Placebo-controlled Phase 2a Research Articles

A phase 2a trial of brepocitinib for cicatricial alopecia

BackgroundCicatricial alopecias (CA) are chronic, progressive scarring hair-loss conditions. Molecular dysregulation is not fully understood, hindering treatment development. Th1/IFNγ signaling and JAK dysregulation has shown involvement, providing rationale for this phase 2a trial with TYK2/JAK1 inhibitor brepocitinib. MethodsRandomized, placebo-controlled phase 2a trial spanning 52 weeks. Adults (18≥years of age) with lichen planopilaris, frontal fibrosing alopecia, or central centrifugal cicatricial alopecia diagnosis were randomized 3:1 to brepocitinib 45mg daily or placebo for 24 weeks, after which all patients received brepocitinib for another 24 weeks, with a safety follow up 4 weeks later. Lesional scalp biopsies were collected at baseline, week 24, and week 48. Co-primary endpoints were changes in lesional expression of CCL5, changes in lesional expression of fibrosis-related markers, and safety at week 24. ResultsPatients receiving brepocitinib showed significant downregulation in CCL5 expression at week 24 (p=0.004). Enrichment analysis of a subset of fibrosis markers showed trending upregulation in placebo patients (p<0.1). Brepocitinib was well tolerated and improved clinical severity scores. LimitationsSingle-dose regimen, small placebo group. ConclusionBrepocitinib significantly reduces CCL5 expression and was well tolerated at week 24, meeting co-primary endpoints. Brepocitinib reduces inflammatory biomarker expression and improves clinical severity, while maintaining favorable safety profile.

Efficacy and safety of therapeutic alpha-1-microglobulin RMC-035 in reducing kidney injury after cardiac surgery: a multicentre, randomised, double-blind, parallel group, phase 2a trial

Cardiac surgery invariably triggers acute kidney stress causing adverse renal outcomes. The AKITA study evaluated the efficacy and safety of RMC-035, a novel analogue of alpha-1-microglobulin, for reducing cardiac surgery-associated kidney injury. In this randomised double-blind placebo-controlled phase 2a study, we randomly assigned (1:1) adult hospitalised patients undergoing open-chest cardiac surgery at high risk for acute kidney injury (AKI) at 21 sites in North America and Europe to receive either RMC-035 (1.3 or 0.65mg/kg) or placebo (1:1) for 2 days (5 intravenous infusions), stratified by region and renal function. Eligible patients had at least one pre-defined AKI risk factor. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30mL/min/1.73m2) were excluded. The co-primary efficacy and safety endpoints were AKI (Kidney Disease: Improving Global Outcomes definition) within 72h after surgery and nature, frequency, and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints included eGFR and Major Adverse Kidney Events (MAKE) up to Day 90. Randomised patients who had received at least one dose of study drug were analysed for primary and safety analyses. Participants, investigators and sponsor were masked to treatment allocation. This study is registered at ClinicalTrials.gov (NCT05126303) and EudraCT (2021-004040-19). Patient enrolment was stopped at interim analysis due to futility. Between March 31, 2022 and July 12, 2023, 177 patients (RMC-035: 89, placebo: 88) were randomised and treated. AKI rate for RMC-035 vs placebo was 50.6% (n=45) and 39.8% (n=35) (relative risk [RR]: 1.30, 90% confidence interval [90% CI]: 0.99, 1.71; p=0.12). A short-lived creatinine increase was observed with the higher RMC-035 dose. Treatment with RMC-035 was associated with improved secondary renal outcomes at Day 90: placebo-adjusted eGFR change from baseline 4.3mL/min/1.73m2, 90% CI 0.51-8.12, p=0.06; and MAKE 6.7% (n=6) vs 15.9% (n=14); RR: 0.41, 90% CI: 0.19, 0.88, p=0.05. The most frequently reported TEAEs for RMC-035 were chills (30.3%), nausea (21.3%), anaemia (20.2%); and atrial fibrillation (29.5%), anaemia (20.5%), hypervolemia (14.8%) for placebo. The majority of TEAEs in both treatment groups were mild or moderate in severity. In the RMC-035 group, 26 (29.2%) patients experienced at least one severe or life-threatening TEAE and in the placebo group 16 (18.2%) patients. There were 4 deaths per treatment arm (one treatment-related, in placebo group). In this proof-of-concept study, RMC-035 did not reduce AKI 72h after cardiac surgery. Evaluations may have been confounded by a drug-induced transient creatinine increase in a subgroup of patients. RMC-035 was associated with improved secondary renal outcomes. These results merit further investigation and should be interpreted with caution, as the study was not powered for these outcomes. Guard Therapeutics.

P75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial

p75 neurotrophin receptor (p75NTR) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75NTR with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. Here we conducted a 26-week randomized, placebo-controlled, double-blinded phase 2a safety and exploratory endpoint trial of LM11A-31 in 242 participants with mild to moderate AD with three arms: placebo, 200 mg LM11A-31 and 400 mg LM11A-31, administered twice daily by oral capsules. This trial met its primary endpoint of safety and tolerability. Within the prespecified secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), significant drug–placebo differences were found, consistent with the hypothesis that LM11A-31 slows progression of pathophysiological features of AD; no significant effect of active treatment was observed on cognitive tests. Together, these results suggest that targeting p75NTR with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration. EU Clinical Trials registration: 2015-005263-16; ClinicalTrials.gov registration: NCT03069014.

Safety and immunogenicity of Ad26.COV2.S in adults: A randomised, double-blind, placebo-controlled Phase 2a dose-finding study

BackgroundA single dose of Ad26.COV2.S is well-tolerated and effective in preventing moderate-to-severe disease outcomes due to COVID-19. We evaluated the impact of dose level, number of doses, and dose interval on immunogenicity, reactogenicity, and safety of Ad26.COV2.S in adults. Anamnestic responses were also explored. MethodsThis randomised, double-blind, placebo-controlled, Phase 2a study was conducted in adults aged 18–55 years and ≥ 65 years (NCT04535453). Four dose levels (1.25 × 1010, 2.5 × 1010, 5 × 1010, and 1 × 1011 viral particles [vp], single and 2-dose schedules, and dose intervals of 56 and 84 days, were assessed. Four or 6 months post-primary vaccination, Ad26.COV2.S 1.25 × 1010 vp was given to evaluate anamnestic responses. Humoral and cell-mediated immune responses were measured. Reactogenicity and safety were assessed in all participants. ResultsAll Ad26.COV2.S schedules induced humoral responses with evidence of a dose response relationship. A single dose of Ad26.COV2.S (5 × 1010 vp) induced antibody and cellular immune responses that persisted for up to at least 6 months. In the 2-dose regimens, antibody responses were higher than 1-dose regimens at comparable dose levels, and the magnitude of the immune response increased when the interval between doses was increased (84 days vs 56 days). Rapid, marked immune responses were observed in all groups after vaccine antigen exposure indicating immune memory. Durable immune responses were observed in all groups for up to at least 6 months post-antigen exposure. Strong and consistent correlations between neutralising and binding antibodies were observed CD4 + and CD8 + T cell responses were similar after all regimens. Reactogenicity within 7 days post-vaccination tended to be dose-related. ConclusionThe study supports the primary, single dose schedule with Ad26.COV2.S at 5 × 1010 vp and homologous booster vaccination after a 6 month interval. Rapid and marked responses to vaccine antigen exposure indicate induction of immune memory by 1- and 2-dose primary vaccination.

OA04 Efficacy and safety of nipocalimab in patients with moderate to severe active rheumatoid arthritis: the multicenter, randomised, double-blinded, placebo-controlled phase 2a IRIS-RA study

Abstract Background/Aims Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with autoantibodies. Despite the use of targeted therapies, up to half of patients fail to achieve remission or low disease activity (LDA). Anti-citrullinated protein antibodies (ACPAs), key autoantibodies that predict progression of joint destruction in RA, are largely an immunoglobulin G (IgG) isotype. Nipocalimab is a high affinity, fully human, IgG1 monoclonal antibody that is designed to selectively block the neonatal Fc receptor (FcRn), preventing recirculation and thereby lowering IgG levels, potentially including ACPAs and other pathogenic antibodies. In this phase 2a proof-of-concept study (IRIS-RA; NCT04991753), we report the efficacy and safety of nipocalimab in patients with moderate to severe, active RA. Methods Eligible adult patients with moderate to severe RA (≥6 swollen/tender joints), positive for ACPA or rheumatoid factor, and ≥1 advanced therapies, were randomized 3:2 to receive intravenous 15 mg/kg nipocalimab or placebo every 2 weeks for 10 weeks. The primary endpoint was the change from baseline in the Disease Activity Score 28 using C-reactive protein (DAS28-CRP) at Week 12. Secondary endpoints included the proportion of patients who achieved ACR20, ACR50, ACR70, and ACR90 responses, DAS28-CRP remission, and change from baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 12. Results In total, 53 patients were enrolled (nipocalimab, n = 33; placebo, n = 20). Most patients were female (67.9%) and white (90.6%) with a median age of 59 (range, 26-74) years. Demographic and baseline disease characteristics were comparable between groups except higher CRP in placebo. At Week 12, patients treated with nipocalimab showed a numerically greater mean (standard deviation [SD]) change in DAS28-CRP score compared to the placebo group (-1.17 [1.34] vs -0.62 [0.96]; mean difference [95% confidence interval], -0.45 [-1.17-0.28]; p=0.224). A numerically higher proportion of patients achieved ACR20, ACR50, ACR70, and ACR90 responses compared to placebo. In the nipocalimab group, 7 (21.2%) patients achieved DAS28-CRP remission compared to 2 (10.0%) patients in the placebo group (treatment difference, 9.9% [-9.5-29.3%]; p=0.456). Similarly, patients in the nipocalimab group had a numerically greater mean (SD) improvement in HAQ-DI score (-0.27 [0.55] vs -0.11 [0.36], respectively). The proportion of patients with treatment-emergent adverse events (TEAEs) were 81.8% vs 60.0% in the nipocalimab vs placebo groups. In the nipocalimab group, 3 serious TEAEs were reported, including burn infection, infusion-related reaction, and deep-vein thrombosis. There were no TEAEs that led to death. Conclusion Treatment with nipocalimab resulted in consistent and numerically higher improvements across ACR20, ACR50, ACR70, and ACR90 responses, as well as DAS28-CRP, DAS28-CRP remission, and HAQ-DI, with acceptable safety profile. Nipocalimab showed activity in patients with moderate to severe RA and warrants further investigation to understand the predictors of nipocalimab response. Disclosure P.C. Taylor: Consultancies; AbbVie, Biogen, Eli Lilly, Fresenius, Galapagos, Gilead Sciences, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Inc, Sanofi, Aqtual, and UCB. Grants/research support; Galapagos. G. Schett: None. F. Ibrahim: Corporate appointments; Employee of Janssen Research &amp; Development. B. Zhou: Corporate appointments; Employee of Janssen Research &amp; Development. J. Leu: Corporate appointments; Employee of Janssen Research &amp; Development. S. Liva: Corporate appointments; Employee of Janssen Research &amp; Development. Q. Wang: Corporate appointments; Employee of Janssen Research &amp; Development. R. Rojo Cella: Corporate appointments; Employee of Janssen Research &amp; Development. C.S. Karyekar: Corporate appointments; Employee of Janssen Research &amp; Development. K. Fei: Corporate appointments; Employee of Janssen Research &amp; Development.

Efficacy and safety of MP1032 plus standard-of-care compared to standard-of-care in hospitalised patients with COVID-19: a multicentre, randomised double-blind, placebo-controlled phase 2a trial

Efficacy and safety of MP1032 plus standard-of-care compared to standard-of-care in hospitalised patients with COVID-19: a multicentre, randomised double-blind, placebo-controlled phase 2a trial

Trials in Progress: The Randomized, Double-Blind, Placebo-Controlled Phase 1b CROSSWALK-a and Phase 2a CROSSWALK-c Trials - Crovalimab for the Treatment and Prevention of Vaso-Occlusive Episodes in Sickle Cell Disease

Background and Significance In sickle cell disease (SCD), a single point mutation in the beta-globin gene results in hemoglobin S (HbS) production, which can polymerize upon deoxygenation. Polymerization distorts the red blood cell (RBC) membrane and generates sickled RBCs, contributing to microvascular occlusions, which may present as acute, painful vaso-occlusive episodes (VOEs). For patients (pts) with SCD, 70% of emergency department visits and 90% of hospitalizations are VOE-related. 1,2 Despite existing treatments for VOE prevention, considerable morbidity and mortality remain; acute VOE treatment is limited to supportive care due to a lack of targeted therapies. Accumulating nonclinical data suggest a multimodal role for complement dysregulation in SCD pathophysiology, including in vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage. 3 Crovalimab is a novel, engineered, anti-complement C5 monoclonal antibody that allows for small-volume subcutaneous (SC) injection after an initial intravenous (IV) loading dose. 4 Here, we describe two randomized, double-blind, placebo-controlled trials evaluating crovalimab in pts with SCD: CROSSWALK-a (Phase 1b; NCT04912869) and CROSSWALK-c (Phase 2a; NCT05075824). Study Design and Methods CROSSWALK-a evaluates the safety of crovalimab in managing acute uncomplicated VOEs. CROSSWALK-c evaluates the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs. Pts 12-55 years old, weighing ≥40 kg with a confirmed diagnosis of sickle cell anemia (homozygous HbSS or heterozygous HbS/β 0 thalassemia) and vaccinated against N. meningitidis, H. influenzae type B and S. pneumoniae are eligible (Fig. 1 and 2). Concurrent SCD-directed therapies are allowed. CROSSWALK-a Pts must present with an acute uncomplicated VOE requiring hospitalization and parenteral opioid analgesics, and have had ≤10 VOEs in the 12 months prior to randomization. Eligible pts will be randomized 2:1 to receive a single IV weight-based tiered dose of crovalimab or placebo, and monitored during hospitalization and in an 84-day observational period followed by a safety follow-up period for a total study duration of 322 days (10.5 months). The primary objective of CROSSWALK-a is to evaluate safety up to Day 84, including: Incidence and severity of adverse eventsIncidence and severity of infusion-related reactions and hypersensitivityChange from baseline in targeted vital signs and clinical laboratory test results Efficacy, pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and exploratory biomarker endpoints will also be evaluated. CROSSWALK-c Pts with 2-10 VOEs in the 12 months prior to randomization are eligible. Eligible pts will be randomized 1:1 to receive weight-based tiered doses of crovalimab or placebo, consisting of initial loading doses (IV: Day 1; SC: Day 2 and weekly for Weeks 2-4) and monthly maintenance SC doses Weeks 5-49 for 48 weeks of treatment. The primary objective of CROSSWALK-c is to evaluate crovalimab efficacy vs placebo up to 48 weeks, on the basis of: The annualized rate of medical facility VOEs Key secondary efficacy objectives are: Annualized rate of home VOEsAnnualized rate of acute chest syndromeAnnualized rate of days hospitalized for medical facility VOEsPt-reported fatigue in adults Safety, PK, PD, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Primary results will be published upon trial readout.

Efficacy of Wharton Jelly Mesenchymal Stromal Cells infusions in moderate to severe SARS-Cov-2 related acute respiratory distress syndrome: a phase 2a double-blind randomized controlled trial.

The COVID-19 pandemic caused a wave of acute respiratory distress syndrome (ARDS) with a high in-hospital mortality, especially in patients requiring invasive mechanical ventilation. Wharton Jelly-derived Mesenchymal Stromal Cells (WJ-MSCs) may counteract the pulmonary damage induced by the SARS-CoV-2 infection through pro-angiogenic effects, lung epithelial cell protection, and immunomodulation. In this randomized, double-blind, placebo-controlled phase 2a trial, adult patients receiving invasive mechanical ventilation for SARS-CoV-2 induced moderate or severe ARDS were assigned to receive 1 intravenous infusion of 1 × 106 WJ-MSCs/kg or placebo within 48 h of invasive ventilation followed by 2 infusions of 0.5 × 106 WJ-MSCs/kg or placebo over 5 days. The primary endpoint was the percentage of patients with a PaO2/FiO2 > 200 on day 10. Thirty patients were included from November 2020 to May 2021, 15 in the WJ-MSC group and 15 in the placebo group. We did not find any significant difference in the PaO2/FiO2 ratio at day 10, with 18 and 15% of WJ-MSCs and placebo-treated patients reaching a ratio >200, respectively. Survival did not differ in the 2 groups with a 20% mortality rate at day 90. While we observed a higher number of ventilation-free days at 28 days in the WJ-MSC arm, this difference was not statistically significant (median of 11 (0-22) vs. 0 (0-18), p = 0.2). The infusions were well tolerated, with a low incidence of anti-HLA alloimmunization after 90 days. While treatment with WJ-MSCs appeared safe and feasible in patients with SARS-CoV2 moderate or severe ARDS in this phase 2a trial, the treatment was not associated with an increased percentage of patients with P/F > 200 at 10d, nor did 90 day mortality improve in the treated group. https://beta.clinicaltrials.gov/study/NCT04625738, identifier NCT04625738.

Efficacy and Safety of Eliapixant in Overactive Bladder: The 12-Week, Randomised, Placebo-controlled Phase 2a OVADER Study

BackgroundEffective, well-tolerated novel treatments for overactive bladder (OAB) are lacking. The P2X3 receptor antagonist eliapixant demonstrated potential to reduce OAB symptoms in preclinical studies. ObjectiveTo evaluate the safety, tolerability, and efficacy of eliapixant in patients with OAB with urgency urinary incontinence (UUI). Design, setting and participantsOVADER was a 12-wk, randomised, placebo-controlled, double-blind, parallel-group, multicentre, phase 2a study (NCT04545580) conducted between 2020 and 2022 in private and institutional clinical practices. Eligible patients were aged ≥18 yr with wet OAB symptoms (urgency, urinary frequency, and urinary incontinence) for ≥3 mo before screening. InterventionRandomisation (1:1 ratio) to oral eliapixant 125 mg or placebo twice daily. Outcome measurements and statistical analysisThe primary endpoint was the mean change from baseline in the mean number of UUI episodes/24 h over weeks 4, 8, and 12 according to an electronic bladder diary, evaluated using a repeated-measurement model in a Bayesian framework. Results and limitationsOf 202 patients enrolled, 85 were valid for per-protocol analysis. The primary efficacy endpoint was not met. The posterior probability for eliapixant superiority over placebo was 40% (point estimate 0.05, 95% credible interval −∞ to 0.38), which did not meet the predefined criterion of ≥90% probability. Secondary and exploratory endpoints were not met. The incidence of adverse events was similar in the eliapixant (n = 32, 63%) and placebo (n = 27, 56%) groups; most were mild and five led to discontinuation of eliapixant. ConclusionsOVADER did not meet its clinical efficacy endpoints. Potential reasons include the nonspecific OAB symptom complex, the poorly understood pathophysiology, and the coinciding COVID-19 pandemic. Patient summaryWe tested whether a new drug called eliapixant would reduce symptoms of overactive bladder in comparison to placebo. We found that the drug did not work. More knowledge on how overactive bladder occurs is needed to find new drugs to treat this condition.

LBP-22 - Twelve-week treatment with BOS-580, a novel, long-acting Fc-FGF-21 fusion protein, leads to a reduction in liver steatosis, liver injury, and fibrosis in patients with phenotypic NASH: a randomized, blinded, placebo-controlled phase 2A trial

LBP-22 - Twelve-week treatment with BOS-580, a novel, long-acting Fc-FGF-21 fusion protein, leads to a reduction in liver steatosis, liver injury, and fibrosis in patients with phenotypic NASH: a randomized, blinded, placebo-controlled phase 2A trial

A Randomized, Double-Blind, Placebo-Controlled Phase 2a Study of Tildrakizumab Efficacy and Safety in Patients With Active Ankylosing Spondylitis.

Tildrakizumab is an anti-interleukin-23p19 monoclonal antibody approved to treat moderate to severe plaque psoriasis. This study evaluated the efficacy and safety of tildrakizumab in patients with ankylosing spondylitis (AS). In this randomized, double-blind, parallel-group, multinational trial (clinicaltrials.gov NCT02980705), patients with active AS, according to modified New York criteria and Bath Ankylosing Spondylitis Disease Activity Index Score ≥4, were randomized 1:1 to tildrakizumab 200 mg or placebo every 4 weeks until week 24. Thereafter, all patients received tildrakizumab 200 mg every 4 weeks until week 48. The primary outcome was proportion of patients achieving 20% improvement from baseline by Assessment in SpondyloArthritis International Society criteria (ASAS20) at week 24. This outcome was analyzed in subgroups defined by prior treatment experience, weight, age, and sex using the full analysis set. Safety was assessed through treatment-emergent adverse events. From December 5, 2017-September 3, 2019, 101 patients (76.2% male, 97% White) enrolled and were randomized to treatment. At week 24, the ASAS20 response rate was 74.0% in patients receiving tildrakizumab 200 mg (n = 50) versus 80.4% in placebo-treated patients (n = 51; treatment difference, -6.31%; 95% confidence interval, -22.34 to 9.71; p = 0.44). No difference in treatment effect by subgroups was observed. Tildrakizumab treatment was generally well tolerated, with no unexpected safety findings. The study was terminated after the week 24 interim analysis due to lack of efficacy. Tildrakizumab treatment was generally well tolerated but did not improve ASAS20 response rate versus placebo in patients with AS.

Opaganib in Coronavirus Disease 2019 Pneumonia: Results of a Randomized, Placebo-Controlled Phase 2a Trial.

BackgroundOpaganib, an oral sphingosine kinase-2 inhibitor with antiviral and anti-inflammatory properties, was shown to inhibit severe acute respiratory syndrome coronavirus 2 replication in vitro. We thus considered that opaganib could be beneficial for moderate to severe coronavirus disease 2019 (COVID-19) pneumonia. The objective of the study was to evaluate the safety of opaganib and its effect on supplemental oxygen requirements and time to hospital discharge in COVID-19 pneumonia hospitalized patients requiring supplemental oxygen.MethodsThis Phase 2a, randomized, double-blind, placebo-controlled study was conducted between July and December 2020 in 8 sites in the United States. Forty-two enrolled patients received opaganib (n = 23) or placebo (n = 19) added to standard of care for up to 14 days and were followed up for 28 days after their last dose of opaganib/placebo.ResultsThere were no safety concerns arising in this study. The incidence of ≥Grade 3 treatment-emergent adverse events was 17.4% and 33.3% in the opaganib and placebo groups, respectively. Three deaths occurred in each group. A numerical advantage for opaganib over placebo was observed in in this nonpowered study reflected by total supplemental oxygen requirement from baseline to Day 14, the requirement for supplemental oxygen for at least 24 hours by Day 14, and hospital discharge.ConclusionsIn this proof-of-concept study, hypoxic, hospitalized patients receiving oral opaganib had a similar safety profile to placebo-treated patients, with preliminary evidence of benefit for opaganib as measured by supplementary oxygen requirement and earlier hospital discharge. These findings support further evaluation of opaganib in this population.

Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): a phase 2a, placebo-controlled trial

Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory airway disease. The epithelial-derived IL-33 and its receptor ST2 have been implicated in airway inflammation and infection. We aimed to determine whether astegolimab, a selective ST2 IgG2 monoclonal antibody, reduces exacerbations in COPD. COPD-ST2OP was a single-centre, randomised, double-blinded, placebo-controlled phase 2a trial in moderate-to-very severe COPD. Participants were randomly assigned (1:1) with a web-based system to received 490 mg subcutaneous astegolimab or subcutaneous placebo, every 4 weeks for 44 weeks. The primary endpoint was exacerbation rate assessed for 48 weeks assessed with a negative binomial count model in the intention-to-treat population, with prespecified subgroup analysis by baseline blood eosinophil count. The model was the number of exacerbations over the 48-week treatment period, with treatment group as a covariate. Safety was assessed in the whole study population until week 60. Secondary endpoints included Saint George's Respiratory Questionnaire for COPD (SGRQ-C), FEV1, and blood and sputum cell counts. The trial was registered with ClinicalTrials.gov, NCT03615040. The exacerbation rate at 48 weeks in the intention-to-treat analysis was not significantly different between the astegolimab group (2·18 [95% CI 1·59 to 2·78]) and the placebo group (2·81 [2·05 to 3·58]; rate ratio 0·78 [95% CI 0·53 to 1·14]; p=0·19]). In the prespecified analysis stratifying patients by blood eosinophil count, patients with 170 or fewer cells per μL had 0·69 exacerbations (0·39 to 1·21), whereas those with more than 170 cells per μL had 0·83 exacerbations (0·49 to 1·40). For the secondary outcomes, the mean difference between the SGRQ-C in the astegolimab group versus placebo group was -3·3 (95% CI -6·4 to -0·2; p=0·039), and mean difference in FEV1 between the two groups was 40 mL (-10 to 90; p=0·094). The difference in geometric mean ratios between the two groups for blood eosinophil counts was 0·59 (95% CI 0·51 to 0·69; p<0·001) and 0·25 (0·19 to 0·33; p<0·001) for sputum eosinophil counts. Incidence of treatment-emergent adverse events was similar between groups. In patients with moderate-to-very severe COPD, astegolimab did not significantly reduce exacerbation rate, but did improve health status compared with placebo. Funded by Genentech and National Institute for Health Research Biomedical Research Centres.

Emerging Glycation-Based Therapeutics-Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors.

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)—a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer—particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.

Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study

AMP kinase (AMPK) is an energy sensor implicated in regulation of lipid metabolism, inflammation, and insulin sensitivity. We aimed to assess efficacy and safety of PXL770, a novel direct AMPK activator, in patients with non-alcoholic fatty liver disease (NAFLD). STAMP-NAFLD, a randomised, double-blind, placebo-controlled phase 2a study, was done across 15 US clinical sites. Patients aged 18-75 years with liver fat content of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned (1:1:1:1), via an interactive web response system, to receive oral PXL770 250 mg once daily, 250 mg twice daily, or 500 mg once daily, or matched placebo. Patients were stratified according to type 2 diabetes status and study site. The primary endpoint was relative change in liver fat content from baseline compared with placebo at week 12, assessed by MRI-PDFF. The primary endpoint was analysed in an ANCOVA model with treatment and stratification criteria as factors and baseline liver fat content as a covariate in the modified intention-to-treat population, defined as all as-randomised patients who received at least one dose of study treatment. Safety was analysed in the safety population, defined as all as-treated patients receiving at least one dose of the study treatment. The trial has been completed and the final results are reported. The trial is registered with ClinicalTrials.gov, NCT03763877. Between March 29, 2019, and March 13, 2020, 387 patients were screened, of whom 120 were included in the modified intention-to-treat and safety analyses (30 in the 250 mg once daily group, 30 in the 250 mg twice daily group, 29 in the 500 mg once daily group, and 31 in the placebo group). The mean relative change from baseline in liver fat content at week 12 was -1·1% in the placebo group, -1·0% in the 250 mg once daily group (mean difference versus placebo 0·1% [95% CI -15·4 to 15·7], p=0·99), -14·3% in the 250 mg twice daily group (-13·1% [-28·1 to 1·8], p=0·084), and -14·7% in the 500 mg once daily group (-13·5% [-28·5 to 1·4], p=0·076). At least one treatment-emergent adverse event occurred in 23 (77%) of 30 patients in the 250 mg once daily group, 20 (67%) of 30 patients in the 250 mg twice daily group, 21 (72%) of 29 patients in the 500 mg once daily group, and 21 (68%) of 31 patients in the placebo group. The most common treatment-emergent adverse event was diarrhoea (five [17%] of patients in the 250 mg once daily group, seven [23%] in the 250 mg twice daily group, six [21%] in the 500 mg once daily group, and none in the placebo group). No life-threatening events or treatment-related deaths occurred. PXL770 treatment did not meet the primary outcome of liver fat improvement compared with placebo. Treatment was well tolerated. Given indications that metabolic features improved with PXL770 treatment, AMPK activation might be a promising pharmacological target for patients with type 2 diabetes and NAFLD, and could also be considered for further assessment in patients with non-alcoholic steatohepatitis. Poxel.

Anti-granulocyte-macrophage colony-stimulating factor antibody otilimab in patients with hand osteoarthritis: a phase 2a randomised trial.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a key mediator of signs and symptoms in preclinical models of osteoarthritis. We explored the efficacy, safety, and pharmacokinetics of an anti-GM-CSF antibody, otilimab, in patients with hand osteoarthritis. This double-blind, randomised, placebo-controlled phase 2a study was done in 16 centres in the Netherlands, Germany, Poland, the UK, and the USA. Patients aged 18 years or older with inflammatory hand osteoarthritis, who had received at least one course of unsuccessful non-steroidal anti-inflammatory drugs, with two or more swollen and tender interphalangeal joints (on the same hand), signs of inflammation or synovitis identified with MRI in the affected hand, and a self-reported 24 h average hand pain intensity over the past 7 days of 5 or more on a 0-10 numerical rating scale were eligible for inclusion. Patients were randomly assigned (1:1) via interactive response technology (blocked randomisation; block size of four) to receive either subcutaneous otilimab 180 mg or placebo, administered weekly from week 0 to week 4, then every other week until week 10. Patients, investigators, and trial staff were masked to treatment; at least one administrator at each site was unmasked to prepare and administer treatment. The primary endpoint was change from baseline in 24 h average hand pain numeric rating scale averaged over 7 days before the visit at week 6. Secondary endpoints were: change from baseline in 24 h average and worst hand pain intensity at each visit; proportion of patients showing 30% and 50% reductions in 24 h average and worst hand pain intensity at each visit; change from baseline in Australian and Canadian Hand Osteoarthritis Index (AUSCAN) 3·1 numeric rating scale questionnaire components at each visit; change in number of swollen and tender hand joints at each visit; change from baseline in Patient and Physician Global Assessment of disease activity; serum concentration of otilimab; and safety parameters. Efficacy endpoints were assessed in the intention-to-treat population. The safety population included all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT02683785. Between March 17, 2016, and Nov 29, 2017, 44 patients were randomly assigned (22 in the placebo group and 22 in the otilimab group). At week 6, difference in change from baseline in 24 h average hand pain numeric rating scale between the otilimab and placebo groups was -0·36 (95% CI -1·31 to 0·58; p=0·44); at week 12, the difference was -0·89 (-2·06 to 0·28; p=0·13). Patients receiving otilimab showed greater improvement in AUSCAN components versus placebo at each visit. The change from baseline in the 24 h worst hand pain numeric rating scale in the otilimab group at week 6 showed a difference over placebo of -0·33 (95% CI -1·28 to 0·63; p=0·49); at week 12, this difference was -1·01 (95% CI -2·22 to 0·20; p=0·098). The proportion of patients achieving 30% or higher or 50% or higher reduction from baseline in the 24 h average and worst hand pain numeric rating scale scores was consistently greater (although non-significant) with otilimab versus placebo. Similarly, patients receiving otilimab showed greater improvement in AUSCAN pain, functional impairment, and stiffness scores versus placebo at each visit. No differences were observed between otilimab and placebo in the change from baseline in the number of swollen and tender joints across the study. The Patient Global Assessment was consistently lower than placebo at all visits; the Physician Global Assessment showed reductions across the study period, but the changes were similar in both treatment groups. Median otilimab serum concentrations increased during weekly dosing from 1730 ng/mL at week 1 to a maximum of 3670 ng/mL at week 4, but declined after transitioning to dosing every other week (weeks 6-10). In total, 84 adverse events were reported by 24 patients: 54 adverse events in 13 (59%) patients in the otilimab group and 30 adverse events in 11 (50%) patients in the placebo group. The most common adverse events were cough (reported in 4 [9%] patients; 2 in each group), and nasopharyngitis (in 3 [7%] patients; 1 in the placebo group and 2 in the otilimab group). Three serious adverse events occurred in this study (all in the otilimab group) and were deemed not related to the study medication. There were no deaths during the study. There was no significant difference between otilimab and placebo in the primary endpoint, although we noted a non-significant trend towards a reduction in pain and functional impairment with otilimab, which supports a potential role for GM-CSF in hand osteoarthritis-associated pain. There were no unexpected safety findings in this study, with no treatment-related serious adverse events reported. GlaxoSmithKline.

Is there a role for insulin-like growth factor inhibition in the treatment of COVID-19-related adult respiratory distress syndrome?

Adult respiratory distress syndrome (ARDS) is the leading cause of death associated with SARS-CoV-2 infection and COVID-19. IGF-1 has been implicated in ARDS, yet its role in relation to COVID-19-related lung injury has not been investigated. We hypothesize that blockage of the IGF-1 receptor (IGF-1R) mitigates lung injury and decreases the risk of death in patients COVID-19-related ARDS. Patients with fibroproliferative ARDS have been shown to have increased IGF-1 and IGF-1R staining in lung tissue specimens. Rising levels of IGF-1 in bronchioalveolar fluid (BAL) and increased IGF-1 mRNA expression in lung tissues (but declining serum IGF-1 levels) have been found in late stage ARDS compared with early lung injury. Blockage of IGF-1R decreases lung tissue damage and increases survival in bleomycin-induced as well as H1N1 influenza-related lung injury in animal models. Teprotumumab is a monoclonal antibody directed against the IGF-1R that was FDA-approved in 2020 for the treatment of Graves’ orbitopathy. In order to determine if teprotumumab may reduce lung injury and death related to ARDS in the setting of COVID-19, preliminary clinical data is needed. IGF-1 levels in serum and BAL fluid must be measured in patients with COVID-19-related ARDS. Histopathology from lung samples from patients with COVID-19-related ARDS must be examined for increased expression of the IGF-1R. Once these are ascertained, and if the data support IGF-1 involvement, a randomized, placebo-controlled phase 2A trial of teprotumumab therapy in the setting of COVID-19-related ARDS and non-COVID-19-related ARDS designed to generate initial data on short-term efficacy, safety, dosing and administration should be performed.

Tail-phase safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in HIV-uninfected adults: a secondary analysis of the HPTN 077 trial

Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial. HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18-65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t1/2app) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52-76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov, NCT02178800. Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p<0·0001). At 52-60 weeks after final injection, nine (23%) of 40 male participants had detectable cabotegravir concentrations and at week 76, four (13%) of 30 male participants had detectable cabotegravir concentrations compared with 52 (63%) of 82 female participants and 27 (42%) of 64 female participants at the same timepoints. The median time from the last injection to the time when cabotegravir concentration decreased below the LLOQ was 43·7 weeks (IQR 31·1-66·6; range 20·4-152·5) for male participants and 67·3 weeks (29·1-89·6; 17·7-225·5) for female participants (p=0·0003). t1/2app was longer for female participants than male participants (geometric mean fold-change 1·33, 95% CI 1·06-1·68; p=0·014), and longer for participants with a high body-mass index (BMI) than those with a low BMI (1·31, 1·06-1·63; p=0·015). The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials. National Institute of Allergy and Infectious Diseases.

Mitigating Damage Response with CD24 Fusion Protein for Prevention of Acute Graft-Versus-Host Disease

Danger-associated molecular patterns (DAMPs) released during conditioning have been shown to amplify experimental GVHD. CD24 fusion protein (CD24Fc; OncoImmune), a glycoprotein linked to human IgG₁ Fc, binds to Siglec-10 to negatively regulate host response to DAMPs. We have reported that infusion of CD24Fc prior to HCT significantly decreased GVHD-related mortality in murine models of HCT (Toubai, Blood 2015 & Toubai, JCI Insight 2017). We hypothesized that enhancing Siglec10-CD24 interactions by administration of CD24Fc would prevent acute GVHD. A randomized, prospective, multi-site, placebo controlled phase 2a clinical trial was initiated to investigate safety of three dose levels of CD24Fc (or blinded placebo) plus standard GVHD prophylaxis with tacrolimus and methotrexate (MTX) in matched unrelated donors. T cell replete PBSC or BMT was infused. Randomization (3:1 ratio of CD24Fc:Placebo) was in 3 cohorts of 8 pts: 240mg single dose on D -1, 480mg single dose on D -1, and a 480mg, 240mg, and 240mg multiple dose regimen on D -1, 14 and 28, respectively. The primary endpoint was safety and determination of a recommended dose. Pts were followed for secondary endpoints of aGVHD, relapse and survival at D180. The trial enrolled 24 pts (CD24Fc, n=18; Placebo, n=6) with minimum follow up on one year (Table1). All planned dosages were administered without reaching an MTD. There were no infusion-related toxicities or DLTs. In placebo treated pts, there was one DLT resulting in death from pneumonia. Between groups there were no overall differences in AEs, although CD24Fc was associated with fewer days of severe (≥ Grade III) mucositis. There was no infection-related mortality related to CD24Fc treatment. The CD24Fc pts achieved neutrophil and platelet engraftment at a median of D 13 (12-23) and D 13 (9-23), respectively. PK studies demonstrated sustained drug levels through D 100 in the multi-dosing cohort. The incidence of grade II-IV GVHD was 39% (18-62%) and III-IV GVHD was 6% (95% CI 0-20%) at D 180 among CD24Fc treated pts. Grade 3 involvement of the lower-GI tract was observed in 1/18 pts, while the remainder of acute GVHD involved the upper GI tract or skin. All pts receiving treatment for GVHD experienced response. At D 180, relapse occurred in 2/18 pts, and OS was 100%. The endpoint of grade 3-4 GVHD-free survival (AGFS) was 94% at D 180 in pts receiving treatment with CD24Fc versus 50% in pts receiving placebo (HR 0.1; 90% CI 0.0-0.7). AGFS in contemporaneous case matched controls (n=68; CIBMTR) receiving myeloablative 8/8 HLA matched unrelated donor HCT with tacrolimus + MTX was 68% (95% CI: 56-78). In this translational phase 2a trial administration of CD24Fc was safe and tolerable. Additional investigations are required determine efficacy for improving AGFS after HCT. This trial represents the first attempt to prevent GVHD by inhibiting host response to DAMPs.

2775. Safety and Immunogenicity of a Seasonal Influenza Vaccine and Ad26.RSV.preF Vaccine With and Without Co-Administration: A Randomized, Double-Blind, Placebo-Controlled Phase 2a Study in Adults Aged ≥ 60 Years

BackgroundInfluenza and RSV can cause respiratory tract infections leading to severe illness, hospitalization and mortality in at-risk populations, particularly the elderly. The seasonality of influenza and RSV present the potential to co-administer vaccines. This study aimed to demonstrate the non-inferiority of co-administration of the experimental RSV vaccine Ad26.RSV.preF with an influenza vaccine (Fluarix) vs. Fluarix alone in terms of immunogenicity against influenza.MethodsThis was a single-center, randomized, double-blind, placebo-controlled Phase 2a study (NCT03339713) in healthy adults ≥60 years old. Volunteers were randomized 1:1 to receive Fluarix + 1 × 1011 vp Ad26.RSV.preF on Day 1 and placebo on Day 29 (Group 1), or Fluarix + placebo on Day 1 and 1 × 1011 vp Ad26.RSV.preF on Day 29 (Group 2). Blood samples were taken prior to each vaccination and at Day 57. The primary endpoints were geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibody titers against Fluarix strains (A/Michigan, A/Hong Kong, B/Brisbane and B/Phuket) and the safety and tolerability of Ad26.RSV.preF administered with or without Fluarix. A key secondary endpoint was neutralizing antibody titers to RSV A2.ResultsVolunteers (N = 180) were included in Group 1 (n = 90) or Group 2 (n = 90). Most volunteers were white (89%) and female (63%), with a median age of 65 years. Both groups exhibited an increase from baseline in HI antibody response on Day 29. The 95% one-sided upper confidence limit of all GMT ratios were below the non-inferiority margin of 2. The frequency of solicited adverse events (AE) after Ad26.RSV.preF vaccination was similar with and without influenza co-administration. Solicited AEs were mainly of Grade 1 and 2 and of transient duration. Most unsolicited AEs were considered unrelated to the study vaccination and were Grade 1 or 2. There were no serious AEs related to the study vaccine and there were no discontinuations due to AEs. RSV neutralizing antibody titers 29 days post- Ad26.RSV.preF immunization were similar in both groups (1404, Group 1; 1690, Group 2).ConclusionCo-administration of Ad26.RSV.preF with Fluarix was non-inferior to Fluarix alone in terms of immunogenicity against influenza and had an acceptable tolerability profile.Disclosures All authors: No reported disclosures.