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 new study by Chinese researchers to check aerosol and surface distribution of SARS-COV-2 in an Intensive Care Unit (ICU) and General Ward (GW) with COVID-19 infected patients found that the virus can be detected in the air up to 4 metres away from patients. In addition, they found the virus was widely distributed on floors and recommend that persons disinfect shoe soles before walking out of wards containing COVID-19 patients.
They also found the virus on computer mice, trash cans, and sickbed handrails.
The early release study was published April 10 in Emerging Infectious Diseases.
The aerosol distribution of the virus has been controversial with previous findings based on very small studies which may not reflect real conditions in a hospital at full capacity. This new study, however, tested surface and air samples in a busy hospital in Wuhan from February 19 through March 2 at the height of outbreak in that city.
The study is particularly pertinent for healthcare workers treating COVID-19 patients and offers a number of conclusions and recommendations.

1. SARS-CoV-2 was widely distributed in the air and on object surfaces in both the ICU and GW, implying a potentially high infection risk for medical staff and other close contacts.
2. The SARS-CoV-2 aerosol distribution characteristics in the GW indicate that the transmission distance of SARS-CoV-2 might be 4 metres.
3. The environmental contamination was greater in the ICU than in the GW; thus, stricter protective measures should be taken by medical staff working in the ICU.

They also found that as the virus settles on the floor it could be tracked around the hospital where healthcare workers from the ICU and GW had walked, such as the floor of the pharmacy.
On this evidence the authors highly recommend that persons disinfect shoe soles before walking out of wards containing COVID-19 patients.
The researchers note that as of March 30 no healthworkers at the hospital had become infected and point out that appropriate precautions can effectively prevent infection.
The authors note that the results of their nucleic acid test do not indicate the amount of viable virus. And that because the minimal infectious dose is unknown, the aerosol transmission distance cannot be strictly determined.
doi: 10.3201/eid2607.200885

As the COVID-19 pandemic upends life as people know it, changing daily routines, limiting social interactions and shaking their sense of safety, a mental health experts from U.S. hospital Cleveland Clinic’s Mellen Center is stressing that it is perfectly acceptable to feel sad about all of it.
She points out that grief is a natural response to loss – whether it is the loss of a loved one, or the loss of a sense of normalcy.
“We are experiencing a lot of disappointment right now – in both small and big ways – and grief is going to be a factor,” says clinical health psychologist Amy Sullivan, PsyD, ABPP.
“It’s really important that we process this and stay connected to other people in safe ways,” she adds.
Regarding how people should go about dealing with all of these difficult and unexpected feelings bubbling up, she says there is no right or wrong way. However, she offers four suggestions that can help people to cope with current events.
1. Look through the lens of grief and process emotions
She says that the stages of grief can provide a helpful framework for navigating these complex emotions. Experts recognize these stages as denial, anger, bargaining, despair, and acceptance. However, these experts also know that people do not step neatly from one stage to the next in this exact order, she says.
“Grief can come in waves and change on a very regular basis. Our feelings can change on a daily, or even an hourly, basis,” she explains.
Dr. Sullivan adds it is normal to go from feeling despair one day to anger the next.
“The first thing we need to do is to recognize that it is normal to have these waves of emotions that are happening on a regular basis,” Dr. Sullivan says.
Next, she says, acknowledge the loss whether it is knowing or losing someone with COVID-19, losing jobs, missing friends or family.
“Those are all very sad, difficult things for people to manage,” Dr. Sullivan says.
“Feel what you are feeling – whether it is being overwhelmed, anxious, powerless or anything else, it can help to identify and name these emotions,” she advises.
“It can be quite powerful to sit with those feelings for a few moments – to really recognize those emotions and normalize them,” she says.
However, she advises people to set a time limit on this, suggesting they give themselves five minutes to feel that emotion, and then move on to something that they know is a positive coping skill for them.
“It is important for us to accept where our feelings are at the moment and process through them, and then move into a more positive position of acceptance,” she says.
She says this can be done by identifying their own best coping mechanisms
“This is a time when people need to become innovative and develop their own individual sense of coping that works for them during this time,” she says. Examples might include deep breathing, mindfulness exercises, journaling, talking with another person, or going for a walk.
“If it comes to a point where someone cannot handle these feelings on their own, they need to seek mental health help,” Dr. Sullivan says.
2. Fight the urge to disengage
Dr. Sullivan stresses that staying connected is a powerful tool for coping during hard times. Whether that comes in the form of video chatting or sending a good old-fashioned letter, staying in touch with family, friends, neighbours and coworkers can help people to keep a positive attitude, she says.
She adds that many trained mental and behavioural health professionals are currently seeing patients through virtual visits, so that if people are having trouble coping, this could be a solution.
3. Focus on what can be controlled
Dr. Sullivan says that when there is so much uncertainty about the future, it is easy for people to get carried away, playing out the worst-case scenarios in their heads, for example worrying about themselves or someone else getting COVID-19, or wondering if things will ever get back to normal.
“Anticipating negative events can bring a sense of anxiety or fear,” Dr. Sullivan says.
She advises that, instead of agonizing over the things that cannot be known or controlled, people should be aware of what they do have control over. For example, they can choose how much news or social media they consume in a day, and they can decide what they eat. She recommends being mindful about these choices, and focusing on staying in the present.
4. Be open to joy
Lastly, Dr. Sullivan advises people to find joy and gratitude in the small things, like a video chat with family members, or the rush of fresh air when they open a window or step outside. She adds that if they are under a lockdown order, they can find ways to appreciate the opportunity to step back from the hustle and bustle of everyday life and being home.