COVID-19 Drugs: Study Shows That Hypoxia In COVID-19 Patients May Be Treatable With Lanadelumab, A Kinin B2 Receptor Antagonist Drug
: Researchers from COVID-19 Radboud University Medical Center-Netherlands, University Medical Center Utrecht-Netherlands and University of Bonn-Germany in a new study have shown that patients with hypoxia responded positively to treatment with the drug lanadelumab, a Kinin B2 receptor antagonist.
These study findings have led to a follow-up study at ten Dutch hospitals involving Kinin B2 receptor antagonist drugs.
The research findings were published in the journal: JAMA Network Openhttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2769237
Pulmonary edema or rapid fluid overload of the lungs is a hallmark of severe infection with SARS-CoV-2.
The researchers suggested that this involves the ACE2 receptor. The coronavirus enters the cells via this receptor, after which it can multiply. However, the ACE2 receptor not only provides a gateway for the coronavirus, but it also keeps vasodilatory kinins under control. The infection causes most of the ACE2 receptors of the lung cells to dysfunction. Without ACE2, these kinins have free rein and by binding to bradykinin receptors that can make the blood vessels leaky.
Medical internist Dr Frank van de Veerdonk and hospital pharmacist Roger Brüggemann and colleagues hypothesized that this process plays an important role in severe COVID-19 infection in a previous published study.
With regulatory approvals from the Central Committee on Research Involving Human Subjects (CMO)-Netherland and the Health Care and Youth Inspectorate (IGJ), and with the informed consent of the participating patients, the researchers tested their hypothesis with the drug icatibant.
Dr Van de Veerdonk told Thailand Medical News, "This drug is used in patients with the rare condition known as hereditary angioedema. These patients sometimes develop acute subcutaneous fluid deposits due to local leakage of blood vessels. Icatibant blocks the bradykinin receptor B2R, which quickly stops the leakage. To determine whether the drug is also suitable for the specific group of COVID-19 patients with fluid in their lungs, earlier this year we administered this drug to nine patients in the Internal Medicine Department and one patient in the Intensive Care Unit."
In the study, all the COVID-19 patients, which were in need for oxygen treatment due to fluid in their lungs, were given three doses of icatibant by subcutaneous injection at six-hour intervals.
Interestingly, the patient in the ICU recovered sufficiently within 24 hours to be moved to the ward and was discharged after 7 days. Eight of the remaining nine patients needed less oxygen supplementation within 24 hours and the ninth after 38 hours. In 18 comparable patients who served as controls, substantially higher levels of oxygen supplementation were needed over time.
Co-researcher, Brüggemann says, "Although this was not a randomized trial, the results support our hypothesis. In an early phase of the infection with severe oxygen deficit, we see that icatibant improves the situation. A disadvantage is the short-term effect of the drug. Half of the drug is broken down i
n two hours, so the effect diminishes quickly. After the treatment, three patients had to be given oxygen again because the drug had worn off."
The published study findings were actually a proof of concept, which the researchers have already built upon. Improved understanding of the role of the kinin-kallikrein system (KKS) in COVID-19 means that the researchers expect even better results from another drug.
The study team said, "The drug lanadelumab remains active for much longer than icatibant, so you will probably only need to administer it only once or twice".
Dr Van de Veerdonk added, "Lanadelumab also has a much broader effect. It inhibits the activation of the whole system that causes leakage of the blood vessels. It is therefore not only active for longer but might also be more effective."
Dr Van de Veerdonk and Brüggemann have been awarded a grant from ZonMw, a Dutch organization involved with supporting medical and healthcare startups and research, for a phase 2 clinical trial with lanadelumab for this specific group of COVID-19 patients.
Numerous Dutch hospitals are participating in the study. If this approach works, Brüggemann and Dr Van de Veerdonk expect that the research can immediately be rolled out on a large scale internationally. This is not only important for rapid recovery of patients with hypoxia admitted to the hospital but can also reduce the pressure on IC capacity.
The World Health Organization (WHO) and REMAP-CAP are directly involved in this research, and the strategy is currently being considered by several others.
Utilizing this strategy Dr Van de Veerdonk and Brüggemann aim to help patients presenting with hypoxia to recover quickly and thus avoid ICU admission.
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