By Jon Gibbins and Chris Jones

Over half of all phase 3 clinical trials fail, with an estimated cost to a pharmaceutical company of between $800m to $1.4bn per drug failure. Only one in ten drugs make it through clinical trials to market. Safety concerns are responsible for at least 10% of phase 3 trial failures. The reasons are cumulative, beginning in the drug development stages and extending into the later clinical trial phases where adverse events become apparent.

Early identification of on- and off-target effects in drug development greatly reduces costs and enables the mitigation of adverse events in later-stage trials, facilitating the advancement of assets toward regulatory approval and market access.

Surprisingly, the body’s smallest cells – platelets – may hold the key.

In this first article, we explain why platelets may hold the key to improving drug development and the new technologies that are finally making it possible to measure platelets in clinical trials. The second article will focus on the application of platelet function technology, enabling patient stratification and enhancing drug efficacy.

Two decades ago, the consensus was that platelets played a vital role in thrombosis and haemostasis, but had limited physiological relevance. Too much platelet activation can lead to thrombotic events such as heart attack, stroke or pulmonary embolism.

On the other hand, too little platelet activation can lead to bleeding, including gastrointestinal bleeding or haemorrhagic stroke.

The subsequent two decades have shown that, contrary to this initial limited view, platelets also play vital roles in immunity, inflammation, cancer metastasis, Alzheimer’s disease and infections, such as dengue, HIV-1, malaria and, notably, COVID-19.

While circulating through every tissue and organ in the body, platelets respond to a wide variety of changes in health status, disease progression and both on- and off-target effects of an extensive range of drugs. The added advantage of being easily collected from patients in clinical trials makes platelets an ideal biomarker for assessing both the efficacy of drugs and their side effects.

The techniques used to detect gross defects in platelet function have largely remained unchanged since platelet aggregation was introduced by Professor Gustav Born in the 1950s. Point-of-care platelet function tests are also available to assess haemostatic potential during surgery; however, they do not provide detailed information on the variation in platelet function properties within the population or in response to disease or therapy.

Platelet analysis needs to be measured within an hour of blood sample draw, adding geographical, expertise and equipment constraints in many clinical settings. This has historically limited platelet function analysis within multicentre or multinational clinical trials.

The inability to measure platelets means that efficacy concerns or adverse events often come to light later in the drug development pathway. This significantly delays market launch and challenges drug companies to re-investigate earlier pathways without fully understanding the reasons behind the first trial failure. Any repetition of the same process would ultimately lead to failure. The financial impact of this on the pharmaceutical industry is highly significant.

To address the need for platelet function analysis, researchers at HaemAnalytica, a newly formed biotechnology spinout from the University of Reading, and building on research carried out at the Universities of Oxford and Cambridge, and Imperial College London, have developed a unique, patented platform based on platelet phenomic analysis, now termed PLANA.

The Platelet Phenomic Analysis platform has been benchmarked against a range of established research techniques and used to test over 1,500 healthy volunteers and patients (ischaemic heart disease, type 2 diabetes, myeloma, liver disease, immune thrombocytopenia, COVID-19 infection). This comprises high-throughput, comprehensive pharmacological profiling of a range of platelet activators, along with bespoke software that categorises patients into distinct phenotype groups.

HaemAnalytica have developed new ways to stabilise reactions, enabling the assay to be performed anywhere, followed by batched analysis in a single location up to months later. PLANA allows high-quality, clinically actionable and robust platelet function measurement to be performed at any location, by anyone without sacrificing data quality. For the first time, it is possible to collect meaningful platelet function data in multicentre clinical trials.

This technological development, which emphasises the importance of assessing cellular responses to novel therapeutics and embraces physiological diversity, will lead to improvements in clinical trial design and improve subsequent outcomes for both patients and the pharmaceutical industry. This will be vital for assessing drugs targeting platelet function, but also has profound implications for the early identification of off-target adverse effects caused by compounds that shouldn’t target platelet function. Platelets really could be the canary in the coal mine for drug development as well as human health.

Platelet function analysis enables the robust screening and pre-clinical evaluation of the effects of compounds on platelet function, allowing pharmaceutical companies to pre-select drug assets that have high efficacy and low off-target effects, as well as a low risk of initiating adverse events due to their activation of platelets.

PLANA can be applied to pre-clinical or early-phase clinical trials with drugs designed to target indications that are not platelet-related (eg, pain relief, oncology, inflammation, etc) but whose molecular targets are implicated in platelet function. These smaller, lower-cost studies, primarily focused on safety and side effects, enable compounds to be screened out at an earlier stage, thereby reducing the risk of adverse events in subsequent trials. When the effects of drugs on platelet function in pre-clinical or early-phase clinical trials are recognised, clinical trial design can be adapted to further assess platelet function in later-stage trials.

The effects of platelets might also appear later in clinical trial programmes.
Drugs often fail in late-stage clinical trials or are withdrawn from use after pharmacovigilance assessment due to the variability of human populations that is not adequately represented in smaller, early-stage studies, which are often performed on less diverse and healthier cohorts. It is worth noting that there is a 30x difference in platelet function between the lowest and highest responding subjects in healthy cohorts, and this is likely to be exacerbated in patient populations.

The value of using PLANA in later-stage clinical trials will be to detect unwanted side effects in sub-populations (ie, 5-15% of the population who may be low or high responders). These sub-populations cannot be identified in smaller-scale early-phase trials but present a significant and costly risk to the success of later-stage clinical trials. The impact of which is to delay or prevent the approval processes of drugs.

This most obviously applies to any drug being developed to target haemostatic function or in which early phase work implicates disruption to blood clotting.

The implications of platelet activity stretch far beyond blood clotting and bleeding, to conditions such as inflammation and tumour metastasis. Notably, many signalling pathways, cellular processes and drug targets that form the basis of contemporary therapies are shared with platelets. As such, thrombotic or bleeding side effects are therefore a concern across the spectrum of drug discovery and testing programmes.

New technology, such as PLANA, that enables the measurement of platelet function in drug discovery and clinical trials, offers a critical new approach to stratify subjects, simplifying and de-risking drug development and clinical trials. This approach avoids the costs of late-stage failures, which can run into the many hundreds of millions of dollars.

Jon Gibbins is Professor of Cell Biology and Director of the Institute of Cardiovascular and Metabolic Research, University of Reading; Chief Scientific Officer at HaemAnalytica;
Chris Jones is Associate Professor of Thrombosis and Haemostasis, University of Reading; Chief Technical Officer at HaemAnalytica