COVID-19 drugs: Beyond the low hanging fruit
Given that the pandemic is likely to stay through 2021 and beyond and vaccine development is still at early stages, drugs have a critical role to play in the fight against the COVID-19 virus. Despite anecdotal evidence that some people benefit from drugs such as hydroxychloroquine and azithromycin, favipiravir and remdesivir, more data are needed to confirm their efficacy and safety.
The COVID-19 pandemic has put us all on edge, with lives and livelihoods upended globally. As this new virus comes into contact with humans, the range of symptoms and degree of severity have been unpredictable. Most people, particularly if young, seem to suffer relatively minor symptoms. But a small percentage develop moderate to severe lung disease that can progress to multi organ failure and even death. Given that the pandemic is likely to stay through 2021 and beyond and vaccine development is still at early stages, drugs have a critical role to play in the fight against the COVID-19 virus. Despite anecdotal evidence that some people benefit from drugs such as hydroxychloroquine and azithromycin, favipiravir and remdesivir, more data are needed to confirm their efficacy and safety. Hence, efforts to identify new therapeutic options to reduce morbidity and mortality must continue.
Conventional drug discovery processes are not practical
The conventional drug discovery and drug development process involves the systematic testing of compounds in vitro and in vivo, followed by safety/toxicology testing. A safe and efficacious compound that emerges from this preclinical phase is then tested in humans. Novel chemical entities (compounds being tested in humans for the first time) must go through three phases of clinical development before approval to market is granted. The entire process can take 8-10 years and a billion dollars. In the context of COVID-19, this approach is simply not pragmatic. Instead an abbreviated pathway is needed.
Drugs that have been previously approved or tested in clinical studies for other conditions can be repurposed, provided there is an understanding of the mechanism of action and the safety data provide a sufficient therapeutic window. Known antivirals and immunomodulatory compounds are the current drugs of choice for repositioning.
The biology of infection
COVID-19 is caused by a coronavirus, SARS-CoV-2, an enveloped, positive-sense, single-stranded RNA virus. Upon infection, the spike (S) protein on the surface of SARS-CoV2 binds to angiotensin-converting enzyme 2 (ACE2) a transmembrane protein found on the surfaces of epithelial cells of alveoli, trachea and bronch of the respiratory tract. In addition, the entry requires S protein priming by cellular protease, TMPRSS2, which cleaves the S protein and allows the fusion of viral and cellular membranes through the endosomal pathway. Once within the cell, SARS-CoV-2 releases RNA into the host cell. The RNA is translated into viral replicase polyproteins pp1a and 1ab, which are then cleaved into small products by viral proteinases. The polymerase produces a series of sub genomic mRNAs by discontinuous transcription that are translated into relevant viral proteins. Viral proteins and genome RNA are subsequently assembled into virions in the ER and Golgi and then transported via vesicles and released out of the cell. These then go onto infect other cells.
Clinical features of COVID-19 infection vary from asymptomatic presentations to acute, bilateral pneumonias requiring hospitalization. The most common symptoms are fever, fatigue and dry cough. Severe disease is associated with acute respiratory distress syndrome (ARDS) which is driven by the release of pro-inflammatory cytokines, also called the cytokine storm.
The current pipeline
Based on our understanding of SARS CoV-2, there are three possible ways to disable the virus: 1) Prevent entry of the virus into the cell 2) Block replication of the virus and 3) Prevent release of the viral particles. Additionally, one can target inflammatory pathways in the host to reduce the severity of the disease.
An analysis of the current pipeline reveals that there are approximately 300 trials underway. Some early reports of clinical studies that have been completed are promising. For example, randomized, controlled clinical trials for remdesivir and the cocktail of liponavir, ritonavir, ribavirin and interferon-β suggest that these therapies may reduce time to clinical improvement (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31042-4/fulltext). However, the findings need to be confirmed in larger studies.
One of the largest trial is the Solidarity trial, coordinated by the WHO in which four therapeutic approaches for hospitalized patients with confirmed COVID-19 are being assessed. These consist of the RNA polymerase inhibitor remdesivir (inhibits replication), hydroxychloroquine and chloroquine (likely inhibits the entry process), the HIV protease inhibitors lopinavir and ritonavir (inhibits replication), and lopinavir and ritonavir in combination with the immunomodulatory agent interferon beta-1a. The study is enrolling patients across 100 countries via simplified procedures to enable even overloaded hospitals to participate.
Challenges
A quick survey of the small molecule pipeline shows that the trials focus on a very limited number of drugs. Multiple studies are testing the drugs that the Solidarity trial is testing. Others include the antibiotic azithromycin, nucleoside reverse transcriptase inhibitor, emtricitabine, camostat mesylate, a TMPRSS2 inhibitor and IL-6 receptor inhibitors (to modulate the host immune response) (https://www.clinicaltrialsregister.eu/ctr-search/search?query=covid-19). In fact, the explosion in the number of trials and the overlapping sets of drugs prompted Asher Mullard to ask if such efforts were justified (https://doi.org/10.1016/S0140-6736(20)30894-1). Several of these trials are small in size and will need to be followed up with larger studies before efficacy and safety can be conclusively established. Key aspects of clinical studies such as randomization and the use of control groups may be missing, leading to confounding interpretations.
The lack of diversity in the pipeline does not stem from a lack of candidate drugs. In an interesting study that Nevan Krogan’s laboratory rushed to complete before the University of California, San Francisco shut down, are data on human proteins that SARS CoV-2 proteins interact with. They identified 69 FDA-approved drugs, drugs in clinical trials and/or preclinical compounds that target such interactions (https://www.biorxiv.org/content/10.1101/2020.03.22.002386v3.full). Such work could lead to unexpected new drugs to fortify the arsenal.
The way forward
As the initial rush of studies gets underway, the community must pause to ask what future trials must ensure, to optimize success. First, clinical studies must be sufficiently powered to understand the real value of the intervention. This will prevent the duplication of effort and will provide physicians with the necessary data for modifying or improving treatment guidelines. Countries including India, which have rapidly increasing numbers of COVID-19 positive patients must allow clinical research to happen at an accelerated pace. However, even as such clinical studies are made robust, the need for fundamental research to guide drug development cannot be overlooked.
1) Tracking resistance development
It is likely that resistance will develop to antiviral drugs with increasing use, even if administered as a combination. The community of clinician researchers must identify a hierarchy of combination therapies to use as first, second and third line, assuming that ongoing trials identify more than one efficacious treatment regimen. Further, surveillance, tracking of mutations and in vitro testing must be a continuous activity. X-ray co-crystal structures of drugs bound to their viral targets must be undertaken to predict which mutations are likely to affect activity. Compounds that are likely to be efficacious, even with mutations, must be identified. Further, global public health agencies must prepare to work up multiple compounds and take them through early clinical development. Such compounds can be quickly injected into the development pipeline, when needed.
2) Understanding the mechanism of action of compounds
Fundamental R&D principles that are usually part of any drug development process must be invoked. Compounds must be advanced with a deeper understanding of the mechanism of action. Targets must be known and in vitro studies must confirm the mechanism of action. The relationship between drug concentration and reduction in viral titer or immune response must be experimentally shown. These data must be evaluated in the context of maximum tolerated systemic exposures. Animal models must be established and in vivo studies must be undertaken. In all likelihood such models will require primates. Although translatability is not guaranteed, this investment in R&D is much needed, so the best compounds move forward.
3) Validation of new targets
While the current focus has been to repurpose drugs, efforts must be made to identify new compounds that more specifically target SARS CoV-2 proteins. R&D of this nature is necessarily high-risk but must continue, at least at the preclinical stage, to ensure that candidate compounds are available for the future. Many novel strategies can be put to use to improve the success of such efforts. This includes the use of AI in drug discovery, potentially a way to dramatically speed up the discovery process (https://www.nature.com/articles/d41586-019-03846-0). AI tools can help design a drug that can effectively bind to a known target. An obvious target in this case would be the Spike protein. Blocking its interaction with ACE-2 could be the focus of the AI approach. Yet another use of AI could be to identify compounds that are likely to be safe. AI algorithms could be developed based on cytochrome P450 inhibition, for example. Such an algorithm put to use early in drug screening, can help weed out compounds early. AI could also be used to repurpose approved compounds by identifying those that are likely to hit viral targets.
Conclusions
Fighting this pandemic is going to require efficacious drugs, alongside the other efforts to prevent and minimize the spread of the infection. However, the current approach of testing known antivirals and immunomodulators may not be sufficient. Instead a more structured process, leveraging technology, will be needed to deliver new drugs in a meaningful time frame. We must look beyond the low hanging fruit.
Dr. Radha Rangarajan, Ph.D., Chief Scientific Officer, HealthCubed & Dr Ramesh Byrapaneni, MD DM, Managing Director, Endiya Partners
