Repurposing of drugs and lessons learnt in COVID-19

As an Australian scientist working in the US pharmaceutical industry, the coronavirus disease 2019 (COVID-19) pandemic has provided unique insights into repurposing medicines as therapeutic options for patients hospitalized with the disease. Typically, when considering development of a new medicine, a rigorous process exists to demonstrate its safe and effective use. Several pre-clinical and clinical studies (healthy volunteers and patients) over the course of 10 - 20 years serve as evidence which ultimately contribute to the new drug application.

When dealing with an approved medicine for a new indication, this is a much more streamlined process given the basic data (safety, toxicology, PK, PD, formulation etc.) is known, however new challenges now exist due to gaps that may be present in the hypothesis for treatment of disease and in the case of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), the speed at which answers are needed for decision making.

Clinicaltrials.gov shows that there have been over 3000 trials initiated to investigate therapeutic options for the treatment of COVID-19, however to date, there has only been one FDA approved drug, remdesevir, which is considered a ‘controversial’ approval. One may ask with all the cutting edge technology and existing therapeutics available why only one? The answer like, everything related to this pandemic, is complex. The following sections will discuss two of the key challenges of repurposing drugs through the lens of a clinical pharmacologist.

The World Health Organization launched ‘SOLIDARITY’ in March of this year to generate key data around four specific antiviral regimens. Although there was a basic understanding that SARS-COV-2 was a virus and had one primary manifestation, i.e. respiratory failure and ultimately death, many other symptomatic features were also present based on published data and existing drugs could be beneficial to treat these symptoms.

However, complicating the matter was that SARS-COV-2 had a wide spectrum of presentation ranging from asymptomatic patients to those who were hospitalized and severely ill. Therefore, the focus of clinical trials aimed at repurposing drugs was ensuring those with moderate to severe symptoms did not worsen.

One of the hypothesis for treatment was around the ‘cytokine storm’ that was observed in some severely ill patients who demonstrated high levels of pro-inflammatory cytokines, such as interleukin-6, compared to those who only developed mild symptoms. This led many researchers down the track of evaluating existing immune suppressants to slow the progression of the disease to reduce mortality.

Soon after the design of these trials focusing on addressing the inflammatory response caused by the cytokine storm, more clinical cases identified that clot formations were present in patients with severe COVID-19, often appearing in the lungs and extremities of patients (namely the toes) leading to debilitating stroke. Consideration now shifted towards whether antiplatelets or anticoagulants would work best (arterial vs venous clot) and where this new symptom sat on the chain of events that led to severe outcomes. There was also no clear understanding of the rationale for clot formation in severe patients and whether this was a result of the inflammatory response or an intrinsic feature of patients who developed severe symptoms.

Trial designs now had to consider the potential for combination approaches targeting each of these symptoms, however with such uncertainty in the pathophysiology of the disease, complicating trials with combination approaches would have made interpretation of results difficult.

Several other hypothesis and mechanisms have been suggested which are plausible but the key lesson learnt was around the connectivity between many disease processes and therapeutic areas and the increased need to understand mechanism level systems biology before racing into clinical trials.

Dose selection is one of the most challenging aspects of drug development and often a key reason why many drugs fail to show optimal benefit/risk in Phase III trials. Several articles have emphasised the need for optimal dosing for COVID-19 patients and this is true, however there are some practical limitations to investigating this when repurposing a drug.

Unlike earlier stages of drug development where dose strengths can be defined by manufacturing, in the case of most medicines (aside from IV drugs), once approved, there is limited flexibility due to the fact that only 2-3 dose strengths typically exist.

In addition, as discussed above, there is limited understanding whether or not the drug truly has a plausible mechanistic rationale to be effective and therefore any deviation from standard dosing paradigms when initiating a new trial is purely speculative.

Furthermore, background therapy drugs in patients diagnosed with COVID-19 can vastly differ from drugs that are typically given in the approved indication. Aside from pharmacokinetic (PK) interactions there are also pharmacodynamic interactions that must be considered in order to ensure further harm won’t come to the patient.

In classic clinical trials, there is time to collect and analyze data prior to making the next move. In the case of COVID-19, there was a clear urgency to identify a ‘magic bullet’ and therefore this favored a 'real-time' dose adjustment/optimisation approach rather than a traditional approach. Although many hospitals had capabilities to relay information and adjust doses based on thoughtful physicians paying careful attention to key biomarkers, the interconnectivity between physicians, pharmacists and/or clinical pharmacology experts to analyse this data and make informed dosing decisions was far from seamless.

Software tools such as DoseMeRx and InsightRX lay the platform for Bayesian adaptive approaches to select optimal doses of medicine on an individualised basis through real time integration of PK/PD and electronic health records. These types of approaches will be key for quickly identifying those drugs that may not provide any benefit while optimising those that show promise in the future for both a pandemic situation or even for speedy drug development.

The pandemic has demonstrated that the need for innovative scientists with strong knowledge of pharmacy and clinical pharmacology principles, scattered across academic research, government policy, regulatory bodies, pharmaceutical industry and hospitals has never been greater.

Understanding mechanism of disease, drug action, dose optimization and how these can dynamically be integrated into clinical trial design is tailor made for pharmacy and pharmacology students with strong research training in PK and PD principles. These folks will be ideally positioned as leaders in the future for the next pandemic.

About the author
Vidya Perera, BSci (Hons) 2007, PhD 2012

Vidya Perera was the recipient of the Dr Peter Coates PhD Scholarship in Ethnopharmacology (2008-2012) under the tutelage of Professor Andrew McLachlan and Annette Gross at the University of Sydney. He currently serves as the Head of Cardiovascular Clinical Pharmacology and Pharmacometrics at Bristol-Myers-Squibb, Princeton, New Jersey, USA.