Late-stage Clinical Development Research Articles

Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.

Atherosclerosis is a multi-factorial disease, and low-density lipoprotein cholesterol (LDL-C) is a critical risk factor in developing atherosclerotic cardiovascular disease (ASCVD). Cholesteryl-ester transfer-protein (CETP), synthesized by the liver, regulates LDL-C and high-density lipoprotein cholesterol (HDL-C) through the bidirectional transfer of lipids. The novelty of CETP inhibitors (CETPis) has granted new focus towards increasing HDL-C, besides lowering LDL-C strategies. To date, five CETPis that are projected to improve lipid profiles, torcetrapib, dalcetrapib, evacetrapib, anacetrapib, and obicetrapib, have reached late-stage clinical development for ASCVD risk reduction. Early trials failed to reduce atherosclerotic cardiovascular occurrences. Given the advent of some recent large-scale clinical trials (ACCELERATE, HPS3/TIMI55-REVEAL Collaborative Group), conducting a meta-analysis is essential to investigate CETPis' efficacy. We conducted a thorough search of randomized controlled trials (RCTs) that commenced between 2003 and 2023; CETPi versus placebo studies with a ≥6-month follow-up and defined outcomes were eligible. major adverse cardiovascular events (MACEs), cardiovascular disease (CVD)-related mortality, all-cause mortality. stroke, revascularization, hospitalization due to acute coronary syndrome, myocardial infarction (MI). Nine RCTs revealed that the use of a CETPi significantly reduced CVD-related mortality (RR = 0.89; 95% CI: 0.81-0.98; p = 0.02; I2 = 0%); the same studies also reduced the risk of MI (RR = 0.92; 95% CI: 0.86-0.98; p = 0.01; I2 = 0%), which was primarily attributed to anacetrapib. The use of a CETPi did not reduce the likelihood any other outcomes. Our meta-analysis shows, for the first time, that CETPis are associated with reduced CVD-related mortality and MI.

Abstract PS08-06: A Phase Ib/II Study to Assess the Safety and Efficacy of PM8002 (Anti-PD-L1 x VEGF-A Bispecific Antibody) in Combination with Nab-Paclitaxel for First Line Treatment of Locally Advanced or Metastatic Triple-Negative Breast Cancer

Abstract Background: PD-L1 and VEGF play important roles in immune evasion and pro-tumor angiogenesis promoting cancer growth and metastasis. PM8002 is a bispecific antibody targeting PD-L1 and VEGF-A for treating cancer. Here, we present results from a Phase Ib/II study of PM8002 in combination with nab-paclitaxel in patients with locally-advanced or metastatic triple-negative breast cancer (TNBC). Methods: 42 patients with locally-advanced or metastatic TNBC (without prior systemic treatment) were enrolled in this Phase Ib/II study to test the safety and efficacy of PM8002 in combination with nab-paclitaxel. The first 6 patients were enrolled during Phase Ib with safety as the primary endpoint, and the remaining patients were enrolled during Phase II with objective response rate (ORR) as the primary endpoint. Each treatment cycle lasts 28 days. All patients received PM8002 at 20 mg/kg (Q2W) and nab-paclitaxel at 100 mg/m2 on the 1st, 8th, and 15th days of each cycle until unacceptable toxicity or disease progression were observed. Tumor responses were evaluated every 8 weeks according to RECIST 1.1. Safety was evaluated according to CTCAE 5.0. Nab-paclitaxel dose was reduced according to toxicity, while PM8002 dose was kept consistent according to body weight. PD-L1 expression in tumors was tested, and subgroup analysis of ORR data stratified by PD-L1 expression was also included. Results: As of June 30, 2023, 42 patients were treated and evaluated at least once for treatment efficacy. The median duration of drug exposure was 4.6 months (min, max: 2.0, 7.6). The best overall ORR was 76.2% (32/42), including 1 complete response (CR) and 31 partial responses (PRs) with 29 objective responses occurring at the patient's first evaluation. The confirmed ORR was 57.2% (24/42) and the overall disease control rate (DCR) was 95.2% (40/42). The median time to response (TTR) was 1.9 months (95% CI:1.8~2.0) and the median best percentage change from baseline for target lesions was -47.2% (Q1, Q3: -56.9%, -33.5%). Among 13 patients with PD-L1 combined positive scores (CPS) < 1, the best ORR and DCR were 69.2% (9/13) and 100.0% (13/13), respectively. Among 25 patients with PD-L1 CPS ≥1, the best ORR and DCR were 80.0% (20/25) and 96.0% (24/25), respectively. Among 9 patients with PD-L1 CPS ≥10, the best ORR and DCR were both 100.0% (9/9). At the cut-off date of data analysis, 38 patients were still on treatment with a median progression-free survival (mPFS) of 7.4 months (95% CI: 7.4~NA); 38 patients were censored due to no disease progression or death. The incidence of treatment-related adverse events (TRAEs) was 95.2%, of which 26.2% were Grade 3 or 4; no Grade 5 TRAEs were observed. The incidence of drug-related TRAEs related to PM8002 was 92.9%, of which 23.8% were Grade 3 or 4. The incidence of drug-related TRAEs related to nab-paclitaxel was 95.2%, of which 26.2% were Grade 3 or 4. 1 patient (2.4%) reduced nab-paclitaxel dose due to diarrhea. 1 patient (2.4%) discontinued PM8002 and nab-paclitaxel treatment due to diarrhea. The most common TRAEs related to PM8002 and nab-paclitaxel included neutropenia (69.0%), leukocytopenia (59.5%), anemia (52.4%) and proteinuria (26.2%). The incidence of immune-related adverse events (irAEs) was 11.9%, which included hyperthyroidism, hypothyroidism, and rash. No ≥ Grade 3 irAEs were observed. AEs related to targeting VEGF were also analyzed, including hypertension 19.0% (4.8% at Grade 1, 11.9% at Grade 2, and 2.4% at Grade 3) and proteinuria 26.2% (9.5% at Grade 1, and 16.7% at Grade 2). Conclusions: Rapid, deep, and durable tumor responses were observed for the combination of PM8002 and nab-paclitaxel in patients with first line TNBC. PM8002 did not enhance toxicity that is typically observed for nab-paclitaxel. This Phase II study is still ongoing with plans for entering late-stage clinical development for solid tumors. Citation Format: Jiong Wu, Jian Zhang, Zhongsheng Tong, Qingyuan Zhang, Yong-Sheng Wang, Qiao Cheng, Xin Chen, Zhihua Li, Yongmei Yin. A Phase Ib/II Study to Assess the Safety and Efficacy of PM8002 (Anti-PD-L1 x VEGF-A Bispecific Antibody) in Combination with Nab-Paclitaxel for First Line Treatment of Locally Advanced or Metastatic Triple-Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-06.

Successes and pitfalls in orphan drug development for sickle cell disease

AbstractSickle cell disease (SCD) is a hereditary red cell disorder with a large disease burden at a global level. In the United States and Europe, medicines may qualify for orphan designation (OD), a regulatory status that provides incentives to boost development. We evaluated the development of new therapies for SCD using data for OD granted in the United States and Europe over the last 2 decades (2000-2021). We analyzed their characteristics, pathophysiological targets, trends, and OD sponsors. We then investigated the approval outcomes, including the phase success rate and reasons for discontinuation across different variables. We identified 57 ODs for SCD: 43 (75.4%) small molecules, 32 (56.1%) for oral administration, and 36 (63.1%) for chronic use to prevent SCD complications. At the end of the study (2021), development of 34 of 57 ODs was completed. Four ODs were approved with a success rate of 11.8%. Products targeting upstream causative events of SCD pathophysiology had a 1.8 higher success rate compared with products targeting disease consequences. Large companies showed a fourfold higher success rate compared with small-medium enterprises. Failures in clinical development were mainly seen in phase 3 for a lack of efficacy on vaso-occlusive crisis as the primary study end point, likely related to variable definitions and heterogeneity of pain scoring and treatment. Both advances in SCD knowledge and regulatory incentives paved the way for new therapies for SCD. Our finding of high failure rates in late-stage clinical development signals the need for better early-stage predictive models, also in the context of meaningful clinical end points.

Abstract 1245: The histone methyltransferase KMT2D mediates subtype-specific transcriptional regulation and therapeutic response in prostate cancer

Abstract Primary prostate cancer is characterized by its dependence on androgen receptor (AR) and often has hyperactive PI3K signaling, most frequently through loss of PTEN. PI3K/AKT pathway inhibitors are in late-stage clinical development in combination with anti-AR therapy. Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, but the development of castration-resistant prostate cancer (CRPC) eventually occurs. CRPC remains largely dependent on AR for growth with a subset of CRPC that lose AR dependence. There is an urgent need to study the molecular pathways leading to AR activation and the loss of AR reliance in order to identify therapeutic targets. KMT2D is a histone methyltransferase and an important regulator of gene expression. Here we found that KMT2D establishes the chromatin competence necessary for the recruitment of AR and FOXA1 transcription factors (TFs) to activate AR-dependent transcription in AR-high prostate models. In AR-low models such as the stem cell-like (SCL) subtype, KMT2D controls residual AR-FOXA1 gene expression programs and AP-1 TFs such as FOSL1, a driver of the SCL subtype. In SCL, single cell RNA-seq and single cell chromatin assays confirm a key role for KMT2D in the maintenance of a mixed lineage cell state through the regulation of AP-1 and FOXA1 TFs. Combined suppression of PI3K/AKT and KMT2D reduces cell proliferation in prostate cancer cells and patient derived organoids, providing a rationale for epigenetically informed combination therapies with PI3K/AKT inhibitors in PTEN-deficient prostate cancer. Together, these data establish KMT2D as a major mediator of subtype-specific chromatin accessibility and transcriptomic landscape in CRPC, required for prostate cancer growth and therapeutic response. Citation Format: Srushti Kittane, Erik Ladewig, Taibo Li, Jillian Love, Amaia Arruabarrena-Aristorena, Xinyu Guo, Mirna Sallaku, Liliana Garcia-Martinez, Ryan Blawski, Javier Carmona Sanz, Christopher Simpkins, Wanlu Chen, Bujamin Vokshi, Peihua Zhao, Nachiket Kelkar, Laura Baldino, Ingrid Kalemi, Pau Castel, Emiliano Cocco, Lluis Morey, Charles Sawyers, Hongkai Ji, Maurizio Scaltriti, Alexis Battle, Christina Leslie, Wouter Karthaus, Eneda Toska. The histone methyltransferase KMT2D mediates subtype-specific transcriptional regulation and therapeutic response in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1245.

Development of a robust cell-based potency assay for a coxsackievirus A21 oncolytic virotherapy

Oncolytic viruses (OV) are part of a burgeoning field of investigational oncolytic therapy (OT), in which lytic viruses dissolve advanced tumors productively and specifically. One such OT is a Coxsackievirus A21 (CVA21) based OV that is currently under clinical evaluation. A tissue culture infectious dose (TCID50) assay was used for CVA21 potency release and stability testing in early clinical development. The titer measured in this method was an extrapolated value from cytopathic effect (CPE) observed during the serial dilution but doesn't represent direct viral killing of cells. Moreover, the assay was not deemed to be optimal to carry into late phase clinical development due to limitations in assay precision, turn-around time, and sample throughput. To address these points, we developed a plaque assay to measure viral plaque forming units to measure the potency value for drug substance (DS), drug product (DP) and virus seed (master and working) stocks. In this manuscript, we describe the steps taken to develop this plaque assay for the late-stage clinical development, which include the assay qualification, validation, and robustness protocols, and describe statistical methods for data analysis. Moreover, the method was validated for linearity, accuracy, precision, and specificity. Furthermore, the plaque assay quantifies OV infectivity with better precision (32% vs 58%), with higher sample throughput (22 samples/week vs 3 samples/week) and shorter assay turnaround time (4 days vs 7 days) than the TCID50 method. This assay development strategy can provide guidance for the development of robust cell-based potency methods for OVs and other infectious viral products.

“Why has this new vaccine come and for what reasons?” key antecedents and questions for acceptance of a future maternal GBS vaccine: Perspectives of pregnant women, lactating women, and community members in Kenya

ABSTRACT Group B streptococcus (GBS) is a leading global cause of neonatal sepsis and meningitis, stillbirth, and puerperal sepsis. While intrapartum antibiotic prophylaxis (IAP) is a currently available GBS disease prevention strategy, IAP is programmatically complex to implement, precluding use in low- and middle-income countries. In Kenya, 2% of stillbirths are attributable to GBS infection. Two maternal GBS vaccines are in late-stage clinical development. However, licensure of a maternal GBS vaccine does not translate into reduction of disease. We conducted 28 in-depth interviews with pregnant people, lactating people, and community members across two counties in Kenya to better understand the attitudes and informational needs of primary vaccine beneficiaries. We identified two emerging themes from the data. The first focused on antecedents to maternal GBS vaccine acceptability. The most common antecedents focused on the vaccine’s ability to protect the baby and/or the mother, followed by community sensitization before the vaccine was available. The second key theme focused on questions that would need to be addressed before someone could accept a maternal GBS vaccine. Three key categories of questions were identified, including vaccine safety compared to vaccine benefits, who gets the vaccine, and how the vaccine works. Realizing the potential benefits of a future GBS maternal vaccine will require a multifactorial approach, including ensuring that communities are aware of GBS-related harms as well as the safety and effectiveness of a maternal GBS vaccine. Our study contributes to informing this multifactorial approach by elucidating the attitudes and concerns of key populations.

Reassessing potential economic value and health impact of effective Shigella vaccines.

The gram-negative bacterium Shigella is a leading cause of diarrheal morbidity and mortality in children in low- and middle-income countries. Several promising vaccine candidates are in late stages of clinical development against this increasingly antibiotic-resistant pathogen. However, considering the increasingly crowded and costly paediatric immunization schedule, and likely advent of other important new vaccines, it is unclear whether introduction of a Shigella vaccine would represent a high priority for international agencies or health ministries in low- and middle-income countries. To determine whether there is a compelling public health value proposition for a Shigella vaccine, we used the World Health Organization's Full Value of Vaccine Assessment analytic framework and formulated five broad scientific, policy, economic and commercial-related propositions regarding the development of a Shigella vaccine. We also explored the current regulatory, clinical, policy and commercial challenges to a Shigella-containing combination vaccine development and adoption. Through a series of literature reviews, expert consultations, social science field studies and model-based analyses, we addressed each of these propositions. As described in a series of separate publications that are synthesized here, we concluded that the economic and public health value of a Shigella vaccine may be greater than previously recognized, particularly if it is found to also be effective against less severe forms of diarrheal disease and childhood stunting. The decision by pharmaceutical companies to develop a standalone vaccine or a multipathogen combination will be a key factor in determining its relative prioritization by various stakeholders in low- and middle-income countries.

Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis

Non-alcoholic steatohepatitis (NASH) is emerging as a major cause of hepatocellular carcinoma (HCC), however, it is not resolved if compounds in late-stage clinical development for NASH may have additional therapeutic benefits in NASH-driven HCC (NASH-HCC). Here, we profiled monotherapy with semaglutide (glucagon-like-receptor-1 receptor agonist) and lanifibranor (pan-peroxisome proliferator-activated receptor agonist) in a diet-induced obese (DIO) mouse model of NASH-HCC. Disease progression was characterized in male C57BL/6 J mice fed the GAN (Gubra Amylin NASH) diet high in fat, fructose and cholesterol for 12–72 weeks (n = 15 per group). Other GAN DIO-NASH-HCC mice fed the GAN diet for 54 weeks and with biopsy-confirmed NASH (NAFLD Activity Score ≥ 5) and advanced fibrosis (stage F3) received vehicle (n = 16), semaglutide (30 nmol/kg, s.c., n = 15), or lanifibranor (30 mg/kg, p.o., n = 15) once daily for 14 weeks. GAN DIO-NASH-HCC mice demonstrated progressive NASH, fibrosis and HCC burden. Tumors presented with histological and molecular signatures of poor prognostic HCC. Consistent with clinical trial outcomes in NASH patients, both lanifibranor and semaglutide improved NASH while only lanifibranor reduced fibrosis in GAN DIO-NASH-HCC mice. Notably, only semaglutide reduced tumor burden in GAN DIO-NASH-HCC mice. In conclusion, the GAN DIO-NASH-HCC mouse is a clinical translational model of NASH-HCC. Semaglutide improves both NASH and tumor burden in GAN DIO-NASH-HCC mice, highlighting the suitability of this preclinical model for profiling novel drug therapies targeting NASH-HCC.

Pharmacodynamics of zoliflodacin plus doxycycline combination therapy against Neisseria gonorrhoeae in a gonococcal hollow-fiber infection model.

Antimicrobial resistance in the sexually transmitted bacterium Neisseria gonorrhoeae is compromising the management and control of gonorrhea globally. Optimized use and enhanced stewardship of current antimicrobials and development of novel antimicrobials are imperative. The first in class zoliflodacin (spiropyrimidinetrione, DNA Gyrase B inhibitor) is a promising novel antimicrobial in late-stage clinical development for gonorrhea treatment, i.e., the phase III randomized controlled clinical trial (ClinicalTrials.gov Identifier: NCT03959527) was recently finalized, and zoliflodacin showed non-inferiority compared to the recommended ceftriaxone plus azithromycin dual therapy. Doxycycline, the first-line treatment for chlamydia and empiric treatment for non-gonococcal urethritis, will be frequently given together with zoliflodacin because gonorrhea and chlamydia coinfections are common. In a previous static in vitro study, it was indicated that doxycycline/tetracycline inhibited the gonococcal killing of zoliflodacin in 6-h time-kill curve analysis. In this study, our dynamic in vitro hollow-fiber infection model (HFIM) was used to investigate combination therapies with zoliflodacin and doxycycline. Dose-range experiments using the three gonococcal strains WHO F (susceptible to relevant therapeutic antimicrobials), WHO X (extensively drug-resistant, including ceftriaxone-resistant; zoliflodacin-susceptible), and SE600/18 (zoliflodacin-susceptible strain with GyrB S467N substitution) were conducted simulating combination therapy with a single oral dose of zoliflodacin 0.5-4g combined with a doxycycline daily oral dose of 200mg administered as 100mg twice a day, for 7days (standard dose for chlamydia treatment). Comparing combination therapy of zoliflodacin (0.5-4g single dose) plus doxycycline (200mg divided into 100mg twice a day orally, for 7days) to zoliflodacin monotherapy (0.5-4g single dose) showed that combination therapy was slightly more effective than monotherapy in the killing of N. gonorrhoeae and suppressing emergence of zoliflodacin resistance. Accordingly, WHO F was eradicated by only 0.5g single dose of zoliflodacin in combination with doxycycline, and WHO X and SE600/18 were both eradicated by a 2g single dose of zoliflodacin in combination with doxycycline; no zoliflodacin-resistant populations occurred during the 7-day experiment when using this zoliflodacin dose. When using suboptimal (0.5-1g) zoliflodacin doses together with doxycycline, gonococcal mutants with increased zoliflodacin MICs, due to GyrB D429N and the novel GyrB T472P, emerged, but both the mutants had an impaired biofitness. The present study shows the high efficacy of zoliflodacin plus doxycycline combination therapy using a dynamic HFIM that more accurately and comprehensively simulate gonococcal infection and their treatment, i.e., compared to static in vitro models, such as short-time checkerboard experiments or time-kill curve analysis. Based on our dynamic in vitro HFIM work, zoliflodacin plus doxycycline for the treatment of both gonorrhea and chlamydia can be an effective combination.

FRI378 Estetrol Prolongs Anagen In Healthy Female Scalp Hair Follicles By Positively Modulating Dermal Papilla Functions And Generation Of Progenitor Stem Cells Ex Vivo

Abstract Disclosure: C. Gerard: None. A. La Riche: None. S. Altendorf: None. V. Dion: None. L. Epping: None. T. Bíro: None. G. Dixon: None. M. Bertolini: None. The human hair follicle (HF) is a neuroendocrine mini-organ that responds to, but also generates, a wide range of hormones, which affect hair cycle and HF biology. HF functions are profoundly regulated by several intrafollicular neuroendocrine axes like the HF-equivalent of the hypothalamic-pituitary-adrenal and thyroid axes, as well as by local prolactin secretion. In this regard, estrogens exert a direct role in hair cycle regulation, since estrogen receptors are prominently expressed in the epithelium of scalp HFs. It has been shown that postmenopausal women increasingly experience female pattern hair loss (FPHL) due to the decrease in ovarian estrogen secretion. Conversely, elevated estrogen levels were found to correlate with enhanced numbers of anagen HFs during pregnancy. Estetrol (E4) is a natural estrogen produced by the fetal liver during pregnancy. E4 was recently approved as the estrogenic component of a new combined oral contraceptive and is currently in the late stage of clinical development for its use as a menopausal hormone therapy. In this study, we aimed to assess the capacity of E4 to regulate hair growth.Frontotemporal, full-length microdissected HFs from 4 healthy female donors (> 50 years) were exposed to different concentrations of E4 (300nM, 3µM and 30µM) ex vivo. Subsequently, hair cycle staging, hair matrix keratinocyte proliferation (Ki-67), dermal papilla (DP) inductivity (versican expression and alkaline phosphatase activity), fibroblast emigration (cell density in the DP, the dermal cup (DC) and the DP stalk), and the percentage of HFs stem cell (HFSC) progenitors (CD34+) was assessed by quantitative (immuno-)histomorphometry. E4 treatment led to a tendential (300nM and 30µM) or significant (3µM) increase in the number of anagen (growing) HFs, further supported by enhanced hair matrix keratinocyte proliferation. Although neither size nor cell density of DP was affected by the treatment with E4, a significant lower number of cells was detected in the DP stalk and DC, indicating less DP fibroblast emigration. Additionally, E4 treatment stimulated DP fibroblast inductivity as evidenced by a tendential up-regulation of versican expression and alkaline phosphatase activity in the DP, the latter even significantly in only anagen HFs. Moreover, application of 3µM E4 positively affected the generation of stem cell progeny by significantly increasing the percentage of CD34+ cells in the suprabulbar outer root sheath. Taken together, our data suggest that treatment with E4 boosts anagen maintenance, reduces DP fibroblast emigration, stimulates DP inductivity and promotes the expansion of HFSC progeny. Thus, these findings point at a potential role of E4 to prevent catagen development and changes known to be involved in HF miniaturization, and further encourage the exploration of E4 as possible treatment strategy for hair loss disorders such as FPHL. Presentation: Friday, June 16, 2023

Beyond antibiotics: phage-encoded lysins against Gram-negative pathogens.

Antibiotics remain the frontline agents for treating deadly bacterial pathogens. However, the indiscriminate use of these valuable agents has led to an alarming rise in AMR. The antibiotic pipeline is insufficient to tackle the AMR threat, especially with respect to the WHO critical category of priority Gram-negative pathogens, which have become a serious problem as nosocomial and community infections and pose a threat globally. The AMR pandemic requires solutions that provide novel antibacterial agents that are not only effective but against which bacteria are less likely to gain resistance. In this regard, natural or engineered phage-encoded lysins (enzybiotics) armed with numerous features represent an attractive alternative to the currently available antibiotics. Several lysins have exhibited promising efficacy and safety against Gram-positive pathogens, with some in late stages of clinical development and some commercially available. However, in the case of Gram-negative bacteria, the outer membrane acts as a formidable barrier; hence, lysins are often used in combination with OMPs or engineered to overcome the outer membrane barrier. In this review, we have briefly explained AMR and the initiatives taken by different organizations globally to tackle the AMR threat at different levels. We bring forth the promising potential and challenges of lysins, focusing on the WHO critical category of priority Gram-negative bacteria and lysins under investigation for these pathogens, along with the challenges associated with developing them as therapeutics within the existing regulatory framework.

Antimalarial drug discovery: progress and approaches.

Recent antimalarial drug discovery has been a race to produce new medicines that overcome emerging drug resistance, whilst considering safety and improving dosing convenience. Discovery efforts have yielded a variety of new molecules, many with novel modes of action, and the most advanced are in late-stage clinical development. These discoveries have led to a deeper understanding of how antimalarial drugs act, the identification of a new generation of drug targets, and multiple structure-based chemistry initiatives. The limited pool of funding means it is vital to prioritize new drug candidates. They should exhibit high potency, a low propensity for resistance, a pharmacokinetic profile that favours infrequent dosing, low cost, preclinical results that demonstrate safety and tolerability in women and infants, and preferably the ability to block Plasmodium transmission to Anopheles mosquito vectors. In this Review, we describe the approaches that have been successful, progress in preclinical and clinical development, and existing challenges. We illustrate how antimalarial drug discovery can serve as a model for drug discovery in diseases of poverty.

Analytical comparability to evaluate impact of manufacturing changes of ARX788, an Anti-HER2 ADC in late-stage clinical development.

ARX788 is an anti-HER2 antibody drug conjugate (ADC) developed using Ambrx proprietary Engineered Precision Biologics technology. The manufacturing process of ARX788 has been optimized during the course of early to late-phase clinical development. A comprehensive evaluation of side-by-side comparability between pre- and post-change process for ARX788 drug substance and drug product from a quality perspective was conducted based on ICH Q5E guidelines consisting of batch release assays, physicochemical and biophysical characterization, biological characterization, and forced degradation studies. All results have substantiated a high degree of similarity between the pre- and post-change ARX788 drug substance batches and drug product lots, demonstrating that the process manufacturing changes did not impact product quality.

Introduction of industry precompetitive consortium to promote microbiome based drug discovery in Japan

With the advent of next-generation sequencers and subsequent large national projects by the U.S. and Europe, scientific information and knowledge have been dramatically accumulated on the microbiome and data associated with various diseases. Ever since the surprising highly successful efficacy of refractory C. difficile infectious disease by fecal microbiota transplantation is reported, microbiome modulation has been expected as a new approach for drug discovery. Therefore, lots of microbiome drug discovery ventures have sprung up and clinical pipelines in late-stage clinical development have already been created especially in U.S. and Europe. Unfortunately, Japan is lagging behind U.S. and Europe., as is often the case with other modalities such as the genome-based drug discovery. However, since pioneering research on gut microbiota began in Japan and has since been highly successful, the establishment of a domestic microbiome drug discovery infrastructure is long overdue. Under this environment, the Japan Microbiome Consortium, a general incorporated association established in 2017 to promote the industrial application of microbiome research, has been promoting pre-competitive collaborative activities with the participation of more than 30 domestic companies, including pharmaceutical companies, to build the microbiome drug discovery infrastructure. The consortium has been working on the construction of a drug discovery ecosystem that will lead to (1) a reliable measurement platform, (2) microbiome data in the healthy gut, and (3) microbiome drug discovery, by utilizing government projects. In this paper, we introduce the consortium and its activities to promote industrialization through pre-competitive collaborative activities.

Ensifentrine as a Novel, Inhaled Treatment for Patients with COPD.

Ensifentrine is a novel, potent, and selective dual inhibitor of phosphodiesterase (PDE)3 and PDE4 designed for delivery by inhalation that combines effects on airway inflammation, bronchodilation and ciliary function in bronchial epithelia. In Phase 2 studies in subjects with COPD, ensifentrine demonstrated clinically meaningful bronchodilation and improvements in symptoms and health-related quality of life when administered alone or in combination with current standard of care therapies. Ensifentrine is currently in late-stage clinical development for the maintenance treatment of patients with COPD. This review summarizes non-clinical data as well as Phase 1 and Phase 2 efficacy and safety results of nebulized ensifentrine relevant to the maintenance treatment of patients with COPD.

CDK4/6 Inhibitors: Existing and Emerging Differences.

The cyclin-dependent kinase (CDK)4/6 inhibitors palbociclib, ribociclib, and abemaciclib are standard-of-care therapy for hormone receptor-positive advanced/metastatic breast cancer, based on randomized trials showing improved progression-free survival for all 3 drugs, and overall survival for ribociclib and abemaciclib. Results in early breast cancer (eBC) are discordant, with sustained improvement in invasive disease-free survival demonstrated for abemaciclib but not other CDK4/6 inhibitors to date. We review non-clinical studies exploring mechanistic differences between the drugs, the impact of continuous dosing on treatment effect, and translational research into potential resistance mechanisms and prognostic and predictive markers. We focus particularly on how emerging findings may help us to understand similarities and differences between the available CDK4/6 inhibitors. Even at late-stage clinical development, there remains much to learn about how agents in this class exert their varying effects.

Degradable Hydrogel for Sustained Localized Delivery of Anti-Tumor Drugs

Disadvantages of systemically administered immunomodulatory anti-tumor therapies include poor efficacy and high toxicity. Direct intratumoral injection of a drug is often associated with rapid efflux from the site of administration, thus reducing local exposure and therapeutic efficacy, while potentially increasing systemic adverse events. To address this, a sustained release prodrug technology was developed using a transient conjugation (TransConTM) technology to provide long-term high local drug exposure after injection in the tumor while minimizing systemic exposure. TransCon technology for systemic delivery is clinically validated, with multiple compounds in late-stage clinical development and approval of a once-weekly growth hormone for pediatric growth hormone deficiency. As a further application of this technology, this report describes the design, preparation, and functional characterization of hydrogel microspheres as insoluble, yet degradable carrier system. Microspheres were obtained after reaction of PEG-based polyamine dendrimers and bifunctional crosslinkers. Resiquimod, a TLR7/8 agonist, and axitinib, a vascular endothelial growth factor tyrosine kinase inhibitor, were chosen as anti-cancer drugs. The drugs were covalently attached to the carrier by linkers, which released the drugs under physiological conditions. Essentially all resiquimod or axitinib was released over weeks before physical degradation of the hydrogel microsphere was observed. In summary, TransCon Hydrogel technology allows localized sustained-release drug delivery for cancer therapy enabling high local drug concentrations while at the same time ensuring low systemic drug exposure over weeks with a single injection, which may improve the therapeutic index and improve efficacy, while minimizing systemic adverse events. A hydrogel prodrug of resiquimod, TransCon TLR7/8 agonist, is currently being investigated in clinical trials of patients with solid tumors (NCT04799054).

Sequential salvage chemotherapy and lintuzumab-Ac225 results in deep responses and prolonged survival in adverse risk relapsed/refractory AML and in AML patients that received prior venetoclax therapy.

e19030 Background: Lintuzumab-Ac225 is a humanized CD33 antibody conjugated to an alpha emitting isotope, Ac225, delivering high energy radiation to CD33 expressing AML blasts. Preclinical studies indicate Lintuzumab-Ac225 also depletes the anti-apoptotic protein MCL-1, which is a known resistance factor in BCL2-inhibitor (venetoclax (Ven)) exposed patients (pts). We performed a Phase I study where Lintuzumab-Ac225 was administered after salvage chemotherapy, and this study demonstrated safety and encouraging response rates in R/R AML. Herein, we report results of high-risk patients who enrolled to this study. Methods: R/R AML pts deemed fit, and with CD33 expression on >25% of blasts were enrolled onto a Phase I study, Lintuzumab-Ac225 in Combination with Cladribine + Cytarabine + Filgrastim + Mitoxantrone (CLAG-M). Induction consisted of G-CSF, 300mcg/d on D1-6, cladribine 5mg/m2 on D2-6, cytarabine 2g/m2 on D2-6, and mitoxantrone 10mg/m2 on D2-4. Lintuzumab-Ac225 was administered once on D8 ±1 day. The trial enrolled to 4 cohorts, with Lintuzumab-Ac225 at doses ranging from 0.25 uCi/kg to 1.0 uCi/kg. We defined high-risk pts as those who met ELN 2019 criteria for adverse risk disease, or pts who received a Ven combination prior to trial enrollment. Response is descriptively reported, and KM estimator was used to report overall survival (OS). Results: 19 pts on trial met high-risk criteria. Of these, 16 pts had ELN adverse risk disease, a TP53 mutation was detected in 75% (n=12) of pts. Median age was 65 yrs, pts received a median 2 lines of prior therapy, including prior allo-HCT in 58% (n=11), and prior Ven combination in 68% (n=13) of pts. In high-risk pts, 42% (n=8) of pts achieved CRc (CR+CRi), 16% (n=3) achieved MLFS, for an overall response rate (ORR) of 58%. Among evaluable pts achieving CRc, 71% achieved flow MRD negativity. Median OS was 7.4 months. Table reports results in select subgroups. Prior to treatment initiation, 7 pts were deemed eligible for first HCT. 4 (57%) were successfully able to bridge to HCT. Median survival among transplanted pts was 28 months. Post-HCT, one pt died due to GVHD, one due to relapse. Conclusions: CLAG-M in combination with Lintuzumab-Ac225 yielded significantly better clinical outcomes in high-risk populations, particularly in pts previously treated with Ven combinations (median OS 13.8 mo.) and in pts with TP53 mutations (median OS 7.3 mo.), for which recent studies have reported a survival of 4 months or less. The results support further advance in late-stage clinical development of Lintuzumab-Ac225 in combination with CLAG-M in R/R AML, especially in high-risk pts. Clinical trial information: NCT03441048 . [Table: see text]

Potential impact and cost-effectiveness of Shigella vaccination in 102 low-income and middle-income countries in children aged 5 years or younger: a modelling study

Vaccine impact and cost-effectiveness models have mostly focused on acute burden. Shigella-attributable moderate-to-severe diarrhoea has been shown to be associated with childhood linear growth faltering. Evidence also links less severe diarrhoea to linear growth faltering. As Shigella vaccines are in late stages of clinical development, we aimed to estimate the potential impact and cost-effectiveness of vaccination against Shigella burden that includes stunting and the acute burden attributable to less severe diarrhoea and moderate-to-severe diarrhoea. We used a simulation model to estimate Shigella burden and potential vaccination in children aged 5 years or younger from 102 low-income to middle-income countries from 2025 to 2044. Our model included stunting associated with Shigella-related moderate-to-severe diarrhoea and less severe diarrhoea and we explored vaccination impact on health and economic outcomes. We estimate 109 million (95% uncertainty interval [UI] 39-204) Shigella-attributable stunting cases and 1·4 million (0·8-2·1) deaths in unvaccinated children over 20 years. We project that Shigella vaccination could avert 43 million (13-92) stunting cases and 590 000 (297 000-983 000) deaths over 20 years. The overall mean incremental cost-effectiveness ratio (ICER) was US$849 (95% uncertainty interval 423-1575; median $790 [IQR 635-1005]) per disability-adjusted life-year averted. Vaccination was most cost-effective in the WHO African region and in low-income countries. Including the burden of Shigella-related less severe diarrhoea improved mean ICERs by 47-48% for these groups and substantially improved ICERs for other regions. Our model suggests that Shigella vaccination would be a cost-effective intervention, with a substantial impact in specific countries and regions. Other regions could potentially benefit upon the inclusion of the burden of Shigella-related stunting and less severe diarrhoea in the analysis. Bill & Melinda Gates Foundation and Wellcome Trust.

A Point Mutation at C151 of Keap1 of Mice Abrogates NRF2 Signaling, Cytoprotection in Vitro, and Hepatoprotection in Vivo by Bardoxolone Methyl (CDDO-Me).

Bardoxolone methyl (CDDO-Me) is an oleanane triterpenoid in late-stage clinical development for the treatment of patients with diabetic kidney disease. Preclinical studies in rodents demonstrate the efficacy of triterpenoids against carcinogenesis and other diseases, including renal ischemia-reperfusion injury, hyperoxia-induced acute lung injury, and immune hepatitis. Genetic disruption of Nrf2 abrogates protection by triterpenoids, suggesting that induction of the NRF2 pathway may drive this protection. Herein, we examined the effect of a point mutation (C151S) in KEAP1, a repressor of NRF2 signaling, at cysteine 151 in mouse embryo fibroblasts and mouse liver. Induction of target gene transcripts and enzyme activity by CDDO-Me was lost in C151S mutant fibroblasts compared with wild-type. Protection against menadione toxicity was also nullified in the mutant fibroblasts. In mouse liver, CDDO-Me evoked the nuclear translocation of NRF2, followed by increased transcript and activity levels of a prototypic target gene, Nqo1, in wild-type, but not C151S mutant, mice. To test the role of KEAP1 Cys151 in governing the broader pharmacodynamic action of CDDO-Me, wild-type and C151S mutant mice were challenged with concanavalin A to induce immune hepatitis. Strong protection was seen in wild-type but not C151S mutant mice. RNA-seq analysis of mouse liver from wild-type, C151S mutant, and Nrf2-knockout mice revealed a vigorous response of the NRF2 transcriptome in wild-type, but in neither C151S mutant nor Nrf2-knockout, mice. Activation of "off-target" pathways by CDDO were not observed. These data highlight the singular importance of the KEAP1 cysteine 151 sensor for activation of NRF2 signaling by CDDO-Me. SIGNIFICANCE STATEMENT: KEAP1 serves as a key sensor for induction of the cytoprotective signaling pathway driven by the transcription factor NRF2. Mutation of a single cysteine (C151) in KEAP1 abrogates the induction of NRF2 signaling and its downstream cytoprotective actions in vitro and in vivo by bardoxolone methyl (CDDO-Me), a drug in late-stage clinical development. Further, at these bioeffective concentrations/doses, activation of "off-target" pathways by CDDO-Me are not observed, highlighting the singular importance of NRF2 in its mode of action.