What are benefits of drug repurposing and why do clinical drug trials so often fail? Diana Spencer summarises the key messages from the ‘Drug Repurposing: Challenges and Opportunities’ Symposium held at the 19th World Congress of Basic & Clinical Pharmacology (WCP) 2023.
The Drug Repurposing symposium at WCP 2023 was chaired by Oscar Della Pasqua, Chair Clinical Pharmacology & Therapeutics, University College London, London, UK, and Dr Viviana Giannuzzi, Head of Research Department, Fondazione per la Ricerca, Farmacologica, Gianni Benzi Onlus, Italy.
Repurposing and ‘repositioning’ medicines can be a very attractive strategy for the drug discovery industry, Oscar Della Pasqua explained, as researchers are not starting ‘from scratch’. There will probably already be some clinical data for the drug in question and this can save both time and money, as the company can secure regulatory approval without lengthy and costly early-stage clinical trials.
It has been widely reported that capital investment in life sciences has been low this year compared to previous years, which has made repurposing more important than ever. However, even then, companies need a strong business case and a clear development plan to secure investment from the limited funds available.
Lessons learned from Covid-19
The first talk was given by Oscar Della Pasqua and focused on what we can learn from drug repurposing during the Covid-19 pandemic. He began by asking why so many clinical trials are failing, even for drugs that have been previously approved for a different indication, and suggested that drugs are being developed without a “sound pharmacological basis”.
He gave the example of GLP-1 receptor agonist Ozempic, a diabetes treatment, which was successfully repurposed for weight loss as Wegovy. It is important for researchers to have a clear proof of concept before they begin clinical trials, he explained, which would allow them to avoid expensive studies that will ultimately fail.
In September 2020, due to the pressure to find a medical interventions against SARS-Cov-2, there were 2553 active clinical trials into drugs to treat Covid-19, many including antivirals like tenofovir, ivermectin and chloroquine. However, these were rushed to the clinical phase without a proper understanding of dosing and whether they contained sufficient antiviral activity to block Covid-19 replication at safe doses. There was also no appreciation of the half-life of the drugs and therefore in some trials patients were given incredibly high doses and the result in the case of hydroxychloroquine was a high mortality rate.
Della Pasqua explained that, even when there are time pressures, a quantitative, integrative approach is needed to establish the probability of clinical success before a drug is taken to human trials, and this is what was lacking during the pandemic. This approach should include patient population characteristics, drug disposition properties, dose, route and dosage form, as well as variability in response to ensure a successful clinical trial.
Drug repurposing in neurological diseases
The next speaker was Robert Pitceathly, Honorary Consultant at The National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, London, UK. He started by explaining that rare mitochondrial diseases are an attractive target for drug discovery due to the different pathways of treatment, but research is challenging due to the limited number of patients.
There are opportunities in rare diseases due to regulatory flexibility, such as only needing one late-stage clinical trial rather than two, and the availability of incentive schemes, but there is a lack of mouse models and biomarkers and less than 10% of Phase I trials get approval. This makes drug repurposing or reformulation very appealing. However, despite a known safety profile and mechanism of action, the failure rate of 30% is still high.
Pitceathly argued that interdisciplinary collaboration and good preclinical data is key to successful clinical trials. Pharmacokinetic and pharmacodynamic modelling in mice and allometric scaling should be used to refine dose strengths for human studies, and the available safety data may need re-evaluating considering predicted dosages.
Barriers to bringing repurposed medicines to paediatric patients
Dr Viviana Giannuzzi spoke about the challenges faced in paediatric R&D, including the fact that the overall group includes five different age groups, the need for specific biomarkers, the extra length of time needed for trials, and the ethical concerns of conducting clinical trials in children. Less trials obviously results in less approved drugs, and this leads to drugs being used off-label with a low level of evidence.
One advantage is that data from off-label clinical use can be used to inform paediatric approvals of drugs, though companies are often reluctant to begin expensive clinical trials when the medicine is already being used without a licence. Giannuzzi gave several examples of drugs successfully repurposed for paediatric use: Sildenafil, which was approved in 1998 and then in 2009 for children; Propranolol, which was first approved in 1967 and finally licensed in children in 2014; and Thalidomide, which was approved in 1998 for use in children.
To address these issues, in the US, companies are now required to do paediatric studies if their target is also relevant to children, and it is hoped that the European Medicines Agency may introduce a similar policy in the near future.
Drug repurposing: regulatory experience and expectations
Flora Musuamba of the Federal Agency for Medicines and Health Products, Brussels, Belgium was originally going to be a chair of the session but was prevented from travelling due to storms in Europe. Instead, she attended by live feed to give her talk. She began by emphasising the importance of drug repurposing for addressing unmet medical needs and went on to explain the regulatory requirements.
Musuamba explained that in the case of repurposing, published literature can replace some of the clinical data. For a ‘well-stablished use’ application, long-term data from at least ten years of off-label use can be used alongside published scientific literature. In these types of application, a sponsor is required to take responsibility, though this can be an academic institution.
She urged that new methodologies are needed to reduce human and animal testing to establish safety and efficacy. However, as new types of data become more prevalent, such as real-world data, AI-generated data and simulation, it is important that these new analytical methods stand up to the same scrutiny as traditional ones to ensure a positive benefit/risk balance is established.