“Given the rapid spread of COVID-19 and its relatively high mortality, filling the gap for coronavirus-specific drugs is urgent. […] Researchers, ethics boards, and regulators are accustomed to developing trial plans over months, not weeks—a time frame that is not afforded during this emergent situation. It is necessary for all involved to work faster and more efficiently and then position the well-justified drugs for registration-enabling trials during the next peak.”1
In the battle against a global pandemic, time is of the essence.
In some cases, drug developers can circumvent the years of development it takes to make a new therapy by turning to compounds which have already gone through the gamut of preclinical and clinical testing to vet as potential treatments for patients suffering from acute respiratory distress caused by COVID-19. Currently, forerunners including host-factor–targeted drugs hydroxychloroquine, azithromycin, camostat and nafamostat and the viral RdRp–targeted drugs remdesivir and favipiravir may be promising candidates. Many other drugs are now being fast-tracked through evaluation for potential repurpose to combat the pandemic as well; according to public data, there are hundreds of drugs in development to treat or prevent COVID-19, the majority being reporposed from previous indications.
This pandemic has highlighted the actions to revamp drugs previously designed for different indications, but repurposing is a fairly common occurrence and process even in more stable times. Therefore urgency must not come at the sacrifice of due diligence. In repurposing drugs for a new indication, a critical part of the process is to review all available data about the drug’s safety and make sure there are no missing pieces, or ‘gaps’, which could cause safety issues for clinical trial volunteers or patients down the road.
Gap analysis, with the assistance of an expert or team of scientists intimately familiar with drug-drug interaction (DDI) studies from a regulatory and a scientific perspective, can prove invaluable for repurposing drugs. It helps paint an accurate picture of risk for a sponsor that could inform crucial decisions in the clinic and explain results that would otherwise cause roadblocks for getting through clinical stages. As a CRO specializing in helping sponsors take a close look at drug metabolism and DDI potential, we have provided studies or consultation for a variety of the 69 compounds mentioned in the 2020 Nature publication, “A SARS-CoV-2 protein interaction map reveals targets for drug repurposing,”2 to patch holes in existing data to meet current regulatory expectations. Our team of expert consultants have extensive experience working on IND-enabling DDI data packages for new drugs as well as the 505(b)(2) regulatory pathway taken for label expansion or to repurpose drugs already in the market for new indications.
As pharmaceutical companies work to make effective treatments and vaccines available for patients diagnosed with COVID-19, many safety factors are taken into consideration. Among them is the risk of an adverse drug-drug interaction, which can precipitate harmful or even fatal results when medications are taken together. Of course, if taking a drug will save someone’s life then DDI risk is outweighed by benefit, and data such as these may be abbreviated, deferred, or omitted in order to make those drugs available as quickly as possible.3 But because COVID-19 cases range from mild symptoms to acute respiratory distress, it might prove beneficial to have multiple treatment options, and DDI data could differentiate a good option for a patient from a more dangerous one.
“Based on currently available information and clinical expertise,” states the Center for Disease Control and Prevention (CDC) website, “older adults and people of any age who have serious underlying medical conditions might be at higher risk for severe illness from COVID-19.” Because both of these demographics are also most likely to be prescribed other medications, the risk of DDI of potential new or repurposed drugs must be carefully investigated.
Regulatory agencies take into consideration all efficacy and safety data when greenlighting a drug for the market, and thereafter the onus is on prescribers to be mindful of DDI risks when recommending treatment. “The tail doesn’t wag the dog — you don’t let the interactions decide what drug to give. But what we don’t want people to do is forget that there are really important, life-threatening drug interactions and ignore that,” warns Dr. Saye Khoo, an infectious disease physician at Liverpool University Hospitals, in a May 2020 interview with Medscape.4
With so many drugs being developed or repurposed in the fight against COVID-19, it may be reasonable to assume that eventually there will be several options for prescribers, and there is already evidence of the part DDIs may play in choosing the right treatments for COVID-19 patients. The University of Liverpool has put together an interactive database to map out evidence of DDI risk associated with known experimental treatments for COVID-19. Their analysis shows that some commonly prescribed medications including antiarrhythmics, beta blockers, anti-coagulants, calcium channel blockers, and statins may pose dangerous risks to clinical trial volunteers or future patients treated for COVID-19.4
One way drug developers can anticipate potential DDI issues in the clinic is through nonclinical in vitro drug-drug interaction (DDI) studies to experimentally determine a drug’s perpetrator or victim potential in a transporter– or metabolism-mediated DDI. Sufficient in vitro DDI investigation prevents unnecessary exclusion of patients from clinical trials and informs clinical DDI study design if appropriate. With appropriate DDI risk assessment, regulators and drug developers alike can be more confident in the safety of COVID-19 therapies.
In addition to repurposed compounds, many drug developers are ramping up efforts to find new compounds that could interact with infected cells. A new tool many are using for in vitro research are human cell lines, such as JCRB1819, which is a Vero E6 cell line expressing TMPRSS2, a protein vital to viral entry and replication. As Science magazine reports in a May 2020 article, several promising compounds like camostat and nafamostat have gained status as such for their ability to block SARS-CoV-2 replication in TMPRSS2-expressing cells.1
As a contract research organization that has built its name assisting drug developers to get safe, effective drugs to market through reliable ADME and DDI testing, SEKISUI XenoTech is proud to offer fast-tracking for critical studies to sponsors with COVID-19 therapies as well as provide TMPRSS2 cells for testing in many laboratories across the world.
If you have a need for nonclinical drug metabolism or DDI products or services, or would like to learn more about how we can help you obtain defendable data to take your drug to IND with confidence, get in touch with one of our specialists who can help guide you to success.
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1 Kiplin et al. “Rapid repurposing of drugs for COVID-19” Science 22 May 2020: Vol. 368, Issue 6493, pp. 829-830 DOI: 10.1126/science.abb9332
2 Gordon, David E., et al. “A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug Repurposing.” Nature, 2020, doi:10.1038/s41586-020-2286-9.
3 Page 2, ICH M3(R2) Guidance for Industry “Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals” 2010. https://www.fda.gov/media/71542/download. Accessed June 20204 J Pinkowski.“Drug-Drug Interactions Could Imperil COVID-19 Treatment” May 10, 2020 Medscape https://www.medscape.com/viewarticle/930265
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