The Spanish Agency for Medicines and Health Products (AEMPS) has authorized the start of the Phase I clinical trial of AP-2, a potential treatment for Amyotrophic Lateral Sclerosis (ALS) discovered at the Margarita Salas Center for Biological Research (CIB) of the Spanish National Research Council (CSIC), an agency attached to the Ministry of Science, Innovation and Universities.

The trial will be conducted by the CSIC spin-off company Molefy Pharma (Arquimea Group), which has been licensed by the CSIC to develop this drug. The trial is scheduled to begin next April with safety and pharmacokinetic evaluations in healthy volunteers, and the next phase, administration to patients, is expected to start in January 2027.

In October 2025, the EMA (European Medicines Agency) designated AP-2, a drug developed by the Translational Medicinal and Biological Chemistry Group led by Ana Martínez and Carmen Gil at the CIB-CSIC (Center for Biomedical Research - Spanish National Research Council), as an orphan drug. This designation, granted to treatments for rare diseases or those with low commercial profitability, validated its therapeutic potential and provided a decisive boost for clinical development.

Now, following authorization from the AEMPS (Spanish Agency for Medicines and Health Products), Phase I of the clinical trial will begin with its administration to 70 healthy volunteers to evaluate its safety and pharmacokinetics—that is, how the drug is absorbed, distributed, metabolized, and eliminated in the body. Following this first phase, which will begin in April at the Clinical Trials Unit of the La Princesa University Hospital in Madrid, the researchers expect to progress to Phase Ib, which will involve further evaluation of the compound's safety to rule out any potential toxic effects, this time in ALS patients.

The drug AP-2 aims to restore the function of TDP-43, a protein that is pathologically altered in ALS patients and causes the death of motor neurons (cells of the nervous system responsible for transmitting signals from the brain or spinal cord to the muscles) and, consequently, the progression of the disease. The drug AP-2 has successfully reversed the TDP-43 abnormality, thus restoring its natural balance, both in cell models and in transgenic animals.

Although this disease still raises many questions, one common characteristic is evident: "In more than 97% of patients, abnormal accumulations of the TDP-43 protein are observed. This protein moves from the cell nucleus into the cytoplasm. Once there, it undergoes modifications, breaks down, and is phosphorylated, a process that leads to the formation of toxic aggregates," explains Ana Martínez, a researcher at the CIB-CSIC and co-founder of Molefy. The goal of the drug, which is presented in capsules, is for the TDP-43 protein to return to the cell nucleus and resume its cellular function.

To achieve this, the research team designed a molecule that blocks the CK1 kinase, an enzyme that modifies the TDP-43 protein through a process called phosphorylation. “In tests using cell models, we observed that TDP-43 tended to recover, returning to the nucleus and regaining its function. Furthermore, in animal models genetically modified to express the TDP-43 protein, we also obtained promising results. Although it is still early, if these data are replicated, the drug could slow the disease, and hypothetically halt it,” Carmen Gil points out.

ALS, a disease without treatment
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes the progressive death of motor neurons, leading to loss of muscle movement and, therefore, the patient's ability to move, speak, eat, and even breathe. Currently, this rare disease has no cure, and life expectancy after diagnosis is between five and six years. According to data from the Spanish Society of Neurology (SEN), between 4,000 and 4,500 people suffer from this disease in Spain, and between 900 and 1,000 new cases are diagnosed each year.

For the treatment of sporadic ALS (the most common form of the disease, responsible for around 90% of cases), there is only one drug approved in Europe, riluzole, a palliative medication that improves symptoms and extends life expectancy by three to six months. Therefore, the start of the AP-2 clinical trial represents an advance in research and a significant milestone in the search for a definitive cure.