Generales

By: Pedro Correa Ochoa. - Journalist

Roche International Laboratory announced the preliminary results of the clinical trial for the prevention of Alzheimer's disease that was led by the Neurosciences Group of Antioquia (GNA), attached to the Faculty of Medicine of UdeA. Although the drug Crenezumab did not show clinical efficacy, the GNA will continue to evaluate its possible biological efficacy and the complementary information provided by the study to take new routes in the arduous task of finding a cure.

The experimental drug used is called Crenezumab. The trial was supported and approved by INVIMA and supervised by the Ethics Committee of the Pablo Tobón Uribe Hospital. Photo: UdeA Communications Office / Alejandra Uribe F.

"We have made progress and we will continue to do so", said neurologist Francisco Lopera about the preliminary results of the Alzheimer Prevention Initiative (API Colombia) project. The findings of this clinical trial, carried out by the Neurosciences Group of Antioquia (GNA), were announced at an international level this Thursday, June 16, by the Roche Laboratory, one of the sponsors of the study that sought to prove that the drug Crenezumab could "prevent" the damage in healthy people at high risk of developing early-onset hereditary Alzheimer's disease.

The first analyses of the results showed that, although the carriers who received the drug had better scores on the cognitive tests, the differences are not statistically significant compared to those who received a placebo. Despite these preliminary results, the GNA, a Universidad de Antioquia research group attached to the Faculty of Medicine, will continue with the administration of Crenezumab while all the data are being analyzed and final decisions are being made regarding the discontinuation of the drug.

The researchers highlighted that, despite this result of no clinical efficacy, API Colombia is a milestone in Alzheimer's prevention research because it has taught them that the option of exclusively targeting amyloid with this experimental drug does not appear to be sufficient to delay or prevent symptoms of the disease. "That is very important knowledge to design new clinical trials from now on", said Lopera, main researcher of the trial.

In 2013, the GNA enrolled 252 people between the ages of 30 and 60 who met the criteria and voluntarily chose to participate in the study, which cost approximately 150 million dollars and was funded by the U.S. National Institute on Aging, the U.S. National Institute of Health, Arizona’s Banner Institute and Roche and Genentech Laboratories.

For eight years and three months, some of the participants received the drug intravenously every four weeks or subcutaneously every two weeks. In addition, throughout that time, the GNA carefully monitored them with medical, neurological and neuropsychological evaluations, as well as various types of medical and clinical examinations. The study was able to demonstrate that the drug has a favorable safety profile.

“We thank the participants and their families for their commitment to the study", said Lopera, "because, without their valuable contribution, it would not have been possible to gather the experience we now have to take new routes in the trial and error practice that scientific work requires to have a positive outcome one day.

Francisco Lopera Restrepo, director of the Neurosciences Group of Antioquia and main researcher of the clinical trial. In his first year of medicine, his grandmother lost her memory and speech. His fight against Alzheimer's has made him a reference and, in 2020, led him to be the winner of the prestigious Bengt Winblad Lifetime Achievement Award. Photo: UdeA Communications Office / Alejandra Uribe.

The first stage of the study culminated in March 2022 when the GNA announced that, from then on, experts in statistics would be in charge of analyzing the data found and announcing the result. "The study is double-blind, therefore, we know nothing about the results of the data of these eight years and three months, and it takes about four months to analyze them and reach conclusions", the neurologist and main researcher of the study, Francisco Lopera, had explained at the time.

The moment came with the announcement of preliminary results, released Thursday by Roche Laboratory on its website: "We are grateful for the impact this groundbreaking study has had in shaping a new era in Alzheimer's prevention research, and we are extremely grateful to our research participants and their families. This trial and the data, samples and findings that we will share with the research community and the related work we and others are doing promise to further accelerate the evaluation and approval of future prevention therapies", said Eric M. Reiman, MD, executive director of Banner Alzheimer's Institute and one of the study leaders.

A key element in this process has been the systematic follow-up of the largest population group in the world with genetic Alzheimer's disease that the GNA has conducted for more than 30 years. These are 25 families, mainly located in the north of Antioquia, with more than 6,000 heirs and 1,200 living carriers of the so-called "paisa mutation", present in the PSEN1 (presenilin 1) gene of chromosome 14, a mutation also identified by the GNA in collaboration with Alison Goate of the University of Washington in 1995. Those who have this condition suffer or will inevitably suffer from the disease in the coming years, and its symptoms may appear at about 44 years of age.

Therefore, the API clinical trial found in Colombia and in Universidad de Antioquia's research experience the ideal conditions to find a way to delay the emergence of early-onset Alzheimer's disease symptoms in healthy carriers.

This Is How the Trial Was Conducted

In 2013, the GNA, with the support of the sponsoring entities, set out to evaluate the safety and efficacy of Crenezumab. The researchers were able to enroll 252 volunteers, who demonstrated adequate adherence. In 2019, the study was extended for three more years, and, despite the limitations imposed by the COVID-19 pandemic, it closed its first stage with 238 participants: 90% of those who started the process. The rest of the volunteers did not continue because they went to live abroad, became pregnant or made personal decisions that did not allow them to stay in the trial.

The clinical trial divided the participants into three groups: the first was a group of 84 non-carriers of the mutation that causes Alzheimer's who received a placebo —a substance similar to the drug, but with no active component— and the second was a group of 168 carriers of the mutation, divided into two subgroups. One received the study drug, and one received a placebo.

In the development of the trial, the GNA had the support of the University Research Headquarters (SIU), the Faculty of Medicine of UdeA, the Universidad de Antioquia Foundation, the University IPS, the Pablo Tobón Uribe Hospital, Ciclotrón de Medellín, PRA, the Marly Clinic, the Cardiomet Cequin Foundation and the San Juan de Dios de Yarumal Hospital.

Eliminating amyloid, which is extracellular protein waste that is deposited in the brains of people with genetic Alzheimer's at age 28 could reduce the production of tauopathy, an alteration of tau proteins, which, in this population, begins 10 years later, at age 38, and is responsible for Alzheimer's symptoms. According to the researchers, if amyloid is eliminated in the early stages, it could begin to reduce the disease.

For this reason, the research project was based on the so-called amyloid hypothesis, which states that the deposit of this protein waste in the brain is the trigger for the entire cascade of pathological events of the disease. Given that Crenezumab clears amyloid from the brain before it is deposited in the plaques, we assumed that, by controlling this factor early on, it could have a preventive effect.

While the API Colombia clinical trial was taking place, other clinical trials were also conducted in the world with similar monoclonal antibodies, which have shown biological but not clinical efficacy when used in patients. Now, the GNA will continue to analyze the data and, on August 2, 2022, at the Alzheimer's Association International Conference (AAIC), they will present whether Crenezumab showed biological efficacy in the API Colombia clinical trial. 

Alzheimer's Disease, in the Spotlight of Global Public Health

The GNA of UdeA has a neurobank with more than 400 brains of people who had some neurodegenerative disease, which facilitates the study of these diseases. Photo: UdeA Communications Office / Alejandra Uribe F.

Dementia affects 50 million people in the world today and will continue to grow to affect 150 million by 2050. Eighty-five percent of dementias are incurable, and the most common of these is Alzheimer's, a brain disorder that causes loss of mental functions such as memory, attention, speech, numeracy, sense of direction and planning ability. All this leads to a loss of autonomy and independence, which calls for supervision and a caregiver. 
This disease is characterized by three fundamental brain lesions:   
•    Amyloidosis: extracellular deposit of protein waste called "amyloid" in the form of plaques. 
•    Tauopathy: intracellular deposit in the form of tangles of other waste called "abnormal or phosphorylated tau protein".   
•    Neurodegeneration: loss of synaptic connections and death of neurons, which cause atrophy and loss of weight and volume of brain tissue.

These three lesions are responsible for the symptoms of the disease. The cause of these lesions is unknown for 99% of the cases of the sporadic form of the disease, which generally affects people over 65 years of age. As for 1% of those who suffer from the autosomal dominant hereditary form, it is known that the brain lesions are caused by a mutated gene. To date, three genes are known to cause the disease when mutated: the amyloid precursor protein gene on chromosome 21, the presenilin 1 gene on chromosome 14 and the presenilin 2 gene on chromosome 1.

More than 300 mutations have been reported in these three genes that condemn their carriers to suffer from the disease before the age of 65.

"The negative result in the clinical outcome does not mean that we have lost eight years of work and joint effort of all the participants and us researchers to find a solution to Alzheimer's disease. We have made progress and will continue to do so", Lopera emphasized.