Clinical Trials That Will Shape Medicine in 2023

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Editors at the journal Nature Medicine recently asked researchers and public health experts from around the world to identify clinical trials that will shape medicine in 2023.  They came up with a varied list of candidates, from cervical and prostate cancer screening protocols to gene therapy for muscular dystrophy and new drugs for Parkinson’s disease and Alzheimer’s disease.  The selections are arbitrary and idiosyncratic, but they are interesting, nevertheless. 

Here are the eleven from Nature, plus two bonus picks from me.

1. A diabetes drug, exenatide, for Parkinson's disease.  The choice of Dr. Roger Albin, Professor of Neurology at the University of Michigan Medical School, was the Phase 3 (late stage) clinical trial of exenatide for Parkinson's disease (PD). The drug is a GLP-1 agonist, which mimics a type of naturally occurring gut hormone, and is currently used in older patients to treat Type 2 diabetes.

Exenatide showed beneficial effects on nerve cells in laboratory tests, which raised the possibility that it might slow down or stop the degeneration of PD in patients. An open-label trial in patients with PD who self-administered the drug for 48 weeks found that the drug was well tolerated and showed encouraging effects on the movement and non-movement manifestations of the disease. A double-blind placebo-controlled trial involving 60 patients showed that exenatide may be "neuroprotective," slowing the death of nerve cells in PD.

The ongoing Phase 3 trial is intended to confirm the neuroprotective effect in a larger number of patients and with longer administration of the drug.

2. The first antibody-drug conjugate for ovarian cancer. Robert L. Coleman, the chief scientific officer at U.S. Oncology Research, picked the Phase 3 trial of the antibody-drug conjugate mirvetuximab soravtansine, which is underway to confirm the overall safety and efficacy found in the earlier studies that led to the FDA's granting accelerated approval. The MIRASOL trial tests the drug in patients with platinum-resistant, high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancer with high folate receptor alpha (FRα) expression.

This antibody–drug conjugate (ADC) would be the first in this class to treat ovarian cancer, although it is used in other tumors. The MIRASOL trial includes a companion diagnostic test that detects the characteristics of tumors needed for clinical trial eligibility.

3. Gene therapy for muscular dystrophy. Dr. Simone Spuler, who leads the myology research group and the Outpatient Clinic for Muscle Disorders at the Experimental and Clinical Research Center in Berlin, selected gene therapy to treat muscular dystrophy, a group of muscle diseases caused by genetic mutations in muscle proteins. Patients experience muscle degeneration and atrophy that affects the limbs, respiratory muscles, and heart.

Dr. Spuler's group is attempting to correct the genetic abnormalities with CRISPR–Cas9 and other gene editing tools, so that muscle cells and tissue can be rebuilt. They have already shown that in a mouse model, autologous gene-repaired human muscle stem cells can be used to rebuild muscles, and they will test this in a trial called bASKet. It is a Phase 1/2a safety/efficacy trial that will be the first-in-human application of gene-edited stem cells obtained from each patient's muscle tissue and then modified in vitro before transplantation.

4. Cervical cancer screening in the HPV vaccinated. Karen Canfell, the chair of the Cancer Screening and Immunization Committee of Cancer Council Australia, observed that vaccines to prevent human papillomavirus (HPV) and cervical cancer first appeared 15 years ago, so there are increasing numbers of women who were vaccinated as girls who are now eligible for cervical cancer screening. Thus, it is important to identify the most effective screening approaches in a vaccinated population.

Dr. Canfell is undertaking the first large-scale international randomized controlled trial to assess primary HPV screening in a population that is extensively vaccinated against HPV. The Compass Trial compares HPV testing to the Pap smear (cytology testing) for cervical cancer screening. Preliminary research by others has found that a test for HPV types is superior.

5. The Mediterranean diet for weight loss. Jordi Salas Salvadó, Distinguished Professor of Nutrition at Rovira i Virgili University, Spain, offers a suggestion that I thought was somewhat vague, especially in the context of shaping medicine this year: "We hypothesize that an intensive lifestyle-intervention program aimed at weight loss and based on the traditional Mediterranean diet is a sustainable long-term approach for achieving weight loss in overweight and obese adults and that the lifestyle changes achieved will have a beneficial effect on cardiovascular morbidity and mortality."  

The link provided by Professor Salvadó is to the Predimed-Plus clinical trial, which according to the website,

has become the biggest milestone in nutrition investigation accomplished in Spain. Predimed-Plus evaluates the effect of an intensive lifestyle intervention aiming at losing weight with an energy-restricted Mediterranean diet, physical activity promotion, and behavioral support on the primary prevention of cardiovascular diseases.

It notes further that "6,874 participants were recruited in 23 centers and hospitals, with the support of other 7 groups," and that "[t]he recruitment began in September 2013 and ended in December 2016," but there is no mention of any follow-up.

6. Improved treatment for sleeping sickness. Olaf Valverde, the clinical project leader of the human African trypanosomiasis team of the Drugs for Neglected Diseases initiative, selected the clinical trial of fexinidazole, an oral drug for treating the variant of sleeping sickness caused by Trypanosoma brucei rhodesiense (also known as human African trypanosomiasis). The clinical trial assesses the efficacy of fexinidazole compared to current treatments melarsoprol (which is highly toxic) and suramin.

Note: Dr. Valverde did not mention the recent clinical trial results of a drug called acoziborole, which showed an extremely favorable safety and efficacy profile in treating trypanosomiasis. 

7. Prevention of cancer metastasis. Nicola Aceto, associate professor of molecular oncology at ETH Zurich, described his lab's discovery that cancer metastasis is "driven mostly by clusters of circulating tumor cells (CTCs), which are multicellular aggregates of tumor cells that depart from the existing tumor, circulate in the bloodstream, and then metastasize." Their important finding was that CTC clusters can be disaggregated into single cells by treatment with cardiac glycosides such as digoxin and that that reduces metastasis in preclinical models.

Therefore, they are conducting a small phase 1 trial as proof of mechanism. In the single-arm study, investigators screen the blood of patients with advanced metastatic breast cancer, and if CTC clusters are found, the patients receive digoxin for three weeks, and the quantity and characteristics of the clusters are measured.    

8. Lecanemab for Alzheimer's disease. Allan Levey, professor and chair of the Department of Neurology at Emory University School of Medicine, picked the Alzheimer's drug lecanemab, which reduces the amount of beta-amyloid, a protein that clumps together in the spaces between neurons and forms distinctive plaques in the brain of Alzheimer's disease patients.

The results of the Phase 3 study, reported late last year, showed that lecanemab slightly reduced cognitive decline and that it has moderate toxicity. On January 6, 2023, the FDA granted accelerated approval of the drug.

9. COVID-19 vaccination in HIV patients. Glenda Gray, the president and CEO of the South Africa Medical Research Council, described a clinical trial that her organization is conducting to "assess the efficacy of the mRNA-1273 (Moderna) vaccine against COVID-19 in adults infected with human immunodeficiency virus (HIV) or with other comorbidities that increase the risk of severe COVID-19." 

The trial will assess "infection and viral clearance in people who are immunocompromised" and provide data on how many doses of vaccine are needed for adults with HIV and on "whether people who have been infected with the coronavirus SARS-CoV-2 and therefore, probably have some immunity, need as many vaccine doses as those without prior infection."

 10. Gene editing for sickle-cell disease and thalassemia. Luigi Naldini, professor of cell and tissue biology and gene and cell therapy at the San Raffaele University School of Medicine in Milan, selected gene-editing to treat transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD), which are potentially life-threatening diseases caused by mutations in hemoglobin. He referred specifically to an ongoing multi-center, single-arm, open-label, single-dose phase 1/2/3 clinical trial in patients with severe SCD.

In the small number of patients with long-term follow-up reported in 2021, the results were extremely promising. More than a year after the procedure, both patients treated (one with TDT and the other with SCD) showed "high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes."

Additional data on the long-term stability of those treatments is expected to become available during 2023.

11. Reducing harm from prostate cancer screening. Anssi Auvinen, Professor of Health Sciences at Tampere University, Finland, picked a study intended to resolve a vexing public health issue. Elevated values of the widely used Prostate-Specific Antigen (PSA) blood test are considered to be an early indicator of prostate cancer. When used for screening, it can help detect small, early cancers. However, false positives are frequent, and detecting and treating a small tumor often does not reduce the chance of dying from prostate cancer because many tumors found through PSA testing grow so slowly that they are unlikely to be life-threatening and do not require surgery. Therefore, far fewer operations are done now than in the past, and we are able to avoid the cure being worse than the disease.

The large Finnish study that is underway is "a randomized screening trial utilizes three levels of risk assessment (PSA, kallikrein panel and MRI) -- each aimed at eliminating detection of indolent disease -- before the definitive diagnostic procedure, prostate biopsy. The rationale is that by using the novel three-tiered screening algorithm, "the beneficial screening effect (prostate cancer mortality reduction) can be retained, while the overdiagnosis [via biopsy] can be largely eliminated." The estimated completion date for the study is 2032.

To the Nature Medicine list, I would add two that are related to the development of much-needed COVID vaccines:

1. Recent findings by Tang and colleagues illustrate that intramuscular vaccine injections alone do not provide tissue-level mucosal immunity. Achieving this will likely require nasal or orally administered vaccines. Fortunately, there are at least a dozen nasal vaccines in clinical development, four of which are in Phase 3 randomized, placebo-controlled trials.

2. Another valuable COVID vaccine could be one similar to that developed by Caltech Professor Pamela Bjorkman and colleagues, which in mice and monkeys protects against a variety of SARS-like betacoronaviruses, including variants of SARS-CoV-2. Their approach is to present the immune system with pieces of the spike proteins from SARS-CoV-2 and seven other SARS-like betacoronaviruses. In preliminary studies, their vaccines protect against infection even by viruses whose spike proteins are not present in the vaccines.

This table offers a summary of the 11 selections in the Nature article:

11 clinical trials that will shape medicine in 2023 (Source: