We previously reported durable responses and manageable safety of ibrutinib from a 3-year follow-up of treatment-naïve (TN) older patients (≥65 years of age) and relapsed/refractory (R/R) patients ...with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We now report on long-term efficacy and safety with median follow-up of 5 years in this patient population with TN (N = 31) and R/R (N = 101) CLL/SLL. With the current 5-year follow-up, ibrutinib continues to yield a high overall response rate of 89%, with complete response rates increasing over time to 29% in TN patients and 10% in R/R patients. The median progression-free survival (PFS) was not reached in TN patients. The 5-year PFS rate was 92% in TN patients and 44% in R/R patients. Median PFS in R/R patients was 51 months; in those with del(11q), del(17p), and unmutated IGHV, it was 51, 26, and 43 months, respectively, demonstrating long-term efficacy of ibrutinib in some high-risk subgroups. Survival outcomes were less robust for R/R patients with del(17p) and those who received more prior therapies. The onset of grade ≥3 cytopenias, such as neutropenia and thrombocytopenia, decreased over time. Treatment--limiting adverse events were more frequent during the first year compared with subsequent periods. These results demonstrate sustained efficacy and acceptable tolerability of ibrutinib over an extended time, providing the longest experience for Bruton tyrosine kinase inhibitor treatment in patients with CLL/SLL. These trials were registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01109069.
•Our 5-year experience shows sustained single-agent efficacy of ibrutinib in CLL patients, with complete response rates increasing over time.•Long-term ibrutinib was well tolerated with no new safety signals; rates of grade ≥3 cytopenias decreased with continued therapy.
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Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, and tyrosine kinase 2. We aimed to assess the efficacy and safety of upadacitinib ...compared with placebo for the treatment of moderate-to-severe atopic dermatitis.
Measure Up 1 and Measure Up 2 were replicate multicentre, randomised, double-blind, placebo-controlled, phase 3 trials; Measure Up 1 was done at 151 clinical centres in 24 countries across Europe, North and South America, Oceania, and the Asia-Pacific region; and Measure Up 2 was done at 154 clinical centres in 23 countries across Europe, North America, Oceania, and the Asia-Pacific region. Eligible patients were adolescents (aged 12–17 years) and adults (aged 18–75 years) with moderate-to-severe atopic dermatitis (≥10% of body surface area affected by atopic dermatitis, Eczema Area and Severity Index EASI score of ≥16, validated Investigator's Global Assessment for Atopic Dermatitis vIGA-AD score of ≥3, and Worst Pruritus Numerical Rating Scale score of ≥4). Patients were randomly assigned (1:1:1) using an interactive response technology system to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks, stratified by baseline disease severity, geographical region, and age. Coprimary endpoints were the proportion of patients who had achieved at least a 75% improvement in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 clear or 1 almost clear with ≥2 grades of reduction from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2), and are both active but not recruiting.
Between Aug 13, 2018, and Dec 23, 2019, 847 patients were randomly assigned to upadacitinib 15 mg (n=281), upadacitinib 30 mg (n=285), or placebo (n=281) in the Measure Up 1 study. Between July 27, 2018, and Jan 17, 2020, 836 patients were randomly assigned to upadacitinib 15 mg (n=276), upadacitinib 30 mg (n=282), or placebo (n=278) in the Measure Up 2 study. At week 16, the coprimary endpoints were met in both studies (all p<0·0001). The proportion of patients who had achieved EASI-75 at week 16 was significantly higher in the upadacitinib 15 mg (196 70% of 281 patients) and upadacitinib 30 mg (227 80% of 285 patients) groups than the placebo group (46 16% of 281 patients) in Measure Up 1 (adjusted difference in EASI-75 response rate vs placebo, 53·3% 95% CI 46·4–60·2 for the upadacitinib 15 mg group; 63·4% 57·1–69·8 for the upadacitinib 30 mg group) and Measure Up 2 (166 60% of 276 patients in the upadacitinib 15 mg group and 206 73% of 282 patients in the upadacitinib 30 mg group vs 37 13% of 278 patients in the placebo group; adjusted difference in EASI-75 response rate vs placebo, 46·9% 39·9–53·9 for the upadacitinib 15 mg group; 59·6% 53·1–66·2 for the upadacitinib 30 mg group). The proportion of patients who achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg (135 48% patients) and upadacitinib 30 mg (177 62% patients) groups than the placebo group (24 8% patients) in Measure Up 1 (adjusted difference in vIGA-AD response rate vs placebo, 39·8% 33·2–46·4 for the upadacitinib 15 mg group; 53·6% 47·2–60·0 for the upadacitinib 30 mg group) and Measure Up 2 (107 39% patients in the upadacitinib 15 mg group and 147 52% patients in the upadacitinib 30 mg group vs 13 5% patients in the placebo group; adjusted difference in vIGA-AD response rate vs placebo, 34·0% 27·8–40·2 for the upadacitinib 15 mg group; 47·4% 41·0–53·7 for the upadacitinib 30 mg group). Both upadacitinib doses were well tolerated. The incidence of serious adverse events and adverse events leading to study drug discontinuation were similar among groups. The most frequently reported treatment-emergent adverse events were acne (19 7% of 281 patients in the upadacitinib 15 mg group, 49 17% of 285 patients in the upadacitinib 30 mg group, and six 2% of 281 patients in the placebo group in Measure Up 1; 35 13% of 276 patients in the upadacitinib 15 mg group, 41 15% of 282 patients in the upadacitinib 30 mg group, and six 2% of 278 patients in the placebo group in Measure Up 2), upper respiratory tract infection (25 9% patients, 38 13% patients, and 20 7% patients; 19 7% patients, 17 16% patients, and 12 4% patients), nasopharyngitis (22 8% patients, 33 12% patients, and 16 6% patients; 16 6% patients, 18 6% patients, and 13 5% patients), headache (14 5% patients, 19 7% patients, and 12 4% patients; 18 7% patients, 20 7% patients, and 11 4% patients), elevation in creatine phosphokinase levels (16 6% patients, 16 6% patients, and seven 3% patients; nine 3% patients, 12 4% patients, and five 2% patients), and atopic dermatitis (nine 3% patients, four 1% patients, and 26 9% patients; eight 3% patients, four 1% patients, and 26 9% patients).
Monotherapy with upadacitinib might be an effective treatment option and had a positive benefit–risk profile in adolescents and adults with moderate-to-severe atopic dermatitis.
AbbVie.
Primary (week 16) results from the ongoing phase 3, double-blind AD Up study (NCT03568318) demonstrate a positive benefit–risk profile for upadacitinib + topical corticosteroid (TCS) in patients with ...moderate-to-severe atopic dermatitis.
We evaluated the efficacy and safety of upadacitinib + TCS through 52 weeks.
Patients aged 12 to 75 years with chronic moderate-to-severe atopic dermatitis (≥10% of body surface area affected, Eczema Area and Severity Index EASI ≥16, Validated Investigator’s Global Assessment for atopic dermatitis vIGA-AD ≥3, and Worst Pruritus Numerical Rating Scale WP-NRS score ≥4) were randomized 1:1:1 to once-daily upadacitinib 15 mg + TCS, upadacitinib 30 mg + TCS, or placebo (PBO) + TCS (rerandomized at week 16 to upadacitinib + TCS). Safety and efficacy, including proportion of patients experiencing ≥75% improvement in EASI (EASI-75), vIGA-AD of clear/almost clear with improvement ≥2 grades (vIGA-AD 0/1), and WP-NRS improvement ≥4, were assessed through week 52. Missing data were primarily handled by nonresponse imputation incorporating multiple imputation for missing values due to coronavirus disease 2019 (COVID-19).
Of 901 patients, 300 were randomized to upadacitinib 15 mg + TCS, 297 to upadacitinib 30 mg + TCS, and 304 to PBO + TCS. For all end points, efficacy for upadacitinib 15 mg + TCS and upadacitinib 30 mg + TCS at week 16 was maintained through week 52. At week 52, the proportions of patients treated with upadacitinib 15 mg + TCS and upadacitinib 30 mg + TCS who experienced EASI-75 were 50.8% and 69.0%, respectively; 33.5% and 45.2%, respectively, experienced vIGA-AD 0/1; and 45.3% and 57.5%, respectively, experienced WP-NRS improvement ≥4. Upadacitinib + TCS was well tolerated through 52 weeks; no new important safety risks beyond the current label were observed. No deaths were reported; major adverse cardiovascular events and venous thromboembolic events were infrequent (≤0.2/100 patient-years).
Results through 52 weeks demonstrate long-term maintenance of efficacy and a favorable safety profile of upadacitinib + TCS in patients with moderate-to-severe AD.
Summary Background The TP53 gene, encoding tumour suppressor protein p53, is located on the short arm of chromosome 17 (17p). Patients with 17p deletion (del17p) chronic lymphocytic leukaemia have ...poor responses and survival after chemoimmunotherapy. We assessed the activity and safety of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, in relapsed or refractory patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma. Methods We did a multicentre, international, open-label, single-arm study at 40 sites in the USA, Canada, Europe, Australia, and New Zealand. Patients (age ≥18 years) with previously treated del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma received oral ibrutinib 420 mg once daily until progressive disease or unacceptable toxicity. The primary endpoint was overall response in the all-treated population per International Workshop on Chronic Lymphocytic Leukaemia 2008 response criteria modified for treatment-related lymphocytosis. Preplanned exploratory analyses were progression-free survival, overall survival, sustained haematological improvement, and immunological improvement. Patient enrolment is complete, but follow-up is ongoing. Treatment discontinuation owing to adverse events, unacceptable toxicity, or death were collected as a single combined category. This study is registered with ClinicalTrials.gov , number NCT01744691. Findings Between Jan 29, 2013, and June 19, 2013, 145 patients were enrolled. The all-treated population consisted of 144 patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma who received at least one dose of study drug, with a median age of 64 years (IQR 57–72) and a median of two previous treatments (IQR 1–3). At the prespecified primary analysis after a median follow-up of 11·5 months (IQR 11·1–13·8), 92 (64%, 95% CI 56–71) of 144 patients had an overall response according to independent review committee assessment; 119 patients (83%, 95% CI 76–88) had an overall response according to investigator assessment. In an extended analysis with median follow-up of 27·6 months (IQR 14·6–27·7), the investigator-assessed overall response was reported in 120 patients (83%, 95% CI 76–89). 24-month progression-free survival was 63% (95% CI 54–70) and 24-month overall survival was 75% (67–81). Sustained haematological improvement was noted in 72 (79%) of 91 patients with any baseline cytopenia. No clinically relevant changes were noted from baseline to 6 months or 24 months in IgA (median 0·4 g/L at baseline, 0·6 g/L at 6 months, and 0·7 g/L at 24 months), IgG (5·0 g/L, 5·3 g/L, and 4·9 g/L), or IgM (0·3 g/L at each timepoint) concentrations. Common reasons for treatment discontinuation were progressive disease in 34 (24%) patients and adverse events, unacceptable toxicity, or death in 24 (17%) patients. Major bleeding occurred in 13 (9%) patients (11 8% grade 3–4). Grade 3 or worse infections occurred in 43 (30%) patients, including pneumonia in 19 (13%) patients. In the extended analysis, 38 patients died, 18 as a result of adverse events (four pneumonia, three chronic lymphocytic leukaemia, two Richter's syndrome, two sepsis, and one each of acute myocardial infarction, septic shock, encephalopathy, general deterioration in physical health, abnormal hepatic function, myocardial infarction, and renal infarction). Interpretation A high proportion of patients had an overall response to ibrutinib and the risk:benefit profile was favourable, providing further evidence for use of ibrutinib in the most difficult subset of patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma. Ibrutinib represents a clinical advance in the treatment of patients with del17p chronic lymphocytic leukaemia and has been incorporated into treatment algorithms as a primary treatment for these patients. Funding Pharmacyclics LLC, an AbbVie Company.
Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater ...inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis.
In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18–75 years) and adolescents (aged 12–17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index EASI score of ≥16, validated Investigator's Global Assessment for atopic dermatitis vIGA-AD score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 clear or 1 almost clear with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting.
Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 65% of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 77% of 297 patients) than the placebo group (80 26% of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% 95% CI 30·8–45·4 for the upadacitinib 15 mg group and 50·6% 43·8–57·4 for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 40% patients) and upadacitinib 30 mg plus topical corticosteroid group (174 59% patients) than the placebo group (33 11% patients; adjusted difference in vIGA-AD response vs placebo, 28·5% 22·1–34·9 for the upadacitinib 15 mg group and 47·6% 41·1–54·0 for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 10% of 300 patients) and upadacitinib 30 mg (41 14% of 297 patients) groups than the placebo group (six 2% of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four 1% patients in the upadacitinib 15 mg plus topical corticosteroids group, four 1% patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven 2% patients in the placebo plus topical corticosteroids group) and serious adverse events (seven 2% patients, four 1% patients, and nine 3% patients) were similar among treatment groups. No deaths were reported in any treatment group.
Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit–risk profile in adults and adolescents with moderate-to-severe atopic dermatitis.
AbbVie.
Atopic dermatitis (AD) is a chronic, recurrent, inflammatory skin disease with an unmet need for treatments that provide rapid and high levels of skin clearance and itch improvement.
To assess the ...safety and efficacy of upadacitinib vs dupilumab in adults with moderate-to-severe AD.
Heads Up was a 24-week, head-to-head, phase 3b, multicenter, randomized, double-blinded, double-dummy, active-controlled clinical trial comparing the safety and efficacy of upadacitinib with dupilumab among 692 adults with moderate-to-severe AD who were candidates for systemic therapy. The study was conducted from February 21, 2019, to December 9, 2020, at 129 centers located in 22 countries across Europe, North and South America, Oceania, and the Asia-Pacific region. Efficacy analyses were conducted in the intent-to-treat population.
Patients were randomized 1:1 and treated with oral upadacitinib, 30 mg once daily, or subcutaneous dupilumab, 300 mg every other week.
The primary end point was achievement of 75% improvement in the Eczema Area and Severity Index (EASI75) at week 16. Secondary end points were percentage change from baseline in the Worst Pruritus Numerical Rating Scale (NRS) (weekly average), proportion of patients achieving EASI100 and EASI90 at week 16, percentage change from baseline in Worst Pruritus NRS at week 4, proportion of patients achieving EASI75 at week 2, percentage change from baseline in Worst Pruritus NRS (weekly average) at week 1, and Worst Pruritus NRS (weekly average) improvement of 4 points or more at week 16. End points at week 24 included EASI75, EASI90, EASI100, and improvement of 4 points or more in Worst Pruritus NRS from baseline (weekly average). Safety was assessed as treatment-emergent adverse events in all patients receiving 1 or more dose of either drug.
Of 924 patients screened, 348 (183 men 52.6%; mean SD age, 36.6 14.6 years) were randomized to receive upadacitinib and 344 were randomized to receive dupilumab (194 men 56.4%; mean SD age, 36.9 14.1 years); demographic and disease characteristics were balanced among treatment groups. At week 16, 247 patients receiving upadacitinib (71.0%) and 210 patients receiving dupilumab (61.1%) achieved EASI75 (P = .006). All ranked secondary end points also demonstrated the superiority of upadacitinib vs dupilumab, including improvement in Worst Pruritus NRS as early as week 1 (mean SE, 31.4% 1.7% vs 8.8% 1.8%; P < .001), achievement of EASI75 as early as week 2 (152 43.7% vs 60 17.4%; P < .001), and achievement of EASI100 at week 16 (97 27.9% vs 26 7.6%; P < .001). Rates of serious infection, eczema herpeticum, herpes zoster, and laboratory-related adverse events were higher for patients who received upadacitinib, whereas rates of conjunctivitis and injection-site reactions were higher for patients who received dupilumab.
During 16 weeks of treatment, upadacitinib demonstrated superior efficacy vs dupilumab in patients with moderate-to-severe AD, with no new safety signals.
ClinicalTrials.gov Identifier: NCT03738397.
The JAK pathway is a potential therapeutic target in ankylosing spondylitis. This study assessed the efficacy and safety of upadacitinib, a selective JAK1 inhibitor, in patients with ankylosing ...spondylitis.
This multicentre, randomised, double-blind, placebo-controlled, two-period, parallel-group, phase 2/3 study, SELECT-AXIS 1, enrolled adults in 62 sites in 20 countries. Eligible patients had active ankylosing spondylitis, fulfilled modified New York criteria, were previously untreated with biological disease-modifying antirheumatic drugs, and had inadequate response to at least two or intolerance or contraindication to non-steroidal anti-inflammatory drugs. Patients were randomly assigned 1:1 using interactive response technology to take oral upadacitinib 15 mg once daily or oral placebo for the 14-week period 1; only period 1 data are reported here. The primary endpoint was the composite outcome measure of the Assessment of SpondyloArthritis international Society 40 response at week 14. Analyses were done in the full analysis set of patients who were randomly assigned and received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03178487.
Between Nov 30, 2017, and Oct 15, 2018, 187 patients were randomly assigned to upadacitinib 15 mg (93 patients) or to placebo (94 patients), and 178 (95%) patients (89 in the upadacitinib group and 89 in the placebo group) completed period 1 on study drug (by the completion date of Jan 21, 2019). Significantly more patients had an Assessment of SpondyloArthritis international Society 40 response in the upadacitinib group versus in the placebo group at week 14 (48 52% of 93 patients vs 24 26% of 94 patients; p=0·0003; treatment difference 26% 95% CI 13–40). Adverse events were reported in 58 (62%) of 93 patients in the upadacitinib group versus 52 (55%) of 94 in the placebo group. The most common adverse event in the upadacitinib group was increased creatine phosphokinase (eight 9% of 93 patients in the upadacitinib group vs two 2% of 94 patients with placebo). No serious infections, herpes zoster, malignancy, venous thromboembolic events, or deaths were reported; one serious adverse event was reported in each group.
Upadacitinib 15 mg was efficacious and well tolerated in patients with active ankylosing spondylitis who had an inadequate response or contraindication to non-steroidal anti-inflammatory drugs. These data support the further investigation of upadacitinib for the treatment of axial spondyloarthritis.
AbbVie.
Primary results from the Measure Up 1 and Measure Up 2 studies demonstrated upadacitinib efficacy and safety through 16 weeks in patients with atopic dermatitis. Longer-term outcomes remain unknown.
...To evaluate long-term (52 weeks) efficacy and safety of upadacitinib treatment in patients with atopic dermatitis.
Measure Up 1 and Measure Up 2 are ongoing double-blind, placebo-controlled, replicate phase 3 randomized clinical trials that include adults and adolescents with moderate to severe atopic dermatitis at 151 and 154 centers, respectively. Cutoffs for this analysis were December 21, 2020 (Measure Up 1), and January 15, 2021 (Measure Up 2).
Patients were randomized 1:1:1 to receive once-daily oral upadacitinib 15 mg, 30 mg, or placebo. At week 16, patients randomized at baseline to receive upadacitinib 15 mg (273 and 260 patients in Measure Up 1 and Measure Up 2, respectively) and 30 mg (270 and 268 patients) continued assigned treatment; placebo-treated patients were rerandomized 1:1 to receive upadacitinib 15 mg (121 and 120 patients in Measure Up 1 and Measure Up 2, respectively) or 30 mg (123 and 121 patients) in a double-blinded manner.
Safety and efficacy, including 75% improvement in the Eczema Area and Severity Index and Validated Investigator Global Assessment for Atopic Dermatitis score of clear (0) or almost clear (1) with 2 or greater grades of improvement, were assessed.
Measure Up 1 and Measure Up 2 included a total of 1609 patients (mean SD age, 33.8 15.6 years; 727 women 45.2%; 882 men 54.8%). Efficacy at week 16 was maintained through week 52. At week 52, 75% improvement in the Eczema Area and Severity Index was achieved by 82.0% (95% CI, 77.0%-86.9%) and 79.1% (95% CI, 73.9%-84.4%) of patients continuing the 15-mg dose and 84.9% (95% CI, 80.3%-89.5%) and 84.3% (95% CI, 79.6%-89.0%) of patients continuing the 30-mg dose (for Measure Up 1 and Measure Up 2, respectively); Validated Investigator Global Assessment for Atopic Dermatitis score of clear (0) or almost clear (1) with 2 or greater grades of improvement was achieved by 59.2% (95% CI, 52.9%-65.5%) and 52.6% (95% CI, 46.2%-59.1%) and 62.5% (95% CI, 56.3%-68.7%) and 65.1% (95% CI, 58.9%-71.2%) of patients in the Measure Up 1 and Measure Up 2 studies, respectively. Treatment discontinuation due to adverse events was low overall but was slightly higher for the upadacitinib 30-mg dose. Both upadacitinib doses were well tolerated with no new safety signals.
In this analysis of follow-up data from 2 randomized clinical trials, longer-term treatment of adolescents and adults with moderate to severe atopic dermatitis with upadacitinib demonstrated a favorable benefit-risk profile, with sustained efficacy responses through 52 weeks.
ClinicalTrials.gov Identifiers: NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2).
Objective
To report the efficacy and safety of upadacitinib through 1 year in patients with ankylosing spondylitis (AS).
Methods
In the SELECT‐AXIS 1 study, adults with active AS and an inadequate ...response to nonsteroidal antiinflammatory drugs were randomized to receive upadacitinib 15 mg once daily or placebo. At week 14, patients who had been randomized to receive placebo were switched to upadacitinib, and all patients continued in the open‐label extension and received upadacitinib up to week 104; interim data up to week 64 are reported herein.
Results
Of 187 patients, 178 completed week 14 on study drug and entered the open‐label extension. Similar proportions of patients in either group (continuous upadacitinib or placebo‐to‐upadacitinib) achieved Assessment of SpondyloArthritis international Society 40% response (ASAS40) or Ankylosing Spondylitis Disease Activity Score (ASDAS) showing low disease activity at week 64: ≥70% of patients achieved these end points based on nonresponder imputation (NRI) and ≥81% based on as‐observed analyses. Furthermore, ≥34% (NRI) and ≥39% (as‐observed analysis) achieved ASDAS showing inactive disease or ASAS showing partial remission at week 64. Mean changes from baseline (week 0) to week 64 in pain, function, and inflammation showed consistent improvement or sustained maintenance through the study. Among 182 patients receiving upadacitinib (237.6 patient‐years), 618 adverse events (260.1 per 100 patient‐years) were reported. No serious infections, major adverse cardiovascular events, venous thromboembolic events, gastrointestinal perforation, or deaths were reported.
Conclusion
Upadacitinib 15 mg once daily showed sustained and consistent efficacy over 1 year. Patients who switched from placebo to upadacitinib at week 14 showed similar efficacy versus those who received continuous upadacitinib.
First, population pharmacokinetic analyses were used to characterize upadacitinib pharmacokinetics in adolescent and adult participants with atopic dermatitis (AD) and to identify patient covariates ...that may impact upadacitinib pharmacokinetics. Second, the exposure-response relationship for upadacitinib with efficacy and safety endpoints, and the effect of age and concomitant use of topical corticosteroids (TCS) on the exposure-response relationship and dose selection for patients with AD were evaluated.
A two-compartment model with combined first- and zero-order absorption adequately characterized the upadacitinib concentration-time profiles in 911 healthy volunteer adolescent and adult participants with AD who received upadacitinib 15 or 30 mg orally once daily (QD) as monotherapy or in combination with TCS for 16 weeks. Logistic regression models were developed to characterize the exposure-efficacy and safety relationships, and simulations were performed based on final exposure-response models to predict efficacy responses in participants with AD who received placebo or upadacitinib as monotherapy or in combination with TCS.
Upadacitinib exposures were comparable between adolescents and adults. Mild or moderate renal impairment was predicted to increase the upadacitinib area under the plasma concentration-time curve from time zero to 24 h after dosing (AUC
) approximately 12% and 25%, respectively, compared to participants with normal renal function. Female participants were predicted to have 20% higher AUC
compared to male participants. Participants with AD were predicted to have 18% higher AUC
compared to healthy participants. Simulated clinical efficacy responses showed added clinical efficacy benefit for all endpoints evaluated (8-14%) with the upadacitinib 30 mg once-daily regimen compared to 15 mg once-daily in both age groups. In participants receiving upadacitinib in combination with TCS, significant exposure-dependent increases in upadacitinib efficacy endpoints were observed. No significant effects of age or weight were identified in any of the exposure-response models.
The results of these analyses support the dose justification for upadacitinib in adult and adolescent patients with moderate to severe AD.
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