By Saakshi Chadha, PhD, Senior Analyst; Alexandra Dekkers, Analyst; Kristine Mechem, PhD, Vice President; Vivek Mittal, PhD, Partner
- The rapid increase and worldwide spread of COVID-19 has warranted urgent efforts in identifying existing drugs that can battle the disease.
- As of early April, there were 322 registered COVID-19 studies across geographies, including 105 studies investigating the potential of repurposed drugs for treating and preventing COVID-19 infections.
- These trials are currently ongoing in 27 different countries across the six continents, without any coordination of the modalities being investigated in these trials, missing the critical opportunity to collaborate between the different countries in investing efforts to find a treatment for COVID-19.
- Trials investigating a specific drug modality differ in the key primary endpoints as well as the standard of care used in some comparator arms not only across different countries, but also between trials conducted in the same country, preventing meta analyses to better rule out candidates.
- When the need for a therapy is paramount, as we see with the mortality rate for COVID-19, it is critical that there be some guidance for clinical trials so that drug candidates can be ruled out faster and patients be rerouted towards trials where efficacy is better defined and the trial has more clinical merit. Guidance development should consider two overarching themes:
- Guidelines should be provided by the WHO and/or other global governing bodies standardizing the recommended primary and secondary endpoints and standard of care practice in order to determine the most effective outcomes and interventions and allow the prioritization of trials in times of crisis.
- National or geographic trial policy makers should consider a “divide and conquer” strategy to prioritize certain modalities in specific regions allowing trial sizes to be aggregated in order to have larger trial sizes, more meaningful clinical data and faster dissemination of results to identify those repurposed drugs that are proven to be effective.
SARS-CoV-2 Biology – What Do We Know So Far?
As we enter the sixth month since the first wave of COVID-19 cases were reported in China, the search for novel and repurposed therapeutic drugs is still ongoing and urgently needed. Caused by the SARS-CoV-2 virus, this respiratory disease is primarily transmitted via respiratory droplets from infected individuals, resulting in a spectrum of disease symptoms and severity, from high temperatures and coughs on the milder side, to cytokine storms and pneumonia on the more severe side, often resulting in the need for hospitalization.
While much is known about the symptoms and mortality of the disease, much less is known about its pathophysiology. Research so far indicates that the virus, just like the SARS-CoV virus binds the Angiotensin-converting enzyme 2 (ACE2) receptor on epithelial cells in the nasal cavity and starts replicating. Additionally, the TMPRSS2 protein is also shown to be necessary for viral entry. At this stage, the infected individual is still asymptomatic, but the virus can be detected via diagnostic tests using samples from nasal swabs, which can likely confirm infection as well as infectiousness of the individual.
Propagation of the virus down the respiratory tract and conducting airways triggers a more robust innate immune response, resulting in more severe symptoms such as acute respiratory distress syndrome. Additionally, findings also show that increasing viral load not only causes excessive epithelial and endothelial cell death, leading to the activation of pro-inflammatory cytokines and chemokines, but also loss of ACE2 function in the lungs, which causes the dysfunction of the renin-angiotensin system (RAS), further enhancing the immune response, leading to a cytokine storms. Antibody-dependent enhancement (ADE) is also seen in a small proportion of patients, likely those who have very severe infection. Based on the pathophysiology, clinicians have looked to existing therapeutics that can not only limit symptom severity, such as anti-inflammatory drugs, but also treat the viral infection efficiently, such as antivirals and antimicrobial drugs. This blog will look at some of these repurposed drugs that are in clinical trials for the treatment of COVID-19.
Landscape of Repurposed Drugs being Investigated for the Treatment of COVID-19
Since the dramatic rise in the number of COVID-19 cases across the globe, researchers and governments alike have shown enthusiasm around investigating existing drugs as an efficient immediate approach to battle the viral infection, while waiting for a suitable vaccine as a long-term preventive strategy. China initiated investigational studies with repurposed drugs within the first month of reporting COVID-19 cases and was rapidly followed by other countries as the virus spread across the world, with the number of ongoing studies dramatically increasing on a weekly basis. As of early April, there were 322 investigational ongoing studies across 27 countries in six continents, out of which, 105 studies were therapeutic interventions for the treatment and prevention of COVID-19 infections. Of the interventional studies, ~82% of the trials are interventional studies, while the remaining 18% are being conducted on high-risk individuals for investigating the potential of the drug as a preventative agent, amongst which, one is an association study. The urgent need for identifying an efficacious therapy for the COVID-19 infection, driven by the high short term mortality rate, is reflected not only in the number of ongoing trials but also in the number of different drugs being investigated. These trials investigate over 70 different drugs in different concentrations and doses, spanning across different modalities.
The Health Advances Biopharma Practice set out to analyze the current landscape of ongoing trials that are investigating repurposed drugs in patients with COVID-19 infections. In our analysis, we focus on the 86 studies that are investigating the therapeutic potential of these drugs against COVID-19. We conducted a comparative analysis of the geographic spread, drug modality and patient population being enrolled and evaluated the key primary endpoints across the different studies. In this blog post, we utilize comparative data to highlight key aspects of the ongoing trials and posit potential avenues to expedite the search of effective repurposed drugs in the midst of a pandemic.
The repurposed drugs being investigated span across nine different modalities, with antimalarial, antiviral and anti-inflammatory drugs comprising ~75% of the total. The other modalities include vasodilators and traditional Chinese medicine (TCM) -derived drugs amongst others. Chloroquine and hydroxychloroquine are the two antimalarials being investigated in different dosages and in combinations with other drugs. Both these drugs initially displayed antiviral properties against COVID-19 in vitro, soon after which clinical trials in COVID-19 positive patients initiated. Among the antivirals, HIV drugs such as lopinavir and ritonavir as well as remdesivir, an investigational drug that showed potential during the Ebola crisis are also being investigated against COVID-19 and amongst the anti-inflammatory drugs, the IL-6 inhibitors sarilumab and tocilizumab are under investigation. While the antimalarials are being investigated in COVID-19 positive patients across all severity levels, the antivirals and anti-inflammatory drugs are being investigated in the more severe and hospitalized patient populations.
Looking at the geographic spread of these studies, the US seems to have invested in trials for hydroxychloroquine, while Europe has invested in trials for anti-inflammatory drugs and the TCM-derived drugs are only being investigated in China. Despite these nuances, trials for the majority of different modalities are ongoing across the different geographies. For example, hydroxychloroquine, sarilumab and tocilizumab each currently have at least one ongoing trial in the US, Canada, several European countries, and China. Similarly, remdesivir is being investigated in the US, China, and France, and the combination of lopinavir and ritonavir has ongoing trials in China, Hong Kong, France, and Canada. While members of the scientific community from all around the world have been working collaboratively on better understanding the virus and searching for novel and existing therapeutics, the major powers as well as other countries are slow to get on board with coordinating their efforts. In a pandemic, this approach of working in national silos to find a therapy to treat a fast-spreading disease is inefficient and takes significantly longer than a collaborative approach.
Another key observation from the analysis of these trials is the number of different primary clinical endpoints that are being measured by these trials. Half of the trials are investigating at least one aspect of symptom improvement (e.g., rate of improvement, time to improvement, number of patients with improved symptoms), and many of these trials are on moderate to severe patients. Measurement of viral load using RT-PCR is a primary endpoint for only 14% of the studies while some studies also measure symptom worsening in the mild disease patient population. However, there is no standardization of the current primary and secondary endpoints between these trials, not even between trials that are being conducted with the same interventional drug and in similar patient populations. For example, while some trials that are investigating IL-6 inhibitors in moderate-to-severe patients measure patient survival rates, other trials in the same patient population are measuring time to symptom improvement. Some hydroxychloroquine trials that are being conducted in hospitalized patients are measuring the number of patients with symptom improvement, whereas others are measuring either mortality rate or viral load in the same patient population. There are at least two factors that influence the choice of primary endpoints:
- The patient population selected for the study: Whether a trial is conducted in patients with mild disease or severe disease is likely to impact the primary outcome of a trial. Similarly, if a trial is being conducted in hospitalized patients, the primary outcome is likely to differ than that for patients who are not hospitalized. For instance, survival rate or mortality rate as a primary outcome is suitable for patients with severe disease or patients admitted in intensive care units. However, using such an endpoint in patients with mild disease is not going to yield clinically valuable information since the likelihood of survival is high and the likelihood of mortality in patients with mild infection is low. Similarly, measuring clinical symptom worsening over time is a more suitable endpoint for patients for mild infection who are susceptible to more severe symptoms than for patients with severe symptoms who are already hospitalized. Furthermore, trials that target patients across all disease severities need to closely consider how the selected endpoint is likely to be impacted by the variation in severity of infection across the selected patients.
- The investigational drug: The mechanism of action of the interventional drug being investigated also speaks to the choice of primary endpoints. A trial investigating an anti-inflammatory drug such as IL-6 inhibitors should be designed to detect endpoints such as time to symptom improvement, whereas a trial investigating an antiviral is unlikely to provide deep insights into the drug’s efficacy with the same endpoint. Instead, detecting changes in viral load in patients being administered an antiviral drug is likely to be more suitable in understanding the true effect of the intervention. There is also an implication for interpreting the results of key primary endpoints. For instance, an antiviral drug that does not reduce viral load should be considered ineffective against the targeted virus. However, an anti-inflammatory drug like the IL-6 inhibitors may still be effective even though there is no reduction in viral load since they ameliorate severe lung tissue damage induced by cytokine release in patients.
The choice of primary endpoint should consider the above two factors in the trial design in order to truly be clinically meaningful by teasing out and understanding the true effect of the drug being investigated. In addition to selecting an appropriate endpoint, consistency in the scheduled timepoints for collecting patient outcomes is critical in facilitating interpretation of outcomes data across different trials investigating the same class of drugs.
In addition to primary outcomes, there are also discrepancies in how different trials that have a comparator arm are defining “standard of care”, which may or may not be a factor of how it is defined by respective governing bodies in each country. Standard of care ranges from oxygen and ventilation, to antibiotics and certain antivirals, depending on the symptoms, and it is well known that slight variations in the implemented standard of care protocol could affect the resulting outcome when comparing multiple clinical trials. In the case of COVID-19, for example, one trial in China that is investigating the antiviral, favipravir is being compared to a control group which receives regular treatment allowing drug intervention except for specified drugs. Other trials in China compare the investigated drug to “basic treatment”, which is currently undefined. Another study investigating the combination of azithromycin and chloroquine that is being conducted in Canada compares the experimental drugs to standard of care, which has no constraints on any other therapies administered to the patients by the treating physicians. On the other hand, while studies in the US do not define their standard of care protocol, it is highly likely that the definition of “standard of care” differs between the US and other Asian countries with ongoing trials.
The lack of standardization not only in primary endpoints but also in how “standard of care” is defined will delay the search to find the most suitable intervention against COVID-19. It will prohibit a direct apples-to-apples comparison of endpoints in order to determine trial success. There is a critical need for global institutions such as the World Health Organization to put together specific guidelines to standardize the trial design, especially for key aspects such as clinical endpoints and the use of standard of care.
As COVID-19 continues to persist in many countries around the world and the fear of relapse cases continues to loom, there is an urgent need for an immediate solution for treating patients while the world awaits a prophylactic vaccine to be developed. In order to meet this need, significant efforts are underway to investigate the potential of existing drugs that could be repurposed against COVID-19 and become part of the standard of care quickly. However, these drugs still need to show efficacy against the virus and therefore are currently being investigated in clinical trials across the globe. Unfortunately, just when the world needs collaboration and coordination among nations to defeat this pandemic, the current landscape of ongoing trials appears to be more competitive than cooperative. Collaboration and coordination is critical to prevent thousands of patients from dying, since it can enable clinicians to more quickly rule out drugs (e.g., a VA study has shown increased mortality with hydroxychloroquine), conduct clinical trials more cost-effectively, and use a ‘divide and conquer’ approach, where investigators with different drug trials can participate in information sharing. Coordination between endpoints for the various ongoing trials, on the other hand, will enable through meta analyses, the direct and efficient comparison of trial endpoints and speed up the evaluation of drug efficacy. Access to standardized guidelines on key trial aspects such as clinical endpoints, enrollment criteria as well as how the standard of care is defined is critical to ensure clinically meaningful trials can be accelerated and efficacious repurposed drugs can be found. The contradicting trial data released from various hydroxychloroquine trials being conducted all over the world illustrates the need for better coordination as well as collaboration between national/geographic policy makers in order to effectively compare the trial outcomes and to make a decision on the efficacy of the drug against COVID-19. The World Health Organization made a step in this direction when it recently proposed a master protocol for organizations to test potential therapeutics against SARS-CoV-2. This protocol enables these interventions to be compared to a shared control arm and is likely to have a shared set of clinical outcomes. While this protocol is a step in the right direction, it needs to become guidelines not just for SARS-CoV-2 but also for other viral strains in order to ensure that we learn from our mistakes and are better prepared for the next pandemic. Additionally, agencies should also step in and provide guidance on innovative trial design including the use of real world evidence to assess the impact of the investigational drug on patients currently taking anti-inflammatory or vasodilating drugs. Conducting retrospective association studies on the severity of COVID-19 symptoms in patients who are also taking IL-6 inhibitors for chronic indications can provide preliminary insight into the efficacy of such existing drugs against the viral infection. This pandemic crisis can be a great lesson for all nations to realize the need for collaboration and coordination across countries rather than competition, since advancements by one nation or one clinical trial is going to benefit the larger global population.