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 Loughborough University academic is providing guidance to clinicians who are likely to be having – and training people who will have – difficult conversations with patients suffering from COVID-19 or those closest to them. Professor Ruth Parry, an expert in healthcare communication and interaction, has outlined a series of evidence-based principles with the help of her Loughborough colleague Becky Whittaker, Sharan Watson, of the University of Derby, and Dr Ruth England, of Royal Derby Hospital.
The team shared the recommendations with NHS Health Education England and these have been used to develop a series of open access resources that aim to support healthcare staff who will be having difficult conversations in relation to the coronavirus.
The principles, which have also been added to the International Association for Hospice and Palliative Care’s COVID-19 resources list*, are based on research by Professor Parry and other communication scientists worldwide who have recorded and analysed thousands of difficult conversations across various health and social care settings in the UK, Australia, Japan, and the US.
Professor Parry, who receives funding from the National Institute for Health Research (NIHR), says her guidance steers away from providing recommended phrases or scripts as it is important to equip health workers with the tools to communicate flexibly according to individual circumstances.
Having a conversation by phone, conversations where the staff member who is to do the talking is wearing PPE (Personal Protection Equipment), and conversations with people who have varying degrees of knowledge and distress are all examples of circumstances that can impact how a conversation should be constructed.
What’s more, Professor Parry says giving difficult news over the phone or when wearing Personal Protection Equipment are circumstances that staff would normally want to avoid – in normal circumstances, the health services strive to ensure that these difficult conversations are led by highly experienced professionals, face-to-face, and in calm environments.
Professor Parry has divided her advice into key areas. They include (with a brief overview of what they cover):

• Prepare yourself and the environment as best you can

Health workers should clarify in their mind what they want to say and why, and find a comfortable and private setting, as best they can.

• Start the conversation with ‘signposting’

Conversations should be started by giving the person on the receiving end an outline of what will follow – for instance, if it is an update, and/or that there is a decision to be made.

• How to show compassion and empathy throughout

This can be portrayed through tone of voice, phrases that attend to emotion, and showing understanding without claiming one can possibly fully understand how the person on the receiving end is feeling.

• What does the person you are talking to know, expect, and feel?

Health workers should find out what the person they are talking to already knows and how they feel about it as this will help them fit what they go on to say to the individual person they are talking to.

• Are they with someone, can they talk to someone afterwards?

If this is a phone call, finding out who is with a person or who they could talk to afterwards is important, says Professor Parry, but this question should not be asked right at the start of a conversation as it could easily be heard as very bad news. Even when there is very bad news to come, building towards it gradually is better than clearly signalling it from the start; a gradual move towards the news reduces the risk of sending the person on the receiving end into severe shock.

• Bring the person (further) towards an understanding of the situation – how things are, what has happened or is likely to happen

Professor Parry’s advice is to describe some of the things that are wrong with the unwell person, in such a way that the person speaking is forecasting that bad news is going to come. The point is to bring about gradual recognition, rather than shock.

• Dealing with crying

Deliveries should be modified to be softer and more lilting if this happens. Speakers should allow silence, repeat brief further sympathy – ‘I’m so sorry’, and acknowledge the distress before moving on and giving more information.

• Moving towards the end of the conversation with ‘screening’ – ‘are there things you would like to ask, that I have not said, or explained enough?’

Phrases like ‘anything else’ should be avoided because, in some circumstances, this can be interpreted as the speaker not expecting there to be anything else. Offering ‘Are there things I have not covered or explained enough?’ removes the implication that the person has not understood things.

• Moving towards the end of the conversation with words of comfort and attention to what happens next

If possible, health workers should try to deliver something that is of comfort and that they can say truthfully, says Professor Parry. They should also explain what happens next, advise who the person they are talking to can contact for support and, if necessary, explain how pain or other symptoms will be controlled.
Professor Parry has also provided advice to help somewhat reduce the emotional burden on the healthcare worker – for example, she recommends they find someone to debrief with before and after a difficult conversation. Of the importance of the guidance and what she hopes it will achieve, Professor Parry said: “Healthcare workers are now having to have break bad news and have difficult conversations on an unprecedented scale.
“The kind of research I do makes it possible to pin down, to articulate, precisely how skilled, compassionate healthcare staff communicate, and pass this on to others.
“I hope that our guidance will help all staff having to break bad COVID-19 news to patients or their loved ones, to feel confident and able to communicate well, whilst looking after their own wellbeing.”
The full guidance document has been shared on the Real Talk website – a platform for communication training resource designed to use in face-to-face training events for health and social care staff – and can be downloaded as a PDF here.

Scientists at Sanford Burnham Prebys Medical Discovery Institute, the University of Hong Kong, Scripps Research, UC San Diego School of Medicine, the Icahn School of Medicine at Mount Sinai and UCLA have identified 30 existing drugs that stop the replication of SARS-CoV-2, the virus that causes Covid-19. Almost all of the drugs are entirely different from those currently being tested in clinical trials, and weren’t previously known to hold promise for Covid-19 treatment. The new candidates expand the number of “shots on goal” for a potential Covid-19 treatment and could reach patients faster than drugs that are created from scratch. The study was placed on bioRxiv – https://www.biorxiv.org/content/10.1101/2020.04.16.044016v1 – an open-access distribution service for preprints of life science research.
“We believe this is one of the first comprehensive drug screens using the live SARS-CoV-2 virus, and our hope is that one or more of these drugs will save lives while we wait for a vaccine for Covid-19,” said Sumit Chanda, Ph.D., director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys and senior author of the study. “Many drugs identified in this study – most of which are new to the Covid-19 research community – can begin clinical trials immediately or in a few months after additional testing.”
The drugs were identified by screening more than 12,000 drugs from the ReFRAME drug repurposing collection – a library of existing drugs that have been approved by the FDA for other diseases or have been tested extensively for human safety. ReFRAME was created by Scripps Research with support from the Bill & Melinda Gates Foundation to accelerate efforts to fight deadly diseases. Every compound was tested against the live SARS-CoV-2 virus, isolated from patients in Washington State and China, and the final 30 drugs were selected based on their ability to stop the virus’s growth.
“For us, the starting point for finding any new antiviral drug is to measure its ability to block viral replication in the lab,” says Chanda. “Since the drugs we identified in this study have already been tested in humans and proven safe, we can leapfrog over the more than half decade of studies normally required to get approval for human use.”
Highlights of the scientists’ discoveries follow. Each drug or experimental compound requires further evaluation in clinical trials to prove its effectiveness in treating people with Covid-19 before it can be used broadly.

• 27 drugs that are not currently under evaluation for Covid-19 were effective at halting viral replication. 17 of these drugs have an extensive record of human safety from clinical studies in non-Covid-19 diseases, including four—clofazimine, acitretin, tretinoin and astemizole—that were previously approved by the FDA for other indications.
• Thus far, six of the 17 were shown to be effective at concentrations, or doses, likely to be effective and tolerable in humans. Four of these six drugs – apilimod, MLN-3897, VBY-828 and ONO 5334 – have been tested clinically for diseases including rheumatoid arthritis, Crohn’s disease, osteoporosis and cancer.
• In addition to the 27 drug candidates, three drugs currently in clinical trials for Covid-19, including remdesivir and chloroquine derivatives, were also shown to be effective at stopping the growth of SARS-CoV-2. These results reaffirm their promise as potential Covid-19 treatments and support the continuation of ongoing clinical trials to prove their effectiveness in patients.
• Depending on regulatory guidance, the newly identified drug candidates may proceed directly to Covid-19 clinical trials or undergo further testing for efficacy in animal models.

“Based on the extensive data in this study, we believe the four drugs described above—apilimod, MLN-3897, VBY-825 and ONO 5334 – represent the best new approaches for a near-term Covid-19 treatment,” says Chanda. “However, we believe that all 30 drug candidates should be fully explored, as they were clearly active and effective at halting viral replication in our tests.”
“We have chosen to release these findings to the scientific and medical community now to help address the current global health emergency,” Chanda continues. “The data from this drug screen is a treasure trove; and we will continue to mine the data from this analysis, with a goal to find additional candidate therapies – and combinations of drugs – as they are identified.”