DUBLIN – At the best of times, drug development is, of course, a complex problem. It is all the more demanding still in the middle of a pandemic, when the threat to human life is increasing exponentially, and health care systems are buckling under an extraordinary burden. Optimizing the development of drugs and vaccines in order to quickly generate high-quality evidence of their safety and efficacy is, therefore, a critical task, but an online webinar organized by the drug development consultants Certara LP, in conjunction with the Bill and Melinda Gates Foundation, suggested that, at this stage of the crisis, that lesson has yet to be absorbed.

At present, the development effort appears highly fragmented and uncoordinated, Dan Hartman, director of integrated development at the Washington-based Gates Foundation, told the online audience. “The last time I looked in different databases there were over 600 ongoing or completed trials, many of the same drug, and yet we don’t have a single product recognized as having an appropriate risk-benefit profile for treating COVID-19,” he said. “If there were mechanisms in place that would enable coordination and collaboration, this ideally would not be the case.” Hartman added that it was “shocking and dismaying” to learn that there are 37 individual studies exploring the potential of hydroxychloroquine, but there is no collaboration or coordination across those efforts.

Dan Hartman, director of integrated development, Gates Foundation

Even a basic issue such as optimum dosing has to be considered, when critical drugs are in short supply. “Every milligram of drug above optimal is less for others, and manufacturing capacity is wasted,” said Craig Rayner, president of Princeton, N.J.-based Certara’s integrated drug development and strategic consulting services. “And every milligram below optimal is giving the virus a chance to outsmart our inventions.” Multiple factors influence dose requirements, including age, body mass, the stage of the disease, the presence of co-morbidities, patients’ use of other medications and, potentially, genetic polymorphisms.

Those issues are not confined to new investigational agents – the same questions arise with drugs that are being repurposed. “Just because a drug is approved does not mean it is fit for purpose,” Rayner said. “Is it really logical to think that a dose regimen that’s been developed in HIV or malaria – or rheumatoid arthritis – will be fit for purpose for an acute virus infection in the lungs where in vitro susceptibility suggests a 10- or a 100-fold lower potency?”

Craig Rayner, president, integrated drug development and strategic consulting services, Certara

The recent failure of the HIV drugs lopinavir and ritonavir to demonstrate any statistical benefit as compared with standard of care should be seen in that context. The therapy was simply administered too late to have any effect, said Steven Kern, deputy director of quantitative sciences at the Gates Foundation. “One of the messages that comes right away is that the patients’ viral load was already declining at the point at which they were treated with antiviral therapy,” he said. “So that begs the question are we starting this therapeutic too late in the clinical course to actually see its effectiveness – and, if we are, then there’s a need to get effective concentrations quickly established in patients.” In HIV patients, it takes three to four days of dosing to reach a steady state. COVID-19 patients do not have that amount of time. Kern suggested an up-front loading dose may be needed to block viral replication.

Dosing is likely to undermine the case entirely for Merck & Co. Inc.’s anti-parasitic drug, ivermectin, which has long been used to treat river blindness (and which yielded Nobel prizes in 2015 for its co-developers William Campbell and Satoshi Omura). A group of scientists in Australia recently reported that a single dose of the drug attained a 5,000-fold reduction in SARS-CoV-2 RNA in cell culture after 48 hours and called for its consideration in treating COVID-19.

Steven Kern, deputy director, quantitative sciences, Gates Foundation
Although the study gained a lot of attention – and prompted Montpelier, France-based Medincell SA to pursue the development of a long-acting version of the drug – the dose used, when modeled for lung tissue exposure, is far in excess of what is used in clinical practice. “The typical therapeutic profile is 20-fold lower than the necessary IC50 value that’s required to block the viral replication,” Kern said.

Drug development for COVID-19 will have to proceed at a far quicker pace than has been the norm. “The traditional drug development cycle measures time in years,” Rayner said. “Our need for therapeutics for COVID is measured in a very different time scale – it’s the nightly news reports of infections and deaths that we’re hearing.” Making progress will require agility, the use of advanced data science and parallel development strategies. Most of all, it will require an embrace of ambiguity and uncertainty. “The weakest link in developing therapeutics during a pandemic is dogma,” he said.