Drug Development in Times of the COVID-19 Pandemic

By Andreas Wallnöfer, General Partner of Biomed Partners VC, Executive Advisor to Certara, and former Head of Clinical Research & Exploratory Development at F. Hoffmann-La Roche.

Even when we cannot really be surprised by the occurrence of such a viral pandemic, COVID-19 has actually caught the world largely by surprise. Several voices had been warning of a global public health crisis for years. In a 2015 TED Talk, Bill Gates concluded, “A pandemic could happen in the next decade, and the world is not prepared.”  Similarly, Jeremy Konyndyk, former director of USAID’s Office of US Disaster Assistance in the Obama Administration, stated 2017 in an article1,”A virus similar to the 1918 flu pandemic will emerge. A major health crisis is a rather a question of when it will happen, not if it will happen.”

These and other people with similar warnings were not notoriously pessimistic, but were rather rationally extrapolating from cross-species transmissions that regularly occur in nature and are in most cases harmless to man. Now SARS-COV-19 is not harmless to man. Those readers, arguing that these quotes are post-hoc connotations, should be aware and weary of clinical experts warnings on the increasing bacterial resistance that spreads around the globe. While the pharmaceutical and medical community knows these facts, and resistance charts are described in multiple articles with increasing concerns, most pharma companies had closed their infectious disease research already some time ago. Moreover, several biotech companies that were developing novel antibiotics filed for bankruptcy in recent months. The market for antibiotic drug development seemed not to be commercially attractive. When will this social and industry negligence to the next microbial threat change? Only after the next health care crisis? It is clear that the antimicrobial resistance will cause a major problem in many healthcare systems.

Compared to the viral outbreaks of Ebola, SARS, and MERS in the 20th century, SARS-COV-19 has actually a lower fatality rate.  SARS-COV-19 has spread, however, to many more countries and has infected hundreds of thousands of more people. It reached and hit the Western World hard, whereas the other diseases were largely contained to Asia and Africa. US and Europe had institutionalized since the years 1950’s very diligent and solid market authorization approval processes for novel drugs. Those processes are based on three phases of drug development and take several years with average cost of de novo drug development reportedly over $1 billion. Notably, the drug development process has remained amazingly traditional, independent of novel therapeutic modalities that have appeared over the last few decades. Even the advent of personalized medicine and recently the digital revolution have impacted these rock-solid paradigms only modestly.

In times of COVID-19 and in the face of the imminent crisis in the US and around the globe, many things are not the same, and paradigms are shifting. Under the impression of anecdotal reports and data published from a small study conducted in France2, the US President stated at a press conference in mid-March that, “Hydroxychloroquine and azithromycin, taken together, may have a real chance to be one of the biggest game changers in the history of medicine and should be used immediately.”  The FDA commissioner issued a cautionary statement to make clear that the drug had not been approved to treat for SARS-CoV-2 yet by the FDA. Scientifically and methodologically, the French study comparing 19 patients receiving 600 mg hydroxychloroquine to untreated patients from another center could be called out for small sample size and selection bias (open label, non-randomized). The study showed, however, some evidence (but no proof) of viral load reduction and improvements in COVID-19 patients, particularly when its effects were reinforced by azithromycin. WHO Director-General Tedros Adhanom Ghebreyesus cautioned, “The history of medicine is full with examples of drugs that worked on paper or in the test tube, but did not work in humans or were actually harmful.” But what is right in a crisis when there are no thoroughly tested medications with documented efficacy?  It will take some time until controlled study results will be available.  In the meantime, on March 25, 2020 the Indian government preempting such confirmation decided to cease exports of hydroxychloroquine3. On March 29, FDA gave emergency authorization4 for the use of hydroxychloroquine on an experimental basis to be tested in 1,100 SARS-CoV-2 positive patients. The agency can authorize such emergency use when there are no available alternatives and the known and potential benefits of the drug outweigh known and potential risks.

Daily, physicians at the forefront treating COVID-19 patients are faced with the dilemma of empirical benefits.  Prof M. Battegay, Head of the Department of Infectious Diseases at the University Hospital of Basel, stated in an interview with the Swiss journal Neue Zürcher Zeitung5, “There are several enthusiastic reports about postulated beneficial efficacy of certain drugs or combinations. I am certainly not enthusiastic about such reports. Often, however, I am impressed how well a patient responds to a drug or combination of drugs. I remain, however, very conscious and fully aware, that without controlled clinical studies, we cannot know whether these improvements are based on spontaneous recoveries or are really related to the therapy that was administered. Fundamentally, we are in a dilemma, we don’t want to give these drugs such as lopinavir/ritonavir or hydroxychloroquine to patients that do not need them or at worst will even suffer from unnecessary, severe adverse events; but we also don’t want to give them too late or miss a chance that they may help.”

For SARS-COV-19, it is evident, that while all efforts should be made toward prevention and/or containment of the 2019/2020 outbreak, the question remains what are viable strategies to discover potential candidate drugs and to accelerate their development to combat in useful time severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)?  Solutions that could be available to fight SARS-CoV-2 in a time-critical fashion in the near future can obviously come only from successful vaccine development or from drug repurposing – also known as drug reprofiling or repositioning – that promises to identify antiviral agents or therapies that modulate the host response and outcome of the disease. There is an urgent need to accelerate access of effective COVID-19 therapeutics to patients worldwide, applying smarter and more modern approaches to drug development.

As of March 2020, there are a number of therapeutics in clinical trials and more than 20 vaccines in development for COVID-196. The clinical and pharmaceutical community is challenged to deliver facts, (i.e., “science”) to address and verify “perceptions.” Potential treatments include both antiviral medicines and immunotherapies. It is estimated, that there are nearly 80 clinical trials for experimental new treatments and vaccines in development for coronaviruses, including COVID-19, SARS, and MERS.  Another important dimension in this quest for repurposed drugs involves patent protection issued under current national and/or international regulations. A global health emergency of this magnitude calls for a bold, international response at the governmental and political levels. Therefore, the regulatory community must act fast to minimize any financial hurdles implicating private industry and update guidelines for drug licensure through repurposing, if necessary. Some of the urgently launched clinical trials worldwide on investigational medicinal products for COVID-19 should read out within weeks to months. We can anticipate the notion of drug repurposing for emerging viral diseases to be scrutinized based on these results. At a deeper level, this battle is not only against COVID-19 but for the very high medical need of new antimicrobials.

1 Jeremy Konyndyk, Politico, March 1, 2017
2 Philip Gaudret et. al. Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an open-label non-randomized clinical trial
3 www.fdanews.com March 25, 2020 India bans hydroxychloroquine exports as demand soars
4 FDA immediate release, March 29 20205
5 Manuel Battegay, Neue Zürcher Zeitung March 28, 2020
6 IFPMA, Novel coronavirus. Industry’s R&D efforts, ifpma.org. March 19, 2020

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