Drug repurposing: What is it? And why the sarcoma community should be interested in it

Drug repurposing is a strategy that identifies new uses for approved or investigational medicines that are outside the scope of the original medical indication. This means that new treatments are sought from already-licensed products and from compounds that are not authorized for a particular indication. They may have failed to perform as expected in clinical trials or have been overtaken by better therapies.

Why is drug repurposing gaining an increased interest over the years? There are two main reasons:

• it has the potential to bring new treatment options with known safety profiles, and
• it offers faster access to new treatments for patients.

It is also different from traditional drug development by mitigating high costs and associated commercial risks of failure. However, it is not attractive to major pharmaceutical giants whose business model is built on holding patents for their drug discovery investments and maximizing their market penetration to generate revenue.

De novo drug discovery and development[1] is a complex process. In its traditional linear development, it takes an average of 10 to 17 years and comprises different phases, ranging from basic discovery to drug design and production, from in vitro and in vivo experimentation (including identifying safety and efficacy) to clinical trials and finally to drug registration and access to the market.  Safety and efficacy are the two essential requirements of a medicinal product seeking marketing authorization in a specific therapeutic indication.

By contrast, drug repurposing can bypass several processes and timeframes are shorter. There is a lower risk of failure because the safety profile is known already and there are lower development costs.

Drug repurposing can address unmet needs

There are many gaps in the pharmaceutical treatment of sarcoma. We rely on doxorubicin as a first-line treatment in advanced disease for many sarcomas. This is a drug first developed in the 1960s, approved for sarcoma in 1975, and is very toxic. There have been many attempts over the years to identify a replacement chemotherapy. The focus today is more on individual sarcoma sub-types, finding the appropriate therapy to replace doxorubicin, or to act as second-line or third-line treatment for specific histologies.

Drug repurposing can play an important role in ensuring faster and affordable access to new treatments and innovation in any type of disease. It can have a crucial role in all rare cancers, such as sarcomas, and in particular for paediatric patients or adolescent and young adults (AYA) where sarcomas are more common.

The European Commission’s Pharmaceutical Strategy for Europe highlighted that companies are currently not focusing on unmet medical needs “due to the absence of commercial interest”[2]. It is an undeniable fact that commercial drug development is the main pathway for new drugs to the market and to patients. The marketing authorization holder (MAH) of a licensed medicine is the only body which can currently apply for a new use. Only the MAH is allowed to seek a license to extend the treatment indication outside the original indication. Therefore, even if non-commercial clinical trials should confirm the efficacy of a repurposed drug, patient access to this treatment depends on the willingness of a pharmaceutical company to obtain authorization for the new indication and to take responsibility for its risk management. Non-commercial researchers and funders therefore have little interest in following this route for re-purposing. Access to an effective treatment can be denied for commercial reasons.

A game-changing role for not-for-profit organizations

This scenario has the potential to be changed by an ongoing review of the EU Pharmaceutical Regulation.  If agreed by the end of 2025, the revised legislation could come into effect in 2026. The proposed Article 48 aims at facilitating the repurposing of existing authorized drugs, especially in areas of unmet needs, by non-traditional developers generally called “not-for-profit entities”. Article 48 recognizes the crucial role of patient organizations and academic institutions, in generating evidence to submit to the European Medicines Agency (EMA) for assessment, potentially leading to new drug indications and use.

Generating substantive non-clinical and clinical evidence from not-for profit organizations to explore new therapeutic indications for approved drugs and translating this evidence into improved cancer care with adequate assistance and oversight by licensing authorities would be a powerful regulatory gamechanger. This would unleash a potential role for not-for-profit organizations in bringing therapeutic innovation to patients through new pathways, overcoming the traditional commercial development.

Unleashing therapeutic innovations for patients

The Belgian based AntiCancer Fund (ACF) is a valued funder of clinical trials, including sarcoma studies. It has co-ordinated a multi-charity submission to the EU which SPAGN has supported, expressing our commitment to supporting regulatory changes on drug repurposing, opening the way for not-for-profit organizations.

Specifically asking EU policymakers for the adoption of Article 48 of the proposed EU regulation is one of the actions outlined by the AntiCancer Fund Manifesto 2024-2029 “Best cancer treatments to address unmet patient needs.”  SPAGN will be directly involved in supporting the demand to policymakers on the specific issue addressed by Article 48, which could be truly transformative. As a matter of fact, SPAGN – also together with its full member Fondazione Paola Gonzato-Rete Sarcoma  - has contributed to the preparation of the recently published ACF document: “Unleashing Therapeutic Innovation for Patients. By Overcoming Hurdles to New Uses of Authorized drugs”.

To maximize patient benefit, it is crucial to establish a complementary pathway for regulatory approval of therapeutic innovations based on evidence submitted by non-traditional developers.

This means: Regulatory changes are essential to unblock pathways to new medicines re-purposed from old, translate positive outcomes from not-for-profit organizations, thus overcoming commercial development as the sole driver of patient drug access.

Repurposing for sarcoma

Repurposing offers opportunities for sarcoma treatment that, as a community, we need to encourage our scientific colleagues to consider. The range of cancer specific drugs increased hugely following the development of monoclonal antibodies (1980s) and tyrosine kinase inhibitors (1990s). Many of them are now out of patent and available as experimental medicines. Indeed, some of them showed promise in their early phase clinical trials decades ago, although that was not followed through by the developer. Identifying what may be valuable in treating sarcoma today is a challenge and the work of the ongoing EU regulation review should help. There is a need for funding to support the academic work needed to address this challenge.

 

[1] “De novo drug discovery and development “ is the process of developing an entirely new medicine from scratch, beginning with finding a new compound that has never been used as a medicine before.

[2] Communication from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions: Pharmaceutical Strategy for Europe, 2020 (page 4)

Credits:  Photo provided by Ornella Gonzato to SPAGN for publication