In this article, we'll continue talking about the nAb drugs that have entered clinical trial.
REGN-COV2
REGN-COV2 is a new type of mixture composed of two mAbs (REGN10987 and REGN10933, recently named imdevimab and casirivimab, respectively) for the treatment of COVID-19 patients and the prevention of SARS-CoV-2 (
https://www.creativebiolabs.net/search?key=2019-ncov&ty=product&cid=0) infection developed by Regeneron.
REGN10987 and REGN10933 non-competitively bind to different epitopes of SARS-CoV-2 S RBD (
https://www.creativebiolabs.net/symbolsearch_2019-nCoV%20S%20%28RBD%29.htm) simultaneously, thereby preventing the interaction of viral proteins with ACE2. The antigen-binding fragment of REGN10933 binds to the top of the RBD, almost completely covering the area where the ACE2 binding site is located, while REGN10987 acts on the side of the RBD, with little possibility of interfering with ACE2.
REGN-COV2 is currently being evaluated in four late-stage clinical trials that are recruiting volunteers. Two Phase II/III trials (NCT04425629 and NCT04426695) separately studied the efficacy of REGN-COV2 in reducing virus shedding in adult hospitalized and non-hospitalized COVID-19 patients compared with placebo. The two studies will be conducted in the United States, Brazil, Mexico, and Chile, and are expected to enroll 1,850 inpatients and 1,050 non-inpatients.
Early data analysis of 275 non-hospitalized patients showed that REGN-COV2 reduced the viral load and reduced the time required to relieve symptoms. In other patients with high viral load (greater than 107 copies/mL), compared with the placebo group, the average daily viral load of REGN-COV2 within 7 days was significantly reduced. Compared with the placebo group, patients treated with REGN-COV2 had an average 10-fold reduction in viral load on d5, and a greater reduction in viral load was observed in all patients with detectable virus at the baseline examination. Prospective testing was performed on all patients (n=799) before treatment to assess whether they had measurable antiviral antibodies (seropositive patients) or none (seronegative patients). Approximately 38% were seropositive, 51% were seronegative, and 11% had no confirmed serological condition. The virological results, as well as the results of the previous analysis, indicated that seronegative patients and/or patients with a high baseline viral load benefit more from REGN-COV2 treatment. The data showed that there was no significant difference between high-dose (8g) and low-dose (2.4g) REGN-COV2 in terms of virology or clinical efficacy. In addition, these two doses were well tolerated. The clinical results of the overall population (n=799) showed that the antibody combination also reduced the need for further medical care. Compared with placebo, COVID-19-related medical visits reduced by 57% on day 29.
REGN-COV2 is also being tested in the Phase III Prevention Trial (NCT04452318), conducted on high-risk uninfected subjects who are exposed to COVID-19 patients at home. This randomized double-blind study evaluates the efficacy of REGN-COV2 in preventing 2,000 cases of symptomatic and asymptomatic SARS-COV2 infection compared with placebo. The study started in July 2020 and is scheduled to be completed in August 2021.
Regeneron shared all these results with the FDA that recently approved a low-dose emergency use authorization of REGN-COV2 for adults with mild to moderate COVID-19, who are at high risk of poor prognosis.
CT-P59
CT-P59 is a fully human anti-SARS-CoV-2 mAb developed by the Celltrion team selected by the Korean Center for Disease Control, which binds to the SARS-CoV-2 S RBD to inhibit its interaction with the ACE2 and block the virus entry. In addition, CT-P59 has been verified to neutralize the D614G variant, which is one of the most infectious mutations.
In July 2020, the Phase I clinical trial (NCT04525079) was launched, which is a randomized, double-blind, placebo-controlled, parallel group trial designed to evaluate the safety, tolerability, and pharmacokinetics of CT-P59. On September 11, 2020, the Celltrion group announced that the interim results were positive with no obvious adverse drug events. In August 2020, another Phase I clinical trial (NCT04593641) initiated, and so far, there is no result.
In September 2020, the Korean Ministry of Food and Drug Safety approved a Phase II/III trial (NCT04602000) based on the interim results of the Phase I clinical trial to evaluate the safety and curative effect of CT-P59 for patients with mild to moderate COVID-19 symptoms. This is a randomized, double-blind, placebo-controlled, and parallel group trial. The project will recruit 1,020 patients, who will be divided into three treatment groups, two using CT-P59 and one using placebo. The main result is to evaluate the treatment effect from baseline to day 14 and day 28.
All anti-SARS-CoV-2 mAbs currently undergoing late-stage clinical trials target the SARS-CoV-2 spike protein, which are full-length IgG. However, IgM/IgA, IgY-based therapies, bispecific or trispecific antibodies, single domain antibodies derived from phage display libraries, fusion proteins, or others (e.g., DARPin, mRNA encoding mAb, radiotherapy) are under development, some of which will soon make progress in clinical trials.
Engineering is also done in different ways. For example, LALA mutations are introduced into the Fc portion of CB6 to reduce the risk of Fc-mediated acute lung injury. The combination of nAb with the catalytic activity of Cas13 (fusion protein) to cut the viral RNA. These drugs can play a preventive effect as well as an antiviral effect.