As research progresses, it is known that some diseases that have always been considered rare or infrequent are not so much.. This is the case of cardiac amyloidosis due to transthyretin, which has been shown years ago to be one of the most frequent causes of heart failure in people over 65 years of age.

The disease occurs because the body manufactures a substance, the amyloid protein, which is deposited in the form of plaques on the walls of the heart, making them thicker and more rigid (which is why it is popularly called 'stiff heart syndrome').. This leads to patients suffering from fatigue, fluid retention and difficulty exerting themselves because heart failure makes the heart unable to pump the blood the body needs.

“This deposit of the substance can also affect the electrical system of the heart, so that patients can suffer arrhythmias. If the deposit continues to progress, the heart loses a lot of strength and there comes a time when the patient dies,” explains Pablo García-Pavía, head of Family Cardiopathies at the Puerta de Hierro University Hospital and researcher at the National Center for Cardiovascular Research (CNIC). ) and CIBER Cardiovascular (CIBERCV). In fact, the median survival of patients without treatment is only three years.

The García-Pavía team at Hospital Puerta de Hierro is one of the most prestigious internationally in this pathology. In fact, Pavía is the leader of the document on the diagnosis and treatment of cardiac amyloidosis of the European Society of Cardiology (ESC), recommendations that are followed worldwide to diagnose and treat this disease.. Now, his group has led a study with a drug that has achieved very promising results in phase I and could change the outcome of this disease.. The results are published in The New England Journal of Medicine (NEJM) and presented this Saturday at the ESC Heart Failure Congress in Prague.

The disease can have two origins: genetic and age-associated. The genetic origin is due to mutations in the gene for transthyretin (TTR), a protein that transports retinol (vitamin A) and thyroxine, and amyloid can accumulate in the heart and nerves. In this case, patients have difficulties walking, moving, etc.. In fact, the first time the disease was described was due to this symptomatology: the Portuguese neurologist Corino Andrade met several families who had difficulties walking, among other things.. That is why it was called Andrade's disease, although García-Pavía explains that it no longer receives this name because it only refers to a group of patients with transthyretin amyloidosis (when it is hereditary and affects the nerves).

When it is associated with age, there is only involvement of the heart, but no neurological symptoms.. This form is much more frequent, “90-95% of cases, compared to 5-10% that are hereditary forms. We also know that both the hereditary and age-related forms are more frequent in men than in women, although more pronounced in the age-associated form, but we do not know why some people develop the disease over the years and others no”, emphasizes García-Pavía.

almost no treatments

Until a few years ago, there was no type of treatment for transthyretin cardiac amyloidosis.. Over time, the process by which this substance is generated and deposited was learned, and in 2019 an oral drug against the disease, tafamidis, which is a transthyretin stabilizer, was approved in Europe.. “What it does is prevent the deposit of amyloid both in the heart and in the nerves (when this happens). In other words, it slows down the progression of the disease,” says García-Pavía.

In Spain it has not been financed until recently, when an agreement was reached so that it will be on the market from June 1. However, although this drug improves survival and reduces the number of hospitalizations, it does not improve the disease.. “It slows its progression but does not improve patients compared to how they already are because it does not remove the amyloid that is already deposited in the heart,” says Pavía. And that is where this new treatment comes in, whose good results open a door to hope for these patients.

One-year sample from a patient with a lower amount of amyloid in the heart. Hospital U. Iron Gate CNIC

“We are seeing that in some patients, when we can completely stop the production of amyloid, the organism must have some natural mechanism by which it is able to remove the already accumulated amyloid.. And what this new drug seeks is to accelerate this natural amyloid removal system,” says García-Pavía. To do this, the specialist explains that the Swiss laboratory that developed it (Neurimmune) has analyzed “very old and healthy people, has looked for antibodies in their blood and has located one that has the ability to bind amyloid by transthyretin” .

This antibody is used to stimulate the defensive system of patients and that it removes the amyloid attached to the walls of the heart.. “The laboratory has selected and produced it on a large scale. It's like using the natural wisdom of the body of the elderly to make a medicine that works for sick people.”

The drug NI006, as it is called for now, was administered intravenously in the trial at progressively higher doses on a monthly basis for one year.. “Patients who received more doses appeared to have a greater reduction in amyloid deposits in the heart and improvement in various cardiac parameters.”. The study opens the door to a new generation of drugs for a disease that is seen to be becoming more frequent and with the progressive aging of the population it will be increasingly present”, concludes García-Pavía.

In this sense, the cardiologist from Puerta de Hierro indicates that around 2,000 patients with cardiac amyloidosis due to transthyretin must have been diagnosed in Spain, “but we all think that it is a more frequent disease than we knew so far. Before, since there were no treatments for this pathology, we saw that the patient's heart failed, like so many patients we have, and often a specific diagnosis was not reached.”

For Pavía, there are four factors that are going to cause this disease to be diagnosed more and more: “The population is getting older and as it is associated with age, the longer we live, the more patients will suffer from it. Secondly, that more is known, that there is more knowledge leads to more patients being diagnosed. Thirdly, diagnostic techniques have improved: previously this disease could only be diagnosed by heart biopsy, while now there are imaging techniques that allow amyloid deposits to be detected without biopsy. And fourthly, the availability of treatments, which make us learn more about the disease and seek more patients because we can offer them something.”

40 patients from six countries

This first trial has been carried out on 40 patients from six European hospitals (three from France, one from Germany, one from the Netherlands and Puerta de Hierro in Spain).. Like all phase I studies, the safety profile of the drug has been analyzed and at what dose it can be effective. Despite the good results, García-Pavía is prudent and stresses that more studies are needed with a larger number of patients.. “It constitutes an important advance since there was no drug for this disease that would improve the patient and remove the amyloid from the heart, which is why the New England publishes it.. In addition, the fact that it has been led from a Spanish hospital is to be proud of our health system. But although it is a great advance and gives a lot of hope, additional studies must be done.”

The specialist emphasizes this caution: “We have seen that the medication is safe and that doses of more than 10 milligrams per kilo of medication weight seem effective in removing amyloid, but we will have to do a study with many more patients, among 600 and 1,000, and a dose that is considered effective, which will be more than those 10 milligrams per kilo of weight, to see if what we have seen in the phase I trial is confirmed. If it is proven, approval would be requested so that it ends up reaching hospitals. But at this point I don’t think people need to look at this yet as a cure for the disease.”

That phase III study in which the medication will be tested against placebo in a significant number of people will begin after the summer. Countries around the world, including the U.S., will already participate. In fact, the U.S. pharmaceutical company Alexion, the rare disease division of AstraZeneca, has purchased the molecule to conduct this Phase III and market it if it is proven effective and approved.