x
Nature Medicine (2023)Cite this article
Nature Medicine asks leading researchers to name their top clinical trial for 2024, from base editing and a vaccine against HIV to artificial intelligence tools for lung cancer and patient triage.
Pharma’s ongoing financial woes have continued in 2023, which has left insiders wondering when and how the field will rebound. Despite industry-wide belt-tightening, clinical trials continue even amid lingering shortages of staff — and drugs. With so many rollercoaster years since the start of the COVID-19 pandemic, it is impossible to predict exactly what the biomedical world will deliver in 2024.
Credit: Mark Garlick/Science Photo Library
We asked 11 experts which trials in the coming year are likely to have an outsized impact on medicine (Table 1).
Amit Khera: Around 1 in every 300 people is born with heterozygous familial hypercholesterolemia, which makes it one of the most common inherited genetic conditions. The disease is caused by mutations in the PCSK9 gene, which encodes a protein that breaks down receptors for low-density lipoprotein (LDL), a type of cholesterol. Although statins can reduce the risk of cardiovascular disease in these patients, most are unable to achieve optimal LDL cholesterol levels on chronic therapy.
The heart-1 trial is a global first-in-human study of in vivo DNA base editing and has the potential to demonstrate proof of concept for PCSK9-targeted base-editing treatment approaches for durably lowering of LDL cholesterol.
VERVE-101 is an investigational, in vivo, base-editing medicine, designed to be a single-course treatment, that inactivates PCSK9 in the liver to durably decrease disease-driving LDL cholesterol. The components of VERVE-101 are an mRNA that encodes an adenine base editor, plus a guide RNA, that are packaged within a lipid nanoparticle and are delivered by intravenous infusion. Interim results were presented at the American Heart Association’s Scientific Sessions 2023.
Amit Khera is Vice President of Genomic Medicine at Verve Therapeutics, a cardiologist at Brigham and Women’s Hospital and a lecturer at Harvard Medical School, Boston, MA, USA.
David Baldwin: Diagnosing lung cancer early saves lives. Although nearly three quarters of lung cancers are diagnosed late, at stage 3 or 4, earlier diagnosis at any stage allows better and more-effective treatment. A chest X-ray is most often the first test to suggest lung cancer and, if followed promptly by a computed tomography (CT) scan, can bring the diagnosis forward.
Our ongoing randomized control trial of 150,000 patients in six UK hospitals tests if artificial intelligence (AI) applied to chest X-rays as soon as they are taken shortens the time to a CT scan and time to diagnosis. We have previously shown that immediate reporting of chest X-rays by radiographers can make a substantial difference, almost halving the time to diagnosis, from 63 days to 32 days. Patients referred from primary care for chest X-ray are included for analysis by the AI. We will complete recruitment in July 2024, and we hope to have results in 2024. Our hypothesis, based on our previous research, is that we may identify lung cancer earlier, and reduce time to diagnosis as much as 50%.
AI is being implemented in hospitals often without adequate analysis of clinical impacts, something that we are concerned about. If our trial finds a significant improvement in time to diagnosis, it will probably lead to an immediate change in the standard of care to include AI at the time of chest X-ray.
David Baldwin is a respiratory physician at Nottingham University Hospitals and an honorary professor of medicine at the University of Nottingham, Nottingham, UK.
Carey Hwang: The purpose of our trial is to evaluate the safety, reactogenicity and immunogenicity of VIR-1388, a vaccine for the prevention of infection with human immunodeficiency virus (HIV). This phase 1, randomized, double-blind, placebo-controlled, multicenter study comprises adults 18–55 years of age in overall good health and without HIV who will receive one of three dose levels of VIR-1388 or placebo.
VIR-1388 is a cytomegalovirus (CMV) vector vaccine that induces strong, unique and sustained T cell responses that can potentially prevent acquisition of HIV. This follows a proof-of-concept trial of VIR-1111 that demonstrated its safety, although without a strong immune response; VIR-1388 is less attenuated than VIR-1111, and we believe it should be more immunogenic.
The overall study design includes two parts. Part A will be a lead-in phase with enrollment of a small number of people of non-childbearing potential who are seropositive for the CMV vector, with frequent safety monitoring. Part B will expand enrollment to a broader population of participants who are seropositive for CMV, including people of childbearing potential (who will be required to use two forms of contraception), with a safety-monitoring schedule similar to that of Part A. There is an optional long-term follow-up study that would lengthen participation for up to 3 years after the first dose.
We recently dosed the first participants in the study. The trial is being conducted by the HIV Vaccine Trials Network at ten sites in the USA and at two sites in South Africa, with support from the US National Institute of Allergy and Infectious Diseases and the Bill & Melinda Gates Foundation. From a public health perspective, having a vaccine against HIV would obviously have tremendous impact.
