Subcutaneous Placebo Research Articles

Oxytocin antagonists for assisted reproduction.

Oxytocin antagonists for assisted reproduction.

Pharmacometric analysis linking immunoglobulin exposure to clinical efficacy outcomes in chronic inflammatory demyelinating polyneuropathy.

The two main objectives of this analysis were to (i) characterize the relationship between immunoglobulin (Ig) exposure and chronic inflammatory demyelinating polyneuropathy (CIDP) disease severity using data from 171 patients with CIDP who received either subcutaneous Ig (IgPro20; Hizentra®) or placebo (PATH study), and to (ii) simulate and compare exposure coverage with various dosing approaches considering weekly dosing to be the reference dose. IgG pharmacokinetic (PK) parameters, including those from a previous population PK model, were used to predict individual IgG profile and exposure metrics. Treatment‐related changes in Inflammatory Neuropathy Cause and Treatment (INCAT) scores were best described by a maximum effect (Emax) model as a function of ΔIgG (total serum IgG at INCAT score assessment minus baseline IgG levels before intravenous Ig restabilization). Simulations indicate that flexible dosing from daily to biweekly (every other week) provide an exposure coverage equivalent to that of a weekly Ig dose.

In adults with overweight or obesity, continued weekly semaglutide after a 20-wk run-in improved weight loss

Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021;325:1414-25. 33755728.

Modified-Live Feline Calicivirus Vaccination Reduces Viral RNA Loads, Duration of RNAemia, and the Severity of Clinical Signs after Heterologous Feline Calicivirus Challenge.

Feline calicivirus (FCV) is a common cat virus causing clinical signs such as oral ulcerations, fever, reduced general condition, pneumonia, limping and occasionally virulent-systemic disease. Efficacious FCV vaccines protect against severe disease but not against infection. FCV is a highly mutagenic RNA virus whose high genetic diversity poses a challenge in vaccine design. The use of only one modified-live FCV strain over several decades might have driven the viral evolution towards more vaccine-resistant variants. The present study investigated the clinical signs, duration, and amount of FCV shedding, RNAemia, haematological changes and acute phase protein reaction in SPF cats after subcutaneous modified-live single strain FCV vaccination or placebo injection and two subsequent oronasal heterologous FCV challenge infections with two different field strains. Neither clinical signs nor FCV shedding from the oropharynx and FCV RNAemia were detected after vaccination. After the first experimental infection, vaccinated cats had significantly lower clinical scores, less increased body temperature and lower acute phase protein levels than control cats. The viral RNA loads from the oropharynx and duration and amount of RNAemia were significantly lower in the vaccinated animals. No clinical signs were observed in any of the cats after the second experimental infection. In conclusion, FCV vaccination was beneficial for protecting cats from severe clinical signs, reducing viral loads and inflammation after FCV challenge.

Reduction in acute migraine-specific and non-specific medication use in patients treated with erenumab: post-hoc analyses of episodic and chronic migraine clinical trials

BackgroundIn patients with migraine, overuse of acute medication, including migraine-specific medication (MSM) such as triptans and ergots, can lead to adverse health outcomes, including development of medication overuse headache. Here, we examined the effect of erenumab on reducing acute medication use, in particular MSM, in patients with episodic migraine (EM) and chronic migraine (CM).MethodsThe current post-hoc analyses were based on data from the double-blind treatment phase (DBTP) of two erenumab studies, a pivotal EM (N = 955) and a pivotal CM (N = 667) trial, and their respective extensions. Patients were administered subcutaneous placebo or erenumab (70 or 140 mg) once monthly. Daily acute headache medication use (including MSM and non-MSM) was recorded using an electronic diary during a 4-week pretreatment baseline period until the end of the treatment period. Outcome measures included change in monthly acute headache medication days (HMD) in acute headache medication users at baseline, and changes in monthly MSM days (MSMD) in MSM users at baseline and non-MSMD in non-MSM users at baseline.ResultsIn total, 60 and 78 % of patients (all acute headache medication users) with EM and CM used MSM at baseline, respectively. For acute headache medication users, the change in mean monthly acute HMD over Months 4, 5 and 6 compared with the pre-DBTP was 1.5, 2.5, and 3.0 for placebo, erenumab 70 mg and 140 mg, respectively for the EM study. The respective change in monthly MSMD in MSM users was 0.5, 2.1 and 2.8, and in monthly non-MSMD in non-MSM users was 2.3, 2.6, and 2.7. In the acute headache medication users at baseline, the change in monthly acute HMD at Month 3 compared with pre-DBTP was 3.4, 5.5, and 6.5 for placebo, erenumab 70 mg and 140 mg, respectively for the CM study. The respective change in monthly MSMD in MSM users was 2.1, 4.5, and 5.4, and in monthly non-MSMD in non-MSM users was 5.9, 6.4, and 6.6. Reductions in MSMD versus placebo were sustained in the extension periods of both studies. Erenumab was also associated with a higher proportion of MSM users achieving ≥ 50 %, ≥ 75 and 100 % reduction from baseline in monthly MSMD versus placebo in both EM and CM.ConclusionsIn both EM and CM, treatment with erenumab is associated with a significant and sustained reduction in the use of acute headache medication, in particular MSM.Trial registrationsNCT02456740; NCT02066415; NCT02174861.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Electrophysiological predictors of response to subcutaneous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy

ObjectiveTo assess axonal function prior to subcutaneous immunoglobulin (SCIG) therapy or placebo in relation to relapse in chronic inflammatory demyelinating polyneuropathy (CIDP) to determine whether axonal damage can predict therapy response. MethodsRelapse rates in patients from the Polyneuropathy and Treatment with Hizentra (PATH) study, where patients were treated with placebo or SCIG (IgPro20), were analyzed by baseline (post-intravenous immunoglobulin stabilization) axonal damage (≤1 mV peroneal compound muscle action potential) status. ResultsIn patients with non-axonal damage, relapses were significantly higher with placebo (73.0%) than IgPro20 (0.2 g/kg: 39.1%, 0.4 g/kg: 19.2%). In patients with axonal damage, IgPro20 had no effect on relapse (placebo: 25.0%, IgPro20: 0.2 g/kg: 30.0%, 0.4 g/kg: 19.4%). Patients with axonal damage relapsed significantly less on placebo versus non-axonal damage, but they also demonstrated higher baseline disability. ConclusionAxonal damage may correspond to relapse upon treatment withdrawal; patients with axonal damage relapse less, possibly reflecting poor response to immunoglobulin therapy, while non-axonal damage patients may experience more relapse, perhaps indicating better treatment response. SignificanceIn CIDP patients with axonal loss, immunoglobulin therapy may not be as effective. Assessing axonal damage could help guide therapy, with immunoglobulins ideally used before substantial axonal damage arises.

Novel antibody cocktail targeting Bet v 1 rapidly and sustainably treats birch allergy symptoms in a phase 1 study

The efficacy of an allergen-specific IgG cocktail to treat cat allergy suggests that allergen-specific IgG may be a major protective mechanism elicited by allergen immunotherapy. Extending these findings, we tested a Bet v 1-specific antibody cocktail in birch-allergic subjects. This was a phase 1, randomized, double-blind, study with 2 parts. Part Aadministered ascending doses of the Bet v 1-specific antibody cocktail REGN5713/14/15 (150-900 mg) in 32 healthy adults. Part B administered a single subcutaneous 900-mg dose or placebo in 64 birch-allergic subjects. Total nasal symptom score response to titrated birch extract nasal allergen challenge and skin prick test (SPT) with birch and alder allergen were assessed at screening and days 8, 29, 57, and 113 (SPT only); basophil activation tests (n= 26) were conducted. Single-dose REGN5713/14/15 significantly reduced total nasal symptom score following birch nasal allergen challenge relative to baseline. Differences in total nasal symptom score areas under the curve (0-1 hour) for subjects treated with REGN5713/14/15 versus those given placebo (day 8: -1.17, P= .001; day 29: -1.18, P= .001; day 57: -0.85, P=.024) and titration SPT with birch difference in area under the curve of mean wheal diameters for subjects treated with REGN5713/14/15 versus placebo (all P< .001) were sustained for ≥2 months; similar results were observed with alder SPT. REGN5713/14/15 was well tolerated. Basophil responsiveness to birch-related allergens was significantly decreased in subjects treated with REGN5713/14/15 versus those given placebo on days 8, 57, and 113 (all P< .01). Single-dose REGN5713/14/15 was well tolerated and provided a rapid (1 week) and durable (2 months) reduction in allergic symptoms after birch allergen nasal allergen challenge, potentially offering a new paradigm for the treatment of birch allergy symptoms.

PSY2 Impact of Mepolizumab on Health-Related Quality of Life in Patients With Hypereosinophilic Syndrome

Mepolizumab, an anti–interleukin-5 monoclonal antibody, reduces disease flares in patients with hypereosinophilic syndrome (HES). Here, we assessed the impact of mepolizumab on symptom burden, health-related quality of life (HRQoL), and work productivity and impairment (WPAI). This placebo-controlled, double-blind, parallel-group, Phase III trial enrolled patients ≥12 years old with HES for ≥6 months, ≥2 flares in the previous 12 months, and BEC ≥1000 cells/μL at screening. Patients maintained ≥4 weeks stable HES therapy before randomization (1:1) to 4-weekly subcutaneous mepolizumab (300 mg) or placebo, plus baseline HES therapy, for 32 weeks. Change from baseline at Week 32 in symptom burden was assessed using a modified version of the memorial symptom assessment scale (MSAS-SF) (scale:0–4). Descriptive analyses of HRQoL and WPAI were performed using the short form-36 (SF-36) questionnaire, including an overall derived score (health utility index) and mental/physical component summary scores (scale:0–100) and the WPAI index general health questionnaire (scale:0–100%). At Week 32, MSAS-SF total score improved in patients receiving mepolizumab (n=54) versus placebo (n=54) (median change: -0.19 vs 0.05, P=0.032). Global distress index score, physical symptom subscale score, and psychological symptom subscale score numerically improved with mepolizumab versus placebo but were not statistically significance (median changes: -0.23 vs 0.12, P=0.096; -0.13 vs 0.10, P=0.083; -0.22 vs -0.02, P=0.551, respectively). Likewise, a small numerical improvement in SF-36 score was observed with mepolizumab versus placebo (mean[SD] changes: utility index: 0.08[0.10] vs 0.04[0.08]; mental score: 3.55[9.03] vs 1.46[8.77]; physical score: 6.33[9.47] vs 3.81[5.75]). Mepolizumab treatment was also associated with numerically greater reductions in impairment while working, overall work impairment, and activity impairment versus placebo (mean[SD] % changes: -20.6[22.94] vs -2.4[21.66]; -17.0[39.63] vs -5.4[25.46]; -19.0[27.66] vs -3.7[24.98], respectively). With mepolizumab treatment, patients with HES had a trend for an improvement in disease symptoms, HRQoL, and WPAI versus placebo. FUNDING: GSK(200622/NCT02836496).

106-OR: A First-in-Human Single Ascending Dose Study of Oxyntomodulin Analog LY3305677 in Healthy Subjects

LY3305677 (LY) is an acylated single chain peptide analog of mammalian oxyntomodulin designed for once weekly dosing. It has dual pharmacology of GLP-1 and glucagon and has therapeutic potential for T2D, obesity and NASH. This randomized, double blind, placebo-controlled phase 1 study assessed safety and tolerability of single ascending doses of LY. Healthy subjects (N=48) were randomized (6:2) and 47 received subcutaneous LY (6 doses: 0.03 mg to 5.0 mg) or placebo. Safety biomarkers, LY pharmacokinetics (PK), and key exploratory pharmacodynamic (PD) biomarkers were assessed including fasting insulin, glucagon, triglyceride levels, and body weight. Most common LY-related AEs were gastrointestinal events. Dose-dependent increase in nausea, decreased appetite, and vomiting were seen. Most of the events were mild and transient. Increase in heart rate was noted, which returned to baseline for most groups at follow-up visit. No injection site reactions were seen. Median time to maximum LY concentration ranged from 18.2 to 72.1 h, and geometric mean half-life ranged from 7.5 to 9.8 days. Generally, mean fasting insulin level increased within 24 h and lasted over 8 days. At Day 8, LY 2.5 mg and 5.0 mg reduced mean fasting glucagon levels by 2.33 pmol/L and 2.67 pmol/L, respectively as compared with placebo. At Day 5, mean fasting triglyceride levels reduced from baseline by 0.5 mmol/L with LY 5.0 mg as compared to 0.1 mmol/L with placebo. Change from baseline in body weight reached a maximum -2.4 kg with the 5 mg dose, versus -0.5 kg for placebo at Day 8 and this effect was sustained through Day 29 at 5 mg. LY3305677 PK properties are suitable for once-weekly dosing with a safety and tolerability profile similar to other incretins in Phase 1 trials, supporting future clinical evaluation. Disclosure L. Tham: Employee; Self; Eli Lilly and Company. M. K. Thomas: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. C. Benson: Employee; Self; Eli Lilly and Company. R. Bray: None. C. Tang: Employee; Self; Eli Lilly and Company, Employee; Spouse/Partner; Novartis AG. C. Loghin: Employee; Self; Eli Lilly and Company. Funding Eli Lilly and Company

P508 Dose adjustment in patients with moderate to severe ulcerative colitis: results from year 3 of the UNIFI maintenance study long-term extension

Abstract Background The UNIFI randomized-withdrawal maintenance study and long-term extension (LTE) evaluated the safety and efficacy of subcutaneous (SC) ustekinumab (UST) in patients with moderately to severely active ulcerative colitis (UC) who had responded to intravenous (IV) UST during induction. We evaluated the efficacy of UST dose adjustment through Week (Wk) 152 of the long-term extension (LTE). Methods 523 intravenous UST induction responders were randomized to SC maintenance therapy (SC placebo [PBO], n=175; UST 90mg every 12 weeks [q12w], n=172; or UST 90mg q8w, n=176). 284 UST patients who completed wk44 entered the LTE. PBO patients were discontinued after wk44 unblinding. Based on the investigator’s clinical judgement of their UC disease activity, patients in the LTE were eligible to receive dose adjustment starting at Wk 56: PBO to q8w, q12w to q8w, and q8w to q8w (sham adjustment). Patients in PBO or q8w groups were only eligible for dose adjustment or sham dose adjustment before unblinding. Patients were assessed for symptomatic remission, partial Mayo scores, and inflammatory markers ≥16 wks after dose adjustment. Results Overall, 60 patients (42.6%) in the q12w group and 40 patients (28.0%) in the q8w group underwent dose adjustment (or sham dose adjustment) prior to Wk 156 of the LTE; 51 and 39 patients in each group, respectively, had dose adjustment at Wk 136 or before, providing≥16 wks of data after dose adjustment (Table). At the first visit ≥16 weeks after dose adjustment, 70.6% of patients who adjusted from q12w to q8w and 61.5% who sham dose adjusted from q8w to q8w were in symptomatic remission. At the time of dose adjustment, 27/51 patients (52.9%) in the q12w group and 25/39 patients (64.1%) in the q8w group were in symptomatic remission. Of those who were in symptomatic remission at the time of dose adjustment, the majority (81.5% and 68.0%, respectively) were maintained in symptomatic remission at the first visit ≥16 wks after dose adjustment. Of those who were not in symptomatic remission at the time of dose adjustment, 58.3% and 50.0%, respectively, were in symptomatic remission at the first visit ≥16 wks after dose adjustment. Mean partial Mayo scores and CRP levels decreased after dose adjustment (Table). Conclusion Patients may benefit from UST dose adjustment to q8w.

P427 Efficacy and safety of vedolizumab and adalimumab in Asian adults with moderately to severely active ulcerative colitis: Post-hoc analysis of the VARSITY trial

Abstract Background The VARSITY trial, the first head-to-head study comparing the efficacy and safety of biologics in patients with moderately to severely active ulcerative colitis (UC), demonstrated superior clinical remission with vedolizumab (VDZ) versus adalimumab (ADA) at week 52. This post-hoc analysis describes outcomes in patients from Asia included in the VARSITY trial. Methods Adult patients with moderately to severely active UC (Mayo score 6–12; endoscopic sub-score ≥2), refractory to conventional therapies and anti–tumour necrosis factor-naïve or -experienced (exposure capped at 25%) were included. This analysis focussed on patients from Hong Kong, Taiwan and South Korea. Patients were randomised (1:1) to receive intravenous (IV) VDZ (300mg) and subcutaneous (SC) placebo on day 1 of weeks 2, 6, 14, 22, 30, 38 and 46 or SC ADA, at weeks 1 (total dose:160mg) and 2 (80mg) and every 2 weeks (40mg) plus IV placebo thereafter until week 50. The primary endpoint was clinical remission at week 52. Secondary endpoints included rates of endoscopic improvement, corticosteroid (CS)-free remission and histological remission at week 52. Patients with missing endpoint assessment at week 52 were considered non-responders. Data were analysed descriptively. Results A total of 45 patients (VDZ: n=21; ADA: n=24) were included. At baseline (VDZ and ADA, respectively), the mostly male population (71.4% and 58.3%) had a mean (SD) age of 46.4 (14.7) and 40.4 (15.1) years; severe disease: 33.3% and 54.2%; mean (SD) disease duration: 6.8 (5.5) and 5.4 (3.5) years; and were biologic-naïve: 85.7% and 79.2%. At week 52, a higher rate of clinical remission was achieved in VDZ- vs. ADA-treated patients (28.6% vs. 16.7%; Table). Adverse events (AEs) occurred in 71.4% (VDZ) and 87.5% (ADA) of patients; serious AEs occurred in 4.8% (VDZ) and 16.7% (ADA) of patients. AEs led to study drug discontinuation in 4.8% (VDZ) and 8.3% (ADA) of patients; no deaths occurred. Conclusion Patients from Asian countries with moderately to severely active UC achieved higher rates of clinical, CS-free, and histological remission as well as endoscopic improvement with VDZ vs. ADA. VDZ and ADA were both generally safe and well tolerated. Descriptive trends were consistent with findings in the larger VARSITY cohort.

DOP83 Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 3 Years: UNIFI Long-term Extension

Abstract Background Ustekinumab (UST) is an IL-12/23p40 antagonist used to treat pts with moderate-to-severe ulcerative colitis (UC). The ongoing UNIFI long-term extension (LTE) evaluates subcutaneous (SC) 90mg UST maintenance therapy, with efficacy (wk152) and safety (wk156) results reported here. Methods 523 intravenous UST induction responders were randomized to SC maintenance therapy (175 SC placebo [PBO]; 172 UST 90mg every 12 weeks [q12w]; 176 UST 90mg q8w). 284 UST pts who completed wk44 entered the LTE. PBO pts were discontinued after wk44 unblinding. Starting at wk56, randomized pts with UC worsening could adjust to q8w. Symptomatic remission (Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0) was evaluated in randomized pts. Safety was evaluated for all 588 pts treated in the LTE, including the randomized and nonrandomized populations; 188 received PBO and 457 received UST. The nonrandomized population included responders to PBO induction and UST induction nonresponders at wk8 who received SC UST, responded 8 wks later and received UST 90mg q8w. Results Among all pts randomized to UST at maintenance baseline (intent-to-treat population with nonresponder imputation for missing data and treatment failure criteria), 55.2% were in symptomatic remission at wk152 (biologic naïve, 66.1%; biologic failures, 43.5%; Table 1); 96.4% (185/192) of pts in symptomatic remission at wk152 were corticosteroid-free. Overall, 20.1% (39/149 biologic failure, 16/149 biologic naïve) of pts who were randomized to UST and treated in the LTE discontinued treatment between wks44 and 156. Among randomized pts treated with UST in the LTE, 67.6% were in symptomatic remission at wk152; 76.4% of those in clinical remission at wk44 were in symptomatic remission at wk152; and 84.1% of pts with observed data at wk152 were in symptomatic remission. From maintenance wk0-156, combined UST and PBO pts had 1281.6 and 425.0 pt-years of follow-up, respectively; and safety events per 100 pt-years of follow-up for combined UST vs PBO were AEs: 235.81 vs 204.48, SAEs: 7.73 vs 7.53, and serious infections: 2.34 vs 2.35 (Table 2). From wks96-156, there were no reported deaths or major adverse cardiovascular events. One UST-treated pt with fair skin and a prior history of basal cell carcinoma (BCC) reported 2 BCC. One 90 mg q8w UST pt receiving concomitant 6-MP reported SAEs of neutropenic sepsis and oral herpes SAE; the latter events were considered potential opportunistic infections. The dose of 6-MP was reduced, pt recovered and continued UST. Conclusion The efficacy of UST in pts with UC was sustained through 3 years. No new safety signals were observed.

Effects of the PCSK9 antibody alirocumab on coronary atherosclerosis in patients with acute myocardial infarction: a serial, multivessel, intravascular ultrasound, near-infrared spectroscopy and optical coherence tomography imaging study–Rationale and design of the PACMAN-AMI trial

The risk for cardiovascular adverse events after acute myocardial infarction (AMI) remains high despite potent medical treatment including low-density lipoprotein cholesterol (LDL-C) lowering with statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies substantially reduce LDL-C when added to statin. Alirocumab, a monoclonal antibody to PCSK9, reduces major adverse cardiovascular events after AMI. The effects of alirocumab on coronary atherosclerosis including plaque burden, plaque composition and fibrous cap thickness in patients presenting with AMI remains unknown. To determine the effect of LDL-C lowering with alirocumab on top of high-intensity statin therapy on intravascular ultrasound (IVUS)-derived percent atheroma volume (PAV), near-infrared spectroscopy (NIRS)-derived maximum lipid core burden index within 4 mm (maxLCBI4 mm) and optical coherence tomography (OCT)-derived fibrous cap thickness (FCT) in patients with AMI. In this multicenter, double-blind, placebo-controlled trial, 300 patients with AMI (ST-elevation or non-ST-elevation myocardial infarction) were randomly assigned to receive either biweekly subcutaneous alirocumab (150 mg) or placebo beginning <24 hours after the acute event as add-on therapy to rosuvastatin 20 mg. Patients undergo serial IVUS, NIRS and OCT in the two non-infarct related arteries at baseline (at the time of treatment of the culprit lesion) and at 52 weeks. The primary endpoint, change in IVUS-derived PAV, and the powered secondary endpoints, change in NIRS-derived maxLCBI4 mm, and OCT-derived minimal FCT, will be assessed 52 weeks post randomization. The PACMAN-AMI trial will determine the effect of alirocumab on top of high-intensity statin therapy on high-risk coronary plaque characteristics as assessed by serial, multimodality intracoronary imaging in patients presenting with AMI. NCT03067844.

P178 The impact of peripheral articular manifestations on the efficacy of ixekizumab in patients with radiographic axial spondyloarthritis

Abstract Background/Aims Axial spondyloarthritis (axSpA) is characterised by chronic inflammation of the axial skeleton and is commonly associated with peripheral articular manifestations (PA), which further increases disease burden. Ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets IL-17A, is approved for treating both nonradiographic and radiographic (r-) forms of axSpA. We explored the efficacy of IXE in patients with raxSpA with (PA+) and without (PA−) PA at baseline. Methods Week 16 data from two Phase 3, randomized, double-blind, placebo (PBO)-controlled trials, with patients who fulfilled the Assessment of Spondylo-Arthritis International Society (ASAS) criteria for r-axSpA and were either biologic-naïve (COAST-V, NCT02696785) or TNFi-experienced (COAST-W, NCT02696798), were analysed. Patients were randomly assigned 1:1:1:1 to subcutaneous PBO, 80 mg IXE every 4 (Q4W) or 2 (Q2W) weeks (80 mg or 160 mg starting dose, assigned 1:1) or 40 mg adalimumab (ADA) Q2W in COAST-V or 1:1:1 in COAST-W. We present a post-hoc analysis of data from COAST-V and -W and an integrated dataset, with patients categorized by baseline PA status. Presence of PA was defined as a 44-joint swollen joint count (SJC) ≥1 or a 46-joint tender joint count (TJC) ≥1. Efficacy and health-related quality of life (HRQoL) outcomes were analysed at week 16. Results Data from 656 patients (COAST-V: N = 146 PA−/194 PA+; COAST-W: N = 93 PA−/223 PA+) were analyzed. At baseline, PA+ patients had a higher mean age, more enthesitis (higher Spondyloarthritis Research Consortium of Canada [SPARCC] scores), and higher disease activity (higher CRP levels, Ankylosing Spondylitis Disease Activity Score [ASDAS] and BASDAI). ASAS40, ASDAS &amp;lt;2.1, and BASDAI50 responder rates (Table, section a) were all significantly higher for both IXE dose regimens versus PBO in both PA− and PA+ patients in the integrated dataset and numerically higher in the separate datasets. Furthermore, short-form-36 physical component summary (Table, section b) showed significantly greater improvements from baseline in both IXE groups vs PBO in the separate and integrated datasets, regardless of baseline PA status. Conclusion IXE led to significant improvements versus PBO in all efficacy and HRQoL endpoints at Week 16 in the integrated dataset, irrespective of PA manifestations at baseline. P178 Table 1:a) Responder rates at Week 16 for the intent-to-treat population, number (%)No peripheral articular manifestations at baselinePeripheral articular manifestations at baselinePBOADAQ2WIEQ4WIXEQ2WPBOADAQ2WIXEQ4WIXEQ2WIntegrated datasetaN=71N/AN=63N=66N=119N/AN=132N=115ASAS4011.5N/A29 (46.0)‡28 (42.4)‡18 (15.1)N/A39 (29.5)†45 (39.1)‡ASDAS &amp;lt;2.18 (11.3)N/A24 (38.1)‡23 (34.8)†8 (6.7)N/A31 (23.5)‡28 (24.3)‡BASDAI5010 (14.1)N/A21 (33.3)*26 (39.4)†15 (12.6)N/A38 (28.8)‡33 (28.7)†COAST-VbN=34N=39N=35N=38N=52N=51N=46N=45ASAS408 (23.5)17 (43.6)18 (51.4)*18 (47.4)8 (15.4)15 (29.4)21 (45.7)†25 (55.6)‡ASDAS &amp;lt;2.17 (20.6)18 (46.2)*14 (40.0)17 (44.7)*4 (7.7)16 (31.4)†21 (45.7)†18 (40.0)‡BASDAI507 (20.6)16 (41.0)13 (37.1)16 (42.1)8 (15.4)13 (25.5)21 (45.7)†20 (44.4)†COAST-WbN=37N/AN=28N=28N=67N/AN=86N=70ASAS403 (8.1)N/A11 (39.3)†10 (35.7)*10 (35.7)*N/A18 (20.9)20 (28.6)ASDAS &amp;lt;2.11 (2.7)N/A10 (35.7)‡6 (21.4)*4 (6.0)N/A10 (11.6)10 (14.3)BASDAI503 (8.1)N/A8 (28.6)*10 (35.7)*7 (10.4)N/A17 (19.8)13 (18.6)Non-responder imputation was used for missing responses.P-values vs. PBO (aCochran-Mantel-Haenszel test, adjusted by study;bFisher’s exact test):*P&amp;lt;0.05,†P&amp;lt;0.01,‡P&amp;lt;0.001.b) Change from baseline in SF-36 PCS scores at Week 16 for the intent-to-treat population, LSM (SE)No peripheral articular manifestations at baselinePeripheral articular manifestations at baselinePBOADAQ2WIXEQ4WIXEQ2WPBOADAQ2WIXEQ4WIXEQ2WIntegrated dataseta1.6 (0.90)N/A7.2 (0.95)‡6.1 (0.92)‡3.8 (0.69)N/A7.7 (0.67)‡8.2 (0.71)‡COAST-Vb2.3 (1.15)7.0 (1.10)†6.9 (1.13)†6.4 (1.07)*4.6 (1.00)6.9 (1.01)8.3 (1.07)*9.3 (1.10)†COAST-Wc0.64 (1.57)N/A7.1 (1.75)†5.4 (1.72)*1.9 (0.96)N/A6.4 (0.85)‡6.3 (0.97)‡P-values vs. PBO (MMRM analysis with treatment,a,b,c study,a baseline value,a,b,c visit,a,b,c baseline value-by-visit,a,b,c treatment-by-visit interaction,a,b,c geographic region,b,c baseline CRP status,b,c and number of prior TNF inhibitorsc included as fixed factors):*P &amp;lt; 0.05,†P &amp;lt; 0.01,‡P &amp;lt; 0.001.ADAQ2W = adalimumab every 2 weeks; ASAS = Assessment of Spondyloarthritis International Society criteria; ASDAS = ankylosing spondylitis disease activity score; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; CRP = c reactive protein; IXEQ2W = ixekizumab every 2 weeks; IXEQ4W = ixekizumab every 4 weeks; MMRM = mixed-effects model of repeated measures; N/A = not applicable; PBO = placebo; PCS = physical component summary; SE = standard error; SF-36 = short-form-36; TNF = tumour necrosis factor. Disclosure R. Sengupta: None. P. Bird: Grants/research support; Pfizer, Eli Lilly, Gilead, Abbvie, Novartis. D. Aletaha: Consultancies; Abbvie, Amgen, Celgene, Eli Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, Genzyme. Grants/research support; Abbvie, Novartis, Roche. M. Magrey: Consultancies; Novartis, Pfizer, Eli Lilly, Abbvie, UCB. Other; Clinical trials with: Abbvie and UCB. Y. Kadono: Member of speakers’ bureau; Abbie, Lilly, Novartis. E. Soriano: Consultancies; Abbvie, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Sandoz. Member of speakers’ bureau; Abbvie, Amber, Bristol-Myers Squibb, Eli Lilly, Novartis, Pfizer, Roche, UCB. Grants/research support; Abbvie, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Sandoz, UCB. A.J. Bradley: Shareholder/stock ownership; Eli Lilly. Other; Employee of Eli Lilly and Company. S. Liu-Leage: Shareholder/stock ownership; Eli Lilly. Other; Employee of Eli Lilly and Company. Y. Schymura: Other; Employee of Eli Lilly and Company. M.J. Nissen: Corporate appointments; Abbvie, Celgene, Lilly, Novartis, Pfizer. Member of speakers’ bureau; Abbvie, Celgene, Novartis, Pfizer. Other; Member of EuroSpA (supported by Novartis).

Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial

The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics. This study evaluated astegolimab efficacy and safety in patients with severe asthma. This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured ∼30 patients who were eosinophil-high (≥300 cells/μL) and ∼95 patients who were eosinophil-low (<300 cells/μL) per arm. Overall, adjusted AER reductions relative to placebo were 43% (P= .005), 22% (P= .18), and 37% (P= .01) for 490-mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P= .002), 14% (P= .48), and 35% (P= .05) for 490-mg, 210-mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab- and placebo-treated groups. Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.

Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1

BackgroundPrimary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase.MethodsIn this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6.ResultsA total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was −53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was −39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients.ConclusionsLumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.)

Clinical Evaluation of an Investigational 5mL Wearable Injector in Healthy Human Subjects.

An investigational wearable injector (WI), the BD Libertas Wearable Injector (BD Libertas is a trademark of Becton, Dickinson and Company), was evaluated in an early feasibility clinical study for functional performance, tissue effects, subject tolerability, and acceptability of 5 mL, non‐Newtonian ~ 8 cP subcutaneous placebo injections in 52 healthy adult subjects of 2 age groups (18–64 years and ≥ 65 years). Randomized WI subcutaneous injections (n = 208, 4/subject) were delivered to the right and left abdomen and thigh of each subject, 50% (1 thigh and 1 abdomen) with a defined movement sequence during injection. Injector functional performance was documented. Deposition was qualified and quantified with ultrasound. Tissue effects and tolerability (pain) were monitored through 24 hours with corresponding acceptability questionnaires administered through 72 hours. WI (n = 205) automatically inserted the needle, delivered 5 mL ± 5% in 5.42 minutes (SD 0.74) and retracted. Depots were entirely (93.2%) or predominantly (5.4%) localized within the target subcutaneous tissue. Slight to moderate wheals (63.9%) and erythema (75.1%) were observed with ≥ 50% resolution within 30–60 minutes. Subject pain (100 mm Visual Analog Scale) peaked mid‐injection (mean 9.1 mm, SD 13.4) and rapidly resolved within 30 minutes (mean 0.4 mm, SD 2.6). Subjects’ peak pain (≥ 90.2%), injection site appearance (≥ 92.2%) and injector wear, size, and removal (≥ 92.1%) were acceptable (Likert responses) with 100% likely to use the injector if prescribed. Injection site preference was divided between none (46%), abdomen (25%), or thigh (26.9%). The investigational WI successfully delivered 5 mL viscous subcutaneous injections. Tissue effects and pain were transient, well‐tolerated and acceptable. Neither injection site, movement or subject age affected injector functional performance or subject pain and acceptability.

Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity

The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown. To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly. Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes. A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups. The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]). Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%). Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks. ClinicalTrials.gov Identifier: NCT03548987.

Once-Weekly Semaglutide in Adults with Overweight or Obesity

BackgroundObesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.MethodsIn this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.ResultsThe mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).ConclusionsIn participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).