ADA reduces drug response, an effect that can be attenuated by concomitant immunosuppression, which reduces ADA frequency. Drug immunogenicity should be considered for the management of patients receiving biological therapies.

Immunogenicity assessment might help to optimise therapeutic decisions, leading to a better control of disease activity with significantly better clinical outcomes in patients with RA receiving TNFi.

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.

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Ixekizumab, a high-affinity monoclonal antibody that selectively targets IL-17A, is efficacious for moderate to severe plaque psoriasis. We examined relationships between serum ixekizumab concentrations, treatment-emergent anti-drug antibodies (TE-ADAs), and efficacy during 60 weeks of treatment in a randomized, controlled, phase 3 study. Steady-state ixekizumab serum trough concentrations were rapidly achieved and associated with high clinical responses at week 12 with a starting dose of 160 mg followed by 80 mg every 2 weeks. During the long-term extension period dosage of 80 mg every 4 weeks, stable serum trough concentrations maintained high clinical responses through week 60. Most (82.6%, 308/373) patients never developed TE-ADA. In TE-ADA-positive patients (17.4%, n = 65), variations in ADA titers, neutralizing capacity, and persistence were observed. Fifty-six patients (15%) developed low or moderate maximum titers, with serum concentrations and efficacy comparable to those of TE-ADA-negative patients. Nine patients (2.4%) developed high titers, with variable individual clinical responses; four of these nine patients achieved at least PASI 75 at week 60. Median serum concentrations in the TE-ADA-high titer group were generally comparable to the median serum concentrations in the lower titer groups. For most patients, TE-ADA had a negligible impact on ixekizumab serum concentrations and efficacy. Clinicaltrials.gov: NCT01646177.

No abstract

Background This analysis characterizes the immunogenicity profile of galcanezumab, a humanized monoclonal antibody that selectively binds calcitonin gene-related peptide and inhibits its activity, in phase 3 migraine trials. Methods Immunogenicity data were analyzed from baseline and double-blind, placebo-controlled phases of the 3-month chronic migraine study REGAIN, the 6-month episodic migraine studies EVOLVE-1 and EVOLVE-2, and from baseline and open-label phases of the 12-month chronic and episodic migraine Study CGAJ. The incidence of baseline antidrug antibodies, treatment-emergent antidrug antibodies, neutralizing antidrug antibodies, and the effect of antidrug antibody titer on pharmacokinetics and pharmacodynamics were assessed. The relationship between antidrug antibody status and efficacy was explored using average change in monthly migraine headache days. Safety analyses assessed the potential relationship between treatment-emergent antidrug antibodies and hypersensitivity events or adverse events related to injection sites. Findings Across studies, 5.9–11.2% of patients had baseline antidrug antibodies. The incidence of treatment-emergent antidrug antibodies was 2.6–12.4% in the galcanezumab group and 0.5–1.7% in the placebo group. The majority of treatment-emergent antidrug antibodies were detected approximately 3–6 months after first study drug dose. Overall, the observed antidrug antibody titer did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or galcanezumab efficacy. There was no evidence that hypersensitivity events or adverse events related to injection sites were mediated by treatment-emergent antidrug antibodies. Interpretation These data showed that immunogenicity did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or the efficacy and hypersensitivity profile of galcanezumab in patients with migraine.

BackgroundThe efficacy and safety of ixekizumab (IXE) in patients with radiographic axial spondyloarthritis (r-axSpA) were investigated in the COAST trial program.ObjectivesTo report the long-term safety of IXE in r-axSpA patients using integrated safety data from the COAST trials program.MethodsSafety data for r-axSpA patients treated with IXE were integrated from COAST-V (biologic-naïve; NCT02696785) and COAST-W (Inadequate responders or intolerant to 1 or 2 TNF inhibitors; NCT02696798) studies. Patients fulfilled ASAS criteria for r-axSpA and mNY criteria for ankylosing spondylitis. Trial eligibility criteria were previously reported.1,2 In these studies, participants were randomized to placebo (n=191), adalimumab (n=90, active reference arm, COAST-V only), or ixekizumab (n=376). Study participants initially randomized to IXE in both trials were treated with a starting dose (80-mg or 160-mg) and then 80-mg IXE every 2 weeks (IXEQ2W) or 4 weeks (IXEQ4W). Patients initially treated with placebo or adalimumab were re-randomized at Week 16 to receive either IXEQ2W or IXEQ4W following a 160-mg starting dose. The analysis population included all ixekizumab-exposed patients in both trials. Incidence rates (IR) per 100 person years with 95% confidence intervals (CI) and the number of patients are reported. Adverse Event (AE) codes were derived from MedDRA (v21.0). Integrated safety data presented here include all data collected between May 6. 2016 and Sept. 20, 2018.ResultsThe integrated population consisted of 641 patients with 749.6 total patient-years of exposure to IXE. Mean follow up time was 427 days. Mean baseline age was 43.8±12.3 years. Mean and median baseline disease symptom duration (since onset) were 17.2±10.8 years and 15.5 years (Min: 1.1, Max: 56.2), respectively. Safety data are presented in Table 1. Among these patients, 489 (76.3%) reported ≥1 treatment emergent AEs with an IR of 65.2. Serious AEs (≥1) were reported for 51 (8.0%) patients with an IR of 6.8. Discontinuations due to AEs were reported for 38 (5.9%) patients with an IR of 5.1. One death was reported, a suicide, in a patient with a documented prior history of depression and judged by the blinded principal investigator to be unrelated to the investigational product. The overall infection IR was 39.4, with both serious and opportunistic infections reported with an IR of 1.7. Among opportunistic infections, no Tuberculosis infections or reactivations were reported and the Candida infection IR was 1.2. No infections were associated with grade 3 or 4 neutropenia. The confirmed major adverse cardiovascular events IR was 0.1. The malignancy IR was 0.4 with acute promyelocytic leukemia, bladder cancer, and ovarian cancer reported. The depression IR was 0.8. The adjudicated inflammatory bowel disease (IBD) IR was 1.5 with 4 of 11 patients having prior history of IBD. The Anterior uveitis (AU) IR was 3.9 with 24 of 29 patients having prior history of AU. The injection site reaction IR was 11.3.ConclusionThe reported safety profile for IXE in r-axSp...