Clinical trials that promise to revolutionize medicine in 2023

The pandemic has turned every aspect of medicine upside down. And the world of medicine was no less: if on the Covid side we have witnessed the development of therapies and vaccines in record time, progress has practically stopped in many other fields. Held back by problems and delays that have slowed down, almost to a standstill, the entire infrastructure that governs clinical trials. Fortunately, with the pandemic finally loosening its grip, clinical trials have also begun to return, with difficulty, to normal. Important innovations in the pharmaceutical field are expected in 2023, and to find out which ones are worth keeping an eye on, Nature Medicine asked 11 leading experts which is the most awaited trial in their field of specialization. Here’s how they responded.

Parkinsons

For Roger Albin, neurologist and director of the Center for Movement Disorders at the University of Michigan, the real game changer in the world of Parkinson’s could prove to be exenatide, an antidiabetic that is also being studied in the field of neurodegenerative diseases, after showing a probable efficacy in slowing the development of motor symptoms of the disease. Since this is a drug already in use, a positive result from the phase 3 trial which will end this year would have very concrete consequences for patients: the low cost of the drug, and the already extensively tested safety profile, would allow for rapid adoption also in the treatment of Parkinson’s. Even a negative response, if unequivocal, would be just as important – Albin is keen to point out – because after years of debate it would allow attention to be focused on other promising therapeutic strategies.

Ovarian cancer

Mirvetuximab soravtansine is a latest generation drug, which belongs to the family of conjugated antibodies: molecules that combine a monoclonal antibody capable of identifying tumor cells with high specificity with a chemotherapy that is responsible for destroying them. They are already in use against several solid tumors and hematologic malignancies, but mamirvetuximab soravtansine is the first to receive accelerated approval in the US for the treatment of ovarian cancer in women who have failed first-line therapy and have a malignancy that expresses folate receptor alpha (a protein that contributes to tumor growth). As Robert Coleman, scientific director of US Oncology Research explains, a drug approved with an accelerated procedure is made available to patients even in the absence of definitive data because of the potential benefits it can bring in a field where there is no alternative, but needs one confirmatory clinical study that certifies its safety and efficacy in order to obtain definitive approval. This is what the Mirasol trial is testing, the results of which are expected in the coming months. If positive, as it is hoped, mirvetuximab soravtansine will remain an important therapeutic strategy for women with ovarian cancer who fail first-line therapy. And more generally, it will pave the way for increased use of conjugated antibodies in the field of gynecological oncology.

Muscular dystrophies

Muscle stem cells are essential for the regeneration of the tissues that form muscles. In those suffering from muscular dystrophies, a class of disorders that includes about 50 genetic diseases, these cells have mutations that compromise their functionality, quickly leading to loss of mobility and the appearance of respiratory dysfunction. Thanks to Crispr-Cas9 today it is possible to correct in a very specific way genetic alterations such as those affecting the muscle stem cells of these patients. And as Simone Spuler, director of the muscle disorders clinic at the Experimental and Clinical Research Center in Berlin, explains, this is what they are trying to do with the bASKet trial, a clinical trial designed to evaluate the safety and efficacy of autologous muscle stem transplantation modified with Crispr-Cas9 to restore its functionality, in patients with muscular dystrophies. The results are expected between June and July of this year, and could represent a revolution in the lives of many patients who are now condemned by their disease to spend their lives in a wheelchair.

Cervical cancer

HPV vaccination has been a routine vaccination in many countries for years. And with a growing population of vaccinated women moving into adulthood, it’s time to figure out how to update screening procedures for HPV and cervical cancer. The Compass trial will take care of it, a controlled and randomized clinical study that will end this year. The results – assures Karen Canfell, of the Australian Cancer Council – will set new standards for the prevention of cervical cancer.

Weight loss and heart

Losing weight through diet and exercise is crucial if you are obese or overweight. We know that it is good for health, but to date no clinical trial has ever demonstrated that it is an effective strategy also in reducing the risk of developing cardiovascular disorders. Fortunately, recalls Jordi Salas Salvadó, of the Rovira i Virgili University of Tarragona, the results of the Predimes-Plus study are expected this year, which recruited almost seven thousand Spaniards to study the effectiveness of a low-calorie diet based on the Mediterranean diet. associated with a program of physical activity, both in terms of weight loss and incidence of cardiovascular pathologies.

Sleeping sickness

Sleeping sickness, or more precisely human African trypanosomiasis, is a neurological disorder caused by the protozoan Trypanosoma brucei. It is a disease that can kill patients within a few weeks, and for which only extremely toxic drugs have been available for a very long time, which are lethal in almost 5% of cases. Since 2018, one of the two subvariants of the disease, caused by the T. brucei gambiense parasite, has been treatable with a new oral drug, fexinidazole, which has proven to be safe and effective. If the causative agent of the disorder is instead the T. brucei rhodesiense, at the moment the doctors still have to resort to the old drugs. However, a new clinical trial is also testing fexinidazole for these patients and the results will be presented to the EMA in the coming months for approval which, looking at the available data – explains Olaf Valverde of the Drugs for Neglected Diseases initiative – fortunately seems almost obvious.

Circulating tumor cells

Metastases are the real enemy in oncology: when a primary tumor recurs elsewhere, in fact, the long-term chances for patients are significantly reduced. Research in recent decades has made it possible to understand that they are mainly caused by what are defined as circulating tumor cells (Ctc), aggregates of cells detached from the primary tumor that circulate in the blood, and can take root in other organs causing the appearance of secondary tumors. A drug used in the cardiovascular field, digoxin, has been shown to have the ability to break down Ctcs, greatly limiting the chances that they give rise to a metastasis, at least in the laboratory. For this reason, a phase 1 trial is underway which will evaluate the efficacy of the drug in disrupting clusters of circulating tumor cells in patients with metastatic breast cancer. If the results are positive, Nicola Aceto – an expert in molecular oncology at ETH Zurich – believes that they will open the door to the development of a new generation of drugs, specifically aimed at preventing tumor metastases through the disruption of circulating tumor cells.

Alzheimers

In America, a drug against Alzheimer’s has just been approved, with an accelerated procedure: it is called lecanumab, and in the phase 3 Clarity AD trial it has demonstrated a certain ability to slow the progression of the symptoms of the disease 18 months after the start of the administration. Further analyzes and new studies should arrive during the year, with which the manufacturer will ask for definitive approval from the American and European authorities. Allan Levey, Dean of the Department of Neurology at Emory University, believes that they will be very important to confirm the efficacy that emerged from the preliminary data of the study, the safety of the drug (not without serious side effects) and the possible duration of the clinical benefits observed until ‘Now.

Covid and HIV

The mRna vaccines against Covid 19 have demonstrated their effectiveness worldwide in the last two years. But open questions still remain, such as the effectiveness they can have in people living with HIV, or with other pathologies that increase the risk of severe forms of Covid, and what is the optimal number of doses necessary to optimize protection in these patients. Glenda Gray, President and CEO of the South Africa Medical Research Council, assures that the missing answers will come from a study that began in 2021 in sub-Saharan Africa, which enrolled over 14,000 patients with HIV and other frailties to evaluate the effectiveness of the vaccine produced by Moderna.

Sickle cell anemia

The preliminary results of a trial that is evaluating the efficacy of Crispr-Cas9 for the treatment of sickle cell anemia should arrive in 2023. Luigi Naldini, scientific director of the San Raffaele Telethon Institute for gene therapy, explains that these data are anxiously awaited by the scientific community, because they will serve not only to demonstrate the usefulness of the therapy for patients suffering from sickle cell anemia, but more generally they will help to understand how stable the genetic modifications made using Crispr-Cas9 are. The trial also represents the first clinical test of a new strategy that Naldini calls “Writing back” genes, ie the correction of harmful genetic mutations through the introduction of modifications of longer gene sequences.

Prostate cancer

The dosage of PSA has always been a rather controversial screening, because it does not allow to accurately discriminate between malignant tumors and prostate tumors that pose no risk to patient health. A new screening algorithm that incorporates three different levels of analysis could help minimize the risk of future overdiagnosis, and limit biopsies and operations to only truly dangerous tumors. It is being studied in Finland, and as Anssi Auvinen, professor of Health Sciences at the University of Tampere assures, it could already give important results in the course of 2023.