Gene editing, AI, an HIV vaccine and more: 11 clinical trials that will shape medicine in 2024

Bio-health predictions usually get the what right, but rarely the when. The most optimistic ones in 1989 predicted an HIV vaccine “in five years,” which, despite remarkable advances, has not been achieved in over 30 years. Clinical trials can be promising and then fade before they materialize into a vaccine or treatment. Or they may have limited effect. For example, the Covid-19 vaccine was a turning point, but reinfections, mutations and primary care were required to slow the pandemic.

Clinical trials are an area where big headlines are rare, and good news comes in bits and pieces. Perhaps for that reason, since 2018, Nature Medicine has been highlighting the clinical trials that will shape the year ahead (and probably for years thereafter as well). “Of course, it’s always hard to predict the future, and some trial results are inevitably delayed or have less impact on patient care than expected,” Ben Johnson, the journal’s editor in chief, acknowledges in an email exchange. But he notes that these trials have been chosen by experts in the field and that three of the experiments mentioned in last year’s list have already been approved by different health authorities.

The journal has highlighted 11 studies to keep an eye on in 2024. Before the lists of cultural, business and technology trends flood the news, we’re underscoring the ones that really matter and will impact our health.

Gene editing to fight cholesterol

In the future, some diseases will be cured by rewriting genetic code, essentially erasing and correcting errors in the human instruction manual. The editing tool for that is CRISPR, a kind of molecular scissors and glue that won the Nobel Prize in Chemistry in 2020. Defective genes, such as PCSK9, could be modified with CRISPR. This gene contains the guidelines for making the protein that destroys bad cholesterol, and it can have mutations in one in 300 people. Before, such people were doomed to taking pills and avoiding ham forever. But thanks to CRISPR, things could change. The U.S. company Verve Therapeutics has already successfully tested this technique in monkeys. Now the Heart1 trial will do so in humans, marking the first study of DNA base-editing on humans in vivo. “This is indeed a major breakthrough,” geneticist Lluís Montoliu, of the National Center for Biotechnology in Madrid, Spain, told EL PAÍS. “These editors have already been used ex vivo, outside the patient, to treat, for example, Alyssa, the British girl with untreatable acute lymphoblastic leukemia. But with the PCSK9 gene, the treatment is administered directly to the patient, which opens up the possibility of unwanted side effects that we will have to monitor.” Montoliu is optimistic about the possibilities these treatments offer but warns that we must be vigilant. “Two of the ten patients treated [by this company] have developed cardiovascular problems afterward.”

Stem cells for Parkinson’s disease

Most clinical trials for Parkinson’s disease study patients in advanced stages of the disease. The STEM-PD trial takes a different approach, focusing on the early stages of the ailment. The stem cells are made from the patient’s own skin or blood cells; the idea is that they replace neurons in the brain that are lost with the disease. In February 2023, researchers began working on patients between 50 to 75 years of age with moderate Parkinson’s disease. We will have the first preliminary results at the end of 2024.

T-cell HIV vaccine

After the Mosaic experiment’s failure, all hopes for ending HIV are pinned on VIR-1388. “The importance of this study stems from the fact that it is a new attempt that takes a different approach than previous ones,” Josep Mallolas, head of the HIV-AIDS Unit at the Hospital Clinic in Barcelona, Spain, explains to EL PAÍS. “It tries to obtain a strong immune response based on T-cells that would supposedly prevent HIV infection.” The vaccine will be tested in uninfected and HIV-positive patients with an optional three-year follow-up. For 40 years, the diversity of HIV — which has a tremendous capacity for mutation and hiding from the immune system — has stymied the creation of an effective vaccine. The failure of the Mosaic clinical trial in early 2023 was a blow to the scientific community. It was the first vaccine in over a decade to reach the so-called Phase III stage, the last step in developing new drugs. VIR-1388 is in Phase I. As Mallolas points out, the clinical trial has support from important centers. He adds, “Honestly, I don’t think we can venture what the outcome will be, but in any case, a new attempt after so many failures is of value.”

There are other vaccines that could make a difference as well. The clinical trial of a malaria vaccine in African children aged five to 36 months in Burkina Faso, Kenya, Tanzania and Mali stands out. One of the main problems with malaria vaccines, and one of the reasons it has taken over 100 years to develop one, is that an antibody response is required for it to work. Forty vaccines with the same circumsporozoite protein antigen have been tested, and only two of them have been shown to be of useful efficacy. This year, one of them, R21/Matrix-M, is entering the third phase of development.

“Nature Medicine is a global journal and covers the health needs of all populations,” says Ben Johnson of including this breakthrough in the fight against a disease that has already been eradicated in many countries. “But it is also worth noting that many diseases that currently predominantly affect low- and middle-income countries are expanding their geographical reach, due to climate change, so we should all be concerned.”

An app to treat perinatal depression

Irritability, apathy, appetite or sleep disorders and depression are some of the symptoms that some women suffer during the perinatal period, between the beginning of pregnancy and the first year after childbirth. But the problem is not in developed countries; it is in low- and middle-income countries where access to mental health specialists is difficult. A team led by the University of Liverpool has developed an app that allows a peer (a woman from the same community without previous healthcare experience) to offer a cognitive therapy-based intervention for severely depressed women in the second or third trimester of pregnancy.

This trial will compare the implementation of the app with the standard face-to-face version of therapy delivered by health care workers in rural Pakistan. “Approaching a psychological intervention of this type is always a challenge,” reflects Ana Carcedo, a perinatal psychologist with expertise in bereavement and trauma. “Although it will not be enough, it can help open people’s eyes to this global public health problem,” she notes. According to Carcedo, this “should not be the only [measure taken] in a field as complex as perinatal mental health,” but she believes that it can be a first step and is valuable for shining a light on a problem that has been invisible for years, especially in the contexts of poverty and in developing countries.

Another mental health trial, the Best Services Trial, will investigate the efficacy and cost-effectiveness of an intervention model for child mental health related to social care services for children aged zero to five in foster care in Glasgow and London.

Machine learning to assess risk of death

As one might imagine, emergency rooms serve to deal with medical emergencies. But once these have been addressed, it is necessary to determine the patients’ risks of relapse or worsening. Triaging these patients falls to physicians, but they could rely on data analysis from a computer program called Risk Index. The MARS-ED clinical trial evaluates the benefits of an artificial intelligence (AI) that predicts the 31-day mortality risk of patients seen in an emergency room. The tool was developed and evaluated in four Dutch hospitals that saw 266,327 patients with 7.1 million laboratory results available. The Risk Index outperformed internal medicine specialists in its analysis, but it is still unknown whether these AI models are beneficial in clinical practice.

Advances against cancer

Cancer is the world’s leading cause of death: in 2020, almost 10 million deaths were attributed to this disease; that is, cancer accounts for almost one in six deaths recorded, according to data from the World Health Organization. So, it makes sense that four of the 11 scientific trials highlighted in Nature deal with this disease. Despite the disease’s prevalence, there is reason for hope. Half of cancers have already been cured, and there is very active research to find cures for the other half. The scientific war on cancer is being waged on many different fronts. The following efforts will begin in 2024.

AI to detect lung cancer earlier

Lung cancer is a silent tumor, often presenting when it is already too late. In over half of the cases, it is only diagnosed when metastases are already present. That is why early detection is especially important for this disease. Chest X-rays and CT scans, the first tests that suggest a diagnosis of lung cancer, often take time to get results because of the number of tests performed and the shortage of specialized imaging personnel. AI could serve as a substitute for such staff. Nottingham University Hospital is conducting a trial to determine its effectiveness; the trial involves 150,000 patients at six U.K. hospitals. “There may be a substantial difference,” David Baldwin, a pulmonologist at Nottingham University Hospitals, notes in the study. “Our hypothesis, based on this research, is that we can identify lung cancer earlier and reduce the diagnostic time by up to 50%,” from 63 days to 32 days.

Another trial also targets lung cancer. The 4-IN THE LUNG RUN project is a randomized controlled trial involving 24,000 people to assess when it is safe to increase screening intervals to detect lung cancer. It will evaluate whether screening every two years (by CT scan) is as effective as annual testing for those who have no abnormalities in their first scan.

Another cancer-focused trial, in this case skin cancer, could be a game changer. The NADINA trial aims to compare the efficacy of neoadjuvant ipilimumab with that of adjuvant nivolumab in stage III melanoma, to determine which of these two immunotherapies may be more effective.

Finally, an antibody-drug conjugate (ADC) trial is being conducted for breast cancer patients. In Spain, a woman learns that she has breast cancer every 15 minutes. Thirty-six thousand cases are diagnosed each year. Eighty percent of patients are cured, but there are cases in which it spreads uncontrollably. Metastasis to the brain is a major problem in advanced breast cancer that affects many patients, but there is only one approved treatment for such cases. DESTINY-Breast12 is an open-label, multicenter international study evaluating the efficacy and safety of trastuzumab deruxtecan (Enhertu), an ADC, in breast cancer patients with and without metastasis to the brain.

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