BackgroundInterleukin (IL)-13 plays a key role in type 2 inflammation and is an emerging pathogenic mediator in atopic dermatitis (AD).ObjectiveWe investigated the efficacy and safety of lebrikizumab, an IL-13 monoclonal antibody, as an add-on to topical corticosteroid (TCS) treatment.MethodsA randomized, placebo-controlled, double-blind, phase 2 study. Adults with moderate-to-severe AD were required to use TCS twice daily and then randomized (1:1:1:1) to lebrikizumab 125 mg single dose, lebrikizumab 250 mg single dose, lebrikizumab 125 mg every 4 weeks for 12 weeks, or placebo every 4 weeks for 12 weeks, after a 2-week TCS run-in. The primary endpoint was percentage of patients achieving Eczema Area and Severity Index (EASI)-50 at week 12.ResultsIn total, 209 patients received the study drug. At week 12, significantly more patients achieved EASI-50 with lebrikizumab 125 mg every 4 weeks (82.4%; P = .026) than placebo every 4 weeks (62.3%); patients receiving a single dose of lebrikizumab showed no statistically significant improvements in EASI-50 compared with placebo. Adverse events were similar between groups (66.7% all lebrikizumab vs 66.0% placebo) and mostly mild or moderate.LimitationsProtocol-mandated twice daily TCS treatment limits our understanding of the efficacy of lebrikizumab as a monotherapy. The short study duration did not enable long-term efficacy or safety evaluations.ConclusionWhen combined with TCS, lebrikizumab 125 mg taken every 4 weeks led to a significant improvement and was well tolerated in patients with moderate-to-severe AD.
Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, has been shown to improve lung function, pulmonary exacerbation rate, respiratory symptoms, and weight gain compared with placebo in patients with cystic fibrosis aged 12 years or older with a G551D-CFTR mutation.This randomized, double-blind, placebo-controlled trial evaluated ivacaftor in patients with cystic fibrosis aged 6-11 years with a G551D-CFTR mutation on at least one allele.Patients were randomly assigned to receive ivacaftor administered orally at 150 mg (n = 26) or placebo (n = 26) every 12 hours for 48 weeks in addition to existing prescribed cystic fibrosis therapies.Despite near-normal mean baseline values in FEV1, patients receiving ivacaftor had a significant increase in percent predicted FEV1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P < 0.001). Effects on pulmonary function were evident by 2 weeks, and a significant treatment effect was maintained through Week 48. Patients treated with ivacaftor gained, on average, 2.8 kg more than those receiving placebo at Week 48 (P < 0.001). The change from baseline through Week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor was -53.5 mmol/L (P < 0.001) versus placebo. The incidence of adverse events was similar in the two groups.In patients who are younger and healthier than those in previously studied populations, ivacaftor demonstrated a significant improvement in pulmonary function, weight, and CFTR activity compared with placebo. Clinical trial registered with www.clinicaltrials.gov (NCT00909727).
Trial design Pemphigus is a rare, but life-threatening autoimmune disease requiring long-term treatment that minimizes corticosteroid (CS) exposure while providing consistent disease control. The phase 2 pemphigus study of oral, reversible, covalent Bruton tyrosine kinase (BTK) inhibitor rilzabrutinib demonstrated rapid and sustained efficacy with well-tolerated safety. Methods Adults (18–80 y) were randomized 1:1 to rilzabrutinib 400 mg (n=65) or placebo (n=66) twice daily (with CS ≤0.5 mg/kg/d) for 37 weeks in the phase 3 PEGASUS study in moderate-to-severe pemphigus vulgaris/foliaceus (PV/PF). Results The primary endpoint of complete remission (CR) from week 29–37 with the amended endpoint CS dose ≤10 mg/d was not significant for 13/54 (24%) rilzabrutinib vs. 10/55 (18%) placebo patients with PV (P=0.45). Secondary endpoints showed numerical, but non-significant, improvements with rilzabrutinib (vs. placebo) in reduced CS use, prolonged CR duration, and faster time to first CR. Conclusions Overall, rilzabrutinib was well-tolerated with similar adverse events reported in both groups. Using minimal CS dose ≤10 mg/d and excluding remote observations, the primary efficacy endpoint was not met. However, results from a prespecified sensitivity analysis using CS dose ≤5 mg/d, considering all observations, and including all patients support BTK inhibition as a viable therapeutic approach for pemphigus.
Abstract Introduction/Background Targeting and binding OX40 ligand (OX40L) expressed on antigen-presenting cells may inhibit the persistent immune response that drives atopic dermatitis (AD) pathophysiology. Amlitelimab (SAR445229; KY1005) is a potential first-in-class, fully human, non-depleting anti-OX40L monoclonal antibody that blocks OX40L-OX40 interactions and has shown efficacy and an acceptable safety profile in a Phase 2a trial in adults with moderate-to-severe AD. Here, we present 24-week efficacy and safety results (Part 1) from an ongoing dose-ranging Phase 2b trial. The study remains blinded to individual patient data (Part 2 ongoing). Objectives To evaluate the efficacy and safety of amlitelimab in adults with moderate-to-severe AD. Methods STREAM-AD (NCT05131477) is a 52-week, randomised, double-blinded, placebo-controlled Phase 2b monotherapy trial. This study is designed with 2 parts (double-blind throughout): a 24-week treatment period (Part 1, completed and presented here) and a 36-week maintenance/withdrawal period (Part 2, ongoing). Adults (18 to <75 years; n=390) with moderate-to-severe AD were randomised 1:1:1:1:1 to receive subcutaneous amlitelimab Q4W (250 mg with 500 mg loading dose [LD], n=77; 250 mg without LD, n=78; 125 mg without LD, n=77; or 62.5 mg without LD, n=79) or placebo Q4W (n=79). The primary endpoint was percentage change in Eczema Area and Severity Index (EASI) from baseline at Week 16. Key secondary endpoints included percentage change in EASI at Week 24 and percentage of patients with at least 75% reduction from baseline in EASI (EASI-75), percentage of patients with Investigator Global Assessment response of 0 (clear) or 1 (almost clear) and a reduction from baseline of ≥2 points (IGA 0/1), and proportion of patients with a weekly average reduction of Peak Pruritus Numerical Rating Scale (PP-NRS) ≥4 points from baseline. The primary efficacy analysis included all randomised patients who completed Week 24 or discontinued treatment or study prior to Week 24 visit (n=390), whereas the safety analysis included all treated patients (n=388). Results Treatment with amlitelimab resulted in statistically significant improvements in percentage change in EASI from baseline to Week 16 compared to placebo for all four doses studied. The 250 mg with LD group had the numerically highest response versus placebo at Week 16, with a least-squares mean change from baseline of –32.1% (95% CI: –43.9, –20.3; P<0.0001); the remaining groups without LD had the following responses versus placebo: 250 mg, –27.3 (95% CI: –39.1, –15.6; P<0.0001); 125 mg, –22.2 (95% CI: –34.0, –10.4; P=0.0002); and 62.5 mg, –30.2 (95% CI: –41.9, –18.5; P<0.0001). There were also clinically meaningful improvements in all key secondary efficacy outcome measures, with all amlitelimab dose groups demonstrating nominally significant (P<0.05) efficacy versus placebo for EASI-75, IGA 0/1, and PP-NRS ≥4, except 250 mg (no LD) in IGA 0/1 at Week 16 (P=0.0562). Continued improvements were generally observed through Week 24 in primary and key secondary efficacy outcomes. Amlitelimab was well tolerated across all dose groups, with no safety concerns identified. Conclusions In this dose-ranging Phase 2b trial of amlitelimab in adults with moderate-to-severe AD, amlitelimab demonstrated clinically meaningful efficacy over 24 weeks with an acceptable safety profile across all four dose groups.
Amlitelimab, a fully human nondepleting mAb targeting OX40 ligand on antigen-presenting cells, could prevent T-cell-driven inflammation seen in atopic dermatitis (AD). This trial evaluated the efficacy and safety of amlitelimab in adults with AD. In this 2-part, phase 2b, randomized, double-blinded placebo-controlled trial (ClinicalTrials.gov identifier NCT05131477), patients received subcutaneous amlitelimab every 4 weeks at doses of 250 mg plus a 500-mg loading dose, 250 mg, 125 mg, or 62.5 mg or placebo for 24 weeks in Part 1 (1:1:1:1:1 randomization). In Part 2, clinical responders were reallocated 3:1 to stop taking amlitelimab or continue the previous dose regimen for 28 weeks. The primary end point was percentage of change in Eczema Area and Severity Index (EASI) from baseline to week 16. In all, 390 and 190 patients enrolled in Part 1 and Part 2, respectively. A significant percentage of change decrease in EASI was observed with amlitelimab doses versus with placebo (P < .001). Clinical responses at week 24 (Investigator Global Assessment 0/1 and/or a 75% reduction in EASI) were maintained at week 52 in patients continuing or stopping amlitelimab. Of the patients maintaining clinical response at week 52 after no longer receiving treatment, more than 80% had serum amlitelimab concentrations less than the 4-μg/mL threshold for several weeks before week 52. Reductions in AD-related biomarkers during Part 1 were maintained through Part 2. Amlitelimab was well tolerated over 52 weeks. Amlitelimab treatment significantly reduced clinical and biomarker responses, and was well tolerated in adults with AD through week 52. Sustained responses were observed in the majority of patients for 28 weeks after they had stopped taking amlitelimab.
Objectives: Ivacaftor was evaluated in 2 48-week Phase 3 studies. This 96-week open-label extension (PERSIST) evaluated the safety and efficacy of long-term ivacaftor in subjects who completed the prior trials (STRIVE and ENVISION). Methods: 192 subjects who completed treatment in STRIVE or ENVISION enrolled in PERSIST. All subjects received ivacaftor 150 mg q12h in addition to prescribed therapies. Here we report the results of 96 weeks of treatment for subjects who were in STRIVE (n=144) and 72 weeks for those in ENVISION (n=48). Results: For subjects who received ivacaftor in the placebo-controlled studies, the FEV 1 improvements were sustained in PERSIST. For STRIVE subjects, the mean (SD) absolute change from STRIVE baseline in % predicted FEV 1 was 9.4% (8.3%) on Day 1 of PERSIST (Week 48 in STRIVE), 10.3% (9.3%) at Week 72, and 9.5% (10.1%) at Week 96. For ENVISION subjects, the mean (SD) absolute change from ENVISION baseline was 10.2% (15.7%) on Day 1 of PERSIST, 9.1% (15.6%) at Week 60, and 10.1% (14.2%) at Week 72. For placebo subjects in STRIVE or ENVISION, the FEV 1 improvements in PERSIST were similar to those observed in ivacaftor subjects during the placebo-controlled studies. The mean (SD) absolute change from PERSIST baseline was 9.4% (8.5%) at Week 96 for STRIVE placebo subjects and 8.1% (12.5%) at Week 72 for ENVISION placebo subjects. The safety profile observed in PERSIST was generally consistent with the safety profile observed during ivacaftor treatment in STRIVE and ENVISION. Conclusions: Ivacaftor-related improvements in lung function were sustained with additional ivacaftor treatment. No new clinically important safety concerns were identified. Sponsored by Vertex.
Abstract Background Amlitelimab is a fully-human, non-depleting, anti-OX40 ligand (OX40L) monoclonal antibody that binds to OX40L on antigen-presenting cells. Amlitelimab blocks the interaction of OX40L with OX40 on activated T-cells, inhibiting T-cell dependent inflammation without depleting T-cells. Objective To evaluate the efficacy and safety of amlitelimab (Part 1), and explore the maintenance of clinical response over a 28-Week period (Part 2) in patients with moderate-to-severe AD. Methods STREAM-AD (NCT05131477), was a randomized, double-blind, placebo-controlled Phase 2b trial, that included a 24-Week, double-blind, treatment period (Part 1), a 28-Week maintenance/withdrawal period (Part 2), and a 16-Week safety follow-up. In Part 1, adult participants were randomized 1:1:1:1:1 to subcutaneous amlitelimab Q4W (250mg with 500mg loading dose [+ LD], n=77; 250mg, n=78; 125mg, n=77; 62.5mg, n=79) or placebo Q4W (n=79). In Part 2, Clinical responders (defined as those achieving EASI-75 and/or IGA 0/1 at Week-24) in Part 1, were rerandomized 3:1 to withdraw or continue pre-Week 24 Q4W dose (250mg + LD, n=34 [withdrawal]/n=13 [continuing]; 250mg, n=28/n=12; 125mg, n=33/n=12; 62.5mg, n=35/n=7; placebo responders continuing placebo, n=16), and were followed to Week-52 to evaluate maintenance of clinical response. Primary efficacy endpoint was percent change in EASI from baseline at Week-16. Key secondary endpoints were proportion of patients achieving IGA 0/1, EASI-75, PP-RNS≥4. The statistical analysis was performed using two methods: 1) imputing the endpoint as nonresponder after rescue medication use (NRI); and 2) including all measurements regardless of rescue use (treatment policy). Results Out of 390 participants enrolled in Part 1, 190 entered Part 2. In Part 1, all four doses of amlitelimab demonstrated statistically significant improvements in percent change in EASI from baseline to Week-16 vs placebo; the highest response was seen with 250mg + LD group. Clinically meaningful improvements in key secondary endpoints were observed at Week-16, with continued improvements through Week-24. In Part 2, maintenance of EASI-75 and/or IGA 0/1 response at Week-52 was observed in 59%, 63%, 55%, and 66% of clinical responders withdrawn from 250mg + LD, 250mg, 125mg, and 62.5mg, respectively (NRI). Using treatment policy, 77%, 82%, 67%, and 74% maintained response off-drug, respectively. Those continuing amlitelimab treatment had numerically higher maintenance response rates. AD-related biomarkers were reduced during Part 1 and remained decreased over Part 2. Amlitelimab was well tolerated across all dose groups, with no new safety concerns identified during the 52-Weeks. Conclusion Clinically meaningful efficacy with amlitelimab was demonstrated over 52-Weeks, with an acceptable safety profile. Clinical responses were maintained in most patients 28-Weeks after treatment discontinuation.
VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro.
Methods
A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo.
Results
The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens.
Conclusions
In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit.
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