Today there remains an urgent need for life-saving drugs for COVID-19, which has infected over six million patients globally and killed nearly 400,000. In a series of recent posts, we explored the global race to create SARS-CoV-2 vaccines and outlined the types of partnership that could help accelerate their path to market. Developing a vaccine will be key to controlling the pandemic. From both public health and economic standpoints, preventive measures can mitigate health risks while reducing consumer and government cost of care. And while vaccines may be most effective to reverse the course of the pandemic, therapies are still critical. Here's why:
- Widespread, global access to a safe and effective vaccine takes time. If successful, the earliest vaccine candidates could be available in 2021, but the current record timeline for vaccine development is four years (mumps); it may take longer to meet global demand and reach herd immunity.
- Infected patients still need to be treated. Vaccines can prevent infections but may vary in availability, uptake and efficacy. Moreover, patients already exposed to COVID-19 still need treatments to address active infection.
At the time of writing, there were over 550 unique treatments and vaccines in development for COVID-19. In this post, we dive into the different types of therapies in the pipeline, examine their potential role in managing infection, and highlight key milestones of some noteworthy therapies. Given the urgent need to find a therapy quickly, the majority of therapies currently in clinical testing were previously developed for other indications and “repurposed” for the disease, several of which have received extensive media coverage in recent months. There is also a small but rising number of therapies in development specifically for SARS-CoV-2, the virus that causes COVID-19. These therapies, however, are generally in earlier stages of development compared to repurposed products.
To understand the types of treatments in development, it helps to understand what stage of COVID-19 the treatments may target. SARS-CoV-2 is an RNA virus that uses spike proteins to attach to proteins on the surface of host cells. Once attached to a cell, the virus hijacks the host cell’s machinery to replicate itself, repeating this process to spread throughout the body. In some patients, the host’s immune system may succeed in overcoming the virus. In others, the immune system may overreact, setting off a cytokine storm—the excessive release of immune system proteins—and damaging organ function in an effort to combat the virus.
COVID-19 therapies may target the virus at any point during its life cycle or may modulate the immune response to the virus. These potential COVID-19 treatments fall into three broad categories:
- Therapies that target the virus before an infection is established, including neutralizing antibodies specific to SARS-CoV-2, and convalescent plasma
- Therapies that aim to eradicate an established infection, including antivirals
- Therapies that help modulate the immune response to the infection, including anti-inflammatories
Many of the novel therapies are still early stage and are further from commercialization and face risks at each phase of development. Conversely, many therapies repurposed for COVID-19 were able to bypass these early trial stages and are therefore de-risked and closer to commercialization.
Figure 1: COVID-19 treatment categories
Therapies attacking the virus prior to infection may provide the greatest benefit, such as through novel antibodies or convalescent plasma, which are considered both potential prophylactic treatments—therapies designed for disease prevention either pre- or post-exposure—and curative therapies for patients already infected. As an example, Eli Lilly recently announced its initiation of human studies of LY-CoV555, an intravenously administered neutralizing IgG1 monoclonal antibody (mAb) designed specifically to target the SARS-CoV-2 spike protein. Similarly, Regeneron announced its plans to initiate clinical trials for one of its two antibody cocktail therapies sometime this month. But developing a therapy that specifically addresses a novel virus can be both challenging and time-consuming. LY-CoV555, the neutralizing antibody furthest in development, has only just entered human safety testing.
Sample COVID-19 neutralizing monoclonal antibodies
Eli Lilly
· Phase I
· COVID-19 patients
Regeneron
· Pre-clinical
· VelocImmune mice
AstraZeneca
· Pre-clinical
· COVID-19 patients, immunized mice, and phage display
Celltrion
· Pre-clinical
SAB Biotherapeutics
· Pre-clinical
· Genetically engineered bovine
In the nearer term, patients with an active infection need treatments that improve the course of disease. The first of these to gain traction is remdesivir, an intravenous antiviral developed by Gilead for the treatment of Ebola. Remdesivir can be administered by healthcare providers in the inpatient setting and may therefore provide the greatest benefit to patients in late stages of disease and in critical condition. Clinical trial data to date indicates that remdesivir can improve time to recovery and suggests a survival benefit; however, the mortality difference was not statistically significant. Phase 3 trials evaluating the efficacy in hospitalized patients are still ongoing. Moreover, an IV administration may pose barriers for early-stage patients, who are more likely to be managed in the outpatient setting.
Given some of the challenges in development and use cases for remdesivir, oral antivirals may provide incremental benefit to COVID-19 patients. Merck and Ridgeback Bio recently announced their collaboration to develop the oral antiviral EIDD-2801, which, like remdesivir, interrupts the virus life cycle by causing mutations in the virus genome. If able to demonstrate improved outcomes, EIDD-2801 may prove beneficial for patients in earlier stages of the disease. Results from human safety studies of EIDD-2801 are anticipated in June, with phase 2 studies launching thereafter.
Many treatments being investigated for COVID-19 aim to address the host response to the virus, including those that aim to mitigate the dangerous cytokine storm that may be seen in advanced infections. There are multiple potential targets, and several anti-IL-6 products are currently being investigated in COVID-19. Among these are Sanofi’s anti-IL-6 drug Kevzara, which demonstrated no benefit in severe patients, and Roche’s Actemra, whose phase III trial results are expected this summer. Several JAK inhibitors, which may help dampen cytokine signaling, are also in late-stage trials. Perhaps the most well-known immunomodulator includes the antimalarial hydroxychloroquine, which recently failed a randomized trial in hospitalized patients, prompting some doctors to call for an end to its use in COVID-19 patients.
But while there are numerous mechanisms being tested in late-stage trials, these symptomatic therapies will likely be taken alongside antivirals in efforts to combat the infection while simultaneously controlling the immune response. Just as numerous are the types of agents that aim to treat COVID-19, so too are the permutations based on various combinations of the aforementioned therapies. For example, remdesivir will be tested both in combination with Actemra and in combination with JAK inhibitor Olumiant.
Taken together, there are many promising potential products in the pipeline to address different facets of COVID-19 infection. While repurposed drugs might have a head start through late-stage testing, clinicians need safe and effective ways to prevent infection or treat the virus head on. In an upcoming blog, we will highlight when we might expect some of these products to hit the market and potential pitfalls in the development timeline.
As we continue to monitor the COVID-19 pipeline in our biweekly tracker, we aim to better understand not only the volume of different therapy types but also the potential timelines based on key milestones. In our next post, we will reassess the pipeline landscape and outline the timing of potential approvals based on the latest clinical evidence.
