Investigators hope ATR-002 drug will also be effective against ‘Long-Covid’

Tübingen, Germany-based Atriva Therapeutics, a biopharmaceutical company that is pioneering the development of host-targeting antiviral therapies, has enrolled its first patient in its Phase II RESPIRE [1] trial in COVID-19. Prof. Martin Witzenrath, M.D., Vice Director Department of Infectious Diseases and Respiratory Medicine, supervised the first administration of study medication (MEK inhibitor ATR-002 or placebo) at the Charité – Universitätsmedizin Berlin, Germany.

Dr Rainer Lichtenberger, CEO of Atriva Therapeutics, commented: “We are excited to assess the efficacy of ATR-002 in treating COVID-19 and are looking forward to the results of the clinical trial. We can now test our lead candidate against SARS-CoV-2 because our pharmacological target is a common cellular mechanism that RNA viruses use. ATR-002 leaves the virus itself untouched but blocks a cellular factor that the virus needs for its replication and has the potential to reduce the viral load in the infected host.

“Host-directed approaches maintain efficacy also against mutated viruses – a problem that we are commonly seeing in the influenza virus and, unfortunately, in SARS-CoV-2 as well. If we were to see the positive outcomes of the trial we hope for, ATR-002 could provide efficient help against COVID-19 regardless of the given genetic subtype of the underlying viral strain.”

Prof. Gernot Rohde, M.D., Head of Pneumology and Professor for Respiratory Medicine and Allergology at the Goethe University Hospital, Frankfurt am Main, Germany and Global Coordinating Investigator of the RESPIRE trial, said: “While we have been lucky that SARS-CoV-2 vaccines were developed at unprecedented speed, we still are in desperate need for effective therapies against COVID-19. The pandemic situation remains very critical and is far from being under control.

“Being able to contribute to the development of a COVID-19 therapy, I am very much looking forward to the effects that we may see with ATR-002. I am convinced that a medication that can prevent hospitalized patients with a moderate to severe stage of COVID-19 from deteriorating and requiring ICU admission and ventilator support would mean huge progress and could also play a role in impeding the severe long-term effects that are being described as “Long COVID” Syndrome (PASC).”

RESPIRE trial

RESPIRE is a randomized, double-blind, placebo-controlled, international, multi-center Phase II clinical trial in 220 adult patients with moderate to severe COVID-19, requiring hospitalization, but not requiring ICU admission or ventilator support at the time of screening or randomization. On top of standard of care, half of the patients will receive ATR-002 900 mg, administered as tablets once daily on day 1, followed by ATR-002 600 mg once daily on days 2 to 6. Patients in the control group will receive placebo in a matching scheme, on top of standard of care.

The primary objective of the study is to demonstrate the efficacy of ATR-002 versus placebo in addition to standard of care; secondary endpoints include the measurement of changes in clinical signs and symptoms as well as other relevant clinical parameters. Outcomes will be assessed based on the clinical severity status on day 15, using a 7-point ordinal scale as suggested by the WHO COVID-19 Therapeutic Trial Synopsis [2]. All patients will be followed-up for 90 days. The study will also evaluate the pharmacokinetics of ATR-002.

ATR-002’s mode of action

Atriva’s lead product ATR-002 is developed specifically to treat diseases such as influenza and COVID-19, caused by RNA viruses. ATR-002 is a clinical stage MEK inhibitor drug candidate targeting the intracellular Raf/MEK/ERK signaling pathway. This pathway is central for replication of many RNA viruses, such as the influenza virus, hantavirus or respiratory syncytial virus (RSV) and also SARS-CoV-2, the virus that causes COVID-19.

In influenza virus infected cells, the interaction of ATR-002 with MEK (MAPK/ERK kinase) prevents export of the viral genome protein complexes (ribonucleoprotein, RNP) from the nucleus to the cytoplasm, thus blocking the formation of functional new viral particles. This ultimately reduces the viral load in the body. In addition, ATR-002 has the potential to modulate the pro-inflammatory cytokine response of the body, avoiding overshooting cytokine response that can be caused by such viral infections. MEK inhibition can reduce the gene expression of some of the cytokines involved, like TNF-α, IL-1ß, IP-10, IL-8, MCP-1 and MIP-1a, and thus mitigate the overactive inflammatory response in the lungs of patients who are severely ill with influenza or COVID-19.

References

[1] RESPIRE – A Randomized, Double-Blind, Placebo-Controlled, Multi-Centre Clinical Trial to Evaluate the Safety and Efficacy of ATR-002 in Adult Hospitalized Patients with COVID-19.

[2] https://www.who.int/publications/i/item/covid-19-therapeutic-trial-synopsis.

SARS-CoV-2 mutations similar to those in the B1.1.7 UK variant could arise in cases of chronic infection, where treatment over an extended period can provide the virus multiple opportunities to evolve, say scientists.

Given that both vaccines and therapeutics are aimed at the spike protein, which we saw mutate in our patient, our study raises the worrying possibility that the virus could mutate to outwit our vaccines

Writing in Nature, a team led by Cambridge researchers report how they were able to observe SARS-CoV-2 mutating in the case of an immune-compromised patient treated with convalescent plasma. In particular, they saw the emergence of a key mutation also seen in the new variant that led to the UK being forced once again into strict lockdown, though there is no suggestion that the variant originated from this patient.

Using a synthetic version of the virus Spike protein created in the lab, the team showed that specific changes to its genetic code – the mutation seen in the B1.1.7 variant – made the virus twice as infectious on cells as the more common strain.

SARS-CoV-2, the virus that causes COVID-19, is a betacoronavirus. Its RNA – its genetic code – is comprised of a series of nucleotides. As the virus replicates itself, this code can be mis-transcribed, leading to errors, known as mutations. Coronaviruses have a relatively modest mutation rate at around 23 nucleotide substitutions per year.

Of particular concern are mutations that might change the structure of the ‘spike protein’, which sits on the surface of the virus, giving it its characteristic crown-like shape. The virus uses this protein to attach to the ACE2 receptor on the surface of the host’s cells, allowing it entry into the cells where it hijacks their machinery to allow it to replicate and spread throughout the body. Most of the current vaccines in use or being trialled target the spike protein and there is concern that mutations may affect the efficacy of these vaccines.

UK researchers within the Cambridge-led COVID-19 Genomics UK (COG-UK) Consortium have identified a particular variant of the virus that includes important changes that appear to make it more infectious: the ΔH69/ΔV70 amino acid deletion in part of the spike protein is one of the key changes in this variant.

Although the ΔH69/ΔV70 deletion has been detected multiple times, until now, scientists had not seen them emerge within an individual. However, in a study published today in Nature, Cambridge researchers document how these mutations appeared in a COVID-19 patient admitted to Addenbrooke’s Hospital, part of Cambridge University Hospitals NHS Foundation Trust.

Reference:

https://doi.org/10.1038/s41586-021-03291-y

A pan-European consortium of biotech companies announced April 23 that they will collaborate to develop and manufacture on a large scale a novel adenoviral vector-based vaccine against COVID-19.
The vaccine candidate is expected to enter clinical trials mid 2020 with vaccine production planned to start following the successful trials. If all goes according to plan, approximately 6 million doses of the vaccine are expected to be available early in 2021.
The consortium comprises Italian company ReiThera, German LEUKOCARE, and Belgian Univercells. They provide expertise in vector-based vaccine development, vaccine formulation and manufacturing, respectively. Their combined expertise is expected to enable efficient and ultra-fast vaccine development.
The vaccine technology is based on a novel, ReiThera-proprietary simian adenoviral vector with strong immunological potency and low pre-existing immunity in humans. Vaccines based on simian adenoviral vectors have been extensively evaluated in Phase 1 and 2 clinical trials and proved to be safe and immunogenic. ReiThera is currently preparing for a COVID-19 first-in-human trial to be started in Italy in mid 2020.
In parallel to its clinical development, the consortium will start manufacturing and stockpiling the vaccine. With these pilot scale processes, approximately 6 million doses of the vaccine are expected to be available early in 2021. Based on the Phase 1/2 clinical results and a path agreed with regulatory authorities, the intention with these doses will be to vaccinate the most exposed people such as medical and healthcare professionals and highly vulnerable individuals.
LEUKOCARE will contribute to the drug product development by developing a highly stable liquid vaccine formulation based on its well-established technology platform for formulations of viruses and viral vectors.
Univercells will take advantage of the previous successes of its scale-X bioreactor and NevoLine biomanufacturing platform to adapt and scale-up the technology platform and enable the mass production of ReiThera’s vaccine candidate.
Michael Scholl, Chief Executive Officer of LEUKOCARE, commented: “By combining the experience of the partners, the advanced stages of this vaccine development will allow for a swift response to the COVID-19 pandemic. Facing the current challenges, our approach for the fast and low-risk development of drug products with superior stability characteristics is even more important regarding timelines and social impact.”

Using laser light techniques, University of Amsterdam physicists and medical researchers have found that small cough droplets, potentially containing virus particles, can float in the air in a room for many minutes, especially when the room is poorly ventilated. Good ventilation in public spaces (e.g. public transport, nursing homes) is therefore crucial to slow down the spread of the coronavirus. The results were published in The Lancet Respiratory Medicine on 28 May 2020.
The research was carried out by physicists Daniel Bonn, Stefan Kooij and Cees van Rijn from the UvA Institute of Physics, together with medical researchers Aernout Somsen (Cardiology Centers of the Netherlands) and Reinout Bem (Amsterdam University Medical Centers).
The researchers asked healthy test persons to speak and to cough, and used laser light to analyse the droplets that were produced. Both during speech and coughing, large amounts of small droplets (between roughly 1 and 10 micrometres in size) were observed. During coughing, larger droplets (up to 1 millimeter in size) are also produced. Those droplets fall to the ground within one second, however, and therefore have a much smaller probability of transmitting viruses.
The small droplets only move very slowly to the ground due to the large amount of air drag they experience. The researchers found that such droplets can stay in the air for several minutes. After a single cough, it takes about five minutes for the number of small droplets in the air to be halved. These tiny droplets are therefore much more dangerous when it comes to possible transmission of the coronavirus.
Ventilation
When the same measurements were repeated in a well-ventilated room, the results improved dramatically. With only mechanical ventilation turned on, half of the droplets disappeared within 2.5 minutes, but in a room that also had a door and window open, the number of droplets was halved after 30 seconds – ten times faster than in the unventilated room.
The result is important for making better policies to slow down the spread of the coronavirus. Despite physical distancing, spaces like public transportation and nursing homes can still be centres for spreading the virus if insufficiently ventilated. When droplets remain in the air for a long time, proximity tracing via smartphone apps is also an insufficient precaution. The researchers therefore recommend healthcare authorities consider recommendations to ensure adequate ventilation wherever possible in public spaces
Small droplet aerosols in poorly ventilated spaces and SARS-CoV-2 transmission – The Lancet Respiratory Medicine https://doi.org/10.1016/S2213-2600(20)30245-9 Indoor environments
Meanwhile, in a similar study, scientists from Surrey’s Global Centre for Clean Air Research (GCARE), with partners from Australia’s Queensland University and Technology, argue that the lack of adequate ventilation in many indoor environments – from the workplace to the home – increases the risk of airborne transmission of Covid-19.
They note that Covid-19, like many viruses, is less than 100mn in size but expiratory droplets (from people who have coughed or sneezed) contain water, salts and other organic material, along with the virus itself. However, as the water content from the droplets evaporate, the microscopic matter becomes small and light enough to stay suspended in the air and over time the concentration of the virus will build up, increasing the risk of infection – particularly if the air is stagnant like in many indoor environments.
The study highlights improving building ventilation as a possible route to tackling indoor transmission of Covid-19.
Could fighting airborne transmission be the next line of defence against COVID-19 spread? www.sciencedirect.com/science/article/pii/S2590252020300143 Modelling
Additionally, a study carried out in March this year by four Finnish research organisations modelled the transport and spread of coronavirus through the air. They note that preliminary results indicate that aerosol particles carrying the virus can remain in the air longer than was originally thought, so it is important to avoid busy public indoor spaces. This also reduces the risk of droplet infection, which remains the main path of transmission for coronavirus.
The research has been has been submitted for peer-review and published on https://arxiv.org/abs/2005.12612. The paper details how they have modelled the airborne transport of different-sized droplets. These are emitted through coughing, so the study evaluated the quantities of particles that someone could come into contact with upon entering a supermarket or any other indoor public space.
Assistant professor at Aalto University, and project coordinator, Ville Vuorinen, says that both previous related research, and a number of well-known infection spikes, indicate a substantial risk of coronavirus through inhalation of aerosol particles, as well as direct droplet transmission and transmission from surfaces. The 3D flow simulations and analyses carried out in the project also support these ideas.
The 3D simulation shows how droplets of varying size travel in an indoor airflow https://youtu.be/f7I0O0C_eqg credit: Aalto University / Finnish Meteorological Institute / VTT / University of Helsinki / IT Center for Science CSC. Animation: Jyrki Hokkanen, CSC – IT Center for Science Ltd.