Teplizumab, authorized in the US, delays the onset of the disease in high-risk people by two years, which improves their quality of life and prevents complications.
While the range of drugs for type 2 diabetes has not stopped growing in recent times, until now the only therapy available in type 1 diabetes has been insulin. In the United States (USA) a very different new treatment is already available: teplizumab, an immunotherapy capable of delaying the onset of the disease by two years in patients considered to be at high risk. It will arrive in Europe in 2024 according to the consultancy Clarivateand it will be the first, but probably not the last immunotherapeutic to curb the disease.
The American agency FDA gave the green light in November to teplizumab (target), of the biotechnological Provention Biowhich has a co-promotion agreement with Sanofi for USA. This monoclonal antibody targets CD3, a molecule present on T lymphocytes involved in the development of the disease, and stops the destruction of insulin-producing beta cells. It is indicated in children from 8 years of age and adults considered at high risk of developing type 1 diabetes.
Teplizumab vial
Immunotherapy does not prevent the development of diabetes, but it does come close to this ambitious goal. The experts consulted by this means agree that it is highly relevant news: “It represents a milestone in the research and treatment of this disease”, in the words of Eduard Montanya, scientific director of the Biomedical Research Center on Diabetes and Diseases Network Associated Physicians (Ciberdem) and head of the Diabetes Section of the Hospital de Bellvitge. “Although its initial impact may be limited, for the first time a treatment capable of modifying the course of type 1 diabetes is available.”
The American approval is based on a phase II trial published in The New England Journal of Medicine in 76 participants considered at high risk of developing type 1 diabetes; all of them with a first degree relative with the disease, two or more autoantibodies in the blood and dysglycemia. Of these, 55 were between 8 and 18 years old.
In this study, it delayed the onset of the disease by two years in 70% of the participants, “which suggests that the clinical impact with this drug and in these conditions would be moderate,” says the expert from the Spanish Diabetes Society (SED). ) Marta Vives-Pi, who is head of the Diabetes Immunology Unit of the Germans Trias i Pujol Research Institute (IGTP) and scientific director of the spin-off Ahead Therapeutics.
“This fact is relevant, since it is a pioneering therapy that shows that autoimmunity can be stopped by immunotherapy, temporarily preserving the remaining beta cells, and for anyone in the preclinical phase, especially children, the delay in diagnosis affects the quality of the disease. of life and in future secondary complications”, explains the researcher.
Delaying the onset of the disease between one and three years “is very important in pre-adolescent children,” explains researcher Iria Gómez Touriño, from the Center for Research in Molecular Medicine and Chronic Diseases (Cimus) of the University of Santiago de Compostela. “This extra time for the pancreas to grow to adult size has been shown to lead to a more benign diagnosis and reduce long-term disease progression.”
It also indicates that the drug reduces the risk of diabetic ketoacidosis and long-term complications in people at risk of type 1 diabetes. “Therefore, the clinical impact is enormous, especially on quality of life expectations.”
risks
As a counterpart, it is a systemic immunotherapy that is associated with lymphopenia, an increase in infections and exacerbation of latent infectious processes. “At another level, it can cause hypersensitivity reactions and systemic symptoms produced by the cytokine release syndrome,” warns the scientific director of Ciberdem.
As with other biologics such as anti-TNF, Vives-Pi understands that its immunogenicity profile will have to be monitored and whether anti-teplizumab antibodies are generated after its administration, which can cause a loss of efficacy and adverse effects.
Another drawback of this therapy is that its administration requires a daily intravenous infusion for 14 consecutive days. In the trial, the infusion was administered over 30 minutes and then the patient remained for two hours for observation.
Identification of candidates
But a greater challenge will be to identify people at risk of developing type 1 diabetes. Experts consider it feasible among first-degree relatives of patients with type 1 diabetes since, according to Montonya, the determination of antibodies and the practice of a Oral glucose loads are easily achievable.
Another issue the rest of the general population. “Up to 90% of new cases of type 1 diabetes occur in people who do not have affected relatives, so it would also be necessary to identify these people, which does pose challenges that have not yet been resolved,” explains the expert.
Without the implementation of screening in the general population, the administration of the drug to candidates “may be reduced to individual cases,” agrees the Cimus researcher.
Gómez Touriño points to examples to look at, such as the ELSA study in the United Kingdom, which seeks to screen 20,000 children between the ages of 3 and 13 and assess their risk of suffering from type 1 diabetes. Meanwhile, in Europe, the The public-private consortium Innodia offers the possibility to relatives of patients with type 1 diabetes to enter a screening program to assess their predisposition to suffer from the disease.
Other factors that health administrations will have to take into account when making decisions with teplizumab and assessing its cost-benefit are the growing incidence of type 1 diabetes and the price of the drug that is approved in each country, taking into account that the monoclonal antibodies is usually high, reflects Vives-Pi.
Questions without answer
This biologic, which brings the promise of preventing type 1 diabetes closer, raises many questions. The Ciberdem expert points out that although delaying the onset of diabetes and therefore exposure to hyperglycemia should result in a delay in the onset of complications, “it is unknown what the long-term evolution of the people treated or What can the administration of a new round of treatment achieve?
Clinical development of teplizumb continues and is currently being investigated in the Phase III trial. Protect in children and adolescents recently diagnosed with type 1 diabetes. Vives-Pi announces that this study will answer a fundamental question, and that is whether this drug is capable of reversing type 1 diabetes.
But there is more to come: “Can a second cycle of the drug continue to delay the diagnosis? Does teplizumab open the door to combination therapies and new drugs capable of reversing type 1 diabetes in patients already diagnosed?” asks the IGTP expert.
more research
There are already several molecules in an advanced phase of research, which aim to prevent diabetes or prevent progression in people with a recent onset of the disease.
“Closer to seeing the light of day is an anti-TNF monoclonal antibody and an inhibitor of the IL-8, CXRC1 and CXRC2 receptors, which could be approved in the next two or three years,” explains the Ciber researcher. “The results obtained with these treatments that act on the immune system and inflammation will allow us to better understand if they can be enough on their own or if it will be necessary to combine them with strategies aimed at regenerating already destroyed beta cells.”
Along with monoclonal antibodies, other approaches in immunotherapy include cell therapies, nanoparticles, cytokines, and combination therapies. Because Vives-Pi understands that “for a definitive cure, it is necessary to stop the autoimmune response and restore the mass of lost beta cells.” For this reason, “regenerative medicine strategies must go hand in hand with immunotherapies.”
Beyond therapeutics, Gómez Touriño highlights the interest of other lines of research, such as projects focused on unraveling the molecular mechanisms of the disease and understanding its origin in order to interfere with its development, such as studies on microbiota, autoreactive T lymphocytes and stress of beta cells, among others.
Also from research on biomarkers, to identify people at risk of developing the disease and to help predict the response of treatments under development.
The Cimus researcher understands that the development of this immunotherapy highlights the importance of financing the studies. “The approval of teplizumab is the result of the effort of many years of research by basic and clinical laboratories to transfer the results to patients and their families.”
A commitment to research that, he recalls, has allowed him to find the first modifying therapy: “Since the discovery of insulin 100 years ago, the injection of this hormone has been the only real treatment for patients; but insulin does not act on the causes of the disease, which is an attack by the immune system, but only on its effects”. Naiara Brocal (DM)