Abstract
Objective
An unmet need exists for glucocorticoid‐sparing treatments for patients with polymyalgia rheumatica (PMR). The antibody‐drug conjugate ABBV‐154 comprises adalimumab conjugated to a glucocorticoid receptor modulator. We evaluated ABBV‐154 versus placebo in patients with glucocorticoid‐dependent PMR.
Methods
In this phase 2, randomized, double‐blind, placebo‐controlled, dose‐ranging study, eligible patients had confirmed PMR, glucocorticoid response and two or more unequivocal PMR flares while tapering glucocorticoids and still on ≥5 mg daily prednisone equivalent. Randomized patients received subcutaneous placebo or ABBV‐154 40, 150, or 340 mg once every other week. The primary efficacy endpoint was time to flare. The sponsor voluntarily terminated the study early.
Results
Overall, 181 patients were randomized (placebo, n = 50; ABBV‐154: 40 mg, n = 42; 150 mg, n = 45; 340 mg, n = 44), and 67.4% completed study drug at week 24. Time to flare was longer for patients receiving ABBV‐154 than those receiving placebo, with Kaplan‐Meier estimate of 24‐week flare‐free rate being lower for placebo. The hazard ratios of ABBV‐154 versus placebo were 0.49 (95% confidence interval [CI], 0.27–0.88), P = 0.017 for 40 mg; 0.44 (95% CI, 0.25–0.79), P = 0.006 for 150 mg; 0.20 (95% CI, 0.09–0.42), P < 0.001 for 340 mg. Incidences of treatment‐emergent adverse events were similar between groups, and the most common across ABBV‐154 cohorts was COVID‐19 (16.0%).
Conclusion
Treatment effects were observed for ABBV‐154 cohorts compared with placebo for time to flare. ABBV‐154 was generally well tolerated. Due to early study termination, results should be interpreted with caution.
INTRODUCTION
Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease characterized by shoulder, neck, and hip pain and morning stiffness. 1 EULAR and American College of Rheumatology (ACR) treatment guidelines for PMR recommend oral glucocorticoids (prednisone or equivalent) for the shortest effective duration with individualized dose‐tapering after achieving remission. 2 Unfortunately, glucocorticoid reduction can lead to PMR flares, resulting in continued long‐term glucocorticoid use and potential glucocorticoid‐associated morbidity. 3 , 4 , 5 In one meta‐analysis (>2,000 patients), glucocorticoid usage was 77%, 51%, and 25% at one, two, and five years, respectively. 6 In a registry study of 16,703 patients with PMR in the United States, 64% were still receiving glucocorticoids beyond one year. 7 Higher mean cumulative glucocorticoid doses are associated with adverse events (AEs) such as osteoporosis (P < 0.0001), fragility fractures (P < 0.0001), and arterial hypertension (P = 0.01), especially in patients receiving glucocorticoids for more than two years. 8 Long‐term glucocorticoid use has been associated with development of hyperglycemia, insulin resistance, and other metabolic effects. 9
Although interleukin‐6 receptor antagonists (sarilumab or tocilizumab) or methotrexate are used to treat patients with PMR, glucocorticoids remain the primary treatment option. 2 , 7 , 10 , 11 Thus, an unmet need exists for glucocorticoid‐sparing treatments for PMR, but PMR pathophysiology remains poorly defined, making identifying potential therapeutic targets a challenge.
ABBV‐154 is a novel antibody‐drug conjugate (ADC) comprising adalimumab (a human monoclonal anti–tumor necrosis factor [TNF]) antibody) conjugated to a proprietary glucocorticoid receptor modulator (GRM payload; an agonist of the glucocorticoid receptor that stimulates anti‐inflammatory glucocorticoid‐like effects). 12 By delivering the GRM payload to cells expressing transmembrane TNF, including activated immune cells, ABBV‐154 was designed to reduce systemic glucocorticoid exposure and risks of related side effects. 13 ABBV‐154 has been evaluated for PMR, rheumatoid arthritis, and Crohn disease in phase 2 clinical trials. 12 Although elevated levels of TNF were reported in symptomatic patients with PMR, 14 , 15 studies of anti‐TNF treatments have yielded mixed results, leaving the role of TNF in the disease pathology unclear. 16 , 17 , 18 , 19 , 20 , 21 Therefore, the primary mechanism of action of ABBV‐154 is expected via the anti‐inflammatory effects of the intracellular GRM payload.
We report the results of a placebo‐controlled study (AIM‐PMR) evaluating efficacy and safety of ABBV‐154 in patients with glucocorticoid‐dependent PMR receiving doses of ≥5 mg/day prednisone or equivalent.
PATIENTS AND METHODS
Study design and treatment
AIM‐PMR (study M20‐370; NCT04972968) was a phase 2, randomized, double‐blind, placebo‐controlled, dose‐ranging study conducted September 9, 2021, to July 24, 2023, across 70 centers in Australia, Austria, Canada, France, Germany, Hungary, Italy, Japan, Netherlands, New Zealand, Poland, Spain, United Kingdom, and the United States. The sponsor voluntarily terminated the study on April 27, 2023, after review of interim data and determining that ABBV‐154 did not demonstrate an adequately differentiated benefit‐risk profile compared with available therapies. Development of ABBV‐154 was discontinued based on the totality of data reviewed from studies on PMR, rheumatoid arthritis, and Crohn disease. The study was terminated before the planned primary analysis, which would have occurred after all patients had completed the week 24 visit or withdrawn from the study.
Per the study protocol, patients were randomized to treatment arms in a 2:1:1:1 ratio of placebo administered subcutaneously (SC) or ABBV‐154 SC once every other week in 40‐mg, 150‐mg, or 340‐mg doses. All patients received study drug in combination with an identical glucocorticoid taper (see Supplementary Table 1). The protocol was amended (February 2022) to a randomization ratio of 1:1:1:1 for each treatment arm, thereby decreasing the number of patients randomized to placebo. At baseline, patients received the same dose of oral prednisone/prednisolone (5–15 mg/day, rounded to the nearest milligram [provided by the sponsor]) as they had received immediately before the baseline visit. Beginning at week 3, all patients tapered glucocorticoid per identical schedules (Supplementary Table 1), based on the baseline glucocorticoid dose, to reach 0 mg/day by week 24. Patients remained off glucocorticoids unless a confirmed PMR flare occurred. Study visits occurred at baseline, week 1, week 2, and every other week for 52 weeks (per protocol), with a safety follow‐up visit performed approximately 70 days after the last study drug dose.
The independent ethics committee or institutional review board at each study site reviewed and approved the study protocol, informed consent forms, and recruitment materials before patient enrollment. The study was conducted in accordance with the International Conference for Harmonisation guidelines, applicable regulations, and the Declaration of Helsinki. All patients provided written informed consent before screening or undergoing any study‐specific procedures.
Patients and eligibility criteria
Enrolled patients (aged ≥50 years) met the 2012 EULAR/ACR provisional classification criteria for PMR 22 and had a confirmed PMR diagnosis. Eligible patients must have experienced a clinical response to glucocorticoids following PMR diagnosis and must have had two or more episodes of unequivocal PMR flare while attempting to taper glucocorticoids (prednisone dose ≥5 mg/day or equivalent at the time of flare and the most recent flare within 24 weeks of baseline). Unequivocal PMR flare was defined as clinical signs and symptoms of PMR (shoulder and/or hip girdle pain with inflammatory stiffness, neck pain with inflammatory stiffness, or new or worsened limited range of motion in the hips and/or shoulders) resulting in increased glucocorticoid dose. Inflammatory stiffness associated with flares was determined by the expert clinical judgments of the investigators based on patient‐reported symptoms and findings on physical examination; however, the study protocol did not specify any assessment of specific markers of inflammation. Patients must not have exhibited any clinical signs or symptoms of PMR within two weeks of baseline. They must have received a stable glucocorticoid dose (prednisone 5–15 mg/day or equivalent) for two or more weeks before baseline and must not have been treated with a prior TNF antagonist. Patients with giant cell arteritis, rheumatoid arthritis, inflammatory arthritis not due to PMR, or a positive test for anticitrullinated protein were ineligible.
Assessments
The primary efficacy endpoint was time to flare (defined as the presence of clinical signs and symptoms of PMR and requirement to increase the glucocorticoid dose per investigators). A subgroup analysis of time to flare by time since most recent flare before baseline (≤12 weeks vs >12 weeks) was conducted. Secondary efficacy endpoints were achievement of flare‐free state up to week 24, mean cumulative glucocorticoid dose by week 24, and change from baseline in glucocorticoid dose at week 24. Additional efficacy endpoints at week 24 were achievement of erythrocyte sedimentation rate (ESR) ≤30 mm/h, achievement of high‐sensitivity C‐reactive protein (hsCRP) less than or equal to the upper limit of normal (ULN), and time to flare based on Polymyalgia Rheumatica Activity Score (PMR‐AS) increase from baseline by ≥6.6 and also by ≥9.35. The PMR‐AS is a composite score that combines hsCRP, patient‐reported pain on a numerical rating scale (NRS; 0–10, higher scores indicating worse pain), Physician Global Assessment of Disease Activity (NRS 0–10; higher scores noting more activity), morning stiffness duration in minutes × 0.1, and elevation of upper limbs (scale of 3–0, with higher scores specifying less elevation).
Patient‐reported outcome endpoints included pain severity measured by NRS, stiffness severity measured by NRS (0–10, with higher scores indicating more stiffness), duration of morning stiffness, and the Health Assessment Questionnaire Disability Index (HAQ‐DI; scale of 0–3, with higher scores noting more disability). Pain and stiffness severity were based on patient‐recorded daily diaries. Analyses of stiffness duration and HAQ‐DI were based on data collected at site visits every four weeks. All patient‐reported outcome endpoints were evaluated for change from baseline to week 24.
Concentrations of ABBV‐154 (ie, serum ADC), serum total antibody, and plasma unconjugated GRM payload were measured at multiple postbaseline timepoints, including week 24 in patients who received ABBV‐154. Development of antidrug antibodies (ADAs) to ABBV‐154 was also evaluated from blood samples taken at baseline and every four weeks afterwards through the end of the study; if confirmed positive, titers were measured. Samples with confirmed ADA positivity were further evaluated using a validated neutralizing antibody (nAb) assay.
Safety assessments included monitoring treatment‐emergent AEs (TEAEs), defined as AEs that begin or worsen either on or after the first dose of study drug and within 70 days after the last dose of study drug. Any AEs of special interest (AESIs) were also monitored, including serious infections, opportunistic infections, active tuberculosis, serious allergic reactions, hypersensitivity reactions, malignancies, systemic glucocorticoid side effects, adrenal insufficiency, and iatrogenic Cushing syndrome. Investigators monitored signs and symptoms of adrenal insufficiency (eg, nausea, vomiting, lightheadedness, paleness, weight loss, hypotension, electrolyte abnormalities); if suspected, further assessment and management followed local standard of care. All TEAEs were coded using the Medical Dictionary of Regulatory Activities version 26.0. Safety assessments included laboratory analyses (hematology, clinical chemistry, and urinalysis parameters), vital signs, body weight monitoring, and 12‐lead electrocardiogram evaluations.
Statistical analyses
Because the goal of this study was to obtain initial data on efficacy and dose‐response relationships, a sample size of 40 patients in each treatment group was planned to ensure appropriate accrual of flares, based on an assumption of a total of 37 flares in the ABBV‐154 340‐mg group and the placebo group, and provided >90% power to detect a hazard ratio (HR) of 0.296 at a two‐sided significance level of 0.1. The primary analysis was planned to occur when the last patient reached their week 24 visit, and at that point in time, many other patients could have completed subsequent visits or the entire study. Thus, the HR of 0.296 was determined on the assumption that flares would occur during glucocorticoid tapering and up to 12 weeks afterward (up to week 36) and that 70% and 30% of patients would still be flare free by week 36 in the ABBV‐154 340‐mg and placebo groups, respectively. However, due to the voluntary early study termination, data were limited due to sample size and duration of study drug exposure.
Efficacy was evaluated in the intent‐to‐treat population (randomized patients who received one or more doses of study drug). Safety was evaluated in the safety population (randomized patients who received one or more doses of study drug).
For time‐to‐event endpoints, the number of events was compared between each ABBV‐154 dose and placebo based on log‐rank test with stratification factors. Median time to event and flare‐free rate (point and 95% confidence interval [CI]) for each group were reported based on Kaplan‐Meier curves. HRs and corresponding CIs for each ABBV‐154 group compared with placebo were estimated using Cox regression analysis adjusting for stratification factors. P values were provided by log‐rank test with stratification factors. For all analyses of time‐to‐event endpoints, patients without an event at the time of the analysis were administratively censored at the time of the last available assessment.
Categorical variables were assessed by comparison between each ABBV‐154 dose and placebo using the Cochran‐Mantel‐Haenszel test, adjusting for stratification factors, with nonresponder imputation incorporating multiple imputation to handle missing data due to COVID‐19. To handle missing values, continuous variables, other than glucocorticoid dose, were compared between each ABBV‐154 dose and placebo based on the mixed‐effect model repeated measures adjusting for visit, interaction between treatment and visit, actual values of stratification factors as fixed factors, and baseline value as a covariate. Glucocorticoid dose was analyzed by comparing each ABBV‐154 dose and placebo based on analysis of covariance, adjusting for stratification factors as fixed factors and baseline glucocorticoid dose as a covariate.
RESULTS
Patients
Overall, 235 patients were screened; 181 patients were randomized and dosed (placebo, n = 50; ABBV‐154: 40 mg, n = 42; 150 mg, n = 45; 340 mg, n = 44) (Figure 1). Furthermore, 67.4% of patients completed study drug to week 24; the most common reason for study drug discontinuation was termination of the study by the sponsor (n = 40 [22.1%]). In total, 19.3% of patients completed study drug to week 52, with termination of the study by the sponsor remaining the most common reason for discontinuation from study drug for 112 (61.9%) patients.
Figure 1.
Patient disposition during the double‐blind treatment period (full analysis set).
The mean overall age (69.4 years) of patients was relatively balanced between treatment groups (Table 1). Most patients were female (64.6%) and White (87.8%). The median overall duration of PMR was 1.6 years; 59.6% of patients reported their most recent flare within ≤12 weeks of baseline. Most patients (61.3%) had received glucocorticoid treatment for PMR more than one year before baseline, and the median glucocorticoid dose was 10 mg/day at baseline.
Table 1.
Baseline demographics and disease characteristics (full analysis set)*
| Characteristic | Placebo (n = 50) | ABBV‐154 | ||
|---|---|---|---|---|
| 40 mg (n = 42) | 150 mg (n = 45) | 340 mg (n = 44) | ||
| Female, n (%) | 33 (66.0) | 30 (71.4) | 25 (55.6) | 29 (65.9) |
| Age, y, mean ± SD | 71.0 ± 7.2 | 67.5 ± 8.0 | 69.8 ± 8.3 | 69.1 ± 6.2 |
| Race, n (%) | ||||
| White | 42 (84.0) | 37 (88.1) | 41 (91.1) | 39 (88.6) |
| Asian | 8 (16.0) | 5 (11.9) | 4 (8.9) | 5 (11.4) |
| Hispanic or Latino, n (%) | 1 (2.0) | 0 | 2 (4.4) | 2 (4.5) |
| BMI, mean ± SD | 28.2 ± 5.5 | 28.4 ± 5.5 | 27.9 ± 4.5 | 29.1 ± 5.1 |
| Duration of PMR, y, median (range) | 2.0 (0.2–22.1) | 1.2 (0.3–10.5) | 1.3 (0.3–11.3) | 1.8 (0.3–12.0) |
| Time since last PMR flare, a n (%) | 49 | 40 | 45 | 44 |
| ≤12 wk | 27 (55.1) | 23 (57.5) | 25 (55.6) | 31 (70.5) |
| >12 wk | 22 (44.9) | 17 (42.5) | 20 (44.4) | 13 (29.5) |
| hsCRP ± mg/L, mean ± SD | 8.6 ± 14.4 | 5.0 ± 8.5 | 4.4 ± 6.9 | 5.2 ± 13.0 |
| ESR ± mm/h, mean ± SD | 25.1 ± 17.2 | 22.7 ± 17.6 | 17.6 ± 14.1 | 18.9 ± 15.2 |
| Glucocorticoid dose (mg/day), b mean ± SD | 9.2 (3.8) | 9.5 (3.4) | 9.1 (3.5) | 9.5 (3.3) |
| Duration of prior glucocorticoid treatment for PMR, n (%) | ||||
| ≤1 y | 16 (32.0) | 17 (40.5) | 18 (40.0) | 19 (43.2) |
| >1 y | 34 (68.0) | 25 (59.5) | 27 (60.0) | 25 (56.8) |
| Prior bDMARDs and/or csDMARDs, n (%) | ||||
| bDMARD c | 0 | 1 (2.4) | 0 | 2 (4.5) |
| csDMARD d | 16 (32.0) | 15 (35.7) | 10 (22.2) | 17 (38.6) |
| Pain NRS, mean ± SD; n | 3.4 ± 2.6; 49 | 3.0 ± 2.8 | 2.9 ± 2.4; 44 | 3.2 ± 2.7; 43 |
| Stiffness NRS, mean ± SD; n | 2.0 ± 1.9; 26 | 2.3 ± 2.5; 24 | 3.1 ± 2.0; 29 | 2.6 ± 2.6; 22 |
| HAQ‐DI, mean ± SD; n | 0.7 ± 0.6; 49 | 0.7 ± 0.6; 40 | 0.6 ± 0.6; 41 | 0.7 ± 0.6; 41 |
BMI, body mass index; bDMARD, biologic disease‐modifying antirheumatic drug; csDMARD, conventional synthetic disease‐modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; HAQ‐DI, Health Assessment Questionnaire Disability Index; hsCRP, high‐sensitivity C‐reactive protein; NRS, numerical rating scale; PMR, polymyalgia rheumatica.
Percentages calculated on nonmissing values.
Glucocorticoid dose is calculated based on the prednisone equivalent dose.
Sarilumab or tocilizumab.
Azathioprine, bucillamine, iguratimod, leflunomide, methotrexate/methotrexate sodium, sulfasalazine, or tacrolimus monohydrate.
The mean ± SD duration of study drug exposure in the placebo group was 235.2 ± 109.0 days and in the ABBV‐154 cohorts was 239.9 ± 95.7 days with 40 mg, 234.6 ± 106.3 days with 150 mg, and 230.3 ± 89.8 days with 340 mg.
Efficacy
The primary endpoint, time to flare, was longer for patients in the ABBV‐154 cohorts than in the placebo cohort (Figure 2A), with 24‐week flare‐free rate based on Kaplan‐Meier estimate being lower for placebo. The HRs of ABBV‐154 vs placebo were 0.49 (95% CI, 0.27–0.88), P = 0.017 for the 40 mg ABBV‐154 dose; 0.44 (95% CI, 0.25–0.79), P = 0.006 for 150 mg; and 0.20 (95% CI, 0.09–0.42), P < 0.001 for 340 mg. In a subgroup analysis of time to flare by time since most recent flare before baseline, a numerically higher proportion of patients with flares ≤12 weeks before baseline had flares regardless of treatment group than patients with flares >12 weeks before baseline (placebo, 74.1% vs 59.1%; ABBV‐154 40 mg, 60.9% vs 23.5%; ABBV‐154 150 mg, 44.0% vs 35.0%; ABBV‐154 340 mg, 22.6% vs 15.4%, respectively). Based on Kaplan‐Meier estimate among patients with flares ≤12 weeks before baseline, the estimated 24‐week flare‐free rates were lower with placebo than any ABBV‐154 dose group. The HRs of ABBV‐154 versus placebo were 0.59 (95% CI, 0.29–1.19), P = 0.140 for the 40‐mg dose; 0.37 (95% CI, 0.17–0.78), P = 0.009 for the 150‐mg dose; and 0.15 (95% CI, 0.06–0.38), P < 0.001 for the 340‐mg dose (Figure 2B). The 24‐week flare‐free rate was lower with placebo than with ABBV‐154 in those who experienced their last flare >12 weeks before baseline. The HRs of ABBV‐154 versus placebo were 0.27 (95% CI, 0.08–0.88), P = 0.030 for the 40‐mg dose; 0.44 (95% CI, 0.17–1.15), P = 0.093 for the 150‐mg dose; and 0.22 (95% CI, 0.05–1.03), P = 0.054 for the 340‐mg dose (Figure 2C).
Figure 2.
Kaplan‐Meier curves for time to flare (ITT population). (A) Time to flare overall, (B) time to flare in patients whose most recent flare occurred ≤12 weeks before baseline, and (C) time to flare in patients whose most recent flare occurred >12 weeks before baseline. EOW, every other week; ITT, intent‐to‐treat; Q2W, every two weeks.
Secondary endpoints included achievement of flare‐free state up to week 24, cumulative glucocorticoid dose by week 24, and change from baseline in glucocorticoid dose at week 24. Compared with patients receiving placebo (28.2%; 95% CI, 14.1–42.3), a higher proportion of patients receiving ABBV‐154 achieved a flare‐free state up to week 24 (40 mg: 46.4% [95% CI, 28.0–64.9]; P = 0.107; 150 mg: 46.9% [95% CI, 29.6–64.2]; P = 0.092; 340 mg: 70.6% [95% CI, 55.3–85.9]; P < 0.001) (Figure 3).
Figure 3.
Proportion of patients achieving flare‐free state at week 24 (ITT population). The 95% CI for the response rate is based on the normal approximation to the binomial distribution. The P value for the difference between each ABBV‐154 group and the placebo group is from Cochran‐Mantel‐Haenszel test adjusting for baseline randomization stratification factors (glucocorticoid use at baseline [≥10 mg/day; <10 mg/day prednisone equivalent]) and length of prior glucocorticoid treatment for PMR (≤1 year; >1 year). Patients with missing assessments who were flare free at the previous visit were imputed as flare free for the missing assessment. Missing assessments for patients who had a flare or had intercurrent events were imputed as flare. *** P < 0.001. CI, confidence interval; ITT, intent‐to‐treat; PMR, polymyalgia rheumatica; Q2W, every two weeks.
The mean (95% CI) treatment difference (ABBV‐154 − placebo) showed that cumulative glucocorticoid dose by week 24 was higher for patients receiving placebo than ABBV‐154 (ABBV‐154 40 mg, −88.7 mg [95% CI, −208.0 to 30.7]; P = 0.144; ABBV‐154 150 mg, −164.8 mg [95% CI, −283.6 to −45.9]; P = 0.007; ABBV‐154 340 mg, −182.6 mg [95% CI, −300.5 to −64.6]; P = 0.003) (Figure 4A). Also, the mean (95% CI) treatment difference for change from baseline in daily glucocorticoid dose at week 24 supported that patients receiving placebo experienced smaller reductions in glucocorticoid use than those receiving ABBV‐154 (ABBV‐154 40 mg, −1.6 [95% CI, −3.1 to −0.1]; P = 0.039; ABBV‐154 150 mg, −2.7 [95% CI, −4.2 to −1.2]; P < 0.001; ABBV‐154 340 mg, −3.0 [95% CI, −4.5 to −1.5]; P < 0.001) (Figure 4B).
Figure 4.
Dose of glucocorticoid (ITT population). (A) Mean cumulative dose (mg) at week 24 and (B) mean (95% CI) change from baseline to week 24 (mg/day). Data shown as observed for number of patients with measurements at baseline and week 24. The P values are based on an ANCOVA model adjusting for baseline randomization stratification factors (glucocorticoid use at baseline [≥10 mg/day; <10 mg/day prednisone equivalent]), length of prior glucocorticoid treatment for PMR (≤1 year; >1 year), and baseline glucocorticoid dose to compare ABBV‐154 with placebo. For change from baseline, patients with one or more available change from baseline value and no missing data for the factors and covariates in the model. * P ≤ 0.05; ** P ≤ 0.01; *** P ≤ 0.001. ANCOVA, analysis of covariance; CI, confidence interval; ITT, intent‐to‐treat; PMR, polymyalgia rheumatica; Q2W, every 2 weeks. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.43129/abstract.
Compared with placebo, more patients receiving ABBV‐154 achieved ESR ≤30 mm/h (difference in response rate ABBV‐154 vs placebo: 40 mg, 15.6% [95% CI, −0.1–31.3]; P = 0.051; 150 mg, 23.9% [95% CI, 7.4–40.4]; P = 0.005; 340 mg, 33.5% [95% CI, 17.0–49.9]; P < 0.001) (Supplementary Figure 1A). Similarly, compared with placebo, a higher proportion of patients receiving ABBV‐154 achieved hsCRP less than or equal to the ULN (difference in response rate ABBV‐154 vs placebo: 40 mg, 9.2% [95% CI, −6.1 to 24.4]; P = 0.239; 150 mg, 16.7% [95% CI, 0.2–33.3]; P = 0.047; 340 mg, 30.8% [95% CI, 13.6–48.1]; P < 0.001) (Supplementary Figure 1B).
Patient‐reported outcomes
Patient‐reported outcomes are reported at week 24. The weekly average patient assessment of pain severity was reduced compared with placebo from baseline through the majority of study weeks in the ABBV‐154 340‐mg group (week 24: placebo: 0.3, 95% CI, −0.4 to 0.9; ABBV‐154 340 mg: −1.1, 95% CI, −1.7 to −0.6; P = 0.002) (Supplementary Figure 2A).
Compared with placebo (1.8; 95% CI, 0.7–2.8), stiffness severity reduced in weekly average rating from baseline in the ABBV‐154 150 mg (−0.3, 95% CI, −1.0 to 0.4; P = 0.001) and 340 mg groups (−1.3, 95% CI, −2.1 to −0.5; P < 0.001) (Supplementary Figure 2B).
The duration of morning stiffness did not change from baseline, except in the ABBV‐154 40‐mg group, which had an increase in daily morning stiffness duration from baseline (181.3 minutes/day; 95% CI, 102.7–260.0; P = 0.006) (Supplementary Figure 2C); however, three patients had outlying data during weeks 20 to 24 possibly due to data entry errors.
There were no differences from baseline in HAQ‐DI scores in any treatment group (Supplementary Figure 2D).
Pharmacokinetics and immunogenicity
The geometric mean trough total ABBV‐154 concentrations were 1.70, 6.29, and 25.9 μg/mL for the 40‐, 150‐, and 340‐mg doses, respectively, and the geometric mean trough total antibody concentrations were 1.02, 6.15, and 29.9 μg/mL at week 24, respectively. The unconjugated GRM payload reached geometric trough concentrations of 0.028, 0.065, and 0.177 ng/mL at week 24 in the ABBV‐154 40, 150, and 340 mg dose groups, respectively.
ABBV‐154 showed typical ADC pharmacokinetics in patients with PMR, with antibody‐like pharmacokinetic profiles for the ADC and total antibody, and a formation‐rate–limited pharmacokinetic profile for the unconjugated GRM payload with plasma concentrations that were several orders of magnitude lower than serum concentrations of total ABBV‐154 and total antibody.
At baseline, preexisting ADAs and nAbs were detected in 13.6% (17 of 125) and 0.8% (1 of 125), respectively, of patients who received one or more doses of ABBV‐154 during the study. Treatment‐emergent ADA incidence was 83.1% (108 of 130), while nAb incidence was 19.2% (25 of 130) among evaluable patients receiving ABBV‐154. ADA incidence was associated with lower ADC exposure. However, no clear trends were detected between ADA incidence and efficacy outcomes.
Safety and tolerability
The majority of patients experienced TEAEs with similar rates between groups (Table 2). The most common TEAEs in the ABBV‐154 groups were COVID‐19, nasopharyngitis, and arthralgia, with relatively low rates of grade ≥3 TEAEs, serious AEs, and treatment discontinuations due to TEAEs. The highest rate of treatment discontinuation due to a TEAE occurred in the ABBV‐154 340‐mg group. No deaths occurred during the study.
Table 2.
TEAEs during the double‐blind treatment period (full analysis set)*
| TEAE, n (%) | Placebo (n = 50) | ABBV‐154 | ||
|---|---|---|---|---|
| 40 mg (n = 42) | 150 mg (n = 45) | 340 mg (n = 44) | ||
| Safety overview | ||||
| Any TEAE | 41 (82.0) | 32 (76.2) | 39 (86.7) | 41 (93.2) |
| COVID‐19–related TEAE | 9 (18.0) | 9 (21.4) | 5 (11.1) | 7 (15.9) |
| TEAE with reasonable possibility of being drug related | 17 (34.0) | 15 (35.7) | 21 (46.7) | 29 (65.9) |
| Grade ≥3 TEAE | 9 (18.0) | 6 (14.3) | 7 (15.6) | 8 (18.2) |
| SAE | 8 (16.0) | 5 (11.9) | 8 (17.8) | 9 (20.5) |
| TEAE leading to study drug discontinuation | 3 (6.0) | 1 (2.4) | 1 (2.2) | 7 (15.9) |
| TEAE leading to death | 0 | 0 | 0 | 0 |
| Most common TEAEs a | ||||
| COVID‐19 | 9 (18.0) | 9 (21.4) | 5 (11.1) | 7 (15.9) |
| Nasopharyngitis | 3 (6.0) | 4 (9.5) | 4 (8.9) | 7 (15.9) |
| Arthralgia | 3 (6.0) | 4 (9.5) | 6 (13.3) | 3 (6.8) |
| Urinary tract infection | 5 (10.0) | 3 (7.1) | 2 (4.4) | 7 (15.9) |
| Headache | 2 (4.0) | 3 (7.1) | 4 (8.9) | 4 (9.1) |
| Fatigue | 2 (4.0) | 3 (7.1) | 4 (8.9) | 2 (4.5) |
| Hypertension | 5 (10.0) | 1 (2.4) | 4 (8.9) | 3 (6.8) |
| Nausea | 2 (4.0) | 3 (7.1) | 2 (4.4) | 3 (6.8) |
| Pneumonia | 0 | 2 (4.8) | 1 (2.2) | 5 (11.4) |
| Contusion | 0 | 2 (4.8) | 2 (4.4) | 3 (6.8) |
| Diarrhea | 4 (8.0) | 2 (4.8) | 2 (4.4) | 3 (6.8) |
| Injection site erythema | 0 | 2 (4.8) | 3 (6.7) | 2 (4.5) |
| Rash | 2 (4.0) | 2 (4.8) | 2 (4.4) | 3 (6.8) |
| Upper respiratory tract infection | 2 (4.0) | 2 (4.8) | 3 (6.7) | 2 (4.5) |
| AEs of special interest | ||||
| Serious infections | 1 (2.0) | 1 (2.4) | 3 (6.7) | 6 (13.6) |
| Serious infections excluding COVID‐19–related AEs | 1 (2.0) | 1 (2.4) | 3 (6.7) | 6 (13.6) |
| Opportunistic infections | 0 | 0 | 0 | 0 |
| Active TB | 0 | 0 | 0 | 0 |
| Hypersensitivity reactions | 4 (8.0) | 4 (9.5) | 8 (17.8) | 7 (15.9) |
| Serious allergic reactions | 0 | 0 | 0 | 0 |
| Malignancies | 0 | 2 (4.8) | 2 (4.4) | 2 (4.5) |
| Malignancies excluding NMSC | 0 | 0 | 0 | 2 (4.5) b |
| NMSC | 0 | 2 (4.8) | 2 (4.4) | 0 |
| Lymphoma | 0 | 0 | 0 | 0 |
| Adjudicated systemic glucocorticoid side effects c | 1 (2.0) | 3 (7.1) | 1 (2.2) | 1 (2.3) |
| Adrenal insufficiency | 0 | 0 | 0 | 0 |
| Iatrogenic Cushing syndrome | 0 | 0 | 0 | 1 (2.3) |
AE, adverse event; NMSC, nonmelanoma skin cancer; SAE, serious adverse event; TB, tuberculosis; TEAE, treatment‐emergent adverse event.
Most common defined as >5% incidence of TEAEs in any ABBV‐154 dose cohort.
One event of acute myeloid leukemia (considered by the investigator as possibly related to study treatment) and 1 event of prostate cancer (considered by the investigator as having no reasonable possibility of being related to study treatment).
Reviewed by an Independent Adjudication Committee.
More AESIs occurred in the ABBV‐154 340‐mg group compared with the other treatment groups (Table 2). The most common AESIs were serious infections and hypersensitivity reactions. Serious infections included pneumonia (5 events), urinary tract infection (1 event), and cellulitis (1 event) in the ABBV‐154 340‐mg group; respiratory tract infection (1 event), lower respiratory tract infection (1 event), and urosepsis (1 event) in the ABBV‐154 150‐mg group; and perforated appendicitis (1 event) and peritonitis (1 event) in the same patient in the ABBV‐154 40‐mg group. Possibly treatment‐related serious infections (by investigators’ assessments) in the ABBV‐154 groups were pneumonia (5 events), respiratory tract infection (1 event), lower respiratory tract infection (1 event), and urosepsis (1 event).
All hypersensitivity reactions were mild or moderate. Hypersensitivity reactions in the ABBV‐154 groups considered possibly treatment related were injection site rash (10 events), rash (2 events), injection site urticaria (1 event), and toxic skin reaction (1 event). Malignancies observed in the ABBV‐154 treatment groups included mild‐or‐moderate nonmelanoma skin cancer (40 mg, 2 events; 150 mg, 2 events), severe acute myeloid leukemia (340 mg, 1 event), and severe prostate cancer (340 mg, 1 event). Two malignancies were considered possibly treatment related by investigators (ABBV‐154 150 mg, 1 event of nonmelanoma skin cancer; ABBV‐154 340 mg, 1 event of acute myeloid leukemia). The few observed adjudicated systemic glucocorticoid side effects occurred at a similar rate among placebo and ABBV‐154 treatment groups.
Changes were observed in laboratory values, vital signs, or electrocardiogram assessments. However, a higher proportion of patients in the ABBV‐154 groups experienced a >7% decrease in body weight (40 mg, 11.9% [n = 5]; 150 mg, 15.9% [n = 7]; 340 mg, 18.2% [n = 8]) compared with the placebo group (6.3% [n = 3]).
DISCUSSION
This study reports the efficacy and safety of ABBV‐154, a novel ADC comprising adalimumab conjugated to a proprietary GRM payload 12 versus placebo in patients with glucocorticoid‐dependent PMR. A treatment effect was observed in all three ABBV‐154 groups, with longer time to flare (primary endpoint) in the ABBV‐154 groups compared with placebo.
A higher proportion of patients receiving ABBV‐154 than placebo achieved flare‐free state up to week 24. By week 24, patients receiving ABBV‐154 (vs placebo) had lower cumulative dose of glucocorticoid and greater reduction from baseline in daily glucocorticoid dose. Similarly, a higher proportion of patients receiving ABBV‐154 showed improvement in markers of inflammation by week 24 than those receiving placebo. In patient‐reported outcomes collected to week 24, results reflecting primary symptoms experienced daily by patients revealed potential improvements among some treatment arms; pain severity was reduced from baseline in the ABBV‐154 340‐mg group, and stiffness severity was reduced from baseline in the ABBV‐154 150‐ and 340‐mg groups. The four‐week assessments of morning stiffness duration and physical function (HAQ‐DI) did not improve from baseline regardless of treatment group, which may indicate the need for more precise assessment of these concepts in PMR, with greater frequency of measurement and instruments more specific to PMR for physical function. Furthermore, patients in this study had controlled PMR, making observation of improvement difficult.
Although data were limited due to early study termination, ABBV‐154 was generally well tolerated in patients with PMR. Rates of hypersensitivity reactions were higher in the ABBV‐154 150 mg and 340 mg groups than in the ABBV‐154 40 mg or placebo groups (Table 2). All hypersensitivity reactions were mild or moderate in severity. Serious infections occurred in few patients and were more frequent in the ABBV‐154 340‐mg (n = 6) group than in all other groups (placebo n = 1, ABBV‐154 40 mg n = 1, 150 mg n = 3).
This study had several limitations. Due to the voluntary early termination of the study, the available data set had a limited sample size, variable duration of exposure to study drug, and a wide range of PMR durations. Moreover, as a phase 2 study exploring initial efficacy and dose response, statistical comparisons for efficacy outcomes used a two‐sided α of 0.1 without multiplicity control, which could increase the potential for Type I error. Thus, interpretation of data should be treated with caution. In addition, including an adalimumab comparator arm would have been interesting to elucidate further and confirm the contribution of the GRM payload to efficacy and safety in PMR; however, an adalimumab comparator arm was not included in this study because current EULAR/ACR recommendations for PMR recommend against using anti‐TNF agents (primarily based on small randomized controlled trials with etanercept and infliximab). 2 The safety of ABBV‐154 cannot be directly compared with adalimumab or glucocorticoids due to the early study termination and lack of adalimumab comparator arm; for example, we could not determine whether the higher rate of serious infections in the ABBV‐154 340‐mg group was due to higher antibody exposure, higher systemic exposure to the GRM payload, or chance. The identical 24‐week oral glucocorticoid taper in all arms may be viewed as both a strength and a weakness because it allows for a direct comparison of glucocorticoid use between treatment arms, but it may also be faster than the taper that some other clinical trials have utilized in the placebo group. 23 A subgroup analysis suggested that time since most recent flare may be associated with a likelihood of developing a PMR flare while tapering glucocorticoid. Further studies may benefit from including patients with the most recent PMR flare closer to baseline than the 24 weeks required in this trial, facilitating the enrollment of patients with active disease (albeit controlled at baseline). Finally, comparison with other studies may be limited because the PMR‐AS was not included as a primary or secondary endpoint (see Supplementary Table 2 for PMR‐AS data).
The ADC ABBV‐154, comprising the anti‐TNF antibody adalimumab conjugated to the anti‐inflammatory GRM payload, was developed to reduce the risks of systemic glucocorticoid‐related AEs by delivering the GRM to cells that express transmembrane TNF, including activated immune cells. 12 , 13 However, an interim data review determined that the benefit‐risk profile did not sufficiently differentiate ABBV‐154 from other currently available therapies for PMR; consequently, the sponsor decided to cease development of ABBV‐154 and terminate the study early due to the lack of differentiation and not due to safety reasons.
In conclusion, ABBV‐154 was generally well tolerated with benefits observed versus placebo demonstrating longer time to flare, fewer flares, and reduction in cumulative glucocorticoid dose, markers of inflammation, pain severity, and stiffness severity. However, given the limited sample size and duration of exposure to study drug, no definite conclusions can be drawn from this study of ABBV‐154 in patients with PMR and caution should be exercised when interpreting the results. Nevertheless, this study supports that a GRM payload targeted to transmembrane TNF‐expressing cells, including activated immune cells, could be beneficial in PMR.
AUTHOR CONTRIBUTIONS
All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Spiera confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements. No honoraria or payments were made for authorship.
ROLE OF THE STUDY SPONSOR
AbbVie participated in the study design, research, data collection, analysis, interpretation of data, reviewing, and approval of this manuscript. Publication of this article was not contingent upon approval by AbbVie. Medical writing support was provided by Abegale Templar, PhD, and Ray Beck Jr, PhD, of JB Ashtin and funded by AbbVie.
Supporting information
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Appendix S1: Supplementary Information
ACKNOWLEDGMENTS
AbbVie and the authors thank all study investigators for their contributions and the patients who participated in this study.
ClinicalTrials.gov identifier: NCT04972968.
Supported by AbbVie Inc.
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized individual and trial‐level data (analysis data sets), as well as other information (eg, protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this manuscript for publication. These data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://vivli.org/ourmember/abbvie/ then select “Home. ”
Additional supplementary information cited in this article can be found online in the Supporting Information section (https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.43129).
Author disclosures are available at https://onlinelibrary.wiley.com/doi/10.1002/art.43129.
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Appendix S1: Supplementary Information