AstraZeneca Launches Phase III Trials for Long-Acting Antibody Combination AZD7442 Against COVID-19

Today, AstraZeneca announced that its long-acting antibody combination (LAAB) will initiate a Phase III clinical trial for prevention involving 6,000 participants and a Phase III clinical trial for treatment involving 4,000 participants. The drug, codenamed AZD7442, is a mixture of two antibodies called COV2-2196 and COV2-2130, which bind to two different sites on the SARS-CoV-2 spike protein. This drug was acquired by AstraZeneca from Vanderbilt University in June this year and modified using their Fc modification technology to extend its half-life. AstraZeneca received $460 million in funding from the U.S. government for the development of this project, making it the third antibody drug supported by the U.S. government. The government has committed to providing the product free of charge if it is approved as a preventive medication. According to the agreement, AstraZeneca will supply 100,000 doses of AZD7442 this year and 1 million doses next year.

Drug Source Analysis

The global pandemic of COVID-19 has mobilized pharmaceutical companies, both large and small, to respond to this once-in-a-century health crisis. The earliest efforts to repurpose existing drugs through cell-based screening led to two candidates undergoing rigorous Phase III clinical trials: remdesivir and hydroxychloroquine. Coincidentally, the New England Journal of Medicine (NEJM) published the latest Phase III results for both drugs simultaneously yesterday. Although the two agents demonstrated nearly equivalent activity in cellular assays, their clinical outcomes differed. Remdesivir was shown to shorten hospital stays but failed to reduce four-week mortality, whereas hydroxychloroquine proved ineffective. Recently, the combination of JAK inhibitors with remdesivir has been found to further reduce hospitalization duration. It is worth noting that remdesivir had previously failed in one Phase III trial, while hydroxychloroquine failed in multiple therapeutic Phase III studies. Neither of these former "model students" ultimately met initial expectations. While shortening hospital stays is an achievement, it is mortality rates that continue to cause global alarm.

Currently, the only agent demonstrating a survival benefit is the old steroidal hormone drug dexamethasone; however, this medication does not reduce viral load and is effective only in patients with severe disease. For patients with early-stage mild illness, the optimal outcome is to rapidly reduce viral load and prevent progression to severe disease. Although remdesivir is suitable for patients with mild symptoms, as a direct-acting antiviral agent, it fails to reduce viral load, raising suspicions that its mechanism of action involves components beyond antiviral activity. Recently, Eli Lilly and Regeneron sequentially announced Phase II clinical results for their respective COVID-19 antibodies and antibody cocktails. Despite suboptimal tissue distribution, these antibodies demonstrated potent viral clearance efficacy due to their ability to directly neutralize the virus. In particular, the antibody cocktails REGN-CoV2 and LY-CoV555, which contain two antibodies binding to different sites on the spike (S) protein, can more effectively prevent viral escape via mutation and have shown credible efficacy in reducing viral load. The recent case of U.S. President Trump contracting COVID-19 and subsequently showing signs of improvement after immediate treatment with REGN-CoV2 has further drawn attention to this therapeutic approach.

However, these antibodies require high effective doses, approximately 7–8 grams per four injections. Given the typical half-life of antibodies spanning several weeks, a single dose might suffice for therapeutic purposes; however, this regimen is inconvenient and costly for prophylactic use. AstraZeneca’s long-acting antibody may partially address this issue, with reported efficacy lasting 6–12 months—potentially longer than the protection period offered by vaccines. Nevertheless, long-acting agents are not without risks; adverse reactions, if they occur, are more difficult to reverse. Due to the urgent nature of the pandemic, these antibodies likely did not undergo long-term safety trials, thus posing certain risks if no reversal measures are available. Typically, the adoption of long-acting formulations is justified only after the drug itself has demonstrated a robust safety profile over extended periods of use. For instance, the semiannual PCSK9 RNAi therapy was supported by extensive data from multiple large-scale Phase III clinical trials and post-marketing safety surveillance of its preceding antibody-based treatments. The introduction of a novel drug with a six-month half-life, lacking comprehensive clinical safety data, underscores the exceptional urgency characterizing the COVID-19 pandemic.

Another consideration for engineering the Fc region of these two antibodies may be to avoid the so-called antibody-dependent enhancement (ADE) effect. This adverse effect can also occur via Fc receptors, whereby cells expressing these receptors may internalize antibodies that have already bound to SARS-CoV-2. In most cases, these internalized antibodies and viruses are degraded; however, in rare instances, the host cell may become a new site for viral replication. ADE is a concern in antibody and vaccine development, but there is currently no evidence indicating that this phenomenon occurs with SARS-CoV-2. Therefore, Fc engineering serves a dual purpose: extending half-life (potentially by increasing binding to the neonatal Fc receptor through amino acid substitutions) and reducing the risk of ADE by decreasing binding affinity to Fc receptors on certain immune cells. This approach achieves two goals with one strategy, although the former carries its own risks, while the latter may be an unnecessary concern.