Human IgG1 Monoclonal Antibody Research Articles

226. Higher Doses of Adintrevimab, an Extended Half-Life Monoclonal Antibody, for the Treatment and Prevention of COVID-19: Preliminary Results from a Phase 1 Single Ascending-Dose Study

Abstract Background Adintrevimab is a fully human IgG1 monoclonal antibody engineered to have potent and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like CoVs with pandemic potential. Adintrevimab is being assessed in two separate phase 2/3 clinical trials: the EVADE trial for prevention of COVID-19 in both post-exposure and pre-exposure settings and the STAMP trial for treatment of COVID-19. Here we report higher doses being evaluated in a healthy volunteer study given that emerging variants may have varying susceptibilities to adintrevimab. Previous results 300 mg IM, 600 mg IM, and 500 mg IV cohorts have been reported. Methods This is an ongoing Phase 1, randomized, placebo (PBO)-controlled, single ascending-dose study of adintrevimab administered intramuscularly (IM) or intravenously (IV) to healthy adults aged 18–50 years with no current SARS-CoV-2 infection. Participants were randomized 8:2 in 3 high dose cohorts (N=10/cohort: n=8 adintrevimab, n=2 PBO): adintrevimab 1200 mg IM, 1200 mg IV, and 4500 mg IV. Safety, tolerability, and pharmacokinetics (PK) were assessed up to 21 days post dose. Results Overall, 30 participants received adintrevimab (n=24) or PBO (n=6). Blinded safety data for all cohorts and PK for 1200 mg IV are reported. Through 21 days post dose all doses were well-tolerated, with no study drug-related adverse events (AEs), serious AEs, injection site reactions, or hypersensitivity reactions reported. The observed PK profile of the 1200 mg IV dose included Cmax of 423±105 µg/ml. Comparison of 500 mg and 1200 mg IV doses indicate dose proportionality of Cmax and exposure (AUC Day 21). Conclusion A single dose of adintrevimab, up to 4500 mg, was well tolerated. These preliminary safety data and PK support potential use of higher doses of adintrevimab as needed to address emerging SARS-CoV-2 variants. Disclosures Xia Pu, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Jean Gong, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Ed Campanaro, BSN, MSHS, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Kristin Narayan, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Deepali Gupta, B.Sc, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Frank Engler, PhD, Adagio Therapeutics: Advisor/Consultant Amanda Copans, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Pete Schmidt, MD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds.

1132. Integrated Quantitative Systems Pharmacology (QSP) Characterizing Viral Dynamics After Intramuscular (IM) Adintrevimab (ADI) Administration in Participants with Mild to Moderate Coronavirus Disease (COVID-19)

Abstract Background ADI is a fully human IgG1 monoclonal antibody engineered to have an extended half-life with high potency and broad neutralization against SARS-CoV-2 and other SARS-like coronaviruses. The goal of our analysis was to develop a QSP model in which ADI concentrations in upper airway (UA) epithelial lining fluid (ELF) were linked to a viral dynamic model to describe the impact of ADI on SARS-CoV-2 viral load relative to placebo. Methods The QSP model was fit in NONMEM Version 7.4 using PK data from a Phase 1 study (N=24, IV and IM) and from Phase 2/3 COVID-19 prevention (EVADE; N=659, IM) and treatment (STAMP; N=189, IM) studies. Saliva and NP samples were collected from STAMP study participants (pts) infected with the delta or omicron variants. The viral dynamic model was based on a published model and was modified to include both active (V) and deactivated (DV) virus (Fig). The viral dynamic model was fit to the NP swab viral load data (2 samples/pt) standardized to time since infection based upon recorded symptom onset. Saliva data (7-8 samples/pt) was fit sequentially using a biophase compartment given the peak viral load was modestly lower and peaked later than Day 1. Viral dynamic model (A) and simulated median (90% PI) NP viral load reduction in ADI-treated or placebo participants for delta (B) and omicron (C) variants Results The QSP model provided an excellent fit to serum ADI concentration-time data after estimation of a transit rate to account for IM absorption, plasma volume, and the ADI-neonatal Fc receptor dissociation rate constant. The linked viral dynamic model captured the NP swab viral load data after estimating differences in within-host replication factor (R0) and viral production rate (p) by variant. Maximal ADI-induced effect (Smax) on stimulating viral clearance (c) was fixed to 0.43 based upon prior modeling. ADI concentration in UA ELF resulting in 50% of Smax (SC50) was estimated to be 0.086 for delta and 1.05 mg/L for omicron. Figure B and C show model-based simulated median (90% PI) viral load reduction in ADI-treated or placebo pts for delta and omicron variants. Conclusion This QSP model, in conjunction with information on new variants available early in outbreaks (IC50, infectivity (R0), viral production rate [each a model parameter]), allows for rapid dose identification in response to emerging variants. Disclosures Evan Tarbell, PhD, Adagio Therapeutics: Advisor/Consultant|Adagio Therapeutics: Grant/Research Support Scott A. Van Wart, PhD, Adagio Therapeutics: Advisor/Consultant|Adagio Therapeutics: Grant/Research Support Myra Popejoy, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Kristin Narayan, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Ellie Hershberger, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Xia Pu, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Jean Gong, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics,: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Andrew Santulli, BSE, Adagio Therapeutics: Advisor/Consultant|Adagio Therapeutics: Grant/Research Support Paul Ambrose, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds|Institute for Clinical Pharmacodynamics: President.

Consistency of efficacy results across various clinical measures and statistical methods in the lecanemab phase 2 trial of early Alzheimer’s disease

Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils and slowed clinical decline in an 18-month phase 2 proof-of-concept study (Study 201; ClinicalTrials.gov NCT01767311) in 856 subjects with early Alzheimer's disease (AD). In this trial, subjects were randomized to five lecanemab dose regimens or placebo. The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Composite Score (ADCOMS) at 12 months with Bayesian analyses. The key secondary endpoints were ADCOMS at 18 months and Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) at 18 months. The results have been published previously. Herein, we describe the results of sensitivity analyses evaluating the consistency of the lecanemab efficacy results in Study 201 at the identified dose, the ED90, across multiple statistical methods and multiple endpoints over the duration of the study. The protocol-specified analysis model was a mixed model for repeated measures (MMRM). Sensitivity analyses address the consistency of the conclusions using multiple statistical methods. These include a disease progression model (DPM), a natural cubic spline (NCS) model, a quadratic mixed model (QMM), and 2 MMRMs with additional covariates. The sensitivity analyses showed positive lecanemab treatment effects for all endpoints and all statistical models considered. The protocol-specified ADCOMS analysis showed a 29.7% slower decline than placebo for ADCOMS at 18 months. The various other analyses of 3 key endpoints showed declines ranging from 26.5 to 55.9%. The results at 12 months are also consistent with those at 18 months. The conclusion of the primary analysis of the lecanemab Study 201 is strengthened by the consistently positive conclusions across multiple statistical models, across efficacy endpoints, and over time, despite missing data. The 18-month data from this trial was utilized in the design of the confirmatory phase 3 trial (Clarity AD) and allowed for proper powering for multiple, robust outcomes.

The Impact of Tezepelumab in Uncontrolled Severe Asthma: A Systematic Review of Randomized Controlled Trials.

Asthma, a chronic illness, is characterized by inflammation and airway constriction. Uncontrolled severe asthma is related to poor quality of life and increased utilization of health resources. Conventional treatments are associated with a significant amount of adverse effects. Recent years have seen the identification of various molecular effectors and signaling pathways as interesting targets for the biological therapy of severe asthma that is resistant to current therapies. Because they only target some downstream components of the inflammatory response in asthma, leaving other components unaffected, current biologic treatments only lower the exacerbation rate by 50%. If we focus on the upstream mediators of the inflammatory response in asthma, it might have a greater effect and be more efficient. Tezepelumab is a human monoclonal IgG2 antibody that specifically binds to thymic stromal lymphopoietin (TSLP) at the level of its TSLPR (thymic stromal lymphopoietin receptor) binding site, inhibiting the interaction between human TSLP and TSLPR. It is being used to treat the cytokines on the respiratory epithelial layer known as "alarmins." It is the only biologic drug available for treating severe uncontrolled asthma, despite limitations in biomarker and phenotype. In light of recent developments, the lack of knowledge on tezepelumab prompts us to publish a comprehensive systematic review. We discovered that regardless of blood eosinophil level and fractional exhaled nitric oxide levels, tezepelumab dramatically lowers asthma exacerbation in patients with severe uncontrolled asthma when compared to placebo. Tezepelumab also lessens patients' demand for healthcare resources while improving clinical indicators of lung function, health-related quality of life, and asthma management in patients. Tezepelumab plays a role in enhancing pre-bronchodilator FEV1 and lowering blood eosinophil count and fractional exhaled nitric oxide in patients with or without chronic allergies (FeNO). There have been no reports of fatalities or severe adverse events connected to tezepelumab.

Modeled Impact of APOE4 Genotype on ARIA‐E Incidence in Patients Treated With Lecanemab

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species with activity at insoluble fibrils. A multicenter, double‐blind, placebo‐controlled phase 2 study (Study 201 Core) was conducted in 856 patients with early Alzheimer’s disease (EAD). Patients could optionally participate in an open label extension (OLE) study at a dose of 10 mg/kg bi‐weekly (Q2W). Amyloid related imaging abnormalities — edema/effusion (ARIA‐E) was a main adverse event of special interest. Incidence of ARIA‐E was lecanemab dose‐dependent and greater in APOE4 carriers. A previously presented logistic model found steady‐state Cmax was a predictor of ARIA‐E incidence and more likely in APOE4 carriers (Hussein, 2019).MethodsThis work expands upon the previously developed logistic model by exploring the effect of APOE4 genotype (noncarrier, heterozygous carrier, homozygous carrier) on ARIA‐E incidence. Modeling was conducted using NONMEM 7.4.3 with data from Study 201 Core. Model predictions were compared to the observed incidence in the OLE study among patients newly treated with lecanemab (ie, placebo‐treated in the Core study).ResultsInclusion of APOE4 genotype as a covariate in the model with three categories (noncarrier, heterozygous carrier, homozygous carrier) led to a statistically significant decrease in model objective function (p <0.001). A model utilizing only 2 categories (homozygous carrier, others) was not significantly different from the model with 3 categories (p = 0.5297). Model‐predicted ARIA‐E rates for APOE4 homozygous carriers treated with lecanemab 10 mg/kg Q2W were 22.5% (versus 6.8% in heterozygous or 5.4% in noncarriers) and comparable to the observed 25% incidence in newly‐treated homozygous carriers (1/4) in the OLE study, and less than the 50% incidence in homozygous carriers (5/10) in the Core.ConclusionsThe incidence of ARIA‐E in subjects treated with lecanemab appears highest in APOE4 homozygous subjects. No statistically significant difference in ARIA‐E incidence was found between non‐carriers and heterozygous carriers. Data from the larger CLARITY‐AD study will be needed to confirm these findings.Reference: Hussein, et al., Population Pharmacokinetic (PK) and Exposure‐Response (ER) Analyses for Efficacy and Safety of BAN2401 in Patients with Early Alzheimer’s Disease (AD), International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD), 2019.

Neuropathological autopsy findings in an individual with Alzheimer’s disease who received long‐term treatment with lecanemab (BAN2401)

AbstractBackgroundAnti‐amyloid antibodies administered to patients with Alzheimer’s disease can result in marked reduction of brain amyloid as measured by neuroimaging with amyloid PET ligands. However, there is a lack of pathological data. Here we present neuropathological findings in a patient who received ∼173 weeks of (interrupted) treatment with lecanemab (BAN2401), a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated β‐amyloid species (protofibrils) and insoluble fibrils, in a Phase 2 study (NCT01767311, Alz Res Therapy 2021;13:80).MethodBrain autopsy was performed on an ∼85 year old whose lecanemab treatment history over 6 years was: 79 weeks 10mg/kg monthly in the double‐blind (DB) phase, then 98 weeks without treatment, then 94 weeks at 10mg/kg biweekly in the open‐label extension (OLE) phase, followed by ∼12 weeks of treatment discontinuation prior to death.ResultClinically, memory symptoms started age ∼77. Study entry was at age ∼80, with mild dementia, CDR 0.5, CDR‐SB 3, and MMSE 24. Florbetapir PET scan was positive at baseline, and negative after 53 weeks DB treatment and at start of OLE. These findings and clinical measures are shown in Table 1. ARIA was not observed during the study. Autopsy showed low brain weight (1052g) with diffuse atrophy, including hippocampi, consistent with atrophy seen on clinical MRI scans. Microscopic findings showed tau pathology including tangles and threads (by AT8 antibody and Bielschowsky staining) throughout neocortex (Braak NF stage VI; B3). Beta‐amyloid immunohistochemical stain (6E10) showed only modest amyloid load (Thal phase 2; A1), with near‐absence of diffuse amyloid deposits and only scattered clusters of neuritic plaques (CERAD stage B; C2).ConclusionIn this autopsy of an individual with Alzheimer’s disease treated with lecanemab, neuropathological changes showed tau and β‐amyloid deposits. However, the pattern of significant tau pathology, accompanied by only a mild degree of β‐amyloid deposits, (A1B3C2), is uncommon in typical (untreated) Alzheimer’s disease. For example, in the NACC neuropathology dataset, only 2% of brains with Braak B2 or B3 show Thal stage A0 or A1. This pattern suggests that lecanemab treatment resulted in a reduction in brain amyloid, consistent with the amyloid PET scanning results in this patient.

Subcutaneous Dose Selection of Lecanemab for Treatment of Subjects with Early Alzheimer’s Disease (EAD)

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils. Lecanemab 10 mg/kg IV biweekly dose (10BW) is being evaluated in the Clarity AD Phase 3 study in Early AD. A Phase 1 study was conducted to assess the absolute bioavailability (BA) of subcutaneous (SC) administration relative to IV infusion. Modeling and simulation analysis was conducted to demonstrate equivalence of a fixed weekly SC dose to body weight‐based IV 10BW dose with regard to lecanemab exposure, safety and efficacy.MethodBased on estimates of BA and absorption rate constant from Phase 1 and the population PK model describing lecanemab PK after IV infusion, estimates of the area under the concentration‐time curve (AUC) and maximum concentration (Cmax) at steady‐state were generated for the proposed fixed SC dose and IV 10BW. Exposure‐response simulations were conducted to compare positron emission tomography (PET) standard uptake ratio (SUVr)as a measure of pharmacodynamic effect, and incidence of amyloid related imaging abnormality‐E (ARIA‐E) as a measure of safety between SC and IV doses. The impact of body weight on the lecanemab exposure, reduction in amyloid PET SUVr and ARIA‐E risk when administered as a fixed SC dose and body weight‐based IV dose were explored.ResultPhase 1 data support a proposed fixed lecanemab SC dose of 720 mg administered weekly (720W). PK simulations demonstrate that the AUC of SC 720W were similar to IV 10BW. Exposure‐response simulations demonstrate comparable reduction in amyloid PET SUVr following SC 720W and IV 10BW, and lower incidence of ARIA‐E in SC 720W due to lower Cmax following SC administration. Lecanemab exposure differences between a fixed SC dose and body weight‐based IV dose were observed at the extremes of body weight; however, this did not have a meaningful effect on the reduction in PET SUVr and ARIA‐E risk.ConclusionThis analysis demonstrates that the proposed SC 720W results in equivalent AUC predicted to attain a comparable reduction in amyloid PET SUVr and a lower Cmax predicted to produce a lower incidence of ARIA‐E compared to IV 10BW.

Lecanemab (BAN2401) Infusion Reactions and Immunogenicity: Results from Randomized Phase 2 Study and an Open‐Label Extension (OLE).

AbstractBackgroundTreatment with 10 mg/kg lecanemab (BAN2401), a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species, has been shown to reduce amyloid PET standard uptake value ratio (SUVr) and slow clinical decline in an 18‐month, phase 2 proof‐of‐concept study (Study 201 Core) in early Alzheimer’s disease with an OLE. The present analysis aimed to review infusion related reactions from Study 201 and the results of immunogenicity assessments from the completed lecanemab clinical trial.MethodsInfusion related reactions were summarized by treatment group using descriptive statistics. All adverse events were coded using MedDRA version 24.0 and graded based on CTCAE guidelines.Analysis of anti‐drug antibodies (ADA) and its impact on pharmacokinetics, pharmacodynamics, efficacy, and safety during Study 201 were undertaken. All ADA and NAb assays were developed and validated in accordance with FDA guidance and industry best practice and were performed using a tiered approach.ResultsIn Study 201 Core, 854 treated subjects (lecanemab:609; placebo:245) were randomized across 6 treatment groups. In the OLE phase a total of 180 subjects were treated with lecanemab 10 mg/kg biweekly (LEC10BW). Infusion‐related reactions were the most common adverse event associated with LEC10BW treatment, with 19.9% (32/161) of subjects compared to 3.3% (8/245) of placebo subjects. All events were mild/moderate in severity, most occurred with the first infusion, resulted in a low rate of discontinuations (LEC10BW:2.5%; placebo:0.8%). Over 70% of patients who initially experienced infusion‐related reactions had no further reactions with preventative medications. Infusion reaction data from the OLE were consistent with the Core study. The incidences of ADA for LEC10BW in the Core and OLE were 40.9% and 11.1% (Core placebo‐treated subjects), respectively; titers were very low (most ≤125). Detailed analysis of lecanemab ADA demonstrated no meaningful impact of ADA on pharmacokinetics, pharmacodynamics, efficacy, and safety.ConclusionsIn the lecanemab Study 201 Core and OLE, infusion‐related reactions were the most common adverse event, however were readily manageable with preventative medication, were of low severity, and resulted in minimal discontinuations. Lecanemab is a low‐risk molecule for immunogenicity based on ADA profile and minimal impact of ADA on pharmacokinetics, pharmacodynamics, efficacy, and safety.

Recent advances in atezolizumab-based programmed death-ligand 1 (PD-L1) blockade therapy for breast cancer.

Breast cancer, the most common cancer in women worldwide, is curable in∼70-80% of patients with early-stage, non-metastatic disorder. However, advanced breast cancer with distant organ metastases is incurable with available therapeutics. Thus, scientists have sought emerging strategies for treating metastatic breast cancers., Immune checkpoint inhibitors (ICIs) have represented a significant development in breast cancer immunotherapy. Now, targeting immune checkpoint molecules (e.g., programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1)) have attracted increasing attention in the context of breast cancer therapy, chiefly triple-negative breast cancer (TNBC). Atezolizumab, a humanized IgG1 monoclonal antibody (mAb), has been designed to interfere with the binding of the PD-L1 ligand to its receptor. Targeting PD-L1 using atezolizumab potentiates T-cell responses to the tumor and consequently boosts tumor responses. The results of the IMpassion130 trial have recently led to the approval of the combination of atezolizumab and nab-paclitaxel to treat unresectable locally advanced or metastatic patients with PD-L1-positive TNBC. Herein, we summarize the clinical efficacy of atezolizumab in treating breast cancer and briefly discuss the possible immune-related adverse events (irAEs).

Absolute Bioavailability of a Single, Fixed Subcutaneous Dose of Lecanemab in Healthy Subjects

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils. A subcutaneous (SC) formulation is in development as an alternative to intravenous (IV) infusion. The present study evaluated the absolute bioavailability (BA), pharmacokinetics (PK), safety and immunogenicity of lecanemab following a single fixed 700 mg SC dose.MethodsThis was an open‐label, parallel‐group study conducted in healthy subjects that were randomized into IV or SC dose group; 5 Japanese subjects were randomized to the SC dose group. Serum samples for determination of lecanemab PK parameters were collected after single dose of 10 mg/kg IV infused over approximately 1 hour or fixed 700 mg SC injection in the abdomen. The absolute BA was determined by the ratio of dose normalized area under the curve from zero to infinity (AUC(0‐inf)) for SC versus IV dosing.ResultsThirty subjects received IV infusion and 29 subjects received SC injection. After SC dosing, maximum concentration was observed 72 hours post dose and was 4‐fold lower compared to IV infusion, which reflected the long absorption phase following SC administration compared with IV infusion. The AUC was 2‐fold lower for SC administration compared with IV infusion. Lecanemab half‐life (∼ 7 days) was similar following SC and IV administration. The absolute BA following a single SC 700 mg dose of lecanemab was 49.7% (90% CI: 43.5 – 56.8). PK of lecanemab after SC administration in Japanese subjects was similar to those in non‐Japanese subjects. Mild to moderate injection site reactions were experienced by 6 (20.7%) subjects in the SC dose group. Grade 1 and 2 infusion related reactions were experienced by 10 (33.3%) subjects in the IV dose group. One subject in IV and 2 in SC dose group, had confirmed treatment‐emergent positive anti‐drug antibodies (ADA), with low titers ranging from 16 to 32 with no subject being positive for neutralizing antibodies.ConclusionLecanemab was well tolerated following both SC and IV administrations. The estimate of absolute BA of SC compared to IV dosing will be used to define SC dose and dosing regimen equivalent to IV dosing.

Lifetime clinical benefits of lecanemab in early Alzheimer’s disease using simulation modeling

AbstractBackgroundAlzheimer’s disease (AD) is a progressive, neurodegenerative disease and imposes a substantial societal burden. Treatment strategies that slow disease progression may improve health outcomes and reduce burden. Lecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species. In the phase 2b BAN2401‐G000‐201 trial, lecanemab reduced clinical decline as measured by key global and cognitive scales at 18 months.MethodsA validated disease simulation model was used to assess lifetime health outcomes of lecanemab for patient with early AD (MCI due to AD and mild AD dementia) based on BAN2401‐G000‐201 trial data and published literature. The model captures the pathophysiology and management of AD, with the aim of evaluating the effects of disease modification on disease progression and translating them into meaningful health outcomes.ResultsLecanemab treatment was projected to delay disease progression, resulting in an increase in patient’s expected time in the early AD stages while reducing the time in more severe states. A 26% slowing of clinical decline on CDR‐SB in patients treated with lecanemab corresponded to a 7%, 13%, and 10% reduction in the proportion of patients progressing to mild, moderate, and severe AD dementia, respectively, over a lifetime horizon compared to the standard of care (SoC). Similarly, the estimated mean time to advance to mild, moderate, and severe AD dementia extended for lecanemab treatment by 2.51, 3.13, and 2.34 years, respectively. Scenario analyses indicated the potential lifetime impact of lecanemab was greater at earlier, younger onset AD. The incremental mean times for transition to mild and moderate AD dementia were 3.29 and 3.38 years, respectively, in younger adults (baseline mean age 65 vs. 71.5 years) with MCI due to AD only. Compared with SoC, lecanemab treatment improved patient’s quality of life over lifetime with additional 0.75 quality‐adjusted life‐years per patient (4.97 vs. 4.22).ConclusionsThe findings suggest that lecanemab treatment in early AD may have large health impacts by slowing disease progression to more severe stages of AD and reducing patient, caregiver, and public health burden. Predicted long‐term health outcomes provide a foundation for healthcare decision‐makers to understand the potential clinical and socioeconomic value of lecanemab.

199TiP A first-in-human phase I study of IPH5301, an anti-CD73 monoclonal antibody, alone or in combination with chemotherapy and trastuzumab, in patients with advanced solid tumors (CHANCES)

CD73 is an extracellular ectonucleotidase overexpressed in the tumor microenvironment (TME) of multiple cancers. Extracellular adenosine triphosphate (ATP) released by necrotic cells is hydrolyzed into adenosine monophosphate (AMP), which is subsequently degraded by CD73 into immunosuppressive adenosine. CD73 overexpression has been associated with poor prognosis, conferring resistance to chemotherapy and anti-HER2 therapy. IPH5301 is a humanized IgG1 monoclonal antibody (mAb) with a functionally silent Fc domain, specifically inhibiting both soluble and membrane CD73 enzymatic activity, and restoring proliferation of immune T cells more effectively than other anti-CD73 mAbs in clinical development.

Lecanemab in Early Alzheimer’s Disease

BackgroundThe accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer’s disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer’s disease.MethodsWe conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer’s disease (mild cognitive impairment or mild dementia due to Alzheimer’s disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer’s Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).ResultsA total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, −0.45; 95% confidence interval [CI], −0.67 to −0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, −59.1 centiloids; 95% CI, −62.6 to −55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, −1.44 (95% CI, −2.27 to −0.61; P<0.001); for the ADCOMS, −0.050 (95% CI, −0.074 to −0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.ConclusionsLecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.)

025 Immunological changes in atopic dermatitis patients treated with different dosing intervals of dupilumab

Dupilumab, a fully human IgG4 monoclonal antibody targeting the interleukin-4 receptor alpha (IL4Rα), substantially improves disease severity in patients with atopic dermatitis (AD). While recent daily practice studies have shown that dose reduction of dupilumab is possible in patients with controlled AD, the associated biological effects are currently unknown. Therefore, we studied the dupilumab levels in serum and effects of dupilumab on IL4Rα occupancy, T-cell functions and cytokine production within skin-homing (total CLA+ and CLA+/CCR4+) subpopulations in patients with AD who were treated with 300mg dupilumab subcutaneously every 2 weeks (Q2W), every 4 weeks (Q4W) and every 6 weeks (Q6W).

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Alternative Pathway Masp-3 Inhibitor OMS906 in a Phase 1 Study of Healthy Subjects

Introduction: The alternative pathway of the complement system is implicated in a wide variety of diseases. Complement Factor D (CFD) drives formation of alternative pathway C3 convertase, generating C3b and creating a positive feedback loop of protease complexes. Left unchecked, this amplification cycle leads to inflammation, tissue destruction, and the intravascular and extravascular hemolysis observed in paroxysmal nocturnal hemoglobinuria (PNH). Mannan-binding lectin-associated serine protease-3 (MASP-3) is the activator of CFD, responsible for conversion of its zymogen form (pro-CFD) to mature CFD. OMS906 is a humanized IgG4 monoclonal antibody (mAb) that binds to and inhibits MASP-3. Preclinical studies of OMS906 in mice and cynomolgus monkeys have demonstrated inhibition of alternative pathway activity via MASP-3 inhibition, suggesting therapeutic potential of OMS906 in the treatment of diseases associated with alternative pathway dysregulation. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of OMS906 in healthy subjects. Methods: This was a Phase 1, first-in-human, randomized, double-blind, single-center, placebo-controlled study of OMS906 in healthy subjects. Males or females aged 18-64 years with a body mass index (BMI) of 20-32 kg/m2 were enrolled. Subjects were grouped into 9 single-ascending dose cohorts from 0.1-5 mg/kg intravenous (IV) OMS906 and 3-8 mg/kg subcutaneous (SC) OMS906. Cohorts comprised 8 subjects each (6:2 active:placebo). Study drug was delivered by 30-min infusion (50 mL volume for IV and no dilution for SC). The primary objective was to assess safety and tolerability of OMS906 in healthy subjects. The secondary objectives were to characterize PK and PD of single-ascending IV and SC doses of OMS906, and to assess the presence of anti-drug antibodies (ADAs) against OMS906 in healthy subjects. Results: Seventy-two healthy subjects were studied; 54 received OMS906 (30 IV and 24 SC) and 18 received placebo. Mean age was 43 years (range, 20-63), mean BMI 26.7 kg/m2 (range, 21.0-31.4) and mean weight 77.7 kg (range, 50.8-105.7). Males (n=35, 48.6%) and females (n=37, 51.4%) were represented in nearly equal numbers. Subjects were White (n=40, 55.6%), Black or African American (n=22, 30.6%), Asian (n=3, 4.2%), American Indian (n=2, 2.8%) or designated as Multiple Ethnicity (n=5, 6.9%). There were no serious adverse events (AEs) or discontinuations due to AEs. Most treatment-emergent AEs (TEAEs) were mild in severity; there were no severe TEAEs. Most TEAEs were determined unlikely due to OMS906 with exception of injection site reactions (ISRs), which were the most frequently reported AEs. Reported ISRs comprised: 27 ISRs in 17 of 24 subjects receiving SC OMS906 (70.8%); 1 ISR in a subject receiving IV OMS906 (3.3%); 3 ISRs in 2 of 8 subjects receiving SC placebo (25.0%); and none in subjects receiving IV placebo. There were no hypersensitivity reactions. ADAs were detected in subjects receiving OMS906 and the degree of reactivity increased to Day 85. The overall confirmed positive rate of ADAs was 20.4% (n=11/54 receiving OMS906), consistent with the reported frequency of other mAbs in development (Vaisman-Mentesh A, et al. Front. Immunol. 2020;11:1951). Among subjects with ADAs, there was no obvious dose response or difference in ADA frequencies between IV and SC OMS906 administration and no evidence of neutralizing activity. OMS906 displayed consistent PK properties with dose proportionality and non-linearity for both IV and SC administration (Table). Tmax for SC cohorts was 96-239 hours (median). A long half-life (103-423 hours) was observed, with measurable drug concentrations detected at Day 85 for the 5 mg/kg IV and 8 mg/kg SC OMS906 cohorts. The key pharmacodynamic marker, mature CFD, showed a dose-proportional response with rapid suppression and substantial degree of suppression of long duration. Conclusion: In this Phase 1 study of healthy subjects, MASP-3 inhibitor OMS906 was well tolerated with no safety concerns. There were no serious AEs. The most common AEs were ISRs, predominantly observed in the SC OMS906 cohorts. The observed PK and PD profiles were consistent with predictions from preclinical assessments, showing predictable systemic exposure, evidence of alternative pathway inhibition, and a long duration of action. Further clinical study of OMS906 is warranted, including in patients with PNH. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase I Study of the Anti-Btla Antibody Tifcemalimab As a Single Agent or in Combination with Toripalimab in Relapsed/Refractory Lymphomas

Background: The B- and T-lymphocyte attenuator (BTLA) is an inhibitory receptor expressed on B, T and NK cells. Using Peripheral Blood Mononuclear Cell (PBMC) derived from cancer patients, co-blockade of the BTLA and PD-1 pathways improved antigen specific T cell response compared to either blockade alone. Tifcemalimab (also known as icatolimab, JS004 or TAB004) is a humanized IgG4 monoclonal antibody with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand Herpesvirus Entry Mediator (HVEM). In this first-in-human study, we report the preliminary safety and anti-tumor activity of tifcemalimab as a single agent or in combination with toripalimab (anti-PD-1) in patients with relapsed/refractory (R/R) lymphoma. Methods: Eligible patients with R/R lymphoma were enrolled in this open-label, multicenter study (NCT04477772). Tifcemalimab was administered as a monotherapy at escalating doses of 1, 3 and 10 mg/kg intravenously Q3W, followed by 3 mg/kg and 200 mg monotherapy dose expansion until disease progression or intolerable toxicity. During combination dose escalation, patients received ascending doses of tifcemalimab (100mg and 200mg) plus toripalimab (240mg). Dose-limiting toxicity (DLT) was evaluated by a safety monitoring committee. Study objectives included safety, pharmacokinetics, and efficacy. Results: By the cutoff date of July 21, 2022, a total of 48 patients were enrolled, including 25 in the monotherapy and 23 in the combination subgroup. The lymphoma subtypes included 28 Hodgkin's lymphoma (HL) and 20 non-Hodgkin's lymphoma. The median age was 43.5 (range 19-70) years with 33 (68.8%) male patients. The median prior line of therapy was 4 with 32 (66.7%) progressed upon prior anti-PD-1/L1 therapy. By the cutoff date, the median follow-up was 31.3 weeks. No DLT was observed in either monotherapy or combination dose escalation. Forty-one (83.3%) patients experienced treatment emergent adverse events (TEAEs), 9 (18.8%) of whom experienced grade 3 or above TEAEs. The most common TEAEs were fever (27.1%) and anemia (25.0%). Five treatment-related adverse events led to the discontinuation of the study drug. Ten (40.0%) and 13(56.5%) patients experienced immune related AEs in the monotherapy and combination subgroups, respectively, but all were grade 1 or 2. Among 22 evaluable patients receiving monotherapy, 1 PR (follicular lymphoma) and 7 SD were observed per Lugano criteria. Among all evaluable HL patients receiving the combination regimen (n=12), 1 CR, 4 PR (ORR 41.7%) and 5 SD (DCR 83.3%) were observed. Among them, 11 (91.7%) and 7 (58.3%) patients were refractory to prior anti-PD-1/L1 or anti-CD30 therapy, respectively. The clinical efficacy is durable as all responses are ongoing by the cutoff date, with the duration of response ranges from 2+ to 8+ months. Preliminary data showed a trend of correlation between high HVEM expression and clinical response. Conclusions: Tifcemalimab alone or in combination with toripalimab were well tolerated in all doses evaluated. The combination showed encouraging preliminary clinical efficacy in patients with R/R HL refractory to anti-PD-1/L1 and/or anti-CD30.

Trial in Progress: An Open-Label, Multi-Center Phase 2 Study Evaluating Efficacy and Safety of the Masp-2 Inhibitor Narsoplimab in Pediatric Patients with High-Risk Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy (HSCT-TMA)

Background: Hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA; also known as TA-TMA) is a potentially life-threatening complication associated with multi-organ injury and significant morbidity and mortality. HSCT-TMA incidence rates of up to 39% have been reported in both pediatric and adult allogeneic HSCT (alloHSCT) recipients; high-risk pediatric patients with proteinuria and evidence of terminal complement activation (elevated sC5b-9) had a 1-year post-HSCT survival of <20% versus 100% in those with normal sC5b-9 levels and no proteinuria (Jodele S, et al. Blood. 2014;124:645-653). In the HSCT setting, toxic conditioning regimens, infection, and graft-versus-host disease (GVHD) can cause endothelial injury, which triggers activation of the lectin pathway of complement and in turn the coagulation cascade, together leading to TMA. Narsoplimab (OMS721) is a fully human IgG4 monoclonal antibody that inhibits mannan-binding lectin-associated serine protease-2 (MASP-2), the effector enzyme of the lectin pathway and an activator of the coagulation cascade. Narsoplimab was previously evaluated for safety and efficacy in adults with high-risk HSCT-TMA in an open-label pivotal trial (NCT02222545); narsoplimab treatment was well tolerated and resulted in clinical response and favorable overall survival (Khaled SK, et al. J Clin Oncol. 2022; JCO2102389). Currently, HSCT-TMA has no approved therapy, and therefore represents a significant unmet medical need. Here, we describe the design of the first clinical trial evaluating the efficacy and safety of narsoplimab in pediatric patients with HSCT-TMA. Study Design and Methods: This is an open-label, multi-center Phase 2 trial of narsoplimab in pediatric patients (Figure 1). Eligible patients are aged ≥28 days to <18 years, have received alloHSCT for the treatment of non-malignant or malignant disease, and have been diagnosed with high-risk HSCT-TMA. Exclusion criteria include prior treatment with eculizumab, ravulizumab, or defibrotide within 3 months prior to screening, having Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS), or ADAMTS13 activity <10%. Patients will receive narsoplimab 4 mg/kg via intravenous (IV) infusion twice weekly during the 8-week treatment period (Days 1-56). If a patient meets all clinical response criteria prior to 8 weeks of treatment, dosing may be decreased to 4 mg/kg IV once weekly until the end of the treatment period. Narsoplimab can be used in conjunction with standard-of-care treatments. At the end of the treatment period, patients will enter a 44-week follow-up period (Days 60-365). The planned recruitment is at least 18 pediatric patients, distributed across the age range. The primary endpoint is 100-day survival from date of HSCT-TMA diagnosis. Secondary endpoints include: safety, survival at 52 weeks, overall survival from date of HSCT-TMA diagnosis, anti-drug antibody response, clinical response rate, narsoplimab pharmacokinetics and measurement of lectin pathway activity. Conclusion: Following the favorable results obtained in a pivotal Phase 2 study in adults with HSCT-TMA, further evaluation of narsoplimab efficacy and safety in pediatric patients with high-risk HSCT-TMA is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1b Study to Evaluate Safety and Efficacy of IBI188 in Combination with Azacitidine (AZA) As a First-Line Treatment in Subjects with Newly Diagnosed Higher Risk Myelodysplastic Syndrome

Background: IBI188 is a recombinant fully human IgG4 monoclonal antibody targeting CD47, an antiphagocytic ('don't eat me') signal present on cancer cells. Blockage of this innate immune checkpoint, IBI188 enhances tumor cell phagocytosis. The study reported updated results from a phase 1b study (NCT04485065) that evaluated safety and efficacy of IBI188 in combination with AZA as a first-line treatment in subjects with newly diagnosed higher-risk myelodysplastic syndrome (MDS). Methods: IBI188 plus AZA was given to untreated intermediate to very high risk (IPSS-R > 3.5) MDS patients. An IBI188 priming/intrapatient dose escalation regimen (0.1-30 mg/kg QW) was used. AZA was dosed 75mg/m2 days 1-7 Q4W. Patients received IBI188 until disease progression, unacceptable toxicity, or withdraw ICF. The primary endpoint was to evaluate the safety and tolerability of IBI188 in combination with AZA. Efficacy was assessed by IWG 2006 (MDS). Results: Ninety-three patients (pts) were enrolled (median age: 59.0 years, 58 [62.4%] males). 72% pts were high to very high risk by IPSS-R. With a median follow-up of 9.2 mos (range: 0.1-21.0 mos), the most common IBI188-related AEs (≥30%) were platelet count decreased (49.5%), anaemia (44.1%), blood bilirubin increased (36.6%), neutrophil count decreased (36.6%), white blood cell count decreased (36.6%), and haemolysis (34.4%). Nine pts (9.7%) discontinued treatment due to IBI188-related AE. For 45 evaluable pts with ≥ 6 mos follow-up, 37/45 (82.2%) pts had an objective response with 14 pts (31.1%) achieving a complete response (CR), 16 (35.6%) with marrow CR (9/16 also had hematologic improvement (HI)), and 7 (15.6%) with HI alone. The median duration of response was 12.0 months (95%CI, 6.5-NC). A randomized phase 3 MDS trial is planned. Additional patients/analyses will be updated. Conclusions: IBI188 in combination with azacitidine demonstrated promising efficacy, and a manageable safety profile as a first-line treatment in subjects with newly diagnosed higher risk myelodysplastic syndrome. Keywords: Myelodysplastic syndrome, Immune therapy, CD47, IBI188 Clinical trial information: NCT04485065

IMMU-27. SIMULTANEOUS TARGETING OF THE PD-L1 AND THE TGF-Β PATHWAYS WITH BINTRAFUSP ALFA IN EXPERIMENTAL GLIOMAS

Abstract Currently, immunotherapy is one of the most promising research areas in oncology, but immunotherapeutic strategies do not have proven clinical activity against glioblastoma so far. The immunosuppressive microenvironment of gliomas limits an appropriate anti-tumor immune response and represents a major challenge in the context of immunotherapy. Therefore, novel therapeutic strategies that reactivate the immune system and allow for potent anti-glioma immune responses are needed. Bintrafusp alfa is a bifunctional fusion protein that is composed of the extracellular domain of human transforming growth factor-beta receptor type II (TGF-βRII) and a human IgG1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1). It is designed to target the TGF-β and the PDL-1 pathways simultaneously by specifically localizing to the tumor via the anti-PD-L1 moiety and sequestering TGF-β within the tumor microenvironment. We analyzed interrelations between the immunosuppressive factors TGF-β and PD-L1 in glioblastoma samples from patients and observed a significant correlation that points towards a co-regulation of both targets as part of a gene expression network. Next, we assessed the activity of bintrafusp alfa in human and murine glioma cell lines in vitro and observed interference with TGF-β-induced Smad2 phosphorylation as a bona fide response marker of TGF-β pathway activation and an increase in immune cell-mediated glioma cell killing. In vivo, bintrafusp alfa prolonged the survival of glioma-bearing immunocompetent mice, whereas the survival benefit was absent in immunodeficient Rag1-/- mice lacking T and B cell populations. Characterization of the tumor microenvironment by immunohistochemistry and high-dimensional flow cytometry confirmed the immune-activating effects of bintrafusp alfa. In summary, these encouraging results demonstrate that novel treatment options such as bintrafusp alfa may have the potential to overcome the lack of immunogenicity and reinvigorate anti-tumor immune responses to efficiently combat glioblastoma.

Complement component C3 and C5b-9 deposition on hypoxia reperfused endothelial cells by non-HLA antibodies against RhoGDI2: A player involved in graft failure?

Antibodies against Rho GDP-dissociation inhibitor 2 (RhoGDI2) are associated with inferior graft survival in transplant patients receiving a kidney from deceased donors. Although this suggests that these antibodies contribute to graft injury because of ischemia, it remains unknown whether they are also pathogenically involved in the process of graft loss. To study this, we firstly analyzed the IgG subclass profile of anti-RhoGDI2 antibodies in kidney transplant recipients, and whether antibody titers change over time or because of acute rejection. Next, we investigated the expression of RhoGDI2 on primary kidney and lung endothelial cells (ECs) upon hypoxia reperfusion. In addition, the complement-fixing properties of anti-RhoGDI2 antibodies were studied using imaging flow cytometry. Anti-RhoGDI2 antibodies in patients are mainly IgG1, and titers remained stable and seemed not be changed because of rejection. Antibodies against RhoGDI2, which surface expression seemed to increase upon hypoxia reperfusion, co-localized with C3 on ECs. Binding of human IgG1 monoclonal anti-RhoGDI2 antibodies as well as patient derived antibodies, resulted in complement activation, suggesting that these antibodies are complement fixing. This study suggested a potential pathogenic role of anti-RhoGDI2 antibodies in kidney graft loss. During ischemia reperfusion, the ability of these antibodies to fix complement could be one of the mechanisms resulting in tissue injury.