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 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 ($2.8bn in sales in 2020) has been driven by positive results from the US National Institutes of Health (NIH)-sponsored 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 World Health Organization’s (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, and resulting in the WHO recommending against its use, demand nevertheless increased in Q4. Indeed, in January 2021, Gilead noted that 50-60% of hospitalized US patients were being treated with remdesivir versus ~30% in October 2020, likely due to a lack of alternative options, thus the publisher expects the brunt of the impact of the WHO’s negative recommendation will only be felt once alternative agents become available for hospitalized patients.
- Veklury faces myriad threats from pipeline candidates, including antivirals, immunomodulatory agents, monoclonal antibodies, and hyperimmune globulin therapies. Oral antivirals pose a particular threat, given that their similar mode of action means they are likely to produce comparable results in ongoing trials (or superior results if optimized for greater potency against the SARS-CoV-2 RNA polymerase), and their administration route would be more convenient than Veklury’s IV formulation. Favipiravir is the nearest-term threat, with emergency approvals in India and Russia, and ongoing studies in the outpatient, hospital, and prophylaxis settings, though disappointing results from a study in hospitalized patients in Kuwait suggest favipiravir’s use will be limited to outpatients.
- Dexamethasone is the only 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 standard of care 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 supplant it.
- In a minority of cases, SARS-CoV-2 infection is believed to trigger an overly aggressive immune response in which excessive amounts of pro-inflammatory cytokines are produced (termed a “cytokine storm”), which can subsequently drive extensive lung injury, lower oxygen saturation, multi-organ failure, and death. There is therefore substantial pipeline interest in repurposing immunomodulatory agents approved for various autoimmune indications for the treatment of severe and critical cases of COVID-19. However, results for the IL-6R antagonist class have been largely negative, with the exception of the REMAP-CAP and RECOVERY studies, which suggest Actemra can provide a modest reduction in mortality in severe and critical COVID-19 patients, contradicting more negative results from Roche’s own COVACTA and REMDACTA studies. The difference in outcomes may be partially due to increased use of combination therapy with corticosteroids since the COVACTA study was conducted, as well as earlier intervention with Actemra in the REMAP-CAP study (administered within 24 hours of entering intensive care).
- A range of other immunomodulatory therapies have generated positive preliminary data, but Olumiant (baricitinib) is the only therapy thus far to be granted EUA by the FDA for the treatment of hospitalized COVID-19 (when used in combination with remdesivir). However, Olumiant’s benefit on recovery times is marginal, with an average one-day improvement compared to remdesivir 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.
- 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 are expected to generate blockbuster sales in this setting in the first six to nine months of 2021. Thereafter, anticipated declines in the number of new infections in at-risk populations because of the ongoing rollout of highly effective vaccines will severely restrict their commercial potential in developed markets. In addition, data from pivotal trials of a range of vaccines suggest that they are highly effective at preventing hospitalization, meaning that even if an at-risk individual did acquire infection after vaccination, the subsequent use of monoclonal antibodies is unlikely to provide any additional benefit.
- Eli Lilly’s bamlanivimab ± etesevimab and Regeneron’s REGEN-COV are the most advanced antibody candidates, with both cocktails having gained EUA from the FDA for use in the outpatient setting 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. Finally, the possible spread of the South African viral variant (B1.351) could severely affect the utility of antibodies, as Eli Lilly’s combination has been shown to be ineffective against B1.351 in preclinical studies, while the casirivimab component of REGEN-COV is also ineffective (imdevimab retains neutralizing activity), meaning follow-on antibody combinations may be required.
- 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 standard of care alone. While the FDA’s EUA for convalescent plasma therapy still allows use in hospitalized patients earlier on in the course of the disease, it seems likely that the EUA will be withdrawn altogether following the NIH’s decision in March 2021 to suspend a trial in mild-moderate hospitalized patients following a planned interim analysis which showed the therapy was unlikely to confer any benefit.
- The commercial outlook for COVID-19 therapeutics is expected to decline progressively throughout 2021 due to the phased implementation of global vaccination programs, which should substantially reduce both outpatient and hospital COVID-19 cases. Indeed, several vaccines being developed by Moderna, Pfizer/BioNTech, AstraZeneca, Novavax, and Johnson & Johnson have shown 66-95% effectiveness against symptomatic COVID-19 illness, and are also highly effective against COVID-19 hospitalization, though 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 12.9%, and the average probability a drug advances from Phase III is 68.5%. Antiviral assets, on average, take 8.4 years from Phase I to approval, slightly shorter than the average of 9.0 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.
- Pivotal trial data for a huge range of repurposed drugs are expected in H1 2021, including from Olumiant’s COV-BARRIER study evaluating the drug as a monotherapy against standard of care, and favipiravir’s PRESECO study evaluating its ability to prevent progression to severe infection in outpatients with mild-moderate infections.
Table of Contents
OVERVIEW
DISEASE BACKGROUND
TREATMENT
EPIDEMIOLOGY
KEY REGULATORY EVENTS
LICENSING AND ASSET ACQUISITION DEALS
CLINICAL TRIAL LANDSCAPE
OTHER ANTIVIRALS
OLUMIANT
OTHER IMMUNOMODULATORY AGENTS
MONOCLONAL ANTIBODIES
RECENT EVENTS AND ANALYST OPINION
UNMET NEEDS
LIST OF FIGURES
LIST OF TABLES
