Drug Development
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2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv3-iv3
Author(s):  
Ruthanna Davi ◽  
Antara Majumdar ◽  
Martin Bexon ◽  
Nicholas Butowski ◽  
Chandtip Chandhasin ◽  
...  

Abstract BACKGROUND Drug development in recurrent glioblastoma multiforme (rGBM) is challenging. For randomized controlled trials (RCTs) short survival horizons and limited life-prolonging treatment options may delay accrual and introduce bias through differential dropout of control patients. Comparing results of a single-arm Phase 2b trial of intratumoral delivery of MDNA55 (an interleukin-4 receptor targeted fusion protein) to an external control arm, we sought early efficacy insights and consideration by the FDA of incorporating an ECA in a Phase 3 registrational trial. METHODS Using propensity score weighting, we compared rGBM patients from the Phase 2b trial (NCT02858895) (2017-2019) to patients from rGBM registries who had received standard of care therapies (2011-2019) and met eligibility requirements. Propensity scores were estimated using a logistic regression model with 11 covariates. We compared the propensity score weighted groups according to demographic and disease attributes before and after weighting and compared overall survival between the two groups. RESULTS Through propensity score weighting, 43 (98%, 43/44) MDNA55 patients and 40.80 weighted ECA patients (from 62 unweighted registry patients) were identified for comparison. MDNA55 and ECA patients were balanced on all baseline characteristics (i.e., standardized mean difference ≤ 0.15). Compared to ECA patients, MDNA55 patients had a 37% lower hazard of death (hazard ratio 0.63, 95% confidence interval: 0.39,1.02). CONCLUSION In advance of a Phase 3 trial, comparison of Phase 2b trial results to an ECA suggests that MDNA55 may be efficacious in rGBM. In view of the known challenges associated with drug development for rGBM, these results provided a proof-of-concept for the design of a novel hybrid Phase 3 trial. This planned Phase 3 trial incorporates propensity score weighting to create a composite hybrid randomized and external control arm, an approach preferred by the FDA over full replacement of a randomized control with an external control.


2021 ◽  
Vol 8 ◽  
Author(s):  
Ting Shu ◽  
Yanjiang Xing ◽  
Jing Wang

Pulmonary arterial hypertension (PAH) is a progressive life-threatening disease. The notion that autoimmunity is associated with PAH is widely recognized by the observations that patients with connective tissue diseases or virus infections are more susceptible to PAH. However, growing evidence supports that the patients with idiopathic PAH (IPAH) with no autoimmune diseases also have auto-antibodies. Anti-inflammatory therapy shows less help in decreasing auto-antibodies, therefore, elucidating the process of immunoglobulin production is in great need. Maladaptive immune response in lung tissues is considered implicating in the local auto-antibodies production in patients with IPAH. In this review, we will discuss the specific cell types involved in the lung in situ immune response, the potential auto-antigens, and the contribution of local immunoglobulin production in PAH development, providing a theoretical basis for drug development and precise treatment in patients with PAH.


2021 ◽  
Vol 8 ◽  
Author(s):  
Soubhagya Tripathy ◽  
Deepak Kumar Verma ◽  
Mamta Thakur ◽  
Ami R. Patel ◽  
Prem Prakash Srivastav ◽  
...  

An entirely unknown species of coronavirus (COVID-19) outbreak occurred in December 2019. COVID-19 has already affected more than 180 million people causing ~3.91 million deaths globally till the end of June 2021. During this emergency, the food nutraceuticals can be a potential therapeutic candidate. Curcumin is the natural and safe bioactive compound of the turmeric (Curcuma longa L.) plant and is known to possess potent anti-microbial and immuno-modulatory properties. This review paper covers the various extraction and quantification techniques of curcumin and its usage to produce functional food. The potential of curcumin in boosting the immune system has also been explored. The review will help develop insight and new knowledge about curcumin's role as an immune-booster and therapeutic agent against COVID-19. The manuscript will also encourage and assist the scientists and researchers who have an association with drug development, pharmacology, functional foods, and nutraceuticals to develop curcumin-based formulations.


Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2489
Author(s):  
Massimiliano Andreazzoli ◽  
Ivana Barravecchia ◽  
Chiara De Cesari ◽  
Debora Angeloni ◽  
Gian Carlo Demontis

Inherited retinal degenerations (IRD) affecting either photoreceptors or pigment epithelial cells cause progressive visual loss and severe disability, up to complete blindness. Retinal organoids (ROs) technologies opened up the development of human inducible pluripotent stem cells (hiPSC) for disease modeling and replacement therapies. However, hiPSC-derived ROs applications to IRD presently display limited maturation and functionality, with most photoreceptors lacking well-developed outer segments (OS) and light responsiveness comparable to their adult retinal counterparts. In this review, we address for the first time the microenvironment where OS mature, i.e., the subretinal space (SRS), and discusses SRS role in photoreceptors metabolic reprogramming required for OS generation. We also address bioengineering issues to improve culture systems proficiency to promote OS maturation in hiPSC-derived ROs. This issue is crucial, as satisfying the demanding metabolic needs of photoreceptors may unleash hiPSC-derived ROs full potential for disease modeling, drug development, and replacement therapies.


2021 ◽  
Vol 22 (18) ◽  
pp. 10089
Author(s):  
Alena Randáková ◽  
Dominik Nelic ◽  
Martina Hochmalová ◽  
Pavel Zimčík ◽  
Mutale Jane Mulenga ◽  
...  

A complex evaluation of agonist bias at G-protein coupled receptors at the level of G-protein classes and isoforms including non-preferential ones is essential for advanced agonist screening and drug development. Molecular crosstalk in downstream signaling and a lack of sufficiently sensitive and selective methods to study direct coupling with G-protein of interest complicates this analysis. We performed binding and functional analysis of 11 structurally different agonists on prepared fusion proteins of individual subtypes of muscarinic receptors and non-canonical promiscuous α-subunit of G16 protein to study agonist bias. We have demonstrated that fusion of muscarinic receptors with Gα16 limits access of other competitive Gα subunits to the receptor, and thus enables us to study activation of Gα16 mediated pathway more specifically. Our data demonstrated agonist-specific activation of G16 pathway among individual subtypes of muscarinic receptors and revealed signaling bias of oxotremorine towards Gα16 pathway at the M2 receptor and at the same time impaired Gα16 signaling of iperoxo at M5 receptors. Our data have shown that fusion proteins of muscarinic receptors with α-subunit of G-proteins can serve as a suitable tool for studying agonist bias, especially at non-preferential pathways.


Science ◽  
2021 ◽  
Vol 373 (6561) ◽  
pp. 1304-1306
Author(s):  
Adrian Roth ◽  

2021 ◽  
Vol 3 (1) ◽  
pp. 10-42
Author(s):  
Carrie German ◽  
Alex Boyer ◽  
Andrzej Przekwas ◽  
Suzy El Bader ◽  
Antonio Cabal

Ocular barriers to drug transport make delivery of effective doses to posterior targets exceptionally difficult. Animal models have commonly been used to evaluate drug distribution and penetrability, but translational tools to determine human dosing are lacking. Here we present a framework for modeling interspecies variation by simulating oxygen distribution in the posterior eye, from outer vitreous to the sclera. Posterior eye models of mouse, rabbit, and human are presented with modifications based solely on species-dependent anatomical and physiological differences. The model includes tissue and vascular contributions to transport. In addition to oxygen, nitric oxide and its impact on oxygen metabolism is simulated. Depth-dependent retinal oxygen partial pressure profiles are in good agreement with experimental data for all three species. The model can be further extended to evaluate the variations of retinal oxygenation in response to various drugs, formulations, administration protocols, and treatment plans. Further, this framework of ocular physiologically based pharmacokinetic/pharmacodynamic models could support animal to human translation, a critical step in the drug development process.


2021 ◽  
Author(s):  
Mirxan Farizyan ◽  
Arup Mondal ◽  
Sourjya Mal ◽  
Fritz Deufel ◽  
Manuel van Gemmeren

We describe a palladium catalyzed non-directed late-stage deuteration of arenes. Key aspects include the use of D2O as a convenient and easily available deuterium source and the discovery of highly active N,N-bidentate ligands containing an N-acyl sulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C-H activation step and features an extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labelling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, amongst other applications, will prove useful as a tool in drug development processes and for mechanistic studies.


Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1230
Author(s):  
Supasek Kongsomros ◽  
Ampa Suksatu ◽  
Phongthon Kanjanasirirat ◽  
Suwimon Manopwisedjaroen ◽  
Somsak Prasongtanakij ◽  
...  

The coronavirus disease 2019 (COVID-19) pandemic severely impacts health, economy, and society worldwide. Antiviral drugs against SARS-CoV-2 are urgently needed to cope with this global crisis. It has been found that the biogenesis and release mechanisms of viruses share a common pathway with extracellular vesicles (EVs). We hypothesized that small molecule inhibitors of EV biogenesis/release could exert an anti-SARS-CoV-2 effect. Here, we screened 17 existing EV inhibitors and found that calpeptin, a cysteine proteinase inhibitor, exhibited the most potent anti-SARS-CoV-2 activity with no apparent cytotoxicity. Calpeptin demonstrated the dose-dependent inhibition against SARS-CoV-2 viral nucleoprotein expression in the infected cells with a half-maximal inhibitory concentration (IC50) of 1.44 µM in Vero-E6 and 26.92 µM in Calu-3 cells, respectively. Moreover, calpeptin inhibited the production of infectious virions with the lower IC50 of 0.6 µM in Vero E6 cells and 10.12 µM in Calu-3 cells. Interestingly, a combination of calpeptin and remdesivir, the FDA-approved antiviral drug against SARS-CoV-2 viral replication, significantly enhanced the anti-SARS-CoV-2 effects compared to monotherapy. This study discovered calpeptin as a promising candidate for anti-SARS-CoV-2 drug development. Further preclinical and clinical studies are warranted to elucidate the therapeutic efficacy of calpeptin and remdesivir combination in COVID-19.


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