The LEO Foundation has awarded a research grant to the Vall d'Hebron Research Institute (VHIR) to support TopiDLE, a project aimed at completing the preclinical development of TopiTali, the first topical thalidomide formulation for the treatment of discoid lupus erythematosus (DLE). Led by Dr Cristina Solé, principal investigator of the Rheumatology Research Group at VHIR, the project seeks to provide a safer alternative to currently available treatments and generate the data required to launch a future clinical trial in humans.

The project will focus on demonstrating that the topical administration of thalidomide can maintain the drug's high efficacy while restricting its action exclusively to the skin, with the aim of avoiding the main adverse effects associated with its oral administration. In addition, the research will provide further insight into the molecular mechanisms involved in the disease and identify biomarkers to facilitate monitoring of treatment response.

A disease with limited therapeutic options

Discoid lupus erythematosus is the most common form of chronic cutaneous lupus and affects more than 500,000 people across Europe, mainly women of childbearing age. It is an autoimmune disease that causes persistent inflammatory skin lesions, particularly on the face, ears and scalp, which can lead to permanent scarring and irreversible hair loss. Beyond their physical manifestations, these lesions have a major impact on patients' quality of life, both functionally and psychologically.

Current treatment options include corticosteroids, topical immunomodulators and systemic drugs. However, a proportion of patients do not respond adequately to these therapeutic options. In such cases, orally administered thalidomide achieves remission in approximately 90% of refractory cases, but its long-term use is not feasible because it can cause irreversible peripheral neuropathy and carries a high risk of toxicity during pregnancy. Furthermore, lesions tend to recur once treatment is discontinued, highlighting the need for safer long-term therapeutic alternatives.

"Patients with cutaneous lupus need new therapeutic options that combine efficacy and safety. Our goal is to develop a strategy that allows us to harness the benefits of thalidomide while avoiding the adverse effects associated with its systemic administration," says Dr Cristina Solé.

A formulation that acts directly on the skin

TopiDLE is based on TopiTali, an innovative topical formulation developed by the VHIR Lupus Unit. Unlike oral treatment, this cream is designed so that the active ingredient acts exclusively on skin lesions while minimising systemic absorption.

Preliminary studies carried out in animal models have produced highly promising results*. The formulation reduced skin lesions by approximately 90%, while the drug remained confined to the skin and was not detected in the bloodstream. These findings suggest that this approach could preserve the effectiveness of thalidomide while significantly reducing the risks associated with oral treatment.

Over the next three years, the project will carry out a comprehensive programme of preclinical studies. Among other activities, the researchers will analyse the pharmacokinetics of the formulation to confirm that the drug remains localised in the skin, compare its efficacy with that of currently available topical treatments, and conduct comprehensive safety studies, including the evaluation of reproductive toxicity.

The project will also advance understanding of the molecular mechanisms responsible for the formulation's anti-inflammatory effects. To achieve this, the researchers will use advanced technologies such as spatial transcriptomics and microRNA analysis, enabling them to characterise with great precision the changes that occur in tissues during treatment.

This information will also help identify biomarkers to facilitate monitoring of the therapeutic response and pave the way for the development of new personalised medicine strategies for cutaneous lupus.

The ultimate goal is to obtain all the scientific and regulatory evidence required to initiate a phase I/II clinical trial and bring this new treatment closer to patients.

A multidisciplinary project with a translational approach

TopiDLE is led by Dr Cristina Solé, together with Dr Josefina Cortés-Hernández, Head of the Inflammation and Autoimmunity Section of the Rheumatology Department at Vall d’Hebron University Hospital and Head of the Lupus Unit of the VHIR Rheumatology Research Group. The project involves Dr Diana Fernandes, a researcher in the Clinical Biochemistry, Drug Delivery and Therapy Research Group at VHIR; Dr Gloria Aparicio, from the Dermatology Department at Vall d’Hebron University Hospital; Dr Berta Ferrer and Teresa Moliné, specialists in the Pathological Anatomy Department at the same hospital; Dr Anna Pascual, a researcher at the National Centre for Genomic Analysis (CNAG); Dr Antoni Riera, from the Institute for Research in Biomedicine (IRB Barcelona); and Dr Fernanda Da Silva, a researcher at the University of Barcelona (UB).

This multidisciplinary collaboration brings together expertise in dermatology, immunology, pathology, pharmacology, drug delivery systems and spatial genomics, providing the knowledge required to address every stage of the translational development process.

Beyond the development of a new treatment for discoid lupus erythematosus, the researchers expect the results of TopiDLE to lay the foundations for a new platform of topical immunomodulatory drugs for the treatment of other autoimmune skin diseases. If the project is successful, this strategy could represent an important step towards more precise, safer and more patient-centred therapies.

This project is supported by the LEO Foundation (Grant No. LF-OC-26-002943).

*Institutional statement on research animals