Wendy Komocsar

ABSTRACT Randomised, double-blind, placebo-controlled study to evaluate efficacy and safety of tabalumab in patients with rheumatoid arthritis (RA) with inadequate responses to methotrexate (MTX-IR). 1041 patients with moderate-severe RA despite ongoing MTX enrolled in a 52-week study evaluating subcutaneous tabalumab 120 mg every four weeks (120/Q4W) or 90 mg every two weeks (90/Q2W) versus placebo. Primary endpoints were American College of Rheumatology 20% (ACR20) response rate and Health Assessment Questionnaire-Disability Index change from baseline at 24 weeks and modified Total Sharp Score (mTSS) change at 52 weeks. There were no significant differences in ACR20 responses at week 24 or mTSS change from baseline at week 52 among treatment groups. Declines were seen in CD20+ B cells and immunoglobulin levels in tabalumab groups, but not placebo: B cells (-15.0%, -18.8%, 5.3%, in the 120/Q4W, 90/Q2W, and placebo groups, respectively); IgM (-16.3%, -19.4%, -0.1%), IgA (-11.4%, -4.7%, 1.2%) and IgG (-8.6%, -7.8%, 0.1%). Discontinuations due to adverse events were similar between groups. Numerically more serious infections were reported in tabalumab groups (1.7%, 0.6%, 0.3%); numerically more injection-site reactions were reported in the 90/Q2W group (2.3%, 4.3%, 2.3%). Neither clinical efficacy nor significant safety signals were observed with tabalumab despite evidence of biological activity. This study was terminated early due to insufficient efficacy. NCT01198002. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Methods, Supplemental Table 1, Supplemental Table 2, References. Methods: Description of patient population, study design, endpoints, and analyses. Supplemental Table 1. Baseline demographics and disease characteristics of study groups. Supplemental Table 2. Geometric mean titers of measles and mumps IgG. References for Methods. (DOCX 30 kb)

Background/Purpose: Tabalumab, a monoclonal antibody neutralizing membrane bound and soluble B cell activating Factor (BAFF), has been shown to reduce the signs and symptoms of rheumatoid arthritis (RA)1. To better define tabalumab's molecular mechanism of action, gene expression profiling of whole blood RNA was performed to characterize individual gene expression signatures and to map the associated pathways involved with BAFF blockage in RA. Methods: Whole blood RNA was obtained from 158 RA subjects with inadequate response to methotrexate enrolled in a phase 2 randomized trial in which patients received subcutaneous placebo, 1, 3, 10, 30, 60 or 120 mg of tabalumab every 4 weeks (wks) over 24 wks. At total of 669 RNA samples were obtained at baseline, wk 1, 4 and 16, and follow up visits at wk 32 and 44. Samples from 30 healthy blood donors controls were analyzed. Affymetrix U133 Plus 2.0 expression arrays were used to measure gene expression. Data were normalized using Robust...

The potential immunotoxicity of tabalumab was assessed as a component of standard pre-clinical toxicology studies in cynomolgus monkeys. To evaluate potential tabalumab-associated immunosuppression after antigen challenge, cynomolgus monkeys were administered placebo control or tabalumab in three immunotoxicological safety studies. Study 1, a 4-week pilot study, evaluated biweekly intravenous (IV) control, and 0.3, 1.0, 5.0, and 15.0 mg/kg tabalumab doses. Study 2 evaluated IV control, and 0.1, 1.0, and 30.0 mg/kg tabalumab doses biweekly for 6 weeks. Study 3 evaluated IV control and 0.1, 1.0, 30.0 mg/kg, and subcutaneous (SC) 30.0 mg/kg tabalumab biweekly for 6 months, with recovery (16 weeks) to monitor standard immunotoxicity endpoints. T-cell dependent primary and secondary antibody responses to tetanus toxoid antigen challenge (4-week and 6-week studies) or keyhole limpet hemocyanin (KLH; 6-week and 6-month studies) were evaluated as a measure of immunocompetence, together with...

Objectives To assess the initial and long-term maintenance dosing of biologic medications in pediatric UC and CD patients, using data in the ICN registry. Methods Pediatric patients (2–17 years) in the US who were diagnosed with UC or CD between June 1, 2013 and December 31, 2019, who, after enrollment in the ICN registry, initiated a biologic (adalimumab, infliximab, certolizumab, golimumab, ustekinumab, vedolizumab, and natalizumab) and were actively followed for at least 12 months after first maintenance dose were included in this study. Descriptive statistics of baseline patient demographics were summarized for the overall Inflammatory Bowel Disease (IBD) patient population and separately for UC and CD. Biologic maintenance dosage was calculated for UC and CD patients who had data for both dose and weight for each biologic at the baseline visit (first maintenance dose), 1-year and 3-year time points. Results A total of 1,887 pediatric IBD patients (UC=350; CD=1,537) were include...

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Objectives</jats:title> <jats:p>To assess disease activity, steroid-free remission, and clinical outcome assessments among pediatric UC and CD patients who initiated a biologic after being enrolled in the ICN registry.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Pediatric patients who were diagnosed with UC or CD between June 1, 2013-Dec 31, 2019, who, after enrollment in the ICN registry, initiated a biologic and were actively followed for at least 12 months after first maintenance dose were included in this study. Descriptive statistics of baseline patient demographics were summarized for the overall IBD patient population and separately for UC and CD. PUCAI, partial Mayo score, and PGA were assessed in UC patients; and the sPCDAI and PGA were assessed in CD patients at first maintenance dose, 1-year and 3-year time points. Kappa coefficients were used to assess the level of agreement between the PUCAI, Mayo clinical score, and PGA for UC patients and the level of agreement between the sPCDAI and PGA for CD patients at different time points.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>A total of 1,887 pediatric IBD patients (UC=350; CD=1,537) were included in this study. Patients had a mean age at diagnosis of 12.9 years, 57.1% were male, and 80.6% were White. Mean PUCAI scores of UC patients decreased from 12.1 at first maintenance dose, to 5.7 at 1-year, and 3.7 at 3-years; the proportion of UC patients in steroid-free remission by PUCAI increased from 46.2% at first maintenance dose, to 75.0% at 1 year and 80.4% at 3 years. The proportion of UC patients that were quiescent based on PGA also increased from 67.2% at first maintenance dose, to 84.2% at 1-year and 92.6% at 3-years. The proportion of UC patients that were in remission based on Partial Mayo score also increased from 72.1% at first maintenance dose, to 87.5% at 1-year and 92.3% at 3-years. Mean sPCDAI score of CD patients decreased from 9.5 at first maintenance dose, to 6.7 at 1-year, and 6.3 at 3-years; the proportion of CD patients in steroid-free remission by sPCDAI increased from 63.8% at first maintenance dose, to 81.2% at 1-year and 85.4% at 3-years. The proportion of CD patients who were quiescent based on PGA also increased from 69.2% at first maintenance dose, to 85.3% at 1-year and 89.6% at 3-years. In UC patients, the kappa coefficients between PUCAI and PGA ranged from 0.46–0.66, PUCAI and partial Mayo ranged from 0.52–0.72, and PGA and Partial Mayo score ranged from 0.73–1.00 at different time points. For CD patients, the kappa coefficient between sPCDAI and PGA ranged from 0.40–0.48 at different time points.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>This study found that disease activity scores improved over time, with more pediatric UC and CD patients achieving steroid-free remission 1-year and 3-years after first biologic maintenance dose. There was modest correlation between disease activity assessments, with the correlation between the PGA and Partial Mayo score being the strongest.</jats:p> <jats:p /> <jats:p /> </jats:sec>

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Objectives</jats:title> <jats:p>The objective of this study was to assess current treatment patterns of pediatric ulcerative colitis (UC) and Crohn's disease (CD) patients, using data in the ImproveCareNow (ICN) registry.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Pediatric (2–17 years) patients in the United States who were newly diagnosed with UC or CD between June 1, 2013-December 31, 2019, who had their first recorded ICN visit within 6 months of diagnosis and who were actively followed for at least 12 months (± 90 days) were included in this study. Descriptive statistics of baseline patient demographics were summarized for the overall IBD patient population and separately for UC and CD. Treatment patterns (including use of corticosteroids, 5-aminosalicylic acid (5-ASA), 6-mercaptopurine/azathioprine (6-MP/AZA), methotrexate, tumor necrosis factor inhibitors (TNFi) [adalimumab, infliximab, certolizumab, golimumab, and their biosimilars], ustekinumab, vedolizumab, and other medications [natalizumab and tofacitinib]) were assessed at the initial baseline visit, and at 1-year and 3-year time points.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>A total of 6,504 pediatric IBD patients (UC=1,784; CD=4,720) were included in this study. Patients had a mean age at diagnosis of 13.0 years (UC=13.2; CD=12.9), 57.1% were male (UC=49.6%; CD=60.0%), and 81.0% were White (UC=81.2%; CD=81.0%) (Table 1). At the initial ICN visit, 46.4% of UC patients were prescribed a corticosteroid, while 19.8% received a 5-ASA, 12.6% received a TNFi, 10.4% received a 6-MP/AZA, 3.0% received methotrexate, and 0.3% received vedolizumab. At the initial visit, 40.2% of CD patients were prescribed a corticosteroid, while 29.1% received a TNFi, 18.5% received a 6-MP/AZA, 12.4% received methotrexate, and 3.3% received a 5-ASA. At the 1-year and 3-year time points, rates of 5-ASA and corticosteroid use decreased among UC patients; however, rates of 6-MP/AZA, methotrexate, and TNFi increased (Table 2). Similarly, at the 1-year and 3-year time points, rates of corticosteroids among CD patients decreased; however, rates of methotrexate and TNFi increased (Table 2). There was also an increase in use of ustekinumab and vedolizumab over time among UC and CD patients.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>These results highlight the current treatment patterns of pediatric UC and CD patients in the United States. At the initial ICN visit, the 46% of UC and 40% of CD patients were receiving corticosteroids, however, at 1-year and 3-years after initial visit, over 30% of UC patients and over 60% of CD patients were receiving TNF inhibitors with considerably reduced corticosteroid use.</jats:p> <jats:p /> <jats:p /> </jats:sec>

Background Crohn’s disease (CD) and ulcerative colitis (UC) are chronic gastrointestinal diseases, which often present during one’s most productive years. The objective of this study was to assess the symptomology and most bothersome symptoms of pediatric CD and UC patients. Methods Data from a cross-sectional survey of physicians and their pediatric CD and UC patients (age 2–17 years) conducted in France, Germany, Italy, Spain, United Kingdom, Japan, and United States were analyzed. Data were collected in 2019–2020 via physician-completed patient record forms and patient-self completed forms. Patients age 12–17 years completed their own questionnaires, while caregivers of younger children completed their respective questionnaires. Patient demographics and current symptoms were reported by physicians, while the most bothersome symptoms were reported by the patient/caregiver. All descriptive analyses were conducted for CD and UC patients separately. Results Data from 1,213 CD patient...

<div><p></p><p>The potential immunotoxicity of tabalumab was assessed as a component of standard pre-clinical toxicology studies in cynomolgus monkeys. To evaluate potential tabalumab-associated immunosuppression after antigen challenge, cynomolgus monkeys were administered placebo control or tabalumab in three immunotoxicological safety studies. Study 1, a 4-week pilot study, evaluated biweekly intravenous (IV) control, and 0.3, 1.0, 5.0, and 15.0 mg/kg tabalumab doses. Study 2 evaluated IV control, and 0.1, 1.0, and 30.0 mg/kg tabalumab doses biweekly for 6 weeks. Study 3 evaluated IV control and 0.1, 1.0, 30.0 mg/kg, and subcutaneous (SC) 30.0 mg/kg tabalumab biweekly for 6 months, with recovery (16 weeks) to monitor standard immunotoxicity endpoints. T-cell dependent primary and secondary antibody responses to tetanus toxoid antigen challenge (4-week and 6-week studies) or keyhole limpet hemocyanin (KLH; 6-week and 6-month studies) were evaluated as a measure of immunocompetence, together with quantitation of T- and B-cell subsets. In addition, anti-tabalumab antibody formation (6-week and 6-month studies) was assessed. The results indicated that, despite expected decreases in circulating B-cell populations, no changes in follicle histopathology or organ weights, except decreases in spleen weight (after 6-months of 30 mg/kg IV/SC treatment only), were attributed to tabalumab. Non-adverse microscopic decreases in size or number of germinal centers in spleen, mesenteric, and mandibular lymph nodes occurred, but without an effect on antibody responses to KLH or tetanus. At 16-weeks recovery, microscopic compound-related changes observed after 6 months of treatment were completely reversed (0.1 mg/kg group) and partially reversed (1.0 and 30.0 mg/kg groups), while peripheral blood B cells remained 66–72% reduced from baseline. Despite reduced germinal centres in lymphoid organs, and reductions in circulating B cells, T-cell-dependent humoral immunity was maintained following tabalumab administration in three safety studies in cynomolgus monkeys.</p></div

Systemic lupus erythematosus (SLE) has substantial unmet medical need and its pathogenesis is incompletely understood. This study characterized baseline gene expression and pharmacodynamic (PD)-induced changes in whole blood gene expression from two phase III, 52-week (W), randomized, placebo-controlled, double-blind studies of 1,760 SLE patients treated with the B cell activating factor (BAFF)-blocking IgG4 monoclonal antibody, tabalumab. Patient samples were obtained from ILLUMINATE-1 and -2 while control samples were from healthy donors. Blood was collected in Tempus(TM) tubes at baseline, W16 and W52. RNA was analyzed using the Affymetrix Human Transcriptome Array 2.0 and NanoString(TM) . At baseline there was elevation of interferon responsive genes (IRG) in patients compared to controls, with 75% positive for this IRG signature. There was, however, substantial heterogeneity of IRG expression and complex relationships among gene networks. The interferon signature was a predicto...

ABSTRACT Background Patients with rheumatoid arthritis (RA) exhibit substantial variability in both the magnitude and duration of their clinical response to treatment. Despite considerable research, no biomarker has reproducibly been shown to predict likelihood of clinical response to biologic therapy. There remains significant unmet medical need to identify patients who will have a meaningful clinical response to treatment prior to drug exposure. We have recently demonstrated efficacy of BAFF blockade in RA using tabalumab (previously known as LY2127399)1. We have now used gene expression profiling of whole blood mRNA, obtained prior to drug exposure, to identify a predictive gene expression pattern that helps identify patients that are highly likely to respond to treatment with tabalumab. Methods Whole blood mRNA was obtained at baseline from 158 RA subjects with an inadequate response to methotrexate enrolled in a phase 2 randomized trial in which patientsreceived placebo, 1, 3, 10, 30, 60 or 120 mg of tabalumab every 4 weeks over 24 weeks. Clinical results of BAFF blockade in RA of this study have recently been reported1. In addition to the RA subjects (152 samples passed quality control), samples from 30 healthy blood donor controls were analyzed using Affymetrix U133 Plus 2.0 expression arrays to determine gene expression, and data were compared after normalization using Robust Multichip Average (RMA) algorithm3. Human C-type Lectin Domain Family 4, Member C (CLEC4C) qPCR was performed in validated assays at Covance Genomics Seattle using primers and probes obtained from ABI. Statistical analyses were performed using Messina2, two sample t-test or regression modeling. Results There was a bimodal distribution of CLEC4C mRNA in whole blood from RA patients and controls at baseline. The mean level of CLEC4C gene expression measured by Affymetrix was lower in patients than in controls. Mean expression after normalization for patients (n=152) is 5.79 with a range of 3.18 to 9.69. Mean expression for control healthy blood donors (n=30) is 6.88, range is 4.36 to 9.02. Among patients, those with higher levels of CLEC4C gene expression were more likely to respond to tabalumab (as measured by ACR-N). Messina analysis2 at baseline identified both CLEC4C probe sets as having the largest margin when comparing responder and non-responder group outcome at week 16 using ACR-N/DAS28. A two sample t-test on the same data was significant (p<0.0007). These expression findings from selected Affymetrix probe sets were validated using qPCR; for CLEC4C the change in threshold cycle versus ACR-N was statically significant after correction for multiple comparisons using False Discovery Rate (FDR) and Bonferroni techniques (FDR p=0.013, Bonferroni p=0.013). Conclusions The subgroup of RA patients with higher levels of CLEC4C mRNA expression at baseline was significantly more likely to respond to treatment with tabalumab. Independent replication of these hypothesis generating findings is now in progress in a large phase 3 clinical trial of tabalumab. References Disclosure of Interest E. Dow Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, P. Banerjee Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, M. Penny Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, E. Nantz Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, S. Stepaniants Employee of: Covance Genomics Seattle, A. Ho Employee of: Covance Genomics Seattle, W. Komocsar Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, P.-Y. Berclaz Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, R. Hoffman Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company

Tabalumab is a human monoclonal antibody that neutralises B-cell activating factor. To evaluate tabalumab efficacy and safety in patients with rheumatoid arthritis (RA). This phase 3, randomised, double-blind, placebo-controlled study evaluated 456 patients with active RA after 24-week treatment with subcutaneous tabalumab (120 mg every 4 weeks (120/Q4W) or 90 mg every 2 weeks (90/Q2W)) versus placebo, with loading doses (240 or 180 mg) at week 0. Patients were allowed background disease-modifying antirheumatic drugs and previously discontinued ≥1 tumour necrosis factor α inhibitors for lack of efficacy/intolerance. Primary end point was American College of Rheumatology 20% (ACR20) response at 24 weeks. This study was terminated early due to futility. Most patients had moderate-to-high baseline disease activity. There was no significant difference in week 24 ACR20 responses between 120/Q4W, 90/Q2W, and placebo (17.6%, 24.3%, 20%) per non-responder imputation analysis. Mean percent changes in CD20+ B-cell count (-10.8%, -9.6%, +10.9%) demonstrated expected pharmacodynamic effects. Treatment-emergent adverse events (AEs) were similar (59.5%, 51.7%, 52.6%), as were AE discontinuations (2.6%, 2.7%, 2.6%), serious AEs (4.6%, 4.1%, 3.9%), serious infectious events (1.3%, 0, 0) and events of interest: infections (23.5%, 25.9%, 24%), injection site reactions (13.1%, 25.8%, 11%) and allergy/hypersensitivity (3.9%, 4.1%, 3.9%) reports. Incidence of treatment-emergent antidrug antibodies was similar to placebo (3.9%, 4.8%, 3.9%). No deaths or new/unexpected safety findings were reported. Tabalumab did not demonstrate clinical efficacy in patients with RA in this phase 3 study, despite evidence of biological activity. There were no notable differences in safety parameters between tabalumab treatment groups and placebo. NCT01202773.

The efficacy and safety of 2 different dosing regimens of tabalumab, a monoclonal antibody that neutralizes membrane-bound and soluble B-cell-activating factor (BAFF), were evaluated in patients with rheumatoid arthritis. In this phase 3, multicenter, randomized study, 1004 patients (intention-to-treat population) received subcutaneous 120 mg tabalumab every 4 weeks (120/Q4W), 90 mg tabalumab every 2 weeks (90/Q2W), or placebo over 24 weeks. At baseline, a loading dose double the planned dose (ie, 240 mg, 180 mg, or placebo) was administered. Efficacy analyses were based on a prespecified subset of patients with 5 or more of 68 tender and 5 or more of 66 swollen joints at baseline (efficacy population, n = 849). The primary efficacy end point was ACR20 (20% improvement in American College of Rheumatology criteria) response at week 24. At week 24, there were no differences in ACR20 response rates (120/Q4W = 34.4%, 90/Q2W = 33.5%, placebo = 31.5%) or any other measures of efficacy acr...

Randomised, double-blind, placebo-controlled study to evaluate efficacy and safety of tabalumab in patients with rheumatoid arthritis (RA) with inadequate responses to methotrexate (MTX-IR). 1041 patients with moderate-severe RA despite ongoing MTX enrolled in a 52-week study evaluating subcutaneous tabalumab 120 mg every four weeks (120/Q4W) or 90 mg every two weeks (90/Q2W) versus placebo. Primary endpoints were American College of Rheumatology 20% (ACR20) response rate and Health Assessment Questionnaire-Disability Index change from baseline at 24 weeks and modified Total Sharp Score (mTSS) change at 52 weeks. There were no significant differences in ACR20 responses at week 24 or mTSS change from baseline at week 52 among treatment groups. Declines were seen in CD20+ B cells and immunoglobulin levels in tabalumab groups, but not placebo: B cells (-15.0%, -18.8%, 5.3%, in the 120/Q4W, 90/Q2W, and placebo groups, respectively); IgM (-16.3%, -19.4%, -0.1%), IgA (-11.4%, -4.7%, 1.2%)...

While immunotoxicology evaluations are often conducted in either rodents or non-human primates, findings in standard toxicology studies may trigger additional investigations in dogs. A survey sponsored by the HESI Immunotoxicology Technical Committee, and described herein, was conducted to gather information regarding the extent and nature of immunology and immunotoxicity assessments available in the dog, and the need thereof. The survey was issued via e-mail to scientists affiliated with 39 organizations in industry and academia, including contract research organizations, academic research organizations, pharmaceutical companies, and veterinary practices. Fifteen institutions responded, including 10 biotechnology or pharmaceutical industry organizations, 4 contract research organizations, and 1 academic institution. Responses indicated that indeed, immunological assessments in dogs are necessary for research and/or toxicology purposes. The survey demonstrated that multiple types of assays are used in the dog model, including assessment of T-cell-dependent antibody responses, immunoglobulins, complement CH(50), cytokines and cytokine mRNAs, lymphocyte proliferation in response to T-cell mitogens, neutrophil activation, phagocytosis, and immunophenotyping of several cell types. The survey also revealed that certain assays/endpoints are not available in the dog (complement components, NK immunophenotyping, T-cell activation and memory immunophenotyping) or require further optimization (ex vivo cytolysis assays such as CTL and NK function, B-cell proliferation in response to LPS). In addition, the survey indicated that a greater understanding of the specificity of the available immunophenotyping reagents is needed.

Thrombocytopenic episodes occurring in 18,845 patients treated with the GPIIb/IIIa inhibitors xemilofiban and orbofiban ("fibans") were analyzed by a blinded review panel and 73 patients were classified as having "possible fiban-induced thrombocytopenia". When the treatment codes were broken, a significant association between drug exposure and assignment to this group was found (p <0.001). Twenty-eight (82%) of 34 archived serum samples from these patients contained fiban-dependent antibodies specific for GPIIb/IIIa, but no such antibodies were found in 61 drug treated patients not classified as having…

The development and regulatory approval of immunomodulatory pharmaceuticals to treat many human diseases has increased significantly over the last two decades. As discussed by FDA and ICH guidelines, all human pharmaceuticals in development should be evaluated for potential adverse effects on the immune system. Developmental immunotoxicology (DIT) focuses on the concern that early-life (during pre-/post-natal development) exposure to agents which target the immune system may result in enhanced susceptibility to immune-related disease (e.g., infection, autoimmunity, and cancer, particularly leukemia) compared to adults, unique effects not observed in adults, or more persistent effects in comparison to those following adult exposure. This article provides a substantive review of the literature and presents detailed considerations for DIT testing strategies with a specific focus on pharmaceuticals and biopharmaceuticals. In this regard, differences between small molecule and large molecule therapeutics will be considered, along with recommendations for best practices in the assessment of DIT during drug development. In addition, gaps in the DIT knowledge base and current testing strategies are identified. Finally, a summary of an ILSI-HESI-ITC sponsored Workshop conducted in 2010, entitled 'Developmental Immunotoxicity Testing of Pharmaceuticals' will be presented. This Workshop consisted of participants from the pharmaceutical, biotechnology, academic, and regulatory sectors, where many of the issues relating to DIT outlined in this review were discussed, key points of consensus reached, and current gaps in the science identified.