There are hundreds of therapeutic agents being tested around the world. inDemic experts select the drugs most likely to have a significant impact on patients with COVID-19. The COVID-19 Therapeutics Watchlist is dynamic, so new drugs added and current drugs are dropped off whenever new data prompt change. Selection for the Watchlist is based primarily on clinical trial data, but also compelling mechanisms of action, signals of efficacy in compassionate use programs, and practical considerations such as manufacturing and distribution capacity. Nominations for the Watchlist or other comments can be sent anytime to firstname.lastname@example.org.
See inphronesis.indemic.org for more detailed research updates and analysis on our Therapeutics Watchlist.
See indemic.org/tag/therapeutics for all inDemic Perspectives regarding therapeutics.
Dexamethasone is the standard of care for patients with COVID-19 who require supplemental oxygen. Several phase 3 clinical trials, including UK RECOVERY, show that dexamethasone and other corticosteroids lower risk of dying from COVID-19. Real world data (RWD) may clarify subgroups that benefit more or less from dexamethasone. Furthermore, they are likely to provide additional reassurance on the safety of dexamethasone. For example, dexamethasone may increase risk of secondary bacterial infections. Finally, real world data (RWD) may help in optimizing use of systemic corticosteroids:
RWD is likely to be published on a rolling basis in 2021.
During the first several months of the SARS-CoV-2 pandemic, doctors used convalescent plasma to treat over 80,000 Americans with COVID-19.
Unfortunately, the benefit of convalescent plasma is unclear. Two randomized, controlled phase 2 trials published in BMJ and NEJM have demonstrated no benefit to convalescent plasma in hospitalized COVID-19 patients with moderate and severe pneumonia, respectively. At Johns Hopkins University, where the chair of microbiology is a big proponent of convalescent plasma, several trials are ongoing, including a phase 2 trial in outpatients with COVID-19. We await data from these Johns Hopkins University trials.
We do not believe convalescent plasma has any role in the routine treatment of COVID-19, based on trial data.
REGN-COV2, an antibody cocktail, reduces symptom duration and hospitalizations in outpatients with COVID-19. REGN-COV2 was the first antibody cocktail to be granted an FDA Emergency Use Authorization.
REGN-COV2 and other antibody cocktails filled an unmet need for outpatients. Prior treatments such as remdesivir and dexamethasone were only useful for hospitalized COVID-19 patients, or those on supplemental oxygen, respectively.
Looking ahead, Regeneron’s REGN-COV2 has been included in the UK RECOVERY trial, which has been highly successfully in accruing patients quickly in a nationalized healthcare system. We anticipate the next catalyst for REGN-COV2 to be phase 3 data on its effectiveness in treating severe COVID-19 in hospitalized patients.
LY-CoV555, an antibody against SARS-CoV-2, reduces hospitalizations in patients with mild to moderately symptomatic COVID-19. The FDA granted Emergency Use Authorization (EUA) to LY-CoV555.
Despite an EUA for LY-CoV555, it is not yet being widely used for outpatients. Part of this is logistical, as hospitals and clinics develop workflows for IV infusion of antibody therapies. In addition, for LY-CoV555 & LY-CoV016, we await additional data from the BLAZE-1 trial in outpatients. The BLAZE-1 trial will clarify:
Remdesivir may shorten time to recovery in adult patients hospitalized with COVID-19. On October 21, 2020, remdesivir became the first FDA approved drug for COVID-19. However, in the WHO Solidarity trial, remdesivir did not improve survival or clinical recovery in hospitalized COVID-19 patients. Professional societies do not agree on recommendations for remdesivir.
Given the variations in recommendations, we anticipate that use of remdesivir will be based on regional practice patterns. The next catalyst for remdesivir will be real-world data in 2021.
Lilly’s antibody is the first of its kind to be authorized by the FDA for emergency use in the treatment of outpatients with mild to moderate COVID-19. We anticipate that the next catalyst for Lilly’s antibody will be data from BLAZE-2, which is a phase 3 trial evaluating LY-CoV555 in preventing SARS-CoV-2 infection and COVID-19 in nursing home residents, and ACTIV-2, an NIH-sponsored phase 2/3 trial evaluating LY-CoV555 in outpatients with COVID-19.
IFX-1 blocks C5a, a powerful inflammatory mediator. C5a complement plays a role in several autoimmune diseases, as well as in sepsis. In addition, complement activation (specifically C5a-C5a receptor) has been associated with the pathophysiology of ARDS, and lung tissue in patients with severe COVID-19 show widespread complement activation.
A phase 3 global trial is evaluating IFX-1 in adults with severe COVID-19 on mechanical ventilation.
Interim data for IFX-1 (anti-C5a) ought to be available by early 2021.
To us, IFX-1 is the frontrunner amongst complement inhibitors, especially after a phase 3 trial of ravulizumab (a C5 inhibitor) was stopped. The IFX-1 phase 2 trial was the first randomized controlled clinical trial investigating a complement pathway inhibitor for severe COVID-19.
On September 14, 2020, Eli Lilly and Incyte announced initial data from a phase 3, randomized, placebo-controlled trial sponsored by NIH’s NIAID. Compared to remdesivir alone, remdesivir in combination with baricitinib reduced median recovery time by one day in hospitalized COVID-19 patients. Since then, the FDA has granted Emergency Use Authorization to baricitinib. Some clinicians question its clinical relevance, as it only reduces recovery time by one day. Its uptake by hospitals and physicians will likely be slow unless it can provide additional data on benefit to other clinical endpoints (e.g. survival). We anticipate the next catalyst for baricitinib will be real world data, as well as phase 3 trial data from COV-BARRIER.
Innate Pharma, which is developing avdoralimab (an inhibitor of the C5a complement receptor), started the phase 2 trial FORCE in April 2020. FORCE is a randomized, double-blind trial in France that’s evaluating avdoralimab for COVID-19 patients with severe pneumonia. Recruitment of patients to FORCE declined due to dropping incidence of COVID-19 in France. With recent rises in COVID-19 incidence in France, Innate Pharma is restarting enrollment. Completion of the FORCE trial will likely be delayed to at least December 2020.
Type 1 interferons (IFN) are critical in the immune system’s defense against viral infection. At-risk patients may be deficient in pulmonary IFN-β, and coronaviruses such as SARS-CoV-2 suppress endogenous IFN-β to evade the innate immune system. Hence, exogenous IFN may help COVID-19 patients.
Synairgen, the manufacturer of inhaled IFN-β, has patented its formulation for COVID-19. To our knowledge, Synairgen is the only commercial entity developing inhaled IFN-β to treat COVID-19. Although Synairgen reported promising clinical data on July 20, 2020, it stalled. However, on October 20, 2020, Synairgen partnered with Parexel International, a contract research organization with 20,000 employees. Parexel will assist Synairgen in SG018, a phase 3 trial of inhaled interferon-beta for hospitalized COVID-19 patients. The SG018 trial has started in the UK, and will start shortly in the USA. We anticipate the next catalyst will be interim data from SG018 in 2021.
Colchicine is a cheap, widely available drug, which has been used for centuries to treat gout. Its anti-inflammatory properties may be beneficial for COVID-19 patients. In a phase 2 clinical trial, GRECCO-19, colchicine reduced clinical decline in patients hospitalized with COVID-19. Colchicine is being evaluated in two phase 3 trials, COLCORONA and UK RECOVERY, and data for these trials should be available in 2021.