of the monoclonal antibodies against anti‐TNF factor adalimumab and infliximab. Among studies of adalimumab and infliximab, the immunoassay method used to detect antibodies was reported in 91 of 111 (82%) and 154 of 206 (75%) adalimumab and infliximab studies, respectively. In most adalimumab and infliximab studies, an enzyme‐linked immunosorbent assay or radioimmunoassay was used [85 of 91 (93%) and 134 of 154 (87%), respectively]. ADA incidence varied widely among assays and inflammatory diseases (adalimumab, 0–87%; infliximab, 0–79%). Pharmacokinetic and clinical outcomes were only reported for ADA‐positive patients in 38 of 91 (42%) and 61 of 154 (40%) adalimumab and infliximab studies, respectively. Regardless of assay format or biological used, ADA formation was associated with lower serum concentrations, reduced efficacy and elevated rates of infusion‐related reactions. Consistent with previous recommendations to improve interpretation of immunogenicity data for biologicals, greater consistency in reporting of assay methods and clinical consequences of ADA formation may prove useful. Additional standardization in immunogenicity testing and reporting, application of modern, robust assays that satisfy current regulatory expectations and implementation of international standards for marketed products may help to improve our understanding of the impact of immunogenicity to biologics.

Anti-adalimumab antibodies in a cohort of patients with juvenile idiopathic arthritis: incidence and clinical correlations.

Adalimumab is a TNF-α blocker antibody similar in structure and function to natural human IgG1. Even if adalimumab is fully humanized, the development of anti-drug antibodies has been reported in several inflammatory conditions. The objective of our study was to assess the presence of anti-adalimumab antibodies (AAA) and their clinical relevance in a cohort of juvenile idiopathic arthritis (JIA) patients on adalimumab. This is a prospective observational cohort study recruiting JIA children. Experiments were performed using a validated surface plasmon resonance (SPR)-based optical assay (Biacore® T100). Disease activity was evaluated using the Juvenile Arthritis Disease Activity Score with 10 joint count (JADAS-10). The Mann-Whitney U test, Wilcoxon signed-rank test for paired samples, chi-square, and Fisher exact test were used to compare data. Pearson's and Spearman's correlation tests were used to determine correlation coefficients for entered variables: demographic, clinical, and serological data. Ten (37%) out of 27 patients included in the study had at least one AAA-positive sample. Patients developed AAA between 3 and 38months after starting adalimumab. Seven (70%) out of 10 children with AAA positivity experienced at least a relapse compared to 4 (23.5%) out of 17 AAA-negative children (rs 0.45, p< 0.017). In conclusion, using an innovative and accurate assay method, we found a high incidence of anti-drug antibodies in a cohort of adalimumab-treated JIA patients observed over a mean period of 40weeks; the presence of anti-adalimumab antibodies seemed to be related to the number of relapses.

A phase III study comparing SB3 (a proposed trastuzumab biosimilar) and trastuzumab reference product in HER2-positive early breast cancer treated with neoadjuvant-adjuvant treatment: Final safety, immunogenicity and survival results

BackgroundThe equivalent efficacy between SB3, a proposed trastuzumab biosimilar, and the trastuzumab reference product (TRZ) in terms of the breast pathologic complete response rate after neoadjuvant therapy in patients with early or locally advanced human epidermal growth factor receptor 2-positive breast cancer was demonstrated in the previous report. Here, we report the final safety, immunogenicity and survival results after neoadjuvant-adjuvant treatment. Patients and methodsPatients were randomised 1:1 to receive neoadjuvant SB3 or TRZ for 8 cycles concurrently with chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil/epirubicin/cyclophosphamide). Patients then underwent surgery, followed by 10 cycles of adjuvant SB3 or TRZ as randomised. End-points included safety, immunogenicity, event-free survival (EFS) and overall survival through the adjuvant period. ResultsOf 875 patients randomised, 764 (SB3, n = 380; TRZ, n = 384) completed the study. The median follow-up duration was 437 days in the SB3 group and 438 days in the TRZ group. The incidence of treatment-emergent adverse events was comparable between groups (SB3, 97.5%; TRZ, 96.1%) during the overall study period. Up to the end of study, the overall incidence of antidrug antibody was low in both treatment groups (3 patients each). EFS was comparable between groups with a hazard ratio (SB3/TRZ) of 0.94 (95% confidence interval, 0.59–1.51) and EFS rates at 12 months of 93.7% for SB3 and 93.4% for TRZ. ConclusionsFinal safety, immunogenicity and survival results of this study further support the biosimilarity established between SB3 and TRZ. Trial registrationClinicalTrials.gov (NCT02149524); EudraCT (2013-004172-35).

The Immunogenicity of Biologic Therapies.

Virtually all therapeutic proteins (biologics) elicit an immune response with the consequent production of anti-drug antibodies (ADA). The majority of ADA to therapeutic monoclonal antibodies (mAbs) are directed against the antigen-binding site of the therapeutic mAb, and hence are neutralizing. This nature of the ADA response explains why fully human antibodies can still be highly immunogenic. The detection of ADA is technically challenging and all assays have limitations, namely a limited capacity in detecting ADA in the presence of a drug due to immune complex (IC) formation, which may underestimate the ADA incidence. Refined assays, able to disrupt drug-ADA ICs, have revealed the presence of ADA in a higher proportion of patients. The great heterogeneity among ADA assays prevents a direct comparison of immunogenicity between different molecules and across studies. The formation of drug-ADA ICs can significantly alter pharmacokinetics and directly reduce drug efficacy if the ADA titer (i.e., concentration) is sufficiently high and persistent. In patients with low ADA titer, free drug concentrations may remain high enough to be effective, while in patients developing high ADA titer a substantial part of the drug will be neutralized and clinical non-response is likely to occur. ADA can also increase the risk of adverse events, namely hypersensitivity reactions. Several studies have revealed the presence of ADA before a clinically overt adverse reaction, highlighting their predictive value. Algorithms integrating therapeutic drug monitoring and immunogenicity information in the current clinical evaluation of patients receiving biologics are today available to guide therapeutic decisions in clinical practice, helping us to design safer and more cost-effective therapeutic strategies.

Abstract 5046: Exposure-efficacy (OS) analysis of tremelimumab in unresectable malignant mesothelioma

Abstract Purpose: Tremelimumab is a fully human anti-CTLA-4 IgG2 monoclonal antibody that enhances human T-cell activation. Tremelimumab was evaluated in a Phase IIb (DETERMINE), randomised, double-blind, placebo-controlled study in patients with unresectable pleural or peritoneal malignant mesothelioma, randomised (2:1) to receive either tremelimumab (10 mg/kg, seven doses Q4W followed by Q12W) or placebo. The study demonstrated no clinically meaningful differences in overall survival (OS). The primary objectives of this analysis were to evaluate the relationship of exposure with OS, and the impact of potential confounders. Methods: A population PK model was developed to estimate and derive PK exposure metrics (area under the curve at steady state [AUCss] or clearance [CL]) for exposure-OS analysis. Impact of potential confounders was evaluated using graphical and exploratory approaches. Factors including body weight, age, gender, race, ECOG status, anatomical site (pleural or peritoneal), line of therapy, EORTC status, tumour histology, baseline tumour size, LDH, and CRP were evaluated. The analyses were performed using NONMEM 7.2 and R software. Results: The population PK included 376 patients and 1328 post-first dose PK concentrations. PK was consistent with previous knowledge and low incidence of anti-drug antibodies was observed. A 2-compartment linear PK model adequately described the data. Tremelimumab CL and volume of distribution (V1) were 310 mL/day and 3.85 L, with moderate variability of ~38% and ~32%, respectively. There was an apparent exposure-OS relation when stratified by AUCss. However, at least 3 factors (gender, CRP, and baseline tumour size) were statistically significant PK predictors (p&amp;lt;0.05 on CL) indicating multi-dimensional confounding effect. Higher baseline tumor size, higher CRP levels and males were associated with lower PK exposure of tremelimumab. Conclusions: The observed apparent exposure-OS relationship is the result of imbalance in prognostic factors impacting OS rather than a true association of exposure with efficacy. Citation Format: Paul Baverel, Lorin Roskos, Manasa Tatipalli, Nancy Lee, Paul Stockman, Maria Taboada, Paolo Vicini, Kevin Horgan, Rajesh Narwal. Exposure-efficacy (OS) analysis of tremelimumab in unresectable malignant mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5046. doi:10.1158/1538-7445.AM2017-5046

The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study.

ObjectiveTo assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes.MethodsThis multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6–24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose. Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR). Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected.ResultsBaseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups. The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively. All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive. In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations. There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients. DAS28-ESR LDA and remission rates were higher in patients without ADA. The rate of targeted medical events reported was low.ConclusionADA were detected in ADL- and IFX-treated but not ETN-treated patients. Patients without ADA generally showed numerically better clinical outcomes than those with ADA.Trial registrationThis study was registered on www.ClinicalTrials.gov (NCT01981473).

Clinical Pharmacology and Translational Aspects of Bispecific Antibodies.

Clinical Pharmacology and Translational Aspects of Bispecific Antibodies.

Clinical similarity of biosimilar ABP 501 to adalimumab in the treatment of patients with moderate to severe plaque psoriasis: A randomized, double-blind, multicenter, phase III study

ABP 501 is a biosimilar of adalimumab. We sought to compare the efficacy and safety of ABP 501 with adalimumab. This 52-week, double-blind study randomized patients with moderate to severe psoriasis to ABP 501 or adalimumab. At week 16, those with 50% or more improvement in Psoriasis Area and Severity Index score from baseline on ABP 501 continued the same treatment, whereas adalimumab-treated patients were rerandomized to adalimumab or ABP 501. Clinical similarity in Psoriasis Area and Severity Index percent improvement from baseline to week 16 (primary end point) was established if the point estimate of treatment difference and its 2-sided 95% confidence interval between groups was within equivalence margin of ±15. Patients, including those undergoing a single transition at week 16, were evaluated for safety and immunogenicity. Psoriasis Area and Severity Index percent improvement at week 16 was 80.9 for ABP 501 and 83.1for adalimumab (least-square mean difference -2.18 [95% confidence interval -7.39 to 3.02]). Adverseevents (67.2% [117/174] vs 63.6% [110/173]) and antidrug antibody incidence (55.2% [96/174] vs 63.6% [110/173]) for ABP 501 vs adalimumab were similar. Safety, including immunogenicity, was similar among groups after single transition (week 20). The 52-week data are not reported here. ABP 501 was shown to be clinically similar to adalimumab. Safety and immunogenicity were not impacted immediately after single transition (adalimumab to ABP 501).