Coronavirus Notebook: EMA Begins Assessing AZ’s Evusheld, Apeiron Starts Phase I Trial Of Inhaled APN01
Executive Summary
The UK has explained its strategy for administering COVID-19 vaccines to people who have been partially immunized abroad.
The European Medicines Agency has begun a rolling review of another monoclonal antibody (MAb) combination product for the prevention of COVID-19, this time AstraZeneca PLC’s Evusheld, which contains tixagevimab and cilgavimab.
The agency’s human drugs committee, the CHMP, started the rolling review based on preliminary results from clinical studies that suggest the product could help to protect against the disease in adults. It has also begun evaluating non-clinical data from laboratory and animal studies.
More data on the quality, safety and effectiveness of Evusheld will be assessed as they become available, and the rolling review will continue until enough evidence is available for the company to submit a formal marketing authorization application (MAA), the EMA noted.
“While EMA cannot predict the overall timelines, it should take less time than normal to evaluate an eventual application because of the work done during the rolling review,” it said. “EMA will communicate further when a marketing authorisation application for the medicine has been submitted.”
The agency explained that tixagevimab and cilgavimab have been designed to attach to the spike protein of the SARS-CoV-2 virus at two different parts, stopping the virus from entering the body’s cells and causing infection. Because the antibodies attach to different parts of the protein, using them in combination may be more effective than using either alone, it added.
Rolling reviews are currently under way for three other different MAb-based products for COVID-19: bamlanivimab plus etesevimab, regdanvimab and sotrovimab. (Also see "EMA 'Confident' Of New COVID-19 Vaccine Approvals By Year End" - Pink Sheet, 9 Sep, 2021.)
Earlier this week the EMA said that it had received an MAA for Regeneron Pharmaceuticals, Inc./Roche Holding AG’s Ronapreve (casirivimab + imdevimab), which also underwent a rolling review. ( (Also see "Coronavirus Notebook: CEPI Calls For Reduced-Dose Booster Trials, Regeneron’s Ronapreve Filed In EU" - Pink Sheet, 12 Oct, 2021.)
Apeiron’S APN01 Enters Phase I
Another potential treatment for COVID-19 at an earlier stage of development is Apeiron Biologics AG’s APN01, an inhaled recombinant human angiotensin-converting enzyme 2 (rhACE2) that has just begun a company-sponsored Phase I trial.
APN01 has been developed to treat COVID-19 patients by neutralizing SARS-CoV-2 in the lungs and mitigating lung damage caused by the infection, Apeiron noted.
The ACE2 receptor has been identified as the critical cellular entry receptor for the SARS-CoV-2 virus, it said. In addition, human ACE2 is a key enzyme regulator of the renin angiotensin aldosterone system (RAAS), a peptide system involved in blood pressure, lung disorders, diabetic kidney disease, inflammation, or cardiovascular diseases.
The double-blind, placebo-controlled, dose-escalation study plans to enrol about 40 healthy volunteers in Austria to assess the product’s safety, tolerability, pharmacokinetics and pharmacodynamics.
The primary study objective is to evaluate the safety and tolerability of single and multiple ascending doses of inhaled APN01 when administered via a jet nebulizer in healthy subjects, Apeiron said. Secondary objectives include the maximum tolerated dose and the effect of APN01 on key pharmacodynamic biomarkers of RAAS.
“Delivery of the drug candidate directly to the respiratory tract should block viral entry into the lung cells and control inflammation" – Markus Zeitlinger, principal investigator
“Preliminary data from ongoing studies with inhalation of ACE2 based therapeutics show high efficacy in SARS-CoV-2 preclinical models,” said Markus Zeitlinger of the Department of Clinical Pharmacology at the Medical University of Vienna, and principal investigator of the trial.
“Delivery of the drug candidate directly to the respiratory tract should block viral entry into the lung cells and control inflammation. Importantly, APN01 may also be suitable against infections with variants of SARS-CoV-2 as already shown preclinically.”
Apeiron’s chief scientific and medical officer, Romana Gugenberger, said that offering an inhalation therapy rather than an intravenous product allowed patients at an earlier stage of the disease to treat themselves, optimizing treatment costs and reducing health care professionals’ contact risks.
“This study will form the basis not only for the treatment of COVID-19 with inhaled APN01 but enables further development strategies in chronic respiratory diseases with high unmet medical need such as chronic obstructive pulmonary disease and pulmonary arterial hypertension,” she added.
In parallel, APN01 is to be administered intravenously in a US Phase II trial conducted by the Vanderbilt University Medical Center in Nashville and supported and funded by the National Institutes of Health. The four-arm, randomized, double-blind, placebo-controlled trial is enrolling about 1,600 COVID-19 patients at more than 50 US sites.
UK On Vaccinating Partly Immunized People
The UK government has said that people who have received a first dose of a COVID-19 vaccine abroad and who wish to come to stay in the UK should receive the same vaccine for their second dose unless it is not available in the UK, in which case a shot of the “most similar” vaccine should be offered.
For example, if the person has received Pfizer Inc./BioNTech SE’s Comirnaty as the first dose, they should also be offered this as the second dose. If Comirnaty is not available, they should be offered the Moderna, Inc. vaccine. Both vaccines are authorized for use in the UK.
However, if an individual has received a vaccine not approved in the UK, such as Novavax, Inc.’s Covovax, the Russian Gamaleya Center’s Sputnik V, or Bharat Biotech’s Covaxin, they should be offered “any suitable locally available alternative” in the UK.
The advice, published by the UK Health Security Agency, is needed because while four coronavirus vaccines have been authorized in the UK, other vaccines are being administered around the world. Some have an emergency use authorization from the World Health Organization, while others are currently under review or have not yet been submitted for review, the UKHSA notes.
“The various COVID-19 vaccines differ in their immunogenicity and effectiveness,” it says. “Whilst data on vaccine effectiveness is still evolving and limited for some vaccines, current data indicates that some vaccines appear to have lower effectiveness than others.”
To optimize protection for individuals who have received COVID-19 vaccines abroad and who now plan to stay in the UK, the UKHSA has issued guidance on what further vaccination is recommended.
Each of the vaccines concerned is listed in a table in the guidance together with the name of the manufacturer, the authorized vaccination schedule, advice from the UKHSA, and the UK recommended alternative vaccine. “As knowledge about the effectiveness of the different COVID-19 vaccines is still evolving, some recommendations may change,” it says.
In most cases, if an individual has had only partial primary vaccination, the same (or closest alternative) vaccine should be given with at least an eight-week interval after the previous dose. If more than eight weeks have passed, the second vaccine should be given as soon as possible.
If the primary vaccination course has been completed, no more vaccine will be required unless the individual was severely immunocompromized at or around the time of the first or second dose, in which case a third primary dose should be given.
The recommendations are slightly different for vaccines such as the single-dose Sputnik Light and the Sinopharm Group Co. Ltd. vaccine, which is given in either two or three doses.
Boosters
People who are eligible for a booster dose should be given a full dose of Comirnaty or a half dose of the Moderna vaccine, with a minimum interval of six months after the final primary dose.
“So for those considered fully vaccinated before arrival, the six months is taken from their final dose given overseas; for those requiring one or more UK doses, the six-month interval is taken from the final ‘additional’ dose given in the UK,” the UKHSA explains.
Separate government guidance was recently published for international travelers who have taken part in clinical trials of COVID-19 vaccines but whose vaccination might not be recognized as being fully immunized. Those people will be offered two doses of an approved vaccine, allowing them to have the necessary certification status to travel to countries that do not currently recognize trial vaccinations. ( (Also see "Coronavirus Notebook: CEPI Calls For Reduced-Dose Booster Trials, Regeneron’s Ronapreve Filed In EU" - Pink Sheet, 12 Oct, 2021.)