Challenge:
To anticipate possible adverse drug reactions, a client requested clarification of the mechanisms which induce and sustain bronchoconstriction in asthma patients
Approach:
Research was conducted in a Respiratory PhysioPD™ Research Platform representing a pulmonary neuromuscular junction, the effects of a methacholine (MCh) challenge, and the impact of inflammation on FEV1 (Forced Expiratory Volume) response to the MCh challenge
Results:
An analysis of the bronchoconstriction mechanisms and simulation of the Platform clarified the role of endogenous acetylcholine in sustaining bronchoconstriction, illustrating the mechanisms by which inflammation worsens the FEV1 response to the MCh challenge
Impact:
The Respiratory PhysioPD Platform research provided a prospective evaluation of bronchoconstriction outcomes for therapies that interact with pulmonary muscarinic biology to help guide rational drug development
Challenge:
The client wanted to assess the therapeutic potential of novel oral drugs and anti-cytokine antibodies for psoriasis, identify the mechanistic drivers and the impact of patient variability on their efficacy.
Approach:
A Psoriasis PhysioPD Platform was developed and qualified using published histology and clinical data for standard of care therapies. Sensitivity analyses were conducted to identify pathways and PK characteristics critical for efficacy. Alternative disease phenotypes were simulated to delineate best-and worst-case scenarios and to show the impact of variability in target-related pathways.
Results:
The Platform identified conditions for which the new drugs are superior to standard of care therapies. Key uncertainties related to target expression and drug biodistribution in the skin were found. Follow-up experiments critical to reduce risk throughout drug development were defined.
Impact:
The Platform showed that decreasing the Phase I clinical trial from 12 weeks to 4 weeks would still demonstrate efficacy for the new therapies while significantly decreasing the trial costs.
Challenge:
To identify patient characteristics indicative of therapy responders/non-responders, a client required evaluation of the efficacy and dosing strategies of an interleukin-2 receptor subunit beta (CD122)–biased agonist as a monotherapy and in combination with a programmed cell death protein 1 (PD-1) inhibitor
Approach:
An Immuno-Oncology PhysioPD™ Research Platform and Virtual Patients (VPs) with mechanistic variability that would impact the clinical response to various therapies were used to assess the efficacy of therapies on clinical outcomes.
Results:
PhysioPD Research suggested the CD122 agonist combined with a PD-1 inhibitor showed superior efficacy compared with PD-1 inhibitor monotherapy in PD-1 inhibitor non-responder VPs. Simultaneous dosing of the CD122 agonist and a PD-1 inhibitor may be more efficacious than sequential alternate dosing or preloading with either drug
Impact:
The PhysioPD Platform Research provided a mechanistic-based identification of which patients would have the best response to treatment and support for a drug combination therapy
Challenge:
An FDA review found a perceived inconsistency between reductions in glycated hemoglobin (A1C) and average plasma glucose changes in a clinical trial of a drug with a poorly characterized mechanism of action. A client requested an evaluation of the data and identification of potential reasons for the perceived inconsistency
Approach:
Research utilized a Type 2 Diabetes (T2D) PhysioPD™ Research Platform with Virtual Patients (VPs) consistent with client Phase III trial data to generate hypotheses explaining the observed relationships between A1C and glucose.
Results:
PhysioPD Research found that the selection of clinical trial subjects and sampling times of fasting plasma glucose likely contributed to the perceived mismatch between A1C and glucose. The variability in dietary carbohydrate between clinical trial sites may have impacted the observed response
Impact:
The results of the PhysioPD Research informed the client strategy for planned FDA discussions, and resulted in recommended strategies for future T2D drug trial design
Challenge:
Determining dose for pediatric use of drugs can be problematic due to physiological differences between adults and neonates. A client requested an assessment of the pharmacokinetic/ pharmacodynamic (PK/PD) relationship of ursodiol to select the dosing for pediatric use.
Approach:
A clinical trial using microdosing in newborn infants and the use of accelerator mass spectrometry provided a limited data set with high variability. A PK model and a PhysioPD™ Platform were developed and used to research underlying causes for the variability
Results:
Analysis of the PK model provided key information of the use of AMS data for pediatric PK. PhysioPD™ Research identified and explored the differences in bile acid metabolism between infants and adults
Impact:
Microdosing and AMS can be used to generate usable PK data in infants. Research using the PhysioPD Platform identified mechanistic hypotheses for the causes of the PK variability.
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