Placebo-controlled Phase 2b Trial Research Articles

Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial

Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38β MAPK) for the treatment of facioscapulohumeral muscular dystrophy. We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy. Fulcrum Therapeutics.

279. Inhaled Sargramostim (rhu GM-CSF) Leads to Enhanced SARS-CoV-2 Virus-Specific Immune Response and Viral Clearance: Results of the Biomarker Cohort of a Randomized, Double-Blind, Placebo-Controlled Phase 2b Trial in Non-Hospitalized Patients with COVID-19

Abstract Background Progression from mild to severe SARS-CoV-2 infection correlates with humoral and cellular immune signatures that adjust to a multiplying viral load. Enhancing immunity with host-directed therapy, such as sargramostim (yeast-derived, recombinant human granulocyte-macrophage colony-stimulating factor [GM-CSF]), may prevent disease progression and reduce severity. Methods This prospective, randomized, double-blind, placebo-controlled study enrolled symptomatic vaccinated and unvaccinated non-hospitalized patients with mild/moderate COVID-19 at high risk for progression. Patients received daily sargramostim 250 mcg or placebo, inhaled via nebulizer, for 5 days. Figure 1 lists study endpoints. Results From April 28, 2021 to January 31, 2022, 101 patients consented and provided samples for the biomarker cohort (Fig 2). No difference was seen in the overall study primary endpoint (n=21/301 sargramostim, n=16/299 placebo, p=0.4). Treatment-emergent adverse events were similar in both arms. In the biomarker cohort, SARS-CoV-2 viral clearance by day 14 was enhanced on the sargramostim arm (p=0.0064, Fig 3). Virus was undetectable in a larger proportion on the sargramostim arm. Sargramostim reduced viral load more in vaccinated than unvaccinated patients. Inflammatory cytokine levels did not increase with treatment. Kinetics and magnitude of antibody response against SARS-CoV-2 antigens differed by group. After an initial IgM-titer peak at day 14, IgM titers at day 28 were lower in the vaccinated-sargramostim arm than the vaccinated-placebo arm (Fig 4A). The unvaccinated-sargramostim arm maintained higher IgM titers than the unvaccinated-placebo arm. Overall IgG titers were higher for vaccinated patients across both treatment arms. However, the vaccinated-sargramostim arm had higher IgG4 titers associated with IgG4-isotype-class switching than the vaccinated-placebo arm (Fig 4B). Conclusion The primary clinical endpoint was not met. Biomarker analyses suggest inhaled sargramostim reduces SARS-CoV-2 viral load and alters humoral kinetics and expression, more so in those vaccinated. Results suggest the potential of sargramostim as a virus agnostic, host-directed immunomodulator. Disclosures Ila Joshi, PhD, Partner Therapeutics, Inc.: Patents|Partner Therapeutics, Inc.: Salary|Partner Therapeutics, Inc.: Stocks/Bonds Fiona Garner, PhD, Partner Therapeutics, Inc.: Employment|Partner Therapeutics, Inc.: Stocks/Bonds Debasish F. Roychowdhury, MD, Partner Therapeutics, Inc.: Employment|Partner Therapeutics, Inc.: Ownership Interest|Partner Therapeutics, Inc.: Stocks/Bonds Lorinda Simms, MSc, Partner Therapeutics, Inc.: Advisor/Consultant|Partner Therapeutics, Inc.: Stocks/Bonds Sanjeev Ahuja, MD, Partner Therapeutics, Inc.: Employment|Partner Therapeutics, Inc.: Stocks/Bonds|Scioto Biosciences: Past Employee John L. McManus, n/a, JPEO-CBRND's Joint Project Manager for Chemical, Biological, Radiological, and Nuclear Medical: Project agreement MCDC2006-012. Included references to commercial products do not constitute an endorsement by the US DoD or the JPEO-CBRND.|Partner Therapeutics, Inc.: Employment|Partner Therapeutics, Inc.: Stocks/Bonds Edwin P. Rock, MD, PhD, Partner Therapeutics: Employment Robert Paine III, MD, Partner Therapeutics, Inc.: Advisor/Consultant

Improvements in immune/melanocyte biomarkers with JAK3/TEC family kinase inhibitor ritlecitinib in vitiligo

Vitiligo is an autoimmune depigmenting disorder with no effective and safe treatments. Its pathogenesis is not fully elucidated. This substudy of a randomized, double-blind, placebo-controlled phase 2b trial (NCT03715829) evaluated effects of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on skin and blood biomarkers in participants with nonsegmental vitiligo (NSV). Sixty-five adults with NSV participated in the substudy and received daily treatment for 24 weeks with placebo (n= 14) or ritlecitinib with or without a 4-week loading dose: 200 (loading dose)/50 mg (n= 13), 100/50 mg (n= 12), 50 mg (n= 11), 30 mg (n= 8), or 10 mg (n= 6). Skin (lesional and nonlesional) biopsy samples were obtained at baseline and at 4 and 24 weeks. Changes from baseline to weeks 4 and 24 in skin and blood molecular and cellular biomarkers were evaluated by RNA sequencing, quantitative real-time PCR, proteomic analysis, and flow cytometry. Ritlecitinib-treated groups showed downregulation of immune biomarkers and upregulation of melanocyte-related markers at weeks 4 and 24 compared to baseline and/or placebo. Significant reductions were seen in CD3+/CD8+ T-cell infiltrates, with significant increases in melanocyte markers (tyrosinase; Melan-A) in NSV lesions in the 50 mg ritlecitinib groups (both P< .05). There was significant, dose-dependent downregulation in T-cell activation, NK, cytotoxic, and regulatory markers in lesional skin (IL-2, IL2-RA, IL-15, CCR7, CD5, CRTAM, NCR1, XCL1, KIR3DL1, FASLG, KLRD; P< .05). TH1 and TH2 markers were also downregulated in lesional skin and blood in a dose-dependent manner (P< .05). Changes in immune biomarkers correlated with clinical response. Ritlecitinib significantly downregulated proinflammatory biomarkers and increased melanocyte products in skin and blood of participants with NSV, suggesting its potential in treatment. Ritlecitinib-mediated changes positively correlated with clinical response.

LBO-05 - Pegozafermin for the treatment of non-alcoholic steatohepatitis patients with F2/F3 fibrosis: a multi-center, randomized, double-blind, placebo-controlled Phase 2b trial (ENLIVEN)

LBO-05 - Pegozafermin for the treatment of non-alcoholic steatohepatitis patients with F2/F3 fibrosis: a multi-center, randomized, double-blind, placebo-controlled Phase 2b trial (ENLIVEN)

Carvedilol for prevention of heart failure in anthracycline-exposed survivors of childhood cancer: Results from COG ALTE1621.

10013 Background: Carvedilol improves cardiac function in patients with heart failure (HF), but remains untested as cardioprotective therapy in long-term childhood cancer survivors at risk for HF due to high-dose anthracycline exposure. We hypothesized that low-dose carvedilol would be safe and efficacious in reducing anthracycline-related heart failure risk in long-term survivors without evidence of HF. Methods: This was a randomized, double-blind, placebo-controlled phase 2B trial (NCT02717507) conducted at 28 sites. Eligibility included ≥250 mg/m2 cumulative anthracycline exposure by age 21 years (y), ≥2y from completion of cancer treatment, and preserved systolic function (ejection fraction [EF] ≥55% and/or fractional shortening [FS] ≥28%) at enrollment. Patients were randomized 1:1 to take low-dose carvedilol (12.5 mg/day) or placebo for 2y; dose up-titration started at 3.125 mg/day. The primary objective was to determine the impact of carvedilol on echocardiographic indices of HF risk: standardized left ventricular (LV) wall thickness/dimension ratio (LVWT/Dz; primary endpoint), LV end-systolic wall stress (ESWS), LV chamber diameters, systolic and diastolic function. These indices were obtained every 6 months and measured centrally in a blinded fashion. Common Terminology Criteria for Adverse Events (CTCAE v4.0) was used to assess toxicity. Cardiac event was defined as relative EF/FS decline &lt; 20% from baseline or both &lt; 55% [EF] and &lt; 28% [FS]. Treatment effects were analyzed using the Generalized Estimating Equation for normally distributed data, assuming linear time-trend. Group differences were evaluated by treatment*time interaction. Results: Of 196 participants enrolled, 182 were eligible and randomized. Characteristics (median, range): age at enrollment, 24.7y (10.4-53.9); time from cancer diagnosis, 13.4y (2.9-43.6); anthracycline dose, 374 mg/m2 (250-1760); 19% had received chest-directed radiotherapy. There were no group differences in baseline participant demographics, cardiotoxic treatment exposure, or cardiac endpoints. LVWT/Dz was similar (+0.053, p = 0.15) between arms at 2y. However, treatment effects varied by time since diagnosis (p = 0.008) suggesting greater efficacy among longer-term survivors. Compared to placebo, carvedilol arm participants had significantly better LV end-diastolic diameter (-0.16 cm, p = 0.005) and LVESWS (-7.53, p = 0.027) at 2y. There were no CTCAE grade ≥3 events; all except 2 participants tolerated full dose escalation. Six out of eight cardiac events occurred on the placebo arm; longer-term follow-up of study participants is ongoing. Conclusions: In this randomized trial of long-term survivors of childhood cancer treated with high-dose anthracyclines, low-dose carvedilol was safe and effective in reducing established biomarkers of HF risk and could serve as a risk reduction strategy. Clinical trial information: NCT02717507 .

Treatments for early-stage Dupuytren's disease: an evidence-based approach.

Current treatments for Dupuytren's disease are limited to late-stage disease when patients have developed flexion contractures and have impaired hand function. They all have limitations, including the risk of recurrence and complications. The use of treatments for early-stage disease, such as intralesional steroid injections or radiotherapy which lack a clear biological basis or evidence of effectiveness based robust randomized, double blind, placebo-controlled trials, highlights the desire of patients to access treatments before they develop significant flexion contractures. A detailed understanding of the cellular landscape and molecular signalling in nodules of early-stage disease would permit the identification of potential therapeutic targets. This approach led to the identification of tumour necrosis factor (TNF) as a target. A phase 2a clinical trial identified 40 mg in 0.4 mL adalimumab as the most efficacious dose and a subsequent randomized, double blind, placebo-controlled phase 2b trial showed that four intranodular injections at 3-month intervals resulted in decrease in nodule hardness and size on ultrasound scan at 12 months, and both parameters continued to decrease further at 18 months, 9 months after the final injection. This type of approach provides clinicians with a robust evidence base for advising their patients.

91. Establishing Proof of Concept for a Bivalent RSVpreF Subunit Vaccine for Maternal Immunization

Abstract Background Respiratory syncytial virus (RSV) is a major cause of infant morbidity and mortality worldwide and could be preventable by vaccination in pregnancy. Methods We conducted a randomized, placebo-controlled phase 2b trial evaluating safety, immunogenicity, and potential efficacy of a bivalent RSV prefusion F vaccine (RSVpreF) in pregnant women and their infants. Participants were randomized between 24- and 36-weeks’ gestation to receive 120 or 240 µg RSVpreF, with or without aluminum hydroxide, or placebo. Results This final analysis includes 579 women and 572 infants in 4 countries (Argentina, Chile, South Africa, and the US); 462 (79.8%) women received RSVpreF. Postvaccination reactions, most commonly injection site pain, fatigue, and myalgia, were generally mild-to-moderate. Adverse events (AEs) in the month following vaccination (maternal) or birth (infant) were mostly anticipated events in pregnancy and the neonatal period, respectively, and were similar between vaccine and placebo groups. No AEs were considered related to vaccination. For all RSVpreF groups, 50% neutralizing titers for both RSV-A and RSV-B rose sharply by 2 weeks after vaccination. At delivery occurring a mean of ∼8 weeks later, geometric mean titer (GMT) ratios for combined RSV-A/B between vaccine and placebo recipients’ infants were 10.9 to 13.6. Transplacental transfer ratios (all groups) were 1.39 to 1.83. Infant GMTs were higher in infants whose mothers had received RSVpreF versus placebo through 6 months of life; the estimated half-life of infant combined 50% RSV-A/B neutralizing titers was 41 days. Infants of women immunized across the range of assessed gestational ages had similar cord blood titers and transplacental transfer ratios. Observed efficacy (95% CI) against medically attended and severe medically attended infant RSV lower respiratory tract illness (LRTI) through 180 days in an exploratory analysis was 84.7% (21.5%, 97.6%) and 91.5% (-5.6%, 99.8%), respectively. Conclusion RSVpreF was well-tolerated in pregnant women, elicited robust neutralizing responses with efficient transplacental transfer, and has the potential to prevent infant RSV LRTI. Disclosures Eric A. F. Simões, MD, M.B., B.S., DCH, Abbvie: DSMB|Astra Zeneca: Grant/Research Support|Bill and Melinda Gates Foundation: Grant/Research Support|Bill and Melinda Gates Foundation: DSMB|GSK Inc.: DSMB|Johnson and Johnson: Grant/Research Support|Merck Inc: Advisor/Consultant|Merck Inc: Grant/Research Support|Nivavax: Grant/Research Support|Pfizer Inc: Advisor/Consultant|Pfizer Inc: Grant/Research Support|Regeneron: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant Shabir A. Madhi, MBBCh, FCPaeds, MMed, PhD, AstraZeneca: Funding to institution for conduct of study Kimberly J. Center, M.D., Pfizer: Employee|Pfizer: Stocks/Bonds Jose M. Novoa Pizarro, MD, AstraZeneca: Grant/Research Support|Medimmune: Grant/Research Support|MSD: Grant/Research Support|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support Kena A. Swanson, Ph.D., Pfizer: employee of Pfizer David Radley, MS, Pfizer: Employee|Pfizer: Stocks/Bonds Stephanie B. McGrory, B.S.N., Pfizer: Employee|Pfizer: Stocks/Bonds Emily A. Gomme, Ph.D., Pfizer: Stocks/Bonds Daniel A. Scott, MD, Pfizer: Employee|Pfizer: Stocks/Bonds Kathrin U. Jansen, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds William C. Gruber, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Alejandra C. Gurtman, M.D., Pfizer: employee of Pfizer.

Anlotinib in patients with medullary thyroid carcinoma with negative prognostic factors: A sub-analysis based on the ALTER01031 study.

Medullary thyroid carcinoma (MTC) is a rare type of thyroid cancer; however, it accounted for 13.4% of the disease-specific mortalities. ALTER01031 (NCT02586350) was a randomised, placebo-controlled phase 2b trial that evaluated the efficacy and safety of anlotinib in locally advanced or metastatic MTC. This post hoc analysis aimed to evaluate the efficacy and safety of anlotinib in older patients and those with bone metastases using ALTER01031. In ALTER01031, anlotinib significantly prolonged the median progression-free survival (PFS) from 11.1 months to 20.7 months compared with placebo in the whole population. Patients who were older (≥ 50 years) or had bone metastases were selected. PFS and overall survival (OS) were estimated and compared between patients receiving anlotinib or placebo in each subgroup. A sub-analysis of tumour response and safety was also performed. Patients with older age or bone metastases experienced rapid disease progression as the median PFS was 6.8 months and 7.0 months respectively in the placebo group. Anlotinib significantly improved the median PFS to 17.5 months (P = 0.002) and 20.7 months (P = 0.029) with hazard ratio (HR) of 0.31 (95% CI, 0.15-0.68) and 0.44 (95% CI, 0.20-0.94) compared with placebo. Significant benefit in OS was observed in patients with older age after a longer follow-up (HR = 0.47 [95% CI, 0.22-0.99], P = 0.041). The safety profile of these subgroups was similar to that of the entire population. This sub-analysis demonstrated significant survival benefits and favourable safety of anlotinib in patients with MTC who had old age or bone metastases, supporting the feasibility of anlotinib in these patients.

A detailed analysis of possible efficacy signals of NTHi-Mcat vaccine against severe COPD exacerbations in a previously reported randomised phase 2b trial

BackgroundAn investigational vaccine containing non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) surface proteins did not show vaccine efficacy (VE) against combined moderate and severe (moderate/severe) exacerbations in a randomised, observer-blinded, placebo-controlled phase 2b trial of patients with chronic obstructive pulmonary disease (COPD). Nevertheless, observations on rates of severe exacerbations and hospitalisations encouraged further evaluation. MethodsPatients with stable COPD (moderate to very severe airflow limitation, Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2–4), 40–80 years and at least one moderate/severe exacerbation in the last year received two doses of NTHi-Mcat vaccine or placebo plus standard care. Secondary analyses were conducted on VE against exacerbations according to severity. Potential predictive factors at baseline for VE against severe exacerbations were explored in post-hoc analyses. ResultsOf 606 patients enrolled, 571 were included in the efficacy analysis (279 in NTHi-Mcat vaccine group, 292 in placebo group). VE against severe acute exacerbations of COPD (AECOPD) in various subgroups was 52.11 % (p = 0.015; frequent exacerbators), 65.43 % (p = 0.015; baseline GOLD grade 4), 38.24 % (p = 0.034; previous pneumococcal and/or influenza vaccination). VE was 52.49 % (p = 0.044) for the 6–12 months period after 1 month post-dose 2. Multivariable analysis identified two factors (frequent exacerbator status plus inhaled corticosteroid use at baseline) associated with significant VE against severe AECOPD; in this subpopulation, VE was 74.99 % (p < 0.001). ConclusionResults suggest potential efficacy with the NTHi-Mcat vaccine against severe exacerbations in certain patients with COPD, in particular those who have frequent exacerbations and use inhaled corticosteroids. This potential signal requires confirmation in an appropriately designed prospective clinical trial. Trial registrationClinicalTrials.gov, NCT03281876.

LEISH2b - A phase 2b study to assess the safety, efficacy, and immunogenicity of the Leishmania vaccine ChAd63-KH in post-kala azar dermal leishmaniasis.

Background: The leishmaniases are neglected tropical diseases caused by various Leishmania parasite species transmitted by sand flies. They comprise a number of systemic and cutaneous syndromes including kala-azar (visceral leishmaniasis, VL), cutaneous leishmaniasis (CL), and post-kala-azar dermal leishmaniasis (PKDL). The leishmaniases cause significant mortality (estimated 20 - 50,000 deaths annually), morbidity, psychological sequelae, and healthcare and societal costs. Treatment modalities remain difficult. E.g., East African PKDL requires 20 days of intravenous therapy, andfrequently relapsing VL is seen in the setting of HIV and immunodeficiency. We developed a new therapeutic vaccine, ChAd63-KH for VL / CL / PKDL and showed it to be safe and immunogenic in a phase 1 trial in the UK, and in a phase 2a trial in PKDL patients in Sudan. Methods: This is a randomised double-blind placebo-controlled phase 2b trial to assess the therapeutic efficacy and safety of ChAd63-KH in patients with persistent PKDL in Sudan. 100 participants will be randomly assigned 1:1 to receive placebo or ChAd63-KH (7.5 x10 10vp i.m.) at a single time point. Follow up is for 120 days after dosing and we will compare the clinical evolution of PKDL, as well as the humoral and cellular immune responses between the two arms. Discussion: Successful development of a therapeutic vaccine for leishmaniasis would have wide-ranging direct and indirect healthcare benefits that could be realized rapidly. For PKDL patients, an effective therapeutic vaccination used alone would have very significant clinical value, reducing the need for extensive hospitalization and chemotherapy. Combining vaccine with drug (immuno-chemotherapy) might significantly increase the effective life of new drugs, with lower dose / abbreviated regimens helping to limit the emergence of drug resistance. If therapeutic benefit of ChAd63-KH can be shown in PKDL further evaluation of the vaccine in other forms of leishmaniasis should be considered. Clinicaltrials.gov registration: NCT03969134.

Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline

Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline. To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group. This 12-month randomized, double-masked, placebo-controlled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021. One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (0.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention. Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed. A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, -0.03; 95% CI, -0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups. In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage. ClinicalTrials.gov Identifier: NCT03094546.

FC049: Nefecon® (Budesonide) is an Epigenetic Modifier in IGA Nephropathy

Abstract BACKGROUND AND AIMS In recent years, the dysregulated expression of microRNAs (miRs)—small molecules of noncoding RNA that epigenetically fine-tune post-transcriptional gene expression—has been increasingly implicated in the pathogenesis of IgA nephropathy (IgAN). Extracellular miRs, contained within extracellular vesicles such as exosomes and microvesicles, are thought to function as important intercellular and interorgan modes of communication in health and disease. In the current study, next-generation sequencing (NGS) and subsequent real-time quantitative polymerase chain reaction (RT-qPCR) validation were performed to identify serum miRs associated with a high risk of future kidney function decline in IgAN. We then went on to determine whether treatment with Nefecon® 16 mg/day for 9 months was capable of modifying the serum levels of miRs associated with high-risk IgAN. This study was supported by a grant from Calliditas Therapeutics AB. METHOD NGS was performed by Qiagen (Germany) on serum from patients with IgAN (10 at high risk and 10 at low risk of progression) or membranous nephropathy (MN, n=10), as well as healthy individuals (HS, n=10). Sequencing data were validated by RT-qPCR using TaqMan miR PCR assays in independent sets of serum samples (20 per cohort). Using the Total Exosome Isolation (from serum) reagent (Thermo Fisher Scientific, UK), extracellular exosomes were isolated from the serum of participants of the NEFIGAN trial from the placebo group (n=40) and Nefecon® 16 mg/day group (n=40) at the start of treatment (SOT) and end of treatment (EOT). RNA was isolated and levels of miRs-483-5p and -122-5p were measured by RT-qPCR. The NEFIGAN trial (NCT01738035) was a randomized, double-blind, placebo-controlled Phase 2b trial designed to assess the safety and efficacy of Nefecon® a novel targeted-release formulation of budesonide, designed to deliver the drug to the distal ileum in patients with IgAN. The trial comprised a 6-month run-in, a 9-month treatment and a 3-month follow-up phase. A total of 48 patients received Nefecon® 16 mg/day, 51 patients received Nefecon® 8 mg/day and 50 patients received placebo. The key result of the study was that Nefecon® 16 mg/day, added to optimized renin–angiotensin system blockade, reduced proteinuria and stabilized estimated glomerular filtration rate in patients with IgAN. These findings have now been replicated in the NefIgArd study, which released data in 2021. RESULTS miRs-483-5p and -122-5p were significantly overexpressed in the serum of patients with IgAN at high risk of progression compared with those who had stable IgAN or HS, but not compared with patients with MN. Both miRs were also found to be significantly increased in extracellular exosomes in high-risk IgAN compared with low-risk IgAN, HS and MN. Interestingly, levels of exosomal miRs-483-5p and -122-5p did not correlate with total serum IgA, IgA1, galactose-deficient IgA1 or IgA–IgG immune complex levels, suggesting a novel mechanism of action. Treatment with 16 mg/day of Nefecon® led to a significant reduction in the exosomal levels of miR-122-5p, while no change in miR-483-5p levels was observed in the treated group. CONCLUSION These data reveal a dysregulation of systemic exosomal miR expression in IgAN, and demonstrate for the first time that it is possible to pharmacologically modify the miR content of circulating exosomes in IgAN. Treatment with Nefecon® 16 mg/day for 9 months selectively downregulated exosomal miR-122-5p, while having no effect on exosomal miR-483-5p levels, arguing against a generalized ‘anti-miR’ effect of Nefecon®. Studies are ongoing to both precisely delineate the cellular source(s) of these exosomes and determine the downstream impact of these changes on glomerular and tubulointerstitial biology.

The Design and Rationale of a Phase 2b, Randomized, Double-Blinded, and Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Lomecel-B in Older Adults with Frailty

BackgroundFrailty in older adults is a rapidly growing unmet medical need. It is an aging-related syndrome characterized by physical decline leading to higher risk of adverse health outcomes.ObjectivesTo evaluate the efficacy of Lomecel-B, an allogeneic medicinal signaling cell (MSC) formulation, in older adults with frailty. DESIGN: This multicenter, randomized, parallel-arm, double-blinded, and placebo-controlled phase 2b trial is designed to evaluate doserange effects of Lomecel-B for frailty on physical functioning, patient-reported outcomes (PROs), frailty status, and biomarkers.SettingEight enrolling clinical research centers, including the Miami Veterans Affairs Medical Center.ParticipantsTarget enrollment is 150 subjects aged 70–85 years of any race, ethnicity, or gender. Enrollment criteria include a Clinical Frailty Score of 5 (“mild”) or 6 (“moderate”), a 6MWT of 200–400 m, and serum tumor necrosis factor-alpha (TNF-α) ≥2.5 pg/mL.InterventionA single intravenous infusion of Lomecel-B (25, 50, 100, or 200 million cells) or placebo (N=30/arm). Patients are followed for 365 days for safety, and the efficacy assessments performed at 90, 180, and 270 days.MeasurementsThe primary endpoint is change in 6MWT in the Lomecel-B-treated arms versus placebo at 180 days post-infusion. Secondary and exploratory endpoints include change in: 6MWT and other physical function measures at all time points; PROs; frailty status; cognitive status; and an inflammatory biomarkers panel. A pre-specified sub-study examines vascular/endothelial biomarkers. Safety is evaluated throughout the trial.ResultsThe trial is conducted under a Food and Drug Administration Investigational New Drug (IND), with Institutional Review Board approval, and monitoring by an NIH-appointed independent Data Safety Monitoring Board.ConclusionThis clinical trial investigates the use of a regenerative medicine strategy for frailty in older adults. The results will further the understanding of the potential for Lomecel-B in the geriatric condition of frailty.

LB14. Efficacy and Immunogenicity of an Ad26.RSV.preF-based Vaccine in the Prevention of RT-PCR-confirmed RSV-mediated Lower Respiratory Tract Disease in Adults Aged ≥65 Years: A Randomized, Placebo-controlled, Phase 2b Study

BackgroundRespiratory syncytial virus (RSV) can cause serious lower respiratory tract disease (LRTD) in older adults. Despite a high burden of disease, there is currently no licensed vaccine for RSV. Here, we report the primary efficacy and immunogenicity results from a Phase 2b proof-of-concept trial of an Ad26.RSV.preF-based vaccine for the prevention of RSV-mediated LRTD in adults aged ≥65 years.MethodsCYPRESS (NCT03982199) is a randomized, double-blind, placebo-controlled Phase 2b trial. Adults ≥65 years of age were randomized 1:1 prior to the RSV season to receive an Ad26.RSV.preF-based vaccine or placebo. Symptoms of acute respiratory infection (ARI) were collected through an RSV-specific patient-reported Respiratory Infection Intensity and Impact Questionnaire (RiiQ) and/or by a clinician assessment until the end of the RSV season. The primary endpoint was the first occurrence of RT-PCR-confirmed RSV-mediated LRTD according to any of 3 case definitions: (1) ≥3 symptoms of lower respiratory tract infection (LRTI), (2) ≥2 symptoms of LRTI, or (3) ≥2 symptoms of LRTI or ≥1 symptom of LRTI with ≥1 systemic symptom. The secondary endpoint was the first occurrence of any RT-PCR-confirmed RSV-mediated ARI. Immunogenicity assessments were performed in a subset of approximately 200 participants.ResultsA total of 5782 participants (2891 in each study arm) received study treatment (92.5% white, 57.7% female, median age 71 years). Vaccine efficacy was 80% (94.2% CI, 52.2–92.9%), 75% (50.1–88.5%), and 69.8% (43.7–84.7%) for case definition 1, 2, and 3, respectively (all P values < 0.001). Efficacy for any RSV-mediated ARI was 69.8% (95% CI, 42.7–85.1%). In the vaccine arm of the immunogenicity subset, geometric mean fold increase in antibody titers 14 days after vaccination was 13.5 for RSV neutralizing antibodies and 8.6 for RSV prefusion F-specific binding antibodies. Median frequency of RSV-F-specific INFγ T-cells increased from 34 to 444 SFC/106 PBMC 14 days after vaccination in the vaccine arm; no relevant changes were observed in the placebo arm.ConclusionIn CYPRESS, the Ad26.RSV.preF-based vaccine was highly effective against RSV-mediated LRTD through the first RSV season and elicited robust humoral and cellular immune responses in adults aged ≥65 years.Disclosures Ann R. Falsey, MD, AstraZeneca (Individual(s) Involved: Self): Grant/Research Support; BioFire Diagnostics (Individual(s) Involved: Self): Grant/Research Support; Janssen (Individual(s) Involved: Self): Grant/Research Support; Merck, Sharpe and Dohme (Individual(s) Involved: Self): Grant/Research Support; Novavax (Individual(s) Involved: Self): Other Financial or Material Support, Paid DSMB member; Pfizer (Individual(s) Involved: Self): Grant/Research Support Kristi Williams, PhD, Janssen R&D US (Employee) Efi Gymnopoulou, MSc, Janssen Infectious Diseases BV (Employee) Arangassery Rosemary Bastian, PhD, Janssen Vaccines & Prevention BV (Employee) Joris Menten, n/a, Janssen Infectious Diseases BV (Employee) Els De Paepe, MSc, Janssen Infectious Diseases BV (Employee) Hilde de Boer, MSc, Janssen-Cilag (Employee) Sjoukje Vandenberghe, n/a, Janssen Infectious Diseases BV (Employee) Eric Chan, PhD, Janssen Global Services, LLC (Employee) Jerald Sadoff, MD, Johnson & Johnson (Employee, Shareholder) Macaya Douoguih, MD, MPH, Janssen (Employee) Benoit Callendret, PhD, Janssen Vaccines & Prevention BV (Employee) Christy Comeaux, MD, Janssen Vaccines & Prevention BV (Employee) Esther Heijnen, MD, Janssen Vaccines & Prevention BV (Employee)

CONFIRMing single-drug immune checkpoint blockade efficacy in mesothelioma

Mesothelioma is an uncommon cancer, but, despite a reduction in asbestos use in high-income countries in the past few decades, we are still facing a global epidemic of this disease. Immune checkpoint blockade had an inauspicious start in mesothelioma, when the anti-CTLA-4 antibody, tremelimumab, was shown to not improve overall survival compared with placebo in the second-line setting. 1 Maio M Scherpereel A Calabro L et al. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol. 2017; 18: 1261-1273 Summary Full Text Full Text PDF PubMed Scopus (271) Google Scholar However, outcomes from several subsequent single-arm clinical trials suggested anti-tumour activity of PD-1 or PD-L1 blockade in patients with mesothelioma. 2 Alley EW Lopez J Santoro A et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2017; 18: 623-630 Summary Full Text Full Text PDF PubMed Scopus (335) Google Scholar , 3 Quispel-Janssen J van der Noort V de Vries JF et al. Programmed death 1 blockade with nivolumab in patients with recurrent malignant pleural mesothelioma. J Thorac Oncol. 2018; 13: 1569-1576 Summary Full Text Full Text PDF PubMed Scopus (150) Google Scholar , 4 Okada M Kijima T Aoe K et al. Clinical efficacy and safety of nivolumab: results of a multicenter, open-label, single-arm, Japanese phase II study in malignant pleural mesothelioma (MERIT). Clin Cancer Res. 2019; 25: 5485-5492 Crossref PubMed Scopus (138) Google Scholar Objective tumour response rates ranged from 20–30%. Together with promising progression-free survival and overall survival outcomes, these trials triggered inclusion of single drug PD-1 inhibition as an option for subsequent-line therapy in some—but not all—clinical practice guidelines from as early as 2017. Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trialNivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy. Full-Text PDF Open Access

An evaluation of KBP-5074 in advanced chronic kidney disease with uncontrolled hypertension

ABSTRACT Introduction Resistant hypertension (RH) is more prevalent in the advanced stages of chronic kidney disease (CKD) and contributes to a greater likelihood of poor cardiovascular and renal outcomes. However, RH often goes untreated in this population as the currently available recommended add-on therapy, steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone, may lead to unacceptable side effects, mainly hyperkalemia in a cohort with reduced kidney function. KBP-5074 is a novel non-steroidal MRA that addresses the unmet need of treating RH in the CKD population without hyperkalemia. Areas covered We provide an overview of the current state of RH treatment in stage 3B/4 CKD as it relates to available steroidal MRAs and the current limitations of this treatment. We then explore the emerging data on nonsteroidal MRAs, particularly the novel agent KBP-5074 and its applicability to treatment in this context. Expert Opinion In a randomized, double-blind, placebo-controlled phase 2b trial, the novel nonsteroidal MRA KBP-5074 demonstrated clinical efficacy and safety in treating RH in stage 3B/4 CKD and offers a potential new treatment option in this population at high risk for cardiovascular disease (CVD) and CKD progression.

A Multicenter, Double-Blind, Randomized, Placebo-Controlled Phase 2b Trial of Cytisinicline in Adult Smokers (The ORCA-1 Trial).

IntroductionCytisinicline (known as cytisine), a nicotinic acetylcholine receptor partial agonist, is a smoking cessation aid currently marketed in Central and Eastern Europe using a 1.5-mg/tablet 25-day downward titration schedule. No prior studies have evaluated other doses or administration schedules. This study evaluated the effects of a higher dosage and simplified dosing schedule on drug efficacy and tolerability.MethodsORCA-1 was a double-blind, randomized, placebo-controlled clinical trial that provided cytisinicline or placebo tablets plus behavioral support for 25 days. Adult smokers (>10 cigarettes daily) committed to quitting smoking were randomized to compare 2 cytisinicline doses (1.5 mg and 3 mg) versus placebo, and 2 administration schedules [downward titration versus 3 times daily (TID)]. Primary outcome was a reduction in expected cigarettes smoked at end of treatment; secondary outcomes were biochemically confirmed 7-day abstinence at Week 4 and continuous abstinence from Weeks 5 to 8.ResultsAmong 254 participants, those in cytisinicline arms (regardless of dose or schedule) had greater reductions in cigarettes smoked versus placebo, with differences observed in 3 cytisinicline arms statistically significant versus placebo. All cytisinicline arms had statistically significantly higher abstinence rates at Week 4 versus placebo. Both cytisinicline arms using TID schedules had statistically significantly higher continuous abstinence rates from Weeks 5 to 8 compared with placebo. Participants in the cytisinicline 3-mg TID arm had the highest abstinence rate. There were no safety concerns with either 1.5-mg or 3-mg cytisinicline.ConclusionBased on simpler dose scheduling, excellent tolerability, and best-continued abstinence rate, cytisinicline 3-mg TID was selected for future Phase 3 studies.ImplicationsAlthough the 1.5-mg 25-day titration schedule has been marketed in Central and Eastern Europe for decades, this study explored using a higher dosage and a simplified dosing schedule for impact on cytisinicline efficacy and tolerability. Based on these results, a Phase 3 program was initiated using cytisinicline 3-mg tablets on a TID schedule for potential market approval in the United States.

15989 Safety of tildrakizumab in psoriatic arthritis: An interim analysis from a randomized, double-blind, placebo-controlled phase 2b trial

Background: The safety of tildrakizumab (TIL)—an anti–interleukin-23p19 monoclonal antibody approved for moderate to severe plaque psoriasis—was assessed in a randomized, double-blind, placebo-controlled, multiple-dose, phase 2b trial (NCT02980692) in patients with active psoriatic arthritis (PsA) at week 24.

Efficacy of an intramuscular bivalent norovirus GI.1/GII.4 virus-like particle vaccine candidate in healthy US adults

BackgroundWe performed this first-in-human efficacy trial of Takeda’s bivalent norovirus vaccine candidate (TAK-214) against moderate or severe acute gastroenteritis (AGE) in healthy adults. MethodsThis double-blind, randomized, placebo-controlled phase 2b trial was conducted over two winter seasons in 18–49 year-old US Navy recruits. Participants were randomized (1:1) to receive intramuscular injections of saline placebo (N = 2,357) or TAK-214 [15 μg GI.1 and 50 μg GII.4c VLPs, 0.5 mg Al(OH)3] (N = 2,355), and monitored for 45 days post-vaccination for AGE. Norovirus genotypes were identified by RT-PCR and sequencing of stool/vomitus samples. Sera from AGE cases were used to assess immune responses as genotype-specific histo-blood group antigen (HBGA)-blocking antibodies. FindingsWith low rates of homotypic norovirus AGE detected the statistical analysis was proactively modified to account for AGE due to any norovirus genotype. Of the 48 norovirus AGE cases of “any severity”, 29 in placebo and 19 in vaccinees, causative genotypes were GI.1 (n = 1), G1.7a (n = 1), GII.2 (n = 39) and GII.4 (n = 7). Applying predefined definitions of moderate or severe AGE gave 26 vs. 10 cases due to any norovirus genotype in placebo vs. vaccine groups, a vaccine efficacy (VE) of 61.8% (95.01% CI, 20.8 to 81.6; p = 0.0097). Five vs. one moderate or severe cases due to vaccine GI.1/GII.4 homotypic genotypes in placebo vs. vaccine arms gave a primary endpoint vaccine efficacy of 80.0% (99.99% CI, −1318.1 to 99.7; p = 0.142). Levels of GI.1 and GII.4 HBGA-blocking antibodies were increased in vaccinees and in some placebo AGE cases infected with GII.2, indicating cross-reactivity in the immune responses to different genotypes. InterpretationDespite limited cases of homotypic norovirus AGE meaning the primary endpoint was not fully evaluable, we showed TAK-214 provided statistically significant efficacy against “any moderate/severe norovirus AGE” principally caused by the heterotypic GII.2 genotype, demonstrating induction of cross-genotype protection.

Exploration of associations between adverse drug reactions and clinical outcomes in anlotinib treatment against medullary thyroid carcinoma (MTC): A subgroup analysis based on the ALTER01031 trial.

e18518 Background: Anlotinib demonstrated favorable efficacy in a randomized, placebo-controlled phase 2b trial (ALTER01031, NCT02586350) for MTC which was published in 2019 ASCO annual meeting. Similar with other anti-angiogenesis drugs, hand-foot syndrome (HFS), hypertension and proteinuria were the major adverse drug reactions (ADRs) observed in this trial. We explored the association between common ADRs and the clinical outcomes with anlotinib in this subanalysis. Methods: Patients in the anlotinib group of ALTER01031 were divided into different groups according to the development of ADRs including HFS, hypertension or proteinuria. Kaplan-Meier method was used to estimate median PFS (mPFS) for patients in different groups. The mPFS for patients with or without dose reduction were also evaluated. Results: A total of 62 patients received anlotinib in ALTER 01031. HFS of any grade was observed in 39 patients with a mPFS of 28.5 months, which was longer than in those without HFS (14.0 months, P = 0.079). The hazard ratio for progression was 0.540 (95% CI 0.252, 1.158) although statistical difference was not reached. Similarly, more survival benefit was also observed in 29 and 38 patients who experienced hypertension and proteinuria, with mPFS of 28.5 months and 22.4 months respectively. While the mPFS for patients without corresponding ADRs were only 17.0 months (HR = 0.648 [95% CI 0.320, 1.314], P = 0.237) and 14.0 months (HR = 0.738 [95% CI 0.331, 1.65], P = 0.421). Median PFS had not been reached in 20 patients with dose reduction while was recorded as 17.0 months in those without (HR = 0.707 [95% CI 0.335, 1.496], P = 0.392). Conclusions: This analysis indicated a trend of greater PFS benefit for MTC patients treated with anlotinib who experienced HFS, hypertension or proteinuria although no statistical differences were observed. A possible positive association was also observed between dose reductions and better clinical outcomes. Clinical trial information: NCT02586350.