A first-in-human study of the novel immunology antibody-drug conjugate, ABBV-3373, in healthy participants.

AIMS: ABBV-3373, an immunology antibody-drug conjugate composed of adalimumab conjugated to a proprietary glucocorticoid receptor modulator (the small-molecule payload), has the potential to treat immune-mediated inflammatory diseases. This first-in-human study investigated the pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD) using a safety PD marker, and safety/tolerability of ABBV-3373 in healthy adults. METHODS: Fifty-five participants were randomly assigned to single-dose subcutaneous (SC; 30, 100 or 300 mg) or intravenous (IV; 30, 300 or 900 mg) ABBV-3373 or placebo. Eight additional participants received a single dose of 10 mg oral prednisone for evaluation of systemic glucocorticoid effects. Blood samples were collected for up to 85 days postdose for PK, anti-drug antibody and serum cortisol (safety PD marker) assessments. RESULTS: ABBV-3373 and total antibody displayed antibody-like SC/IV PK profiles and the unconjugated/free payload in circulation exhibited formation rate-limited kinetics with exposure several fold lower than ABBV-3373 or total antibody. Treatment-emergent anti-drug antibody incidence was 69%, with loss of exposure in 6% (SC) and 5% (IV) of participants, but without any impact on safety. ABBV-3373 up to 300 mg SC/IV had no apparent impact on serum cortisol, and only caused a transient decrease at 900 mg IV. Treatment-emergent adverse events were primarily mild in severity, and no pattern emerged with respect to dose or route of administration. CONCLUSIONS: ABBV-3373 had favourable PK profiles, manageable immunogenicity, and was generally well-tolerated. Except for a transient effect at 900 mg IV, there was no apparent impact on serum cortisol. Study results supported further clinical development of ABBV-3373.

Efficacy and Safety of ABBV-3373, a Novel Anti-Tumor Necrosis Factor Glucocorticoid Receptor Modulator Antibody-Drug Conjugate, in Adults with Moderate-to-Severe Rheumatoid Arthritis Despite Methotrexate Therapy: A Randomized, Double-Blind, Active-Controlled Proof-of-Concept Phase IIa Trial.

OBJECTIVE: To assess the efficacy and safety of ABBV-3373, a novel antibody-drug conjugate (ADC) composed of the anti-tumor necrosis factor (anti-TNF) monoclonal antibody adalimumab linked to a glucocorticoid receptor modulator (GRM), compared to adalimumab, in patients with rheumatoid arthritis (RA). METHODS: In this randomized, double-blind, active-controlled, proof-of-concept trial (ClinicalTrials.gov identifier: NCT03823391), adults with moderate-to-severe RA receiving background methotrexate were administered intravenously (IV) ABBV-3373 100 mg every other week for 12 weeks, followed by placebo for 12 weeks, or subcutaneous adalimumab 80 mg every other week for 24 weeks. The primary end point was change from baseline in the Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) at week 12, with 2 prespecified primary comparisons of ABBV-3373 versus historical adalimumab (80 mg every other week or equivalent dose) and versus combined in-trial/historical adalimumab. Secondary end points included change from baseline in the Clinical Disease Activity Index, Simplified Disease Activity Index, and DAS28 using erythrocyte sedimentation rate, as well as the proportion of patients achieving a DAS28-CRP of ≤3.2 and the American College of Rheumatology 50% improvement criteria. RESULTS: Forty-eight patients were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). At week 12, ABBV-3373 demonstrated a reduction in DAS28-CRP compared to historical adalimumab (-2.65 versus -2.13; P = 0.022) and compared to combined in-trial/historical adalimumab (-2.65 versus -2.29; probability 89.9%), with numerically greater improvement than in-trial adalimumab (-2.51). For secondary end points, greater efficacy was observed with ABBV-3373 compared to historical adalimumab; ABBV-3373 was predicted with 79.3-99.5% probability to be more effective than adalimumab based on combined in-trial/historical adalimumab data. Of the ABBV-3373-treated patients who achieved DAS28-CRP ≤3.2 at week 12, 70.6% maintained this response at week 24 despite switching to placebo. Four serious adverse events (SAEs) were reported with ABBV-3373 (noncardiac chest pain, pneumonia, upper respiratory tract infection, and anaphylactic shock) and 2 SAEs with adalimumab (breast abscess and bronchitis). After increasing the duration of IV ABBV-3373 administration from 3 minutes to 15-30 minutes, no similar events of anaphylactic shock were reported. CONCLUSION: Data from this proof-of-concept trial support the continued development of a TNF-GRM ADC for the treatment of RA, with the potential to achieve superior outcomes compared to currently available therapies.

Low Incidence of Inflammatory Bowel Disease Adverse Events in Adalimumab Clinical Trials Across Nine Different Diseases.

OBJECTIVE: Adalimumab is approved for treatment of Crohn's disease and ulcerative colitis. Thus, we postulated that exacerbation or new-onset of inflammatory bowel disease (IBD) would be rare events in patients treated with adalimumab for non-IBD indications. The objective was to evaluate the incidence of IBD adverse events (AEs) across adalimumab trials. METHODS: IBD AE rates in 75 adalimumab clinical trials in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, pediatric enthesitis-related arthritis, uveitis, hidradenitis suppurativa, adult and pediatric psoriasis, psoriatic arthritis, nonpsoriatic arthritis peripheral spondyloarthritis (SpA), axial SpA, including nonradiographic axial SpA, and ankylosing spondylitis, were analyzed. Search terms for IBD AEs (new onset or worsening/flare) included IBD, ulcerative colitis, Crohn's disease, and ulcerative proctitis. RESULTS: This analysis included 24,114 patients, representing 36,508 patient-years of adalimumab exposure. The overall rate of IBD AEs in adalimumab-treated patients was 0.1 (95% confidence interval [95% CI] 0.1-0.2)/100 patient-years (41 events), ranging from no events (psoriatic arthritis, uveitis, and pediatric trials) to 0.8 (95% CI 0.2-2.2)/100 patient-years in peripheral SpA. The rate of IBD in axial SpA was 0.6 (95% CI 0.4-1.0)/100 patient-years. During placebo-controlled trials, the overall IBD rate was 0.1 (95% CI 0.0-0.3)/100 patient-years for adalimumab groups (3 events in 6,781 patients; 2,752 patient-years of exposure) and 0.1 (95% CI 0.0-0.4)/100 patient-years for placebo groups (1 event in 3,493 patients; 1,246 patient-years of exposure). IBD rates in axial SpA were 0.5 (95% CI 0.1-1.4)/100 patient-years for adalimumab and 0.6 (95% CI 0.0-3.1)/100 patient-years for placebo. CONCLUSION: The rates of IBD AEs in adalimumab clinical trials were generally low across the evaluated diseases, including axial SpA; all events occurred in adult patients.

Long-Term Safety of Adalimumab in 29,967 Adult Patients From Global Clinical Trials Across Multiple Indications: An Updated Analysis.

INTRODUCTION: The safety profile of adalimumab was previously reported in 23,458 patients across multiple indications. Here we report the long-term safety of adalimumab in adults with plaque psoriasis (Ps), hidradenitis suppurativa (HS), rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis, non-radiographic axial spondyloarthritis, peripheral spondyloarthritis, Crohn's disease (CD), ulcerative colitis (UC), and non-infectious uveitis (UV). METHODS: Safety data from 77 clinical trials were pooled. Safety assessments included adverse events (AEs) and serious AEs (SAEs) that occurred after the first study dose and within 70 days (5 half-lives) after the last study dose. RESULTS: A total of 29,967 patients were included, representing 56,916 patient-years (PY) of exposure. The most frequently reported SAE of interest was infection (3.7/100 PY) with highest incidences in CD, RA, UV, and UC (3.5/100 PY-6.9/100 PY); serious infections in Ps (1.8/100 PY) and HS (2.8/100 PY) were lower. The observed number of deaths was below what would be expected in an age- and sex-adjusted population for most adalimumab-treated patients (including Ps). Lack of real-life data and limited long-term data (> 5 years) for most patients are limitations of this analysis. CONCLUSION: The safety profile of adalimumab was consistent with previous findings and no new safety signals were observed.

Adverse Medical Conditions Across Treatment Options in Patients With Psoriasis: A Claims-Based Analysis

Objective: To assess the real-world risk of developing adverse medical conditions (AMCs) among patients with psoriasis treated with biologic therapies or conventional systemic/topical therapies (CST/topical). Methods: Adult patients with psoriasis were identified from the Truven MarketScan US claims database (2008 Q3­2015 Q3) and classified into cohorts based on treatment initiated on the index date (adalimumab [ADA], etanercept [ETN], ustekinumab [UST], infliximab [IFX], or CST/topical). Incident AMCs were identified while on treatment from diagnoses recorded in medical claims and included abnormal test results, infections, mental disorders, cardiovascular disease, malignancies (skin and non-skin), and respiratory disease. Cox proportional hazards models were used to compare AMC risk for (1) ADA, ETN, and UST (separately) vs CST/topical, and (2) ADA vs other biologic therapies (ETN, UST, and IFX combined). Regressions were adjusted for age, gender, region, insurance plan type, year, Charlson comorbidity index, and prior AMCs; and based on stepwise selection, comorbidities, specialist encounters, and frequently prescribed treatments. Results: A total of 42,981 patients were identified (ADA: 5,197; ETN: 3,311; UST: 1,370; IFX: 187; CST/topical: 32,916). Across cohorts, median age was 46­50 years, 46.2%­53.1% were female, and median follow-up duration was 3.3­7.9 months. For all cohorts, infection was the most frequent AMC (28.7%­41.8%). Compared with CST/topical, ADA, ETN, and UST were associated with a lower risk of infections (adjusted hazard ratio [aHR]: 0.93, 0.92, and 0.86, respectively, all P<0.05). ADA was associated with a lower risk of malignancies (aHR: 0.71, P<0.05), and ETN was associated with a lower risk of respiratory disease (aHR: 0.80, P<0.05). Compared with biologic therapies, ADA was not associated with higher risk of AMCs. Conclusions: Compared to CST/topical, biologic therapies were associated with similar or lower risk of AMCs. Comparison between ADA and other biologic therapies suggests a similar safety profile with respect to the studied AMCs.

Safety of Adalimumab in Pediatric Patients with Polyarticular Juvenile Idiopathic Arthritis, Enthesitis-Related Arthritis, Psoriasis, and Crohn's Disease.

OBJECTIVE: To evaluate the safety of adalimumab in pediatric patients who participated in clinical trials of juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and pediatric enthesitis-related arthritis), psoriasis, and Crohn's disease. STUDY DESIGN: This analysis included data from 7 global, randomized, and open-label AbbVie-sponsored clinical trials of adalimumab and their open-label extensions conducted between September 2002 and December 31, 2015 (cutoff date for ongoing studies). Patients who received ≥1 dose of adalimumab subcutaneously were included. Adverse events that occurred after the first dose of adalimumab and up to 70 days (5 half-lives) after the last dose were reported and events per 100 patient-years were calculated. RESULTS: The analysis included 577 pediatric patients, representing 1440.7 patient-years of adalimumab exposure. Across indications, the most commonly reported adverse events (events/100 patient-years) were upper respiratory tract infections (24.3), nasopharyngitis (17.3), and headache (19.9). Serious infections (4.0 events/100 patient-years) were the most frequent serious adverse events across indications; the most commonly reported was pneumonia (0.6 events/100 patient-years). Serious infection rates were 2.7, 0.8, and 6.6 events/100 patient-years in patients with juvenile idiopathic arthritis, psoriasis, and Crohn's disease, respectively. No events of malignancies were reported. One death (accidental fall) occurred in a patient with psoriasis. CONCLUSIONS: The safety profile of adalimumab in pediatric patients with polyarticular juvenile idiopathic arthritis, enthesitis-related arthritis, psoriasis, and Crohn's disease was generally similar across indications; no new safety signals were identified in the treatment of pediatric patients with adalimumab. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00048542, NCT00775437, NCT00690573, NCT01166282, NCT01251614, NCT00409682, and NCT00686374.

Lymphoma Risk and Overall Safety Profile of Adalimumab in Patients With Crohn's Disease With up to 6 Years of Follow-Up in the Pyramid Registry.

OBJECTIVES: Real-world, prospective, long-term studies in Crohn's disease (CD) characterizing adalimumab safety data and lymphoma risk were lacking. We present the final results from the PYRAMID registry, which was designed to rule out a doubling of lymphoma risk in adalimumab-treated patients with CD. METHODS: Patients with moderately to severely active CD newly prescribed or currently receiving adalimumab according to local product labels were followed for up to 6 years and analyzed for adverse events (AEs). The registry exposure-adjusted observed rate of lymphoma was compared with the estimated background lymphoma rate from a sex-matched general population in the Surveillance, Epidemiology, and End Results 17 Registry database adjusted for anticipated prior or concurrent thiopurine use in a CD population. RESULTS: A total of 5025 patients were evaluated (16680.4 PY of adalimumab registry exposure, ≈3 years/patient mean follow-up). Registry treatment-emergent AEs included 4129 serious AEs (n = 1853 [36.9%]; 24.8 E/100 PY), 792 serious infections (n = 556 [11.1%]; 4.7 E/100 PY), and 134 malignancies (n = 116 [2.3%]; 0.8 E/100 PY), including ten lymphomas. The observed lymphoma rate (0.060 E/100 PY) was lower than the estimated background rate (0.084 E/100 PY), and the upper bound of the one-sided 95% CI of the observed rate (0.102 E/100 PY) was lower than double the estimated rate (0.168 E/100 PY). CONCLUSIONS: PYRAMID is the longest prospective adalimumab study in routine clinical practice, with up to 6 years of follow-up. No new safety signals were reported. The pre-specified registry objective of ruling out a doubling of lymphoma risk with adalimumab was met.

Long-Term Safety and Effectiveness of Adalimumab for Moderate to Severe Psoriasis: Results from 7-Year Interim Analysis of the ESPRIT Registry.

INTRODUCTION: ESPRIT (NCT00799877) is an ongoing 10-year international prospective observational registry evaluating the long-term safety and effectiveness of originator adalimumab in routine clinical practice for adult patients with chronic plaque psoriasis. Herein, we report the long-term safety, effectiveness, and patient-reported outcomes (PROs) following adalimumab treatment over the first 7 years of the ESPRIT registry. METHODS: All treatment-emergent (All-TE) adverse events (AE) since the initial (first ever) dose of adalimumab were assessed. Physician Global Assessment (PGA) and PROs (PROs for US patients only) were evaluated during registry participation. RESULTS: As of 30 November 2015, 6051 patients in the ESPRIT registry were analyzed, representing 23,660.1 patient-years (PY) of overall adalimumab exposure. The incidence rates for All-TE serious AEs, serious infections, and malignancies were 4.4, 1.0, and 1.0 events per 100 PY (E/100PY), respectively. The standardized mortality ratio for TE deaths in the registry was 0.27 (95% CI 0.18-0.38). During the registry's first 7 years, PGA "clear" or "minimal" was achieved by >50% of patients at each annual visit, and among US patients, the mean improvement from baseline in different PROs was maintained. CONCLUSION: No new safety signals were identified during the first 7 years of the registry, and safety was consistent with the known safety profile of adalimumab. The number of TE deaths was below the expected rate. During the registry's first 7 years, most of the patients remained free of All-TE cardiovascular events, serious infections, and malignancy. As-observed effectiveness of adalimumab and improvements from baseline in PROs were maintained through 7 years of registry participation. FUNDING: Abbvie. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00799877.

Long-term safety and efficacy of adalimumab for intestinal Behçet's disease in the open label study following a phase 3 clinical trial.

BACKGROUND/AIMS: Intestinal Behçet's disease (BD) is an immune-mediated inflammatory disorder. We followed up the patients and evaluated safety profile and effectiveness of adalimumab for the treatment of intestinal BD through 100 weeks rolled over from the 52 week clinical trial (NCT01243671). METHODS: Patients initiated adalimumab therapy at 160 mg at week 0, followed by 80 mg at week 2, followed by 40 mg every other week until the end of the study. Long-term safety and all adverse events (AEs) were examined. The efficacy was assessed on the basis of marked improvement (MI) and complete remission (CR) using a composite efficacy index, which combined global gastrointestinal symptoms and endoscopic assessments. RESULTS: Twenty patients were enrolled in this study; 15 patients received adalimumab treatment until study completion. The incidence of AEs through week 100 was 544.4 events/100 person-years, which was comparable to the incidence through week 52 (560.4 events/100 person-years). No unexpected trend was observed and adalimumab was well tolerated. At weeks 52 and 100, 60.0% and 40.0% of patients showed MI, respectively, and 20.0% and 15.0% of patients showed CR, respectively. CONCLUSIONS: This report demonstrates 2 years safety and effectiveness of adalimumab in intestinal BD patients. Patients with intestinal BD refractory to conventional treatment receiving up to 2 years of adalimumab treatment demonstrated safety outcomes consistent with the known profile of adalimumab, and the treatment led to sustained reduction of clinical and endoscopic disease activity.

A nucleoside- and ritonavir-sparing regimen containing atazanavir plus raltegravir in antiretroviral treatment-naïve HIV-infected patients: SPARTAN study results.

BACKGROUND: Nucleoside and ritonavir (RTV) toxicities have led to increased interest in nucleoside reverse transcriptase inhibitors (NRTIs) and RTV-sparing antiretroviral regimens. SPARTAN was a multicenter, randomized, open-label, noncomparative pilot study evaluating the efficacy, safety, and resistance profile of an investigational NRTI- and RTV-sparing regimen (experimental atazanavir [ATV] dose 300 mg bid + raltegravir [RAL] 400 mg bid [ATV+RAL]). The reference regimen consisted of ATV 300 mg/RTV 100 mg qd + tenofovir (TDF) 300 mg/emtricitabine (FTC) 200 mg qd (ATV/r+TDF/FTC). METHODS: Treatment-naïve HIV-infected patients with HIV-RNA ≥5,000 copies/mL were randomized 2:1 to receive twice-daily ATV+RAL (n=63) or once-daily ATV/r+TDF/FTC (n=31). Efficacy at 24 weeks was determined by confirmed virologic response (CVR; HIV-RNA <50 copies/mL) with noncom-pleters counted as failures based on all treated subjects. RESULTS: The proportion of patients with CVR HIV RNA <50 copies/mL at week 24 was 74.6% (47/63) in the ATV+RAL arm and 63.3% (19/30) in the ATV/r+TDF/FTC arm. Systemic exposure to ATV in the ATV+RAL regimen was higher than historically observed with ATV/r+TDF/ FTC. Incidence of Grade 4 hyperbilirubinemia was higher on ATV+RAL (20.6%; 13/63) than on ATV/r+TDF/FTC (0%). The criteria for resistance testing (virologic failure [VF]: HIV-RNA ≥400 copies/mL) was met in 6/63 patients on ATV+RAL, and 1/30 on ATV/r+TDF/FTC; 4 VFs on ATV+RAL developed RAL resistance. CONCLUSIONS: ATV+RAL, an experimental NRTI- and RTV-sparing regimen, achieved virologic suppression rates comparable to current standards of care for treatment-naïve patients. The overall profile did not appear optimal for further clinical development given its development of resistance to RAL and higher rates of hyperbilirubinemia with twice-daily ATV compared with ATV/RTV.

Determination of rifabutin dosing regimen when administered in combination with ritonavir-boosted atazanavir.

OBJECTIVES: Treatment of HIV/tuberculosis (TB) co-infected patients is complex due to drug-drug interactions for these chronic diseases. This study evaluates an intermittent dosing regimen for rifabutin when it is co-administered with ritonavir-boosted atazanavir. PATIENTS AND METHODS: A randomized, multiple-dose, parallel-group study was conducted in healthy subjects and these subjects received a daily dose of rifabutin 150 mg (n = 15, reference group) or a twice weekly dose with atazanavir 300 mg/ritonavir 100 mg once daily (n = 18, test group). Serial blood samples were collected at steady-state for pharmacokinetic analysis. Modelling and simulation techniques were utilized, integrating data across several healthy subject studies. This study is known as Study AI424-360 and is registered with ClinicalTrials.gov, number NCT00646776. RESULTS: The pharmacokinetic parameters (C(max), AUC(24avg) and C(min)) for rifabutin (149%, 48% and 40% increase, respectively) and 25-O-desacteyl rifabutin (6.77-, 9.90- and 10.45-fold increases, respectively) were both increased when rifabutin was co-administered with atazanavir/ritonavir than rifabutin 150 mg once daily alone. The study was stopped because subjects experienced more severe declines in neutrophil counts when rifabutin was given with atazanavir/ritonavir than alone. A post-hoc simulation analysis showed that when rifabutin 150 mg was given three times weekly with atazanavir/ritonavir, the average daily exposure of rifabutin was comparable to rifabutin 300 mg once daily, a dose necessary for reducing rifamycin resistance in HIV/TB co-infected patients. CONCLUSIONS: The benefits to HIV/TB co-infected patients receiving rifabutin 150 mg three times weekly or every other day may outweigh the risks of neutropenia observed here in non-HIV-infected subjects, provided that patients on combination therapy will be closely monitored for safety and tolerability.