Novartis Submits EUA Application to FDA for Ensovibep, a Novel DARPin Antiviral Therapy, Amid Global COVID-19 Cases Surpassing 400 Million

News on February 10, 2022 /BioValleyBIOON/ -- According to Baidu's "Real-time Updates on the COVID-19 Pandemic"Big DataReport》，As of 00:00 on February 11, 2022, the global cumulative confirmed casesMore than 400 million cases (404.64 million), with more than 5.79 million deaths.

Molecular Partners is a biotechnology company focused on developing a new class of customized protein drugs (DARPin therapies). Recently, the company announced that its partnerNovartis(Novartis) has submitted to the U.S. Food and Drug Administration (FDA) Submitted an Emergency Use Authorization (EUA) application: for the novel DARPin antiviral therapy ensovibep (MP0420) to treat COVID-19.Ensovibep is a unique trispecific DARPin protein therapy., with the ability to bind to synergistic targets, and its molecular size is much smaller than that of monoclonal antibodies. The molecule is designed to bind to three parts of the virus receptor-binding domain,Can improve efficacy and prevent viruses from escaping through mutation. However, through mutation, the virus may limit the effectiveness of single-target antibodies.

This application is based on all data from clinical and preclinical studies, including the positive results from the Phase 2 portion of the global multicenter Phase 2/3 EMPATHY study. EMPATHY is a randomized, double-blind, placebo-controlled study; the Phase 2 portion enrolled 407 symptomatic non-hospitalized adult patients with COVID-19 who were infected with SARS-CoV-2, exploring three doses of ensovibep (75mg, 225mg, 600mg) to determine the dose of ensovibep with optimal safety and efficacy.

December 2021,NovartisPositive results from part of Phase 2 were announced:Compared with placebo, a single dose of intravenous ensovibep treatment significantly reduced viral load within 8 days in a statistically significant manner., achieving the primary endpoint of this part of the study. In addition, compared with placebo, ensovibep also showed clinically meaningful benefits in two secondary endpoints: (1) a composite endpoint of hospitalization and/or emergency room (ER) visits or death; (2) time to sustained clinical recovery. According to the released data,Compared with the placebo group, the risk of COVID-19-related hospitalization and/or ER visits or death was reduced by 78% overall in the ensovibep treatment group.。The treatment groups were generally balanced in terms of demographics, baseline, and disease characteristics. In the placebo group, six events occurred among 99 patients (event rate 6.0%), with five patients hospitalized; two died due to worsening COVID-19, and one additional patient only visited the ER. In the ensovibep treatment group, four events occurred among 301 patients, with two patients hospitalized and two patients visiting the ER (event rate 1.3%). No deaths occurred among patients receiving ensovibep, all doses were well-tolerated, and no unexpected safety issues were identified at any dose. The lowest dose, 75mg, was selected as the dose for further development.

In October 2020, Novartis and Molecular Partners reached a collaboration to develop two DARPin protein therapies targeting COVID-19, namely ensovibep (MP0420) and MP0423. These are two DARPin antiviral therapies that target multiple distinct sites of SARS-CoV-2, enhancing antiviral activity and preventing the virus from escaping through mutations. Based on the positive results from the Phase 2 portion of the EMPATHY study,NovartisConfirmed exercise of option, paying Molecular Partners CHF 150 million for license to ensovibep.

DARPin Module Screening (Top); Comparison of DARPin Molecules with Monoclonal Antibodies (Bottom) (Click image to enlarge)

DARPin (Designed Ankyrin Repeat Proteins) are a new generation of target-binding proteins derived from naturally occurring ankyrin repeat proteins. These proteins have naturally evolved to exhibit high-affinity binding to targets and are typically connected to another protein via a fusion domain, anchoring the latter to a specific site.

DARPin therapy is a new class of protein therapy that will open up additional dimensions of multispecificity and multifunctionality. DARPin candidates include multiple designed ankyrin repeat binding domains, which can target up to six or even more targets, offering additional benefits compared to traditional monoclonal antibodies or other available protein therapies. The DARPin technology is a rapid and highly cost-effective discovery engine capable of producing candidates with desirable developmental characteristics and high production yields.

DARPin Platform Technology Expands the Application Scope of Traditional Protein and Antibody Methods, Enabling Rapid Generation of a Wide Variety of Multifunctional Drug Candidates Capable of Simultaneously Binding to Multiple Targets. DARPin Molecules Are Constructed from DARPin Protein Modules, Which Are Single-Domain Proteins, One-Tenth the Size of a Full Antibody, Featuring a Constant Framework and a Randomized Target-Binding Surface.

Ensovibep Structural Features (Click image to enlarge)

DARPin molecules offer a differentiated approach to treating COVID-19 through a single molecule that can simultaneously bind to three sites on the SARS-CoV-2 virus, neutralizing the virus through multiple mechanisms. This provides potentially broader efficacy, including in both therapeutic and prophylactic settings, while reducing the likelihood of viral resistance. Additionally, DARPins are produced via rapid, high-yield microbial fermentation, offering potential speed and cost advantages compared to antibody production using mammalian cells.

Compared with monoclonal antibodies, DARPin molecules are very suitable for pandemic environments due to their advantages of multi-specific target binding, long half-life supporting sustained activity, and highly scalable production.

Ensovibep is a unique trispecific DARPin protein therapy with synergistic target binding capabilities, reporting one of the strongest viral suppression potencies to date. Ensovibep contains three RBD binding domains, a distinctive design that enhances potency and prevents viral escape through mutation. It has indeed demonstrated potent inhibitory activity against all COVID-19 variants of concern to date and has the potential to maintain suppressive activity against future COVID-19 variants. This broad-spectrum activity is essential for any treatment related to COVID-19 patients.

In addition, ensovibep also has a half-life enhanced DARPin domain, which binds to human serum albumin (HSA) to support prolonged activity. HSA is present at high levels in lung tissue, which may offer further benefits in respiratory viral diseases. (Bioon.com)

Source of the original text:EMERGENCY USE AUTHORIZATION REQUEST FOR ENSOVIBEP SUBMITTED TO THE US FOOD AND DRUG ADMINISTRATION FOR THE TREATMENT OF COVID-19