Phase 2a Research Articles

Safety, tolerability, immunogenicity, and efficacy of UB-311 in participants with mild Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 2a study.

Anti-amyloid vaccines may offer a convenient, affordable, and accessible means of preventing and treating Alzheimer's disease. UB-311 is an anti-amyloid-β active immunotherapeutic vaccine shown to be well-tolerated and to have a durable antibody response in a phase 1 trial. This phase 2a study assessed the safety, immunogenicity, and preliminary efficacy of UB-311 in participants with mild Alzheimer's disease. A 78-week, randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 2a study was conducted in Taiwan. Participants were randomised in a 1:1:1 ratio to receive seven intramuscular injections of UB-311 (Q3M arm), or five doses of U311 with two doses of placebo (Q6M arm), or seven doses of placebo (placebo arm). The primary endpoints were safety, tolerability, and immunogenicity of UB-311. Safety was assessed in all participants who received at least one dose of investigational product. This study was registered at ClinicalTrials.gov (NCT02551809). Between 7 December 2015 and 28 August 2018, 43 participants were randomised. UB-311 was safe, well-tolerated, and generated a robust immune response. The three treatment-emergent adverse events (TEAEs) with the highest incidence were injection-site pain (14 TEAEs in seven [16%] participants), amyloid-related imaging abnormality with microhaemorrhages and haemosiderin deposits (12 TEAEs in six [14%] participants), and diarrhoea (five TEAEs in five [12%] participants). A 97% antibody response rate was observed and maintained at 93% by the end of the study across both UB-311 arms. These results support the continued development of UB-311. Vaxxinity, Inc. (Formerly United Neuroscience Ltd.).

Immunogenicity, safety, and preliminary efficacy evaluation of OVX836, a nucleoprotein-based universal influenza A vaccine candidate: a randomised, double-blind, placebo-controlled, phase 2a trial

OVX836, a recombinant vaccine containing the nucleoprotein of the influenza A virus A/WSN/1933 (H1N1) and the oligomerisation domain OVX313, has displayed a good safety profile and elicited dose-dependent humoral and cellular immune responses at 90 μg or 180 μg (intramuscularly) in previous clinical trials. The aim of this study was to explore higher doses, since no maximum tolerated dose had been reached. In this phase 2a, randomised, double-blind, placebo-controlled study, we recruited 137 healthy adults aged 18-55 years in a single centre in Belgium. Participants were randomly assigned (interactive web response system; block size=4) using SAS (version 9.4) to receive one single intramuscular administration of OVX836 influenza vaccine at three doses (180 μg [n=33], 300 μg [n=35], and 480 μg [n=36]) or placebo (n=33). The two primary endpoints were the safety and the cell-mediated immune response to OVX836 at the three doses in terms of change of nucleoprotein-specific IFNγ spot forming cell (SFC) frequencies in the peripheral blood mononuclear cell (PBMC) population, measured by IFNγ ELISpot, at day 8 versus pre-injection baseline (day 1). The population used for the safety analysis is the modified intention-to-treat cohort. The population used for the immunogenicity analysis is the per-protocol cohort. This trial is registered with ClinicalTrials.gov, NCT05060887, and EudraCT, 2021-002535-39. Participants were recruited between Nov 15, 2021, and Feb 1, 2022. OVX836 had a favourable safety profile up to 480 μg without reaching the maximum tolerated dose, and showed a good safety profile at all doses with mild local and systemic reactogenicity. 7 days after vaccination, although no significant differences were observed between the doses, OVX836 increased the frequency of nucleoprotein-specific IFNγ SFCs per million PBMCs from days 1 to 8 (primary endpoint): by 124 SFCs per 106 PMBCs (95% CI 67 to 180; p=0·002) at 180 μg; by 202 SFCs per 106 PMBCs (95% CI 138 to 267; p<0·0001) at 300 μg; by 223 SFCs per 106 PMBCs (95% CI 147 to 299; p<0·0001) at 480 μg; and decreased by 1 SFCs per 106 PMBCs (95% CI -24 to 22] in the placebo group (Kruskal-Wallis test p<0·0001 followed by Mann-Whitney's tests; per-protocol cohort). Dose-dependent and polyfunctional nucleoprotein-specific CD4 T-cell responses were observed, and CD8 T-cell responses were elicited at 300 μg and 480 μg (secondary endpoints). OVX836 appears to be a safe and well tolerated candidate vaccine that elicits humoral and cellular nucleoprotein-specific immune responses (including CD8 T cells at the highest dose levels) and showed a preliminary signal of protection against influenza. Therefore, OVX836 is a promising vaccine candidate for universal influenza A prevention, that warrants further trials. OSIVAX, Bpifrance, Wallonia Region, and the EUs Horizon 2020 Research and Innovation Program.

Pooled allogeneic faecal microbiota MaaT013 for steroid-resistant gastrointestinal acute graft-versus-host disease: a single-arm, multicentre phase 2 trial

Failure of gastrointestinal acute graft-versus-host disease (GI-aGvHD) to respond to steroid therapy is associated with limited further therapeutic options. We aimed to assess the safety and efficacy of the first-in-human use of the pooled allogeneic faecal microbiota, MaaT013, for the treatment of steroid-refractory GI-aGvHD. This prospective, international, single-arm, phase 2a study reports clinical outcomes from a 24-patient cohort with grade III-IV, steroid refractory GI-aGvHD treated with the pooled allogeneic faecal microbiota MaaT013. MaaT013 involved pooling faecal matter from 3 to 8 screened donors then transplanting the pooled batches into patients to treat GI-aGVHD. The 24 patients were treated in the HERACLES study (Aug 2018 to Nov 2020) at 26 sites in Europe and an additional 52 patients were treated in a compassionate use/expanded access program (EAP) in France (July 2018 to April 2021). The primary endpoint was GI response at day 28, defined as the proportion of patients with GI-aGvHD who had a complete response (CR) or very good partial response (VGPR). GvHD grading and staging were assessed according to the revised Glucksberg criteria. Adverse events and severe adverse events were monitored for 6 months and 12 months, respectively. The HERACLES study was registered with ClinicalTrials.gov (NCT03359980). Compared with single donors, MaaT013 is characterised by higher microbial richness and reduced variability across batches. At day 28 (D28), the GI-overall response rate (ORR) was 38% in the prospective population, including 5 complete responses (CR), 2 very good partial responses (VGPR) and 2 partial responses (PR). In the EAP, the GI-ORR was 58% (17 CR, 9 VGPR and 4PR). The 12-month overall survival (OS) was 25% in the prospective study and 38% in the EAP. Regarding safety, five infectious complications, including 3 sepsis, could not be excluded from being related to the study procedure in HERACLES. Shotgun sequencing analyses of the identified strains suggest that none were found in MaaT013. In the EAP, 18 pharmacovigilance cases were reported among 52 treated patients, including 11 bacteraemia/sepsis. In HERACLES, we observed in stools from responding patients at D28 a higher microbiota richness and increased levels of beneficial bacteria, in particular butyrate producers, along with increased levels of short-chain fatty acid and bile acids. In contrast, stools from non-responding (NR) patients displayed increased levels of pathogenic pro-inflammatory bacteria along with increased systemic inflammatory parameters. Overall, MaaT013 was safe in this population of highly immunocompromised patients and was associated with responses in some patients with GI-aGvHD and deserves further investigation. MaaT Pharma.

Safety, tolerability, and preliminary efficacy of SYN120, a dual 5-HT6/5-HT2A antagonist, for the treatment of Parkinson disease dementia: A randomized, controlled, proof-of-concept trial

BackgroundSYN120 is a dual serotonin receptor (5-HT6/5-HT2A) antagonist hypothesized to improve cognition and psychiatric symptoms. ObjectivesWe evaluated the safety, tolerability, and efficacy of SYN120 in patients with Parkinson disease dementia (PDD). MethodsIn a multicenter, double-blind, parallel-group, 16-week phase 2a proof-of-concept trial in PDD with concomitant cholinesterase inhibitor use, eligible patients were randomized to oral SYN120 (100 mg/day) or placebo. Adverse events (AEs), Unified Parkinson's Disease Rating Scale (UPDRS) scores, and discontinuations assessed safety and tolerability. The primary and key secondary efficacy measures were the Cognitive Drug Research (CDR) computerized assessment system Continuity of Attention and Quality of Episodic Memory scores. Other efficacy measures were: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC), Brief Penn Parkinson's Daily Activity Questionnaire-15 (PDAQ-15), Scales for Outcomes in Parkinson's Disease-Sleep Scale (SCOPA-Sleep), and Neuropsychiatric Inventory (NPI). ResultsEighty-two patients were randomized to SYN120 (N = 38) or placebo (N = 44), AEs occurred in 74% and 77% of patients, and treatment discontinuation in both groups was 16%. Nausea and vomiting were more frequent, and motor symptoms (UPDRS) worsened in the SYN120 group. At week 16, the SYN120 and placebo groups did not differ significantly for any cognitive assessment. Cognitive activities of daily living (PDAQ-15) and the NPI-Apathy/Indifference scores improved nominally in the SYN120 group compared with placebo (unadjusted p = 0.029 and 0.028). ConclusionsSYN120 was adequately tolerated, mild worsening of motor symptoms was noted and it did not improve cognition in PDD patients. Its potential benefits for cognitive activities of daily living and apathy warrant further study. RegistrationClinicaltrials.gov as NCT02258152.

Reducing BMI below the obesity threshold in adolescents treated with once-weekly subcutaneous semaglutide 2.4 mg.

To examine how improvement in body mass index (BMI) with the glucagon-like peptide-1 receptor agonist, semaglutide, translated to changes in BMI category in a post-hoc analysis of the double-blind, phase 3a randomized controlled STEP TEENS trial (NCT04102189). Adolescents with obesity received once-weekly subcutaneous semaglutide 2.4 mg or placebo, plus lifestyle intervention which comprised counseling in healthy nutrition and a goal of 60 minutes of moderate- to high-intensity physical activity per day. Achievement of an improvement in BMI category and attainment of normal weight or overweight BMI category by week 68 were analyzed using logistic regression models. In the overall population, 44.9% of participants receiving semaglutide achieved normal weight or overweight BMI category versus 12.1% receiving placebo at week 68 (odds ratio: 22.7; 95% confidence interval [CI]: 7.6-67.9). The proportion of semaglutide-treated participants in obesity class III decreased from 37.3% to 13.6%, but increased with placebo. The odds ratio for achieving an improvement of ≥1 BMI category was significantly greater with semaglutide versus placebo (23.5; 95% CI: 9.9-55.5); an improvement of ≥1 BMI category was seen in 73.7% of participants receiving semaglutide compared with 19.0% with placebo. Semaglutide was highly effective in reducing BMI category. While on treatment, most trial participants' BMI improved by ≥1 category and > 40% reached a category below the obesity threshold. This article is protected by copyright. All rights reserved.

A pilot phase 2a, randomized, double-blind, placebo-controlled study to explore the antiviral activity, clinical outcomes, safety, and tolerability of rilematovir at two dose levels in non-hospitalized adults with respiratory syncytial virus infection

ObjectivesTo assess the antiviral effect, clinical outcomes, and safety of the respiratory syncytial virus (RSV) fusion inhibitor rilematovir in non-hospitalized RSV-infected adults. MethodsThis phase 2a, double-blind, multicentre study randomly assigned RSV-positive adult outpatients ≤5 days from symptom onset 1:1:1 to receive rilematovir 500 mg, 80 mg, or placebo once-daily for 7 days. Antiviral effect was assessed by RSV RNA viral load (VL), measured by quantitative RT-PCR, and Kaplan-Meier (KM) estimates of time to undetectable VL. Clinical course was assessed by KM estimates of median time to resolution of key RSV symptoms assessed through patient-reported outcomes. ResultsRSV-positive patients (n = 72) were randomly assigned; 66 had confirmed RSV infection and received rilematovir 500 mg (n = 23), 80 mg (n = 21) or placebo (n = 22). Differences versus placebo in mean RSV RNA VL area under the curve (90% CI) through days 3, 5 and 8, respectively, were 0.09 (−0.837; 1.011), −0.10 (−2.171; 1.963), and −1.03 (−4.746; 2.682) log10 copies.day/mL for rilematovir 500 mg, and 1.25 (0.291; 2.204), 2.53 (0.430; 4.634), and 3.85 (0.097; 7.599) log10 copies.day/mL for rilematovir 80 mg. KM estimates of median (90% CI) time-to-first confirmed undetectable VL were 5.9 (3.85; 6.90), 8.0 (6.86; 12.80) and 7.0 (6.62; 10.88) days and 5.7 (2.93; 7.01), 8.1 (6.74; 12.80) and 7.9 (6.62; 11.74) days in patients with symptom onset ≤3 days, for rilematovir 500 mg, 80 mg, and placebo, respectively. KM estimates of median (90% CI) time to resolution of key RSV symptoms were 7.1 (5.03; 11.43), 7.6 (5.93; 8.32), and 9.6 (5.95; 14.00) days for rilematovir 500 mg, 80 mg, and placebo, respectively; and in patients with symptom onset ≤3 days, median 8.0, 7.6, and 11.8 days, respectively. DiscussionRilematovir use, initiated early, suggests a potential clinical benefit in RSV-infected adults, with data supporting development of RSV therapeutic options. Trial registrationThis study is registered with clinicaltrials.gov (NCT03379675).

Abatacept to induce remission of peanut allergy during oral immunotherapy (ATARI): protocol for a phase 2a randomized controlled trial.

While oral immunotherapy (OIT) has been shown to promote the remission of mild peanut allergy in young children, there is still an unmet need for a disease-modifying intervention for older patients and those with severe diseases. In mice models, abatacept, a cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) immunoglobulin fusion protein, has been shown to promote immune tolerance to food when used as an adjuvant to allergen immunotherapy. The goal of this study is to explore the potential efficacy of abatacept in promoting immune tolerance to food allergens during OIT in humans. In this phase 2a proof-of-concept study (NCT04872218), 14 peanut-allergic participants aged from 14 to 55 years will be randomized at a 1:1 ratio to abatacept vs. placebo for the first 24 weeks of a peanut OIT treatment (target maintenance dose of 300 mg peanut protein). The primary outcome will be the suppression of the OIT-induced surge in peanut-specific IgE/total IgE at 24 weeks, relative to the baseline. Sustained unresponsiveness will be assessed as a secondary outcome starting at 36 weeks by observing incremental periods of peanut avoidance followed by oral food challenges. This is the first study assessing the use of abatacept as an adjuvant to allergen immunotherapy in humans. As observed in preclinical studies, the ability of abatacept to modulate the peanut-specific immune response during OIT will serve as a proxy outcome for the development of clinical tolerance, given the small sample size. The study will also test a new patient-oriented approach to sustained tolerance testing in randomized controlled trials.

Viral sequence analysis of chronic hepatitis B patients treated with the capsid assembly modulator JNJ-56136379 in the JADE phase 2a study

Background & aimsIn the monotherapy arms of the phase 2 JADE study (ClinicalTrials.gov Identifier: NCT03361956) evaluating the safety and efficacy of JNJ-56136379 (capsid assembly modulator-class E) with/without nucleos(t)ide analogue (NA), viral breakthroughs (VBT) were observed, leading to JNJ-56136379 monotherapy discontinuation. We present the viral sequencing analysis of JNJ-56136379±NA-treated hepatitis B virus (HBV)-infected patients. MethodsThe HBV full genome was sequenced using next generation sequencing. Baseline amino acid (aa) polymorphisms were defined as changes versus the universal HBV reference sequence (sequence read frequency >15%). Emerging mutations were defined as aa changes versus baseline sequence (frequency <1% at baseline and ≥15% post-baseline). Results6/28 JNJ-56136379 75 mg monotherapy arm patients experienced VBT; all 6 had emerging JNJ-56136379-resistant variants T33N (n = 5; fold change [FC] = 85) or F23Y (n = 1; FC = 5.2). 1/32 JNJ-56136379 250 mg arm patients (genotype-E) had <1 log10 IU/mL decline in HBV DNA at Week 4, experienced VBT at Week 8, and carried the I105T baseline polymorphism (FC = 7.9), but had no emerging variants. Eight additional monotherapy-treated patients had shallow second phases of their HBV DNA profile and emerging T33N (n = 7) or F23Y (n = 1) variants. NA initiation (switch [75 mg arm]; add-on [250 mg arm]) in all monotherapy patients with VBT resulted in HBV DNA decline in all patients. No VBT was observed during JNJ-56136379+NA combination therapy. ConclusionsJNJ-56136379 monotherapy resulted in VBT and was associated with the selection of JNJ-56136379-resistant variants. Efficacy of NA treatment (de novo combination or rescue therapy for VBT) was not impacted, confirming the lack of cross-resistance between these drug classes. Clinical trial numberNCT03361956.

The Oral Transglutaminase 2 Inhibitor ZED1227 Accumulates in the Villous Enterocytes in Celiac Disease Patients during Gluten Challenge and Drug Treatment.

The enzyme transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis. Active TG2 is located mainly extracellularly in the lamina propria but also in the villous enterocytes of the duodenum. The TG2 inhibitor ZED1227 is a promising drug candidate for treating CeD and is designed to block the TG2-catalyzed deamidation and crosslinking of gliadin peptides. Our aim was to study the accumulation of ZED1227 after oral administration of the drug. We studied duodenal biopsies derived from a phase 2a clinical drug trial using an antibody that detects ZED1227 when bound to the catalytic center of TG2. Human epithelial organoids were studied in vitro for the effect of ZED1227 on the activity of TG2 using the 5-biotin-pentylamine assay. The ZED1227-TG2 complex was found mainly in the villous enterocytes in post-treatment biopsies. The signal of ZED1227-TG2 was strongest in the luminal epithelial brush border, while the intensity of the signal in the lamina propria was only ~20% of that in the villous enterocytes. No signal specific to ZED1227 could be detected in pretreatment biopsies or in biopsies from patients randomized to the placebo treatment arm. ZED1227-TG2 staining co-localized with total TG2 and native and deamidated gliadin peptides on the enterocyte luminal surface. Inhibition of TG2 activity by ZED1227 was demonstrated in epithelial organoids. Our findings suggest that active TG2 is present at the luminal side of the villous epithelium and that inhibition of TG2 activity by ZED1227 occurs already there before gliadin peptides enter the lamina propria.

Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes

Once-weekly insulin icodec could provide a simpler dosing alternative to daily basal insulin in people with type 2 diabetes. To evaluate the efficacy and safety of once-weekly icodec vs once-daily insulin degludec in people with insulin-naive type 2 diabetes. Randomized, double-masked, noninferiority, treat-to-target, phase 3a trial conducted from March 2021 to June 2022 at 92 sites in 11 countries in adults with type 2 diabetes treated with any noninsulin glucose-lowering agents with hemoglobin A1c (HbA1c) of 7%-11% (53-97 mmol/mol). Participants were randomly assigned in a 1:1 ratio to receive either once-weekly icodec and once-daily placebo (icodec group; n = 294) or once-daily degludec and once-weekly placebo (degludec group; n = 294). The primary end point was change in HbA1c from baseline to week 26 (noninferiority margin, 0.3% percentage points). Secondary end points included change in fasting plasma glucose from baseline to week 26, mean weekly insulin dose during the last 2 weeks of treatment, body weight change from baseline to week 26, and number of level 2 (clinically significant; glucose level <54 mg/dL) and level 3 (severe; requiring external assistance for recovery) hypoglycemic episodes. Among 588 randomized participants (mean [SD] age, 58 [10] years; 219 [37%] women), 564 (96%) completed the trial. Mean HbA1c level decreased from 8.6% (observed) to 7.0% (estimated) at 26 weeks in the icodec group and from 8.5% (observed) to 7.2% (estimated) in the degludec group (estimated treatment difference [ETD], -0.2 [95% CI, -0.3 to -0.1] percentage points), confirming noninferiority (P < .001) and superiority (P = .002). There were no significant differences between the icodec and degludec groups for fasting plasma glucose change from baseline to week 26 (ETD, 0 [95% CI, -6 to 5] mg/dL; P = .90), mean weekly insulin dose during the last 2 weeks of treatment, or body weight change from baseline to week 26 (2.8 kg vs 2.3 kg; ETD, 0.46 [95% CI, -0.19 to 1.10] kg; P = .17). Combined level 2 or 3 hypoglycemia rates were numerically higher in the icodec group than the degludec group from week 0 to 31 (0.31 vs 0.15 events per patient-year exposure; P = .11) and statistically higher in the icodec group from week 0 to 26 (0.35 vs 0.12 events per patient-year exposure; P = .01). Among people with insulin-naive type 2 diabetes, once-weekly icodec demonstrated superior HbA1c reduction to once-daily degludec after 26 weeks of treatment, with no difference in weight change and a higher rate of combined level 2 or 3 hypoglycemic events in the context of less than 1 event per patient-year exposure in both groups. ClinicalTrials.gov Identifier: NCT04795531.

179-OR: Improved A1C and TIR with Once-Weekly Insulin Icodec vs. Insulin Glargine U100 in Insulin-Naïve T2D—ONWARDS 1

Long-term efficacy and safety of once-weekly insulin icodec (icodec) vs insulin glargine U100 (IGlar), both with non-insulin glucose-lowering agents, including SGLT2i and GLP‑1 RA, were assessed in this randomized, open-label, treat-to-target phase 3a trial (52-week + 26-week extension) in insulin-naïve adults with T2D (NCT04460885). Participants (n=984) were randomized 1:1 to icodec or IGlar. Prespecified primary analysis at week 52 showed A1C reduction from a baseline (BL) of 8.5% to 6.9% with icodec vs 8.4% to 7.1% with IGlar (estimated treatment difference [ETD]: −0.19%-points [95% CI: −0.36, −0.03]), confirming non‑inferiority (p&amp;lt;0.0001) and superiority (p=0.0210) of icodec. Time spent in target glycemic range (TIR, from week 48-52) was significantly improved to 72% (icodec) vs 67% (IGlar), confirming superiority; ETD 4.27%-points (95% CI: 1.92; 6.62, p=0.0004). There were no significant differences in mean weekly insulin dose (week 50-52), or in body weight change from BL. Level 2 or 3 hypoglycemia rates (BL to week 52) were low in both groups, with numerically higher rates with icodec. A higher proportion achieved A1C &amp;lt;7% without level 2 or 3 hypoglycemia with icodec vs IGlar (52.6% vs 42.6%, p=0.0028). In totality, glycemic control (A1C, TIR, A1C &amp;lt;7% without hypoglycemia) was significantly improved by once-weekly icodec vs daily glargine U100 with low rates of hypoglycemia in both arms. Disclosure J.Rosenstock: Advisory Panel; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Intarcia Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Research Support; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck &amp; Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., Sanofi, Intarcia Therapeutics, Inc. S.C.Bain: Advisory Panel; Novo Nordisk, Sanofi, Lilly, Boehringer Ingelheim Inc., AstraZeneca. A.Gowda: Employee; Novo Nordisk A/S. H.Horio: Employee; Novo Nordisk. E.Jodar: Other Relationship; Amgen Inc., AstraZeneca, Eli Lilly and Company, FAES, Novo Nordisk, UCB, Inc., Speaker's Bureau; Merck &amp; Co., Inc., Asofarma, ZP Pharmaceuticals. L.Lang lehrskov: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp &amp; Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. R.Trevisan: Advisory Panel; Novo Nordisk, AstraZeneca, Eli Lilly and Company, Other Relationship; Boehringer Ingelheim Inc., Sanofi. O.Mosenzon: Advisory Panel; Novo Nordisk, AstraZeneca, Boehringer-Ingelheim, Bayer Inc., Employee; BOL Pharma, Research Support; Novo Nordisk, AstraZeneca, Boehringer-Ingelheim, Speaker's Bureau; Novo Nordisk, AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Sanofi. Funding Novo Nordisk A/S

Weekly Icodec versus Daily Glargine U100 in Type 2 Diabetes without Previous Insulin

BackgroundInsulin icodec is an investigational once-weekly basal insulin analogue for diabetes management.MethodsWe conducted a 78-week randomized, open-label, treat-to-target phase 3a trial (including a 52-week main phase and a 26-week extension phase, plus a 5-week follow-up period) involving adults with type 2 diabetes (glycated hemoglobin level, 7 to 11%) who had not previously received insulin. Participants were randomly assigned in a 1:1 ratio to receive once-weekly insulin icodec or once-daily insulin glargine U100. The primary end point was the change in the glycated hemoglobin level from baseline to week 52; the confirmatory secondary end point was the percentage of time spent in the glycemic range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter) in weeks 48 to 52. Hypoglycemic episodes (from baseline to weeks 52 and 83) were recorded.ResultsEach group included 492 participants. Baseline characteristics were similar in the two groups. The mean reduction in the glycated hemoglobin level at 52 weeks was greater with icodec than with glargine U100 (from 8.50% to 6.93% with icodec [mean change, −1.55 percentage points] and from 8.44% to 7.12% with glargine U100 [mean change, −1.35 percentage points]); the estimated between-group difference (−0.19 percentage points; 95% confidence interval [CI], −0.36 to −0.03) confirmed the noninferiority (P<0.001) and superiority (P=0.02) of icodec. The percentage of time spent in the glycemic range of 70 to 180 mg per deciliter was significantly higher with icodec than with glargine U100 (71.9% vs. 66.9%; estimated between-group difference, 4.27 percentage points [95% CI, 1.92 to 6.62]; P<0.001), which confirmed superiority. Rates of combined clinically significant or severe hypoglycemia were 0.30 events per person-year of exposure with icodec and 0.16 events per person-year of exposure with glargine U100 at week 52 (estimated rate ratio, 1.64; 95% CI, 0.98 to 2.75) and 0.30 and 0.16 events per person-year of exposure, respectively, at week 83 (estimated rate ratio, 1.63; 95% CI, 1.02 to 2.61). No new safety signals were identified, and incidences of adverse events were similar in the two groups.ConclusionsGlycemic control was significantly better with once-weekly insulin icodec than with once-daily insulin glargine U100. (Funded by Novo Nordisk; ONWARDS 1 ClinicalTrials.gov number, NCT04460885.)

178-OR: Better Glycemic Control with Once-Weekly Insulin Icodec vs. Once-Daily Insulin Degludec in Insulin-Naïve Type 2 Diabetes (ONWARDS 3)

Efficacy and safety of once-weekly insulin icodec (icodec) vs once-daily insulin degludec (degludec) in insulin-naïve adults with T2D were examined in ONWARDS 3 (NCT04795531), a 26-week, randomized, double blind, double dummy, treat-to-target, phase 3a trial. Participants (n=588) were randomized 1:1 to icodec or degludec. Key outcomes are shown in the table. The primary endpoint was A1C change from baseline (BL) to week 26. Estimated mean A1C change was greater with icodec (−1.57%; BL: 8.55%) vs degludec (−1.36%; BL: 8.48%); estimated treatment difference −0.21%-points (95% CI −0.34, −0.08), confirming non-inferiority (p&amp;lt;0.0001) and superiority (p=0.0016). Level 2 or 3 hypoglycemia rates were numerically but not statistically significantly higher with icodec vs degludec in the on-treatment period. Odds of achieving A1C &amp;lt;7% without level 2 or 3 hypoglycemia were statistically significantly higher with icodec vs degludec. There were no significant differences in weekly insulin dose from week 24 to 26 or body weight change from BL to week 26 between arms. No unexpected safety findings were observed. Overall, once-weekly icodec demonstrated superior A1C reduction vs once-daily degludec with low level 2 or 3 hypoglycemia rates in both arms. Icodec may facilitate insulin treatment acceptance and adherence by reducing basal insulin injections from ≥365 to 52 per year. Disclosure I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp &amp; Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. M.Asong: Employee; Novo Nordisk. C.Desouza: Advisory Panel; Novo Nordisk A/S, Bayer Inc., Consultant; Asahi Kasei Corporation, Research Support; Eli Lilly and Company. P.Gourdy: Advisory Panel; Novo Nordisk, Eli Lilly and Company, Sanofi, Bayer Inc., Merck Sharp &amp; Dohme Corp., Novartis, Intercept Pharmaceuticals, Inc., Research Support; Novo Nordisk, Speaker's Bureau; Novo Nordisk, Eli Lilly and Company, Sanofi, Abbott, AstraZeneca, Boehringer-Ingelheim. S.Kar: None. A.G.Vianna: Advisory Panel; AstraZeneca, Board Member; Abbott Diabetes, Novo Nordisk, Medtronic, Research Support; Novo Nordisk, Anji Pharmaceuticals, Lilly, Speaker's Bureau; AstraZeneca, Novo Nordisk, Medtronic. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. S.M.Vinther: Employee; Novo Nordisk. Y.Mu: Speaker's Bureau; Abbott Diabetes, Boehringer Ingelheim Inc., Novo Nordisk (China), Sanifit. Funding Novo Nordisk A/S

Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study

Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)-rather than the conventional DNA approach-to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells. MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III-IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II-IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov, NCT04146051. We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3-9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were -6 (95% CI -9 to -3) for MG-ADL score, -7 (-11 to -3) for Quantitative Myasthenia Gravis score, -14 (-19 to -9) for Myasthenia Gravis Composite score, and -9 (-15 to -3) for Myasthenia Gravis Quality of Life 15-revised score. In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases. Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health.

392 Safety of amlitelimab in a Phase 2a clinical trial of patients with moderate-to-severe atopic dermatitis

Abstract Amlitelimab (SAR445229), a fully human, nondepleting, noncytotoxic, monoclonal antibody, binds to OX40Ligand (OX40L) on antigen-presenting cells to block OX40-OX40L interactions. Outcomes from a 36-week, double-blind, Phase 2a trial (NCT03754309) in patients with moderate-to-severe atopic dermatitis are described. This study aims to assess the safety of OX40-OX40L signaling blockade with amlitelimab in patients with moderate-to-severe atopic dermatitis. Eighty-nine patients were randomized to amlitelimab low-dose (LD; 200-mg loading/100-mg maintenance Q4W), high-dose (HD; 500 mg/250 mg Q4W) or placebo. The coprimary safety endpoint was treatment-emergent adverse event (TEAE) incidence to W16. Safety was assessed to W36. Amlitelimab was well tolerated. Related TEAE incidence was similar between amlitelimab [LD 35% (10/29); HD 20% (6/30)] and placebo [31% (9/29)] to W16 and W36 [LD 10% (2/20); HD 0 (0/22); placebo 0 (0/17)]. The TEAEs more common with amlitelimab vs. placebo (≥5% difference) to W16 included headache [LD 0; HD 3 (10%); placebo 1 (3.4%)], upper respiratory tract infection [3 (10.3%); 0; 1 (3.4%)], hyperhidrosis [0; 2 (6.7%); 0], pyrexia [2 (6.9%); 0; 0], aspartate aminotransferase increased [0; 2 (6.7%); 0] and iron-deficiency anemia [2 (6.9%); 0; 0]; and to W36, Herpes simplex [0; 2 (9.1%); 0]. Before W16, one severe adverse event (SAE) of infected dermal cyst was reported as possibly related; it resolved, and the patient completed the study. Post-W16, one unrelated SAE of sudden death occurred 87 days following the final amlitelimab dose. No hypersensitivity or tolerability events, or clinically meaningful changes in laboratory values, vital signs or electrocardiogram recordings were reported. Amlitelimab was well tolerated in a Phase 2a trial of patients with moderate-to-severe atopic dermatitis, confirming the unremarkable safety profile observed in Phase 1.

Safety and Efficacy of ApTOLL in Patients With Ischemic Stroke Undergoing Endovascular Treatment

ApTOLL is a TLR4 antagonist with proven preclinical neuroprotective effect and a safe profile in healthy volunteers. To assess the safety and efficacy of ApTOLL in combination with endovascular treatment (EVT) for patients with ischemic stroke. This phase 1b/2a, double-blind, randomized, placebo-controlled study was conducted at 15 sites in Spain and France from 2020 to 2022. Participants included patients aged 18 to 90 years who had ischemic stroke due to large vessel occlusion and were seen within 6 hours after stroke onset; other criteria were an Alberta Stroke Program Early CT Score of 6 to 10, estimated infarct core volume on baseline computed tomography perfusion of 5 to 70 mL, and the intention to undergo EVT. During the study period, 4174 patients underwent EVT. In phase 1b, 0.025, 0.05, 0.1, or 0.2 mg/kg of ApTOLL or placebo; in phase 2a, 0.05 or 0.2 mg/kg of ApTOLL or placebo; and in both phases, treatment with EVT and intravenous thrombolysis if indicated. The primary end point was the safety of ApTOLL based on death, symptomatic intracranial hemorrhage (sICH), malignant stroke, and recurrent stroke. Secondary efficacy end points included final infarct volume (via MRI at 72 hours), NIHSS score at 72 hours, and disability at 90 days (modified Rankin Scale [mRS] score). In phase Ib, 32 patients were allocated evenly to the 4 dose groups. After phase 1b was completed with no safety concerns, 2 doses were selected for phase 2a; these 119 patients were randomized to receive ApTOLL, 0.05 mg/kg (n = 36); ApTOLL, 0.2 mg/kg (n = 36), or placebo (n = 47) in a 1:1:√2 ratio. The pooled population of 139 patients had a mean (SD) age of 70 (12) years, 81 patients (58%) were male, and 58 (42%) were female. The primary end point occurred in 16 of 55 patients (29%) receiving placebo (10 deaths [18.2%], 4 sICH [7.3%], 4 malignant strokes [7.3%], and 2 recurrent strokes [3.6%]); in 15 of 42 patients (36%) receiving ApTOLL, 0.05 mg/kg (11 deaths [26.2%], 3 sICH [7.2%], 2 malignant strokes [4.8%], and 2 recurrent strokes [4.8%]); and in 6 of 42 patients (14%) receiving ApTOLL, 0.2 mg/kg (2 deaths [4.8%], 2 sICH [4.8%], and 3 recurrent strokes [7.1%]). ApTOLL, 0.2 mg/kg, was associated with lower NIHSS score at 72 hours (mean difference log-transformed vs placebo, -45%; 95% CI, -67% to -10%), smaller final infarct volume (mean difference log-transformed vs placebo, -42%; 95% CI, -66% to 1%), and lower degrees of disability at 90 days (common odds ratio for a better outcome vs placebo, 2.44; 95% CI, 1.76 to 5.00). In acute ischemic stroke, 0.2 mg/kg of ApTOLL administered within 6 hours of onset in combination with EVT was safe and associated with a potential meaningful clinical effect, reducing mortality and disability at 90 days compared with placebo. These preliminary findings await confirmation from larger pivotal trials. ClinicalTrials.gov Identifier: NCT04734548.

85-LB: CGM Outcomes and Hypoglycemia Duration with Once-Weekly Insulin Icodec vs. Once-Daily Insulin Glargine U100 in Insulin-Naïve T2D—ONWARDS 1 Exploratory Analysis

In ONWARDS 1, a phase 3a, treat-to-target trial (NCT04460885) in insulin-naïve T2D randomized 1:1 to once-weekly icodec or once-daily glargine U100, time in, above and below range (TIR, TAR, TBR) and hypoglycemia duration were assessed with double-blinded CGM at pre-specified periods throughout the trial. TIR (70-180 mg/dL), TAR (&amp;gt;180 mg/dL), TBR (&amp;lt;70 and &amp;lt;54 mg/dL), median duration of hypoglycemia &amp;lt;70 mg/dL and the proportion of an episode spent &amp;lt;54 mg/dL were assessed at weeks (wks) 0-4, 22-26, 48-52, and 74-78. At wks 22-26, 48-52, and 74-78, mean TIR with icodec met the recommended target of &amp;gt;70%, and TIR and TAR were significantly improved with icodec vs glargine, with no significant difference between arms in TBR &amp;lt;54 mg/dL (table). There was a difference in favor of glargine in TBR &amp;lt;70 mg/dL at wks 48-52 and 74-78, but mean TBR &amp;lt;70 mg/dL and TBR &amp;lt;54 mg/dL were below recommended targets (4% and 1%, respectively) at all time periods for both arms. TIR, TBR and TAR did not differ significantly between arms at wks 0-4. Median duration of hypoglycemia &amp;lt;70 mg/dL and proportion of time &amp;lt;54 mg/dL were similar between arms at all time periods. In summary, TIR and TAR at wks 22-26, 48-52, and 74-78 were significantly improved with icodec vs glargine U100, with no significant difference in TBR &amp;lt;54 mg/dL and a similar duration of hypoglycemia &amp;lt;70 mg/dL between arms. Disclosure R. M. Bergenstal: Advisory Panel; Abbott Diabetes. Research Support; Abbott Diabetes. Consultant; Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc. Research Support; Dexcom, Inc. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company. Consultant; Hygieia. Research Support; Insulet Corporation, Medtronic. Advisory Panel; Medtronic, Novo Nordisk. Research Support; Novo Nordisk. Consultant; Onduo LLC. Advisory Panel; Roche Diabetes Care. Research Support; Sanofi. Consultant; Sanofi. Research Support; UnitedHealth Group. Consultant; Vertex Pharmaceuticals Incorporated. Advisory Panel; Zealand Pharma A/S. S. K. Watt: Employee; Novo Nordisk. A. S. A. Matos: Employee; Novo Nordisk A/S. I. Lingvay: Advisory Panel; Novo Nordisk A/S. Research Support; Novo Nordisk A/S. Advisory Panel; Lilly Diabetes, Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim. Consultant; Carmot Therapeutics, Inc., Merck Sharp &amp; Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc. Advisory Panel; Sanofi. Consultant; Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer. J. K. Mader: Advisory Panel; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S, A. Menarini Diagnostics. Research Support; A. Menarini Diagnostics, Abbott Diabetes. Advisory Panel; Abbott Diabetes. Speaker's Bureau; Abbott Diabetes. Advisory Panel; Roche Diabetes Care. Speaker's Bureau; Roche Diabetes Care. Research Support; Roche Diabetes Care. Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Sanofi. Speaker's Bureau; Sanofi. Advisory Panel; Medtronic. Speaker's Bureau; Boehringer Ingelheim Inc., Becton, Dickinson and Company. Advisory Panel; Becton, Dickinson and Company. Speaker's Bureau; Ypsomed AG, Viatris Inc., Servier Laboratories. Research Support; Dexcom, Inc., Profusa, Inc. Stock/Shareholder; Decide Clinical Software GmbH. Advisory Panel; Pharmasense, embecta. Speaker's Bureau; Medtrust. T. Nishida: Employee; Novo Nordisk Pharma Ltd. Stock/Shareholder; Novo Nordisk A/S. J. Rosenstock: Advisory Panel; Applied Therapeutics Inc. Research Support; Applied Therapeutics Inc. Advisory Panel; Boehringer Ingelheim Inc. Research Support; Boehringer Ingelheim Inc. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company, Merck &amp; Co., Inc., Novartis. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Oramed Pharmaceuticals. Research Support; Pfizer Inc. Advisory Panel; Sanofi. Research Support; Sanofi. Advisory Panel; Zealand Pharma A/S, Intarcia Therapeutics, Inc. Research Support; Intarcia Therapeutics, Inc. Advisory Panel; Hanmi Pharm. Co., Ltd. Funding Novo Nordisk A/S

803-P: Superior Glycemic Control with Once-Weekly Insulin Icodec with a Dosing Guide App vs. Once-Daily (OD) Basal Insulin Analogs in Insulin-Naïve T2D—ONWARDS 5

ONWARDS 5 (NCT04760626), a 52-week, open-label, randomized, phase 3a trial with real-world elements, assessed effectiveness and safety of once-weekly insulin icodec with a dosing guide app (icodec) vs OD basal insulin analogs (degludec, glargine U100 or glargine U300) in insulin-naïve adults with T2D. Participants (mean: 59.3 yrs; 32.8 kg/m2) were randomized 1:1 to icodec or OD analogs. The dose guidance app aided icodec titration; OD analogs were titrated as per standard of care. Estimated mean A1C change from baseline (BL) to week 52 was greater with icodec (-1.68%-points, BL 9.0%) vs OD analogs (-1.31%-points, BL 8.9%) confirming non-inferiority (p&amp;lt;0.0001) and superiority (p=0.009) of icodec vs OD analogs. Patient-reported outcomes (DTSQ and TRIM-D) were statistically significant in favor of icodec vs OD analogs at week 52. Rates of level 2 (&amp;lt;54 mg/dL) or level 3 (severe) hypoglycemia were low for both treatments (0.19 [icodec] vs 0.14 [OD analogs] events per person-year of exposure). There were no significant differences between treatments in time to treatment discontinuation/intensification. Overall, icodec with a dosing guide app showed superiority in A1C reduction, and significant improvement in treatment satisfaction and compliance scores vs OD analogs, with low hypoglycemia rates, in insulin-naïve adults with T2D in a real-world setting. Disclosure H.S.Bajaj: Research Support; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Anji Pharmaceuticals, Eli Lilly and Company, Kowa Company, Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Tricida, Inc. J.Aberle: Advisory Panel; Novo Nordisk, Speaker's Bureau; Novo Nordisk. M.J.Davies: Advisory Panel; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Lexicon Pharmaceuticals, Inc., Pfizer Inc., Medtronic, ShouTi Pharma Inc., Consultant; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Research Support; AstraZeneca, Novo Nordisk, Sanofi-Aventis U.S., Boehringer-Ingelheim, Janssen Pharmaceuticals, Inc., Speaker's Bureau; Lilly, Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, Napp Pharmaceuticals Limited, Novartis, Sanofi. A.M.Donatsky: Employee; Novo Nordisk. M.Frederiksen: Employee; Novo Nordisk A/S. D.Gogas yavuz: Advisory Panel; Sanofi, Speaker's Bureau; Novo Nordisk, Boehringer-Ingelheim. A.Gowda: Employee; Novo Nordisk A/S. I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp &amp; Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. B.W.Bode: Advisory Panel; Ascensia Diabetes Care, MannKind Corporation, Medtronic, Novo Nordisk, Zealand Pharma A/S, Research Support; Abbott Diabetes, Abvance Therapeutics, Better Therapeutics, Inc, Dexcom, Inc., Diasome, Dompé, Insulet Corporation, Lilly Diabetes, Medtronic, Novo Nordisk, Sanvita Medical, Senseonics, Provention Bio, Inc., REMD Biotherapeutics, ViaCyte, Inc., Xeris Pharmaceuticals, Inc., vTv Therapeutics, Speaker's Bureau; Abbott Diabetes, American Diabetes Association, Boehringer Ingelheim and Eli Lilly Alliance, Insulet Corporation, Lilly Diabetes, MannKind Corporation, Novo Nordisk, Sanofi, Xeris Pharmaceuticals, Inc., Stock/Shareholder; Glytec, LLC. Funding Novo Nordisk A/S

Translational predictions of phase 2a first-in-patient efficacy studies for antituberculosis drugs.

Phase 2a trials in tuberculosis typically use early bactericidal activity (EBA), the decline in sputum CFU over 14 days, as the primary end-point for testing the efficacy of drugs as monotherapy. However, the cost of phase 2a trials can range from USD 7 million to USD 19.6 million on average, while >30% of drugs fail to progress to phase 3. Better utilising pre-clinical data to predict and prioritise the most likely drugs to succeed will thus help to accelerate drug development and reduce costs. We aim to predict clinical EBA using pre-clinical in vivo pharmacokinetic (PK)-pharmacodynamic (PD) data and a model-based translational pharmacology approach. First, mouse PK, PD and clinical PK models were compiled. Second, mouse PK-PD models were built to derive an exposure-response relationship. Third, translational prediction of clinical EBA studies was performed using mouse PK-PD relationships and informed by clinical PK models and species-specific protein binding. Presence or absence of clinical efficacy was accurately predicted from the mouse model. Predicted daily decreases of CFU in the first 2 days of treatment and between day 2 and day 14 were consistent with clinical observations. This platform provides an innovative solution to inform or even replace phase 2a EBA trials, to bridge the gap between mouse efficacy studies and phase 2b and phase 3 trials, and to substantially accelerate drug development.

#4321 ACTION3 PHASE 3 STUDY: EVALUATING A NOVEL THERAPEUTIC STRATEGY OF A CCR2 INHIBITOR (DMX-200) WITH ANGIOTENSIN RECEPTOR BLOCKADE IN FSGS

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a disease of podocytes. Complications include nephrotic syndrome and progressive kidney failure. FSGS is a condition with high unmet need and there is no approved treatment. The angiotensin II receptor type 1 (AT1R) and chemokine receptor 2 (CCR2) are G protein coupled receptors that form functional heteromers. Simultaneous antagonism of these receptors suggested synergistic renoprotective effects in preclinical and early phase clinical studies of proteinuric kidney disease. DMX-200 (repagermanium) is a C-C chemokine receptor type 2 (CCR2) inhibitor that, when administered concurrently with an angiotensin II receptor blocker (ARB), is designed to inhibit recruitment of monocytes implicated in the inflammatory chemokine environment of chronic disease. In a Phase 2a open-label study of 27 patients with proteinuric chronic kidney disease, 25% of patients achieved &amp;gt; 50% reduction in uPCR with combined use of DMX-200 and irbesartan. A Phase 2a placebo-controlled cross-over study in 8 patients with primary FSGS receiving stable dose of irbesartan demonstrated evidence of promising efficacy with clinically relevant reduction in uPCR of 17% with DMX-200 compared with placebo. These encouraging data suggest that treatment with DMX-200 may result in clinically meaningful reduction in proteinuria when added to ARB in patients with glomerular diseases such as FSGS. Proteinuria reduction is a positive prognostic sign for preserving kidney function. The observations from earlier trials have led to the initiation of an international randomised double-blind, placebo-controlled Phase 3 clinical trial (ACTION3) to further evaluate the efficacy of DMX-200 in patients with FSGS receiving an ARB. Method Eligible patients are adults (18-80 years) with biopsy-proven primary FSGS, genetic FSGS or FSGS of undetermined cause (FSGS-UC), and uPCR of &amp;gt;1.5g/g based on 24hr urine collection and eGFR of ≥25 ml/min/1.73 m2. Blood pressure ≤160/100 mmHg and BMI ≤40kg/m2. Patients with secondary FSGS or those treated with strong immunomodulatory agents (other than corticosteroids) are excluded. All patients are required to receive concomitant ARB treatment at a dose of at least 50% of the maximum approved dose according to the relevant product label. Patients receiving ACE-inhibitors are required to switch to an ARB. Other background therapies such as SGLT-2 inhibitors and mineralocorticoid receptor antagonists are permitted if receiving a stable dose in the 3 months prior to screening. Patients are randomized in a 1:1 ratio to DMX-200 (120 mg twice daily) or placebo. The primary objective is to evaluate the efficacy of DMX-200 on reduction in PCR after 35 weeks of treatment and eGFR slope after 104 weeks of treatment. Secondary objectives are safety and tolerability of DMX-200 and to evaluate the effect of DMX-200 on response criteria and composite endpoint of worsening kidney function. Exploratory objectives include assessment of changes in inflammatory biomarkers such as MCP-1 and the pharmacokinetic profile of DMX-200. Two interim analyses (IA) are planned, first planned IA for futility will be performed by an Independent Data Monitoring Committee after the first ​72 randomized patients (36 patients per group) complete 35 weeks ​of treatment. A second IA will be performed once approximately​ 144 enrolled patients complete 35 weeks ​of treatment.​ The final analysis will be performed once approximately 286 patients complete 104 weeks of treatment. The study is currently open in 11 countries at approximately 75 investigational sites and will be expanded to include more countries and sites subject to a successful first interim analysis. Results ACTION3 is a trial in progress and is expected to be completed in 2026. Conclusion ACTION3 is a Phase 3 randomized, placebo-controlled efficacy and safety trial which evaluates the novel approach of combining an investigational CCR2 inhibitor, DMX-200, with angiotensin receptor blockade in patients with FSGS.