World ALS Day | “ALS research is currently going through a particularly promising moment”

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, the nerve cells responsible for controlling voluntary muscle movement. As the disease progresses, it leads to a gradual loss of mobility, speech, swallowing, and respiratory function, while cognitive abilities remain preserved in most cases.

On the occasion of World ALS Day, observed on June 21, the Spanish Bioindustry Association (AseBio) is highlighting a condition for which significant unmet medical needs still remain. In Spain, between 4,000 and 4,500 people are currently living with ALS, and around 900 new cases are diagnosed each year, equivalent to nearly three diagnoses per day. The disease is also associated with a high mortality rate, with approximately three people dying from ALS every day. Average survival is typically between two and five years after diagnosis, although there is considerable variability among patients.

Despite advances in the understanding of the disease, therapeutic options remain limited, and there is still no cure capable of stopping or reversing its progression. Diagnosis continues to be challenging and may be delayed by more than a year after the onset of the first symptoms, hindering early access to specialized care and potential clinical trials.

In this context, biotechnology is driving new approaches aimed at addressing the molecular causes of the disease. One of the most promising lines of research focuses on the TDP-43 protein, whose dysfunction is present in the majority of ALS patients and plays a key role in neuronal degeneration.

Molefy Pharma, a CSIC spin-off whose majority investor is the technology group ARQUIMEA, is developing AP-2, an innovative small molecule designed to restore TDP-43 function and modify the course of the disease. The company has received orphan drug designation from the European Medicines Agency (EMA) and has obtained authorization from the Spanish Agency for Medicines and Medical Devices (AEMPS) to initiate its clinical trial in humans, a significant step in the search for new therapeutic options for people living with ALS. On this World ALS Day, we interview Alfonso de Egaña Barrenechea, CEO of Molefy Pharma.

AseBio. On the occasion of World ALS Day, how would you describe the current state of research into this disease, and what are today the main unmet needs of people living with it?

Alfonso de Egaña Barrenechea. ALS research is currently going through a particularly promising moment. Thanks to the awareness-raising efforts driven by patients themselves, their families, and associations dedicated to this disease, the number of research groups—both academic and private—focused on studying this condition has increased significantly in many countries, offering hope for a better future.

However, significant unmet needs for patients and their families or caregivers still remain. Among them is the lack of truly effective pharmacological treatments capable of significantly slowing or halting the progression of the neurodegenerative process. For this reason, it is essential to continue promoting research aimed at developing new therapeutic strategies that can improve both the prognosis and quality of life of people affected by this disease.

AseBio. ALS continues to be associated with major care-related challenges, as well as diagnostic delays and a significant burden for patients and families. What aspects do you consider a priority to improve care and quality of life for those affected while we move toward new therapeutic options?

Alfonso de Egaña Barrenechea. Given that, to date, the only intervention shown to increase the life expectancy of patients with ALS is comprehensive care provided by specialized teams, the implementation of dedicated ALS units in hospital centers should be a priority across all autonomous communities. These units, composed of multidisciplinary teams including neurologists, nurses, psychologists, speech and language therapists, physiotherapists, and other healthcare professionals, make it possible to address patients’ diverse needs in a coordinated manner, significantly contributing to improving both their quality of life and that of their families.

Furthermore, sustained investment in research is essential to establish a stable framework in which long-term projects can be developed, such as those focused on the design and development of new drugs, which will undoubtedly lead to improvements for patients and their environment.

AseBio. As our understanding of the biological mechanisms involved in the disease continues to improve, what is the importance of the TDP-43 protein in ALS, and what potential does it offer as a target for the development of new therapies?

Alfonso de Egaña Barrenechea. ALS can today be defined as a TDP-43 proteinopathy, that is, a disease of the TDP-43 protein. This means that this protein is key to the neurodegenerative process in ALS. TDP-43 is an essential protein for the cells of our nervous system. Several years ago, it was shown that in more than 97% of ALS cases, both familial and sporadic, this protein exhibits abnormal function due to the formation of toxic aggregates in the cytoplasm and a loss of function in the cell nucleus, leading to the dysregulation of mRNA transcription and, consequently, altering the expression or repression of hundreds of proteins. These events ultimately lead to neuronal death. Therefore, our working hypothesis is that restoring TDP-43 function with small molecules represents a promising strategy in the search for a treatment.

AseBio. Molefy Pharma is developing AP-2 as a potential treatment for ALS and has recently achieved key milestones, such as orphan drug designation and authorization to initiate clinical trials. What is the significance of these advances, and what could this approach contribute to the management of the disease?

Alfonso de Egaña Barrenechea. In cells treated with AP-2, a decrease in TDP-43 phosphorylation levels has been observed and, as a consequence, a reduction in the formation of such aggregates. In addition, the nuclear localization of the protein is restored, allowing it to recover its physiological function in the regulation of transcription and mRNA processing. The results also indicate that treatment with AP-2 helps prevent the spread of TDP-43–associated pathology.

If the effects observed in cellular and animal models were replicated in humans, AP-2 could represent a treatment capable of modifying the course of the disease. However, this hypothesis can only be confirmed through clinical trials assessing its safety and efficacy in patients.

In this context, authorization to initiate clinical trials represents a significant milestone for the project, as it marks the beginning of a decisive stage that will allow the therapeutic potential of AP-2 in patients with sporadic ALS to be determined.

AseBio. Looking ahead to the next five to ten years, how does Molefy Pharma envision the future of ALS treatment, and what role do biotechnology and innovation play in transforming patient prognosis?

Alfonso de Egaña Barrenechea. In ALS, as in other neurodegenerative diseases, a multidisciplinary therapeutic approach is emerging as one of the most promising strategies for the future. This approach could take shape through the combination of different drugs with complementary mechanisms of action, the development of multi-target drugs designed to act on multiple therapeutic targets, or the use of compounds capable of modulating proteins involved in several cellular cascades related to the disease.

Likewise, significant progress is expected in the field of precision medicine through various biological approaches. One example is the recent development and approval of an antisense oligonucleotide for the treatment of patients with ALS associated with mutations in the SOD1 gene, whose results suggest a stabilization of disease progression in these patients.

Furthermore, the development of omics technologies is driving major advances in biomarker identification, enabling earlier diagnosis and the design of more efficient clinical trials. These biomarkers will facilitate better patient selection and stratification, as well as more precise monitoring of treatment response, helping to optimize the development and evaluation of new therapies.

Molefy Pharma looks to the future with optimism, while remaining aware of the uncertainties that still surround ALS and the challenges that remain to be overcome. The company is confident that research—not only in drug discovery, but also in the study of the molecular basis of the disease and the development of biomarkers—will lead to a more comprehensive understanding of this condition. This knowledge will undoubtedly contribute to the development of more effective treatments and, ultimately, to improving both the quality and life expectancy of patients.