Disease Analysis: COVID-19 Treatment

Definition

COVID-19 is an infectious disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus that emerged in late 2019 in Wuhan, China. As of October 2021, there have been 245,373,039 confirmed cases of COVID-19, and 4,979,421 deaths globally. SARS-CoV-2 belongs to the coronavirus family, which collectively cause respiratory and intestinal disease in
humans and animals, with other prominent members of the family including Middle East respiratory syndrome (MERS) virus and severe acute respiratory syndrome (SARS) virus.

Latest key takeaways

• Veklury (remdesivir) is the first and only approved antiviral for the treatment of hospitalized COVID-19 patients in the US, and has been rapidly adopted as the global standard of care (SoC) for moderate and severe patients since its initial US Emergency Use Authorization (EUA) in May 2020 (full approval occurred in October 2020). Veklury’s rapid commercial success ($4.2bn sales in Q1–Q3 2021) has been driven by results of the ACTT-1 study, which showed the drug significantly reduced the duration of hospitalization compared to placebo in patients with moderate-severe COVID-19 pneumonia. While negative results from the WHO’s SOLIDARITY trial in October 2020 contradicted these initial findings, suggesting that Veklury does not significantly reduce the duration of hospitalization or the risk of mortality in hospitalized patients, resulting in the WHO recommending against its use, data from three real-world studies (covering ~100,000 subjects) showed that Veklury reduced mortality. Despite the unfavorable recommendation from the WHO, Veklury sales have been largely unaffected. Indeed, in October 2021, Gilead noted that 60% of hospitalized US patients were being treated with remdesivir versus ~30% in October 2020, likely due to a lack of alternative options, thus Datamonitor Healthcare expects that the brunt of the impact of the WHO’s negative recommendation will only be felt once alternative agents become available for hospitalized patients.
• Dexamethasone is an immunomodulatory agent currently approved via emergency pathways in Japan, the EU, and the UK for the treatment of severe and critical COVID-19 pneumonia patients, and is recommended in both WHO and US NIH treatment guidelines. Dexamethasone has the enviable status of being the only therapy shown to significantly reduce the risk of mortality in severe/critical patients, as Veklury failed to do so in the ACTT-1 study. Other key advantages that have aided its rapid adoption as part of the SoC include its flexibility of administration (oral, intramuscular, or IV) and its widespread generic availability, which could act as a substantial barrier for other branded immunomodulatory therapies seeking to displace it.
• Dexamethasone faces significant competition from pipeline products for severe COVID-19 patients, including repurposed immunomodulatory agents such as Actemra and Olumiant, as well as other new agents in development. Results for the IL-6R antagonist class have been largely negative, however the REMAP-CAP and RECOVERY studies have shown that Actemra can provide a modest reduction in mortality in severe and critical COVID-19 patients, contradicting more negative results from Roche’s COVACTA and REMDACTA studies. Despite mixed results, the FDA issued an EUA for the use of intravenous Actemra for the treatment of COVID-19 in hospitalized patients above two years of age who are receiving systemic corticosteroids and require supplemental oxygen, mechanical ventilation (invasive or non-invasive), or extracorporeal membrane oxygenation.
• A range of other immunomodulatory therapies have generated positive data, but Olumiant (baricitinib) was the first therapy to be granted EUA by the FDA for the treatment of hospitalized COVID-19 (when used in combination with Veklury). However, Olumiant’s benefit on recovery times is marginal, with an average one-day improvement compared to Veklury alone. Olumiant also significantly reduced the risk of progression to mechanical ventilation or death, but the success on this composite endpoint was primarily driven by the mechanical ventilation component rather than mortality, meaning there is still substantial room for pipeline therapies to show greater improvements. Other immunomodulators with positive data include SNG001, which has shown a significant mortality benefit in hospitalized, ventilation-free patients, and lenzilumab, which has recorded a 54% increase in ventilator-free survival in patients with severe COVID-19.
• Monoclonal antibodies targeting the SARS-CoV-2 spike protein have been shown to reduce the risk of hospitalization in outpatients with mild-moderate infections at high risk of disease progression, and have generated blockbuster sales in this setting in the first nine months of 2021. Sales are expected to decline owing to the rollout of vaccines which are highly effective in preventing hospitalization and reducing the spread of infection. The use of antibodies is therefore likely to be restricted to at-risk individuals who respond poorly to vaccination.
• Eli Lilly’s bamlanivimab ± etesevimab, Regeneron’s REGEN-COV, and GlaxoSmithKline/Vir’s Xevudy are the most advanced antibody candidates, having gained EUA from the FDA for use in the outpatient setting and as post-exposure prophylaxis, and positive opinions from the CHMP. Key disadvantages of the class include their IV administration, which makes widespread use in outpatients other than those at particularly elevated risk of hospitalization unfeasible, and their relatively high production costs and limited manufacturing capacity. Data in the hospital setting have also been underwhelming, with Eli Lilly suspending a trial in hospitalized patients due to lack of benefit, and Regeneron limiting enrollment to patients not on high-flow oxygen or ventilation due to an unspecified safety concern and poor risk/benefit profile.
• Although REGEN-COV has dominated the mild-moderate and post-exposure prophylaxis markets, Xevudy may usurp it as the leading monoclonal given it is potentially a best-in-class therapy. Xevudy has shown slightly higher efficacy in both settings compared to rival monoclonal antibodies and benefits from its unique epitope (receptor binding domain) which will likely mean it is less susceptible to new variants with mutations in the spike protein.
• Monoclonal antibodies are expected to be under threat of substitution from oral antivirals. Notable threats include proxalutamide, which has shown efficacy in both hospitalized and non-hospitalized patients, Merck & Co’s Lagevrio (molnupiravir), which halved the risk of hospitalization and death, Pfizer’s Paxlovid (data readout expected in Q4 2021), and Atea/Roche’s AT-527 (data expected in early 2022). Oral antivirals benefit from the substantially lower cost of a course of treatment (~$700/course for Lagevrio vs REGEN-COV’s $2,100/dose), the ease of stockpiling oral tablets, and the ease of manufacturing scale-up (Merck & Co is guiding 10 million courses by the end of 2021).
• Convalescent plasma therapy is highly unlikely to confer any benefit in hospitalized patients following a string of negative readouts from randomized controlled trials (PLACID, REMAP-CAP, and RECOVERY), which showed that it provides no mortality benefit or reduced risk of progression to severe disease versus SoC alone. While the FDA’s revised EUA for convalescent plasma therapy still allows use in hospitalized patients earlier on in the course of the disease, it is surprising that the EUA has not been withdrawn altogether following the NIH’s decision in March 2021 to suspend a trial in mild-moderate hospitalized patients after a planned interim analysis showed the therapy was unlikely to confer any benefit.
• The commercial outlook for COVID-19 therapeutics is expected to decline progressively due to the phased implementation of global vaccination programs, which should substantially reduce both outpatient and hospital COVID-19 cases. Indeed, vaccination has been shown to provide 85% effectiveness against symptomatic COVID-19 illness and COVID-19 hospitalization, with breakthrough infections occurring in just 5% of vaccinated individuals. The potential emergence of new SARS-CoV-2 variants which may impair the effectiveness of vaccines against mild/moderate infections could partially revitalize the prospects for therapeutics aimed at the outpatient setting.
• The overall likelihood of approval of a Phase I antiviral asset is 13.0%, and the average probability a drug advances from Phase III is 67.5%. Antiviral assets, on average, take 8.4 years from Phase I to approval, slightly shorter than the average of 8.9 years for all infectious disease assets. However, in the case of COVID-19, development periods have been shortened substantially to as little as 6–9 months as repurposed agents have been rushed through clinical trials and granted rapid reviews by regulators.