Early phase development solutions: Accelerating answers for a global pandemic

A quick response to the COVID-19 pandemic helped a sponsor reduce their IND program from 12 to 5 months. With Labcorp Phase I and II trial work support, the sponsor achieved FDA emergency use authorization.

Personalized Medicine Coalition Conference​ (PMC 2024)

Antibody-drug conjugate bioanalysis: A case study in stability, matrix effects and recovery

APA 2024 -- Antibody-drug conjugates (ADCs) are an increasingly popular approach to selectively deliver a drug, the “payload”, to target cells or tissues with minimal off-target effects. A proprietary ADC with a self-immolative linker is being investigated. Three bioanalytical assays in nonhuman primate (NHP) plasma are to be developed: Total antibody, free payload and conjugated payload. 

LNP vaccine formulation screening for cellular uptake using BODIPY-labelled lipid nanoparticles

CPI RNA Vaccines and Therapeutics Conference 2024 -- RNA vaccines, comprising a mRNA encapsulated in a lipid nanoparticle (LNP), are a new modality for rapid development of synthetic prophylactic and therapeutic vaccines. The LNP acts as a device to deliver the RNA payload into the cell cytoplasm for translation of the transgene; moreover, the precise formulation of cationic/ionisable lipid, phospholipid, PEGylated lipid and cholesterol can affect the LNP cellular interaction. Crucial to the mRNA delivery is cellular uptake and escape from the endosomal compartment. To evaluate the effects of formulation components on cell uptake, a cell-based assay using 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-labelled LNPs has been developed. Using a microfluidic production process, BODIPY-cholesterol has been incorporated into a range of lipid nanoparticle formulations as a potential screen for evaluating LNP formulations and cell uptake.

Key considerations for advancing true innovation at hospitals and health systems

In an executive roundtable sponsored by Labcorp, three Labcorp leaders—Deborah Boles, PhD, vice president of research and development; Bryan Vaughn, senior vice president of hospitals and health systems; and Megann Watters, vice president of corporate development, new ventures and strategic alliances—led a discussion on Labcorp's investments in new technology and programs to help health systems reduce costs and optimize care. 

An alternative to subcutaneous adipose tissue collection in the nonhuman primate

ASR 2024 -- Adipose tissue biopsy is a useful technique for obtaining adipose samples for analysis in numerous research applications such as metabolic and cardiovascular disease studies. Due to the abundance of adipose and ease of access, the subcutaneous (SQ) space is the most common location to perform adipose biopsies. However, obtaining adequate samples can be a challenge in animals with minimal SQ adipose tissue, such as the commonly used cynomolgus macaque (Macaca fascicularis). Based on observations during macaque laparotomy and laparoscopy procedures, we hypothesized that the falciform ligament and omentum may be a useful and convenient source of adipose tissue in cynomolgus macaques. This led us to develop a minimally invasive alternative approach to adipose tissue acquisition in cynomolgus macaques lacking sufficient SQ fat for standard SQ collection. By applying standard in-house laparoscopic tissue biopsy procedures, we were able to successfully obtain repeat adipose tissue samples from cynomolgus macaques. This technique provides a convenient solution to the lack of SQ adipose tissue in young or underconditioned cynomolgus macaques. Additionally, this represents a refinement to current adipose tissue collection techniques in young or underconditioned cynomolgus macaques in which more and larger incisions, as compared to laparoscopic approach, are often required to obtain adequate sampling. 

Visualizing and injecting the tympanic membrane in guinea pigs using a rigid endoscope or an otoscope

ASR 2024 -- Guinea pigs are a commonly used research model for hearing studies. Hearing studies are aimed to determine the ototoxic potential of otic medications in guinea pigs by examining the effects of tympanic membrane injections on hearing function and cochlear histopathology. The normal function of the cochlea and auditory pathways are assessed for results after sustaining noise exposure damage, ototoxic drug treatment, etc. The biggest challenges of this procedure are visualizing the tympanic membrane, which can be done with a rigid endoscope or an otoscope with a small speculum attachment, and then visualizing the needle within the field of view of the camera or speculum. Both techniques are viable ways to visualize the tympanic membrane, but which is the most efficient when also inserting a needle and syringe to inject into the tympanic membrane?

Validation of in-vivo QT ICH E14/S7B Q&A guidance in minipig

SPS 2024 -- The E14/S7B Q&A guidelines introduce the concept of “double negative” (negative hERG and negative in vivo QTc) nonclinical data, which can be used along with negative Phase I clinical QTc data to substitute for a clinical thorough QT study in specific cases (Q&As 5.1 and 6.1). For the in vivo QT assay, best practice recommendations require characterization of individual study sensitivity, verification of independence QTc from heart rate, demonstration of test facility sensitivity and pharmacological translation to human using a positive control. We have previously validated E14/S7B Q&A compliant in vivo QT assays in dog and nonhuman primate (NHP). The objective of this work was to perform the validation in the minipig as the third non-rodent species commonly used for cardiovascular safety assessment. 

Sensitivity of Latin square and ascending dose designs for in vivo QT moxifloxacin positive control to support ICH E14/S7B studies

SPS 2024 -- The Latin square crossover is recommended as best practice for in vivo QT studies. However, an escalating design may instead be required due to long compound half-life, insufficient toxicity data to inform dose level selection, a need to build up tolerance to the test article to enable safe dosing or logistics (e.g., avoiding use of multiple simultaneous inhalation dose generation systems thereby reducing risk of contamination). We have performed ICH E14/S7B Q&A compliant in vivo QT validation studies with oral moxifloxacin using both a Latin square and an ascending dose design in nonhuman primate (NHP), dog and minipig. The objective of this work was to compare the sensitivity of the dosing designs and to generate positive control moxifloxacin QTc data in support of ICH E14/S7B studies when using an ascending dose design. 

Rodent models of anxiety and compulsion: When multiple endpoints add value

SPS 2024 -- Anxiety disorders are the most diagnosed mental illnesses and exist independently or as comorbidity with conditions such as autism spectrum disorder, major depressive disorder and/or substance use disorder. The acute treatment of moderate to severe anxiety includes medications, such as benzodiazepines, whereas for long-term treatment and compulsive disorders, selective serotonin reuptake inhibitors (SSRIs) are often prescribed. The objective of this investigation was to demonstrate the advantages of conducting a battery of behavioral tests to characterize the anxiolytic, anxiogenic and/or anti-compulsive properties of drugs.