Human Data First
Biochemical and physiological differences between animals and humans pose significant challenges in translating preclinical safety and efficacy studies into clinical outcomes. While animal models continue to be an essential tool in biomedical research and drug discovery, the fact that nearly 96% of all animal-tested compounds fail in clinical trials underscores the need to adopt a more modern approach and add human data at the preclinical stage. Our advanced platform bridges the gap between preclinical testing and human-based clinical trials, saving company resources while potentially increasing the number of drugs that make it to market.
AnaBios’ advanced human tissue-based methods are enabling a modernized approach that integrates animal models with human ex vivo studies. This provides a very powerful strategy that combines the benefit of in vivo measurements (in animals) with the ability to generate human data (ex vivo) to overcome the challenges of cross-species translation.
The Benefits of Human Data in Preclinical Phases:
- Accurate identification of drug targets
- Calibrate the translatability of animal model
- Overcome false positive toxicity signals from animal models
- Resolve discordant results that occur in different model species
- Save resources by limiting GLP toxicology studies to compounds with real potential in humans
- Maximize efficacy and safety of lead compounds using authentic human targets
- Enhance the IND application with validated human data
- Guide dose selection for clinical studies
AnaBios offers a unique opportunity to study gene expression, proteomic and metabolomic profiles in authentic human tissues from healthy or diseased donors, providing great value when searching for new molecular targets or validating pre-selected targets.
Diseased and healthy human tissue samples enable the discovery of compounds with the desired selectivity profile. The high quality of samples procured by AnaBios enables the generation of highly dependable data for assessing the potential efficacy-related effects of a drug candidate or its toxicity risks.
AnaBios’ proprietary technology maximizes safety and efficacy of lead compounds with authentic human targets. By utilizing human cells and tissues, drug properties are improved by maintaining focus on the human target while keeping the desired activity in humans and minimizing misleading information due to species differences.
Clinical Candidate Selection
Regulatory requirements mandate the use of animal models for toxicology studies, which are expensive and time consuming. By strategically leveraging the power of AnaBios’ technology to identify the molecules with the highest potential for suitable efficacy and safety profile in humans, programs can focus on conducting GLP toxicological studies on a few high value compounds. In addition, the generation of human data at the preclinical stage offers the opportunity to make informed decisions with regards to dosing in clinical studies.
AnaBios’ proprietary technology supports mechanistic studies to de-convolute clinical stage toxicity signals. Elucidating the mechanism of action enables the generation of risk mitigation strategies and allows continued development of the drug. Utilization of human cells and tissues provides a superior approach for clinical stage de-risking.
In a recent study, the cardiac safety margin was established based on hERG, as well as voltage-gated sodium and calcium channel data. The safety margin was estimated to be more than 30-fold the expected unbound therapeutic plasma concentration.
AnaBios performed a pro-arrhythmia risk assessment in a human ex vivo cardiac action potential assay and identified the potential for serious cardiac problems at a concentration as low as the expected therapeutic level. In fact, the drug candidate was predicted to have no margin of safety. Analysis indicated the problem was most likely related to the inhibition of the inward sodium current.
By focusing on lowering sodium channel inhibitory activity, a new compound series was created and tested in the human ex vivo cardiac action potential assay. These molecules were found to have no toxic effects at 50-fold above the expected therapeutic concentration.
This case study illustrates the difficulty and complexity in measuring drug action against cardiac ion channels. Due to the frequency and voltage dependence of drug-induced inhibition, it is incredibly problematic to measure accurate IC50 values—a problem which often leads to erroneous safety margin estimates.
The use of fully-integrated physiological systems, such as adult human cardiac tissues or cardiomyocytes, provides the most effective strategy to assess ion channel-related risks.
Utilizing proprietary technology, AnaBios evaluated the heart rate-related risk of the compound in a human ex vivo sino-atrial (SA) node model. This unprecedented preparation detects both positive and negative chronotropic effects of drugs by recording the pacemaker activity of the human SA node. The molecule exhibited no measurable chronotropic effects, while positive (isoproterenol) and negative (carbachol) chronotropes exhibited the expected activities.
Unfortunately, species differences in drug-induced chronotropic effects are often observed in drug development programs. Ultimately, this study suggests animal models pose significant challenges in predicting drug-induced heart rate changes in humans. The availability of the human ex vivo SA node preparation opens up new opportunities for assessing this class of toxicities at an early stage in drug development.
Two compounds had significant positive inotropic effects, the third had a mild positive inotropic effect, while the remaining two drugs exhibited negative inotropic activity. These ex vivo results were confirmed during an in vivo dog study that monitored left ventricular pressure.
The same five compounds were subsequently tested using AnaBios’ technology utilizing human ventricular trabeculae in a contractility assay. Surprisingly, only one molecule had a similar effect (small positive inotropic effect) across the two species. The two molecules that were found to be negative inotropes in dog had a positive inotropic effect in human ventricular tissue. The two that were positive inotropes in dog had a small negative inotropic effect in humans. Consequently, the prioritization of these compounds was modified by taking into account the human contractility data.
This study exemplifies the commonly-observed discordance in inotropic effects of drugs across species. Therefore, the assessment of inotropic effects in human tissues or cells at the preclinical stage is a sensible strategy.