Restless citizenry; clinical success and failure; holding China to account

Christopher Rowland writes in the Washington Post that government clinical trial investigators changed the primary metric for judging the success of remdesivir as a coronavirus treatment two weeks before Anthony Fauci’s announcement that the drug would be the new “standard of care.”

Instead of counting how many people taking the drug were kept alive on ventilators or died, among other measures, the National Institute of Allergy and Infectious Diseases said it would judge the drug primarily on a different outcome: how long it took surviving patients to recover.

Death, deterioration in patients condition, the need to transfer patients’ to the ICU, and other negative outcomes were moved to secondary measure status, meaning that they would still be tracked, but they would no longer be the key measure of remdesivir’s performance. This switch — which specialists said is unusual in major clinical trials but not unheard of or uncommon — was publicly disclosed on the government’s clinicaltrials.gov website on 16 April, but did not receive attention at the time.

Rowland notes that the change indicates that medical researchers and government officials dealing with the epidemic share the assessment that remdesivir can make an important contribution to fighting the coronavirus, but that it is not a knockout drug – not a “game changer” — which will change the trajectory of the coronavirus pandemic.

“The data shows that remdesivir has a clear-cut, significant, positive effect in diminishing the time to recovery,” Fauci said on Friday, as he sat in an Oval Office meeting with Trump and other members of the president’s coronavirus task force. “It’s highly significant.”

3. Clinical failure. Hydroxychloroquine and azithromycin have been aggressively promoted by President Trump as “very effective” and possibly “the biggest game changer in the history of medicine.” The right-wing news media also seized on the potential of antimalarial drugs as a treatment.

But in the largest clinal trial yet of the two drugs, the drugs failed to have any benefit for infected patients, while significantly increasing the risk of electrical changes to the heart and cardiac arrhythmias, which could lead to heart attacks, strokes, and death.

Nevan Krogan, Professor and Director of Quantitative Biosciences Institute & Senior Investigator at the Gladstone Institutes, University of California, San Francisco, offers an explanation.

Krogan and his colleagues tested 47 old drugs which might treat the coronavirus. He writes that the results of the tests are interesting for two reasons. “Not only did we find individual drugs that look promising to fight the coronavirus or may make people more susceptible to it; we know, at a cellular level, why this is happening.”

Krogan and colleagues identified two groups of drugs that affect the virus, and the drugs in each group affect the virus in two different ways.

The drugs in the first group work to disrupt viral “translation.” At a basic level, viruses spread by entering a cell, hijacking some of the cell’s machinery and using it to make more copies of the virus. These new viruses then go on to infect other cells. One step of this process involves the cell making new viral proteins out of viral RNA. This is called translation.

The first group of drugs – for example, ternatin-4and zotatifin— disrupts the translation of the virus.

The second group of drugs Krogan and colleagues identified works in an entirely different way. Cell receptors are found both inside of and on the surface of all cells. They act like specialized switches. When a specific molecule binds to a specific receptor, this tells a cell to do a specific task. Viruses often use receptors to infect cells. Krogan and colleagues identified two promising MV cell receptors for drug treatments, SigmaR1 and SigmaR2. Their testing confirmed their suspicions, and they identified seven drugs or molecules that interact with these receptors. 

Hydroxychloroquine belongs in this second group of drugs. The largest clinical trials of hydroxychloroquine were disappointing: the drug was of no benefit to COVID-19-infected patients (note: the patients in these trials had advanced symptoms of the disease) – and was, in fact, dangerous, as it triggered heart problems in trial subjects with no heart ailment history, and exacerbated the heart condition of those with existing heart problems, leading to the death a few of them. Last Friday, the FDA issued a strongly worded warning which urged physicians to use hydroxychloroquine and azithromycin only in hospitals or as part of clinical trials.

There is a reason why hydroxychloroquine has so far failed as an effective and safe treatment for COVID-19, and why its side-effects are so dangerous. Krogan writes:

Another interesting thing to note is that hydroxychloroquine – the controversial drug that has shown mixed results in treating COVID-19 – also binds to the SigmaR1 and SigmaR2 receptors. But based on our experiments in both labs, we do not think hydroxychloroquine binds to them efficiently.

Researchers have long known that hydroxychloroquine easily binds to receptors in the heart and can cause damage. Because of these differences in binding tendencies, we don’t think hydroxychloroquine is a reliable treatment. Ongoing clinical trials should soon clarify these unknowns.

In other words, hydroxychloroquine does not bind efficiently where it could help COVID-19 patients, that is, to SigmaR1 and SigmaR2 receptors, but it binds too well where it can inflict serious damage and death – to cell receptors in the heart.

4. The China syndrome. More and more countries are calling for an impartial and credible investigation of China’s conduct between November 2019 and the end of February 2020 regarding the coronavirus.

The U.S. intelligence community has concluded that the coronavirus was  not man-made – a conclusion the White House appears reluctant to accept – but there is no need to believe in the more breathless conspiracy theories about the origins of the virus to know that China’s conduct has been evasive, dishonest, and irresponsible.

More and more countries are calling for an impartial and credible investigation of China’s conduct regarding the coronavirus between November 2019 and the end of February 2020, and for holding China accountable for its misconduct. Australia has called for an inquiry into the origin of the virus. Britain and Germany are reconsidering allowing Huawei to help build 5G communication infrastructure. Trump, still appearing to believe, despite evidence to the contrary, that the virus has escaped from a Chinese biolab, is blaming China for the contagion and is seeking to punish it. Some governments openly talk of suing China for damages and reparations.

Regardless of whether or not an impartial investigation is conducted, or reparations paid, the way China has mishandled the crisis has intensified the backlash against its attempt to extend its political, economic, and technological sway around the world. China was already facing a growing mistrust in Europe and Africa, and its clumsy and duplicitous conduct has undermined its effort to project itself as a responsible, generous, and capable global actor.