Four Questions with Tomas Cihlar: Committed to the Field of Emerging Viruses
Stories@Gilead - June 22, 2020
Tomas Cihlar, Vice President of Virology, leads Gilead’s antiviral research and for five years led research and development efforts related to remdesivir, the company’s investigational COVID-19 treatment.
He joined Gilead in 1994 as a post-doctorate research fellow from the Institute of Chemistry and Biochemistry in Prague, where he studied under Antonín Holý, the renowned chemist who played an important role in Gilead’s first medicines for HIV and hepatitis B as an inventor of tenofovir. During his time at Gilead, Tomas has contributed to the research of many of Gilead’s HIV medicines before expanding the focus of his team to the field of emerging viruses for the last several years.
We recently interviewed Tomas to discuss the company’s investigational COVID-19 treatment and the role of scientific research in helping to prevent serious viral outbreaks in the future.
Q: Gilead’s investigational COVID-19 treatment has an interesting history. Can you provide some background on the compound’s journey and why the company’s scientists thought it could potentially help address this novel coronavirus?
Tomas: Remdesivir’s roots go back more than a decade, when its precursor was designed by Gilead medicinal chemists as a potential treatment for hepatitis C. Our chemists subsequently designed and tested a range of the precursor prodrugs against multiple viruses, including respiratory syncytial virus and Ebola virus. In these experiments, remdesivir was identified as a promising molecule and was further tested against additional viruses with the potential to cause outbreaks.
Through many partnerships established over the last several years, we have conducted a number of critical in vitro and preclinical experiments demonstrating that remdesivir has broad-spectrum antiviral activity against many pathogenic viruses, including coronaviruses such as SARS and MERS that are similar to SARS-CoV-2, the coronavirus causing COVID-19. When the outbreak began, we had the benefit of this understanding, which positioned us well to quickly decide to study the potential utility of remdesivir in addressing COVID-19.
Q: Based on laboratory studies, what do we know about the way remdesivir works against COVID-19?
Tomas: To understand how remdesivir works to inhibit viral replication, our team collaborated on a study with the University of Alberta that isolated a protein complex of SARS-CoV-2 RNA polymerase, a critical enzyme that enables the replication of viral RNA. With that in hand, we had the essential machinery the virus uses to make copies of its genetic material and were able to investigate whether remdesivir could halt this process.
Remdesivir was specifically designed to generate a metabolite in cells that mimics one of the essential natural building blocks that make up viral RNA. Laboratory studies have shown that remdesivir is incorporated into new viral RNA strands as they form and can stop the process of their replication in these studies. In contrast, human enzymes do not incorporate the remdesivir active metabolite into the host RNA molecules, which adds more scientific evidence to the preclinical profile of remdesivir.
Q: Coronaviruses have not been as widely studied as many other infectious diseases until recently. How is it that Gilead has an investigational treatment with the potential to help address COVID-19?
Tomas: We’re in this position to potentially help today because we made a commitment to the field of emerging viruses more than five years ago. We made this decision based on the unmet needs we saw in the field of emerging viruses and the belief that we were in a unique position to make a difference due to Gilead’s decades of expertise in antivirals.
Because of the broad antiviral profile of remdesivir that was established in laboratory experiments, a number of opportunities were identified through almost a decade of research on how antiviral nucleotides, including remdesivir, could potentially be used. After we completed multiple collaborative preclinical studies testing remdesivir activity in SARS and MERS infection models, the results were quite encouraging. However, until the COVID-19 outbreak, there were too few cases of pathogenic coronavirus infections in humans to support proper clinical safety and efficacy testing.
The work our team did with multiple partners to understand the preclinical profile of remdesivir is one of the reasons we were in a position to bring quickly forward a potential COVID-19 treatment. The other critical factors were human safety data from previous compassionate use and clinical trials of remdesivir, as well as a developed manufacturing process – albeit, scaled to make limited amounts of product for a compound in early development– without which we would not have had enough drug on hand to start COVID-19 studies in such a short time. This all was the result of extensive team efforts building up gradually over the past five years and I am very grateful for the opportunity to be part of it.
Q: Beyond working to develop treatments and vaccines to help address the current pandemic, how can researchers contribute to preventing another similar coronavirus outbreak in the future?
Tomas: Even when effective treatments and prevention methods for COVID-19 become available, the scientific community will have to keep innovating to prepare for future potential outbreaks of viral infections. Coronaviruses are very unpredictable because they have a diverse viral reservoir in animals and, as respiratory infections, can be easier to transmit than other viruses.
At Gilead, we’ve established an expanded team to look beyond the current intravenous formulation of remdesivir and investigate questions such as: Can remdesivir be effectively delivered to patients outside the hospital through other routes such as inhalation or subcutaneous injection? Are there other mechanisms or targets through which we can block a coronavirus? Can we come up with an oral drug with broad-spectrum antiviral activity against viruses posing high risk for future outbreaks? We are working on a comprehensive strategy for future research that would continue expanding our work through collaborations and partnerships, including with other biotech and pharma companies.
This relentless pursuit is part of Gilead’s culture. If we reach one milestone or achieve a goal and there is still more to address or improve for patients, we keep going. Gilead has demonstrated that time and again in HIV, viral hepatitis and now in other disease areas by striving to out-innovate our own medicines. We’re always inspired by the next frontier, and that’s what has kept me at Gilead for more than a quarter century.
Remdesivir is an antiviral product that is being studied in multiple ongoing international clinical trials. In recognition of the current public health emergency and based on available clinical data, the approval status of remdesivir varies by country. Remdesivir has been approved in Japan, Singapore, Taiwan and India, and regulatory submissions continue around the world. In countries where remdesivir has not been approved by the regional health authority, remdesivir is an investigational drug, and the safety and efficacy of remdesivir have not been established.
In the U.S., the U.S. Food and Drug Administration (FDA) granted remdesivir an Emergency Use Authorization (EUA) for the treatment of hospitalized patients with severe COVID-19. This use is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use, unless the authorization is terminated or revoked sooner. Remdesivir has not been approved by the U.S. FDA for any use. For information about the authorized use of remdesivir and mandatory requirements of the EUA in the U.S., please review the Fact Sheets and FDA Letter of Authorization available at www.gilead.com/remdesivir.