Author: Gil

Repurposing drugs to end COVID-19

The Problem

As the pandemic seemingly becomes endemic, two new, purpose-built drugs have just been FDA-approved. Pharmaceutical companies have been busy perfecting these new treatments,  paxlovid and molnupiravir, almost since the pandemic began. The approval and roll-out of vaccines similarly took the better part of a year, on an expedited process no less. But the COVID-19 vaccines were an outlier, usually developing these purpose-built treatments takes years and can cost billions.

But waiting two years is too late. In a pandemic, a rapid response is paramount. Waiting for an effective, low-risk, purpose-built treatment that may only come in years will lead to innumerable deaths in the meantime, as happened during COVID-19.

So, under the constraints of a pandemic, the best way to save lives is to save time. Repurposing mobilizes already existing drugs with a known safety profile into the fight against the pandemic. Limiting ourselves to new drugs when a wealth of potential candidates already exists is extremely harmful. But repurposing does more than just provide a more efficient use of resources: deploying multiple drugs simultaneously limits opportunities for the virus to adapt as opposed to introducing each drug gradually. 

The immediate question, then, is how to identify promising candidates and how to get them widely adopted. There are currently around 20 candidates for repurposing to combat COVID-19. Working out which are the most effective, and recommending them to the public, could end the COVID-19 pandemic.

Those who have read our ivermectin blog post will be familiar with the major stumbling block: no one in industry currently has the incentive to conduct repurposing trials and no one in government has the right combination of access to data and decision-making capacity to pursue a drug repurposing policy. 

Existing Evidence

Despite the lack of incentives, some researchers did manage to conduct trials into drug repurposing for COVID-19. They had to run on shoe-string budgets, resulting in imperfect, flawed results. However, the resulting data is not useless, and careful analysis of all trial data can signal which repurposed drugs are likely enough to work.

There are around twenty candidates which have been discussed or trialled, including: vitamin Dfluvoxamine, antiandrogens, arginine, famotidine, melatonin, quercetin, vitamin K2, CoQ10, various mouthwashes and nasal sprays, nigella sativa and zinc lozenges. All have supporting studies, a strong biological rationale, or demonstrated effectiveness against similar viruses.

Of these, we find four to be the most promising as they have multiple independent sources signalling efficacy. This reduces the possibility of being wrong by only relying on one source, which may turn out to be false, either as a result of fraud, study flaws, or confounding factors. We estimate each treatment has over an 80% likelihood of being very effective, and they all carry near-zero risks. A protocol combining all of them is near certain to be highly effective, and may even end the pandemic.

Examples of signals of efficacy are: randomized controlled trials (RCT), a plausible mechanism of action, and a correlation between the use of the drug and COVID-19 severity. Especially interesting is a study on electronic health records (EHR) from Clalit health services (the largest health provider in Israel), which examined which purchases made in pharmacies were later associated with reduced severity. Only 41 drugs were found to be significantly protective, out of over 1000 examined, including all treatments below. 

Fluvoxamine

Plausible mechanism of action:

  • Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) antidepressant, hypothesized to have multiple mechanisms of action including an anti-inflammatory effect as an agonist for the sigma-1 receptor, reducing platelet aggregation, decreasing mast cell degranulation, and more. 

Correlation studies

  • In the Clalit study, patients purchasing escitalopram (another SSRI) were 17% less likely to later be hospitalized.

Randomized control trials

  • An RCT found fluvoxamine to reduce hospital admissions by 35% and possibly cut deaths dramatically (1 versus 12 among those adhering to protocol).
    Unlike other repurposing trials, this was a large-scale high-quality study, which received unanimous support from experts.
  • As fluvoxamine was already considered a promising candidate prior to this trial, this success validates the whole model, indicating there are many more effective treatments that are currently overlooked.

Vitamin D

Plausible mechanism of action:

  • Vitamin D is an essential hormone of the immune system, and our modern indoor lifestyle causes many to be deficient in it. It is reasonable to assume that these deficiencies result in a suboptimal immune response to COVID-19.  
  • Additionally, it can promote autophagy, the process of replacing older cells with newer ones which can help fight infections better.  

Correlation studies

  • Prior to COVID, a meta-analysis of 25 RCTs found vitamin D supplementation to be protective against respiratory tract infections, especially among those deficient in it.  
  • In the Clalit study, patients buying vitamin D were 9-11% less likely to later be hospitalized. 

Randomized control trials

  • An RCT of 76 patients in Spain found that calcifediol (a more active form of vitamin D) dramatically reduced ICU admission and mortality. Of the 50 patients treated with calcifediol, 1 required an ICU  compared with 13 of the 26 patients in the control group (a risk ratio of x25!). The trial had significant flaws but they are likely not enough to explain such a strong result.

Oral, ocular, and nasal disinfection

Plausible mechanism of action

  • Virus replication is believed to start in these locations, and since they are regularly exposed to the outside world, they are able to survive disinfectants that would be too damaging in internal use. Regular disinfection of these areas is hypothesized to neutralize the virus before it expands into other organs and becomes uncontrollable.

Correlation studies:

  • Impressively, 7 out of the 41 drugs identified in the Clalit study are related to eye hygiene. 

Randomized control trials

  • 10 RCTs have so far been published testing the disinfectant povidone-iodine. Assessed together, they show an overall improvement in symptoms at all stages of infection but are most effective when administered early (81% improvement). 
  • One RCT found that using iota-carrageenan nasal spray as prophylaxis reduced symptomatic cases by 80%.
  • Most notably, one study tested simultaneous disinfection of the mouth, nose, and eyes, with povidone-iodine and showed an astounding 27-fold drop in patients who remained COVID positive after a week (70% vs 2.6%). 

Antiandrogens

Plausible mechanism of action

Correlation studies

  • Males are known to suffer from more severe COVID-19 outcomes.
  • In the Clalit study, patients purchasing the antiandrogen dutasteride were 38% less likely to later be hospitalized.

Randomized control trials

Rootclaim’s Proposal 

We propose the establishment of an independent commission composed of medical and scientific experts with the remit to:

  • Collect all research on repurposed drugs and contact researchers for clarifications. 
  • Determine the weaknesses and reliability of each study.
  • Estimate the probability of efficacy of various repurposed treatments, considering different indicators of efficacy such as their mechanism of action, observational studies, and controlled trials. 
  • Assess the risks and interactions of each, relying on decades of real-world experience.
  • Build protocols of repurposed treatments that best balance risks and benefits. Different protocols should be built, based on patient profiles and disease stages.

These recommendations should form the backbone for a two-front lobbying campaign to convince decision-makers and encourage public adoption.

For decision-makers:

  • Lobby for adoption by public health authorities.
  • Lobby decision-makers and politicians to support the initiative publicly.

For public and doctors:

  • Familiarize doctors and nurses with the late-stage disease protocol.
  • Familiarize GPs and family doctors with the early stage and preventative protocols.
  • Public information campaigns to promote the initiative and reduce scepticism.

At surface level, our proposal seems fairly trivial: use the drugs we already have at our disposal, instead of focusing on developing new ones months or years down the line. Unfortunately, and with catastrophic consequences, implementing this obvious option is extremely difficult within the current incentive structure. But make no mistake – this is the most promising path out of the pandemic.

Ivermectin: both sides are wrong

Do you think ivermectin cures COVID-19? Think carefully: in the age of culture wars, your answer defines your politics. If you think ivermectin is useful, you are an anti-vaxxer, Trump-supporting libertarian; If you think it isn’t, you are a godless, big-government cosmopolitan. Sorry, we don’t make the rules. 

Fine, but still, who is right? The truth is it’s still too early to say. The sorts of bold claims both sides are making are simply premature. The results of the TOGETHER Trial and the flaws recently detected in other trials weaken ivermectin’s case. On the other hand, one trial, that seems to have been well-conducted, points to it being mildly effective if taken at the onset of infection. Overall judgement? it may be useless, or it may be effective under certain circumstances.

But fixating on who is right misses the forest for the trees. Each side blames the other for Covid-19 deaths because of their supposedly wrong answer to this question. But, as it turns out, both sides are promoting deadly policies. 

The damage ivermectin’s die-hard supporters cause is plain to see. Dubbing it a “miracle cure” provides false confidence to the masses to disregard other effective measures. The damage caused by the other side is more insidious, but likely just as lethal. Let us explain why: when dealing with safe, cheap drugs even a moderate probability that they work is reason enough to recommend them. Sure, you may later discover some of the treatments weren’t effective, as may have happened with ivermectin, but that’s negligible compared to the damage of waiting and then discovering some treatments were effective all along.

When experts focus on a study’s flaws, discarding any merit it may otherwise have, what the public hears is: ignore this, vaccines are your only possible hope. 

The only way we’ll get out of this quagmire is probabilistic reasoning coupled with a cost-benefit analysis.

The best demonstration of this is in the FLCCC treatment protocol, which recommends a range of low-risk, potentially-useful repurposed drugs. While the TOGETHER trial showed that their ivermectin recommendation may have been ineffective, it also showed that Fluvoxamine, another drug in their protocol, reduced hospitalizations by 35%, and possibly cuts deaths dramatically (1 death vs 12 among those adhering to the protocol). Similarly, the FLCCC protocol recommended corticosteroids months before those became the standard of care. It is fair to assume that in the future more treatments in their protocol will be discovered to be effective.

So, regardless of the harmful, overconfident statements made by the FLCCC, doctors following their protocol saved lives, and the conservative, supposedly responsible, approach of their detractors has caused millions of deaths. 

So what went wrong?

In a word: incentives. The market is not incentivized to conduct the kind of large, costly clinical trials needed for high confidence results, when the treatment is a repurposed drug that costs a few dollars per patient. 

When the free market fails, the government should step in; after all, it has a massive public health incentive to find cheap, safe, and effective treatments. The trouble is that there is no single person within the government who has the authority, knowledge, and incentive to make the sorts of cost-benefit or probabilistic analyses needed in a pandemic. Authority-wielding politicians are not experts in health, statistics, or probability, and the few knowledge-wielding bureaucrats with the necessary expertise are mostly incentivized to not make mistakes, and don’t really care if one type of mistake exacts a far higher cost on society than the other. No one is at the helm.

Recommending a low-risk treatment that turns out to be ineffective wastes a modest amount of resources. Delaying a treatment that turns out to be effective may easily kill on a mass scale. But this gross asymmetry in results is not manifested in the decision-maker’s incentives.

So, they inevitably take the safe route of recommending we wait for more information and better quality trials. No one is ever blamed for such a “levelheaded” decision. But in a pandemic, there are no neutral options for decision makers.

This happens time and again. Our analysis of vitamin D is that it is likely highly effective at combating COVID-19. Given its low risk, it should be a top priority for health authorities to ensure no patient is left fighting the disease while being deficient in this essential hormone of the immune system. 

Meanwhile, the US National Institute of Health flounders, proclaiming that “There is insufficient evidence to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19”. But what is the risk in recommending it, exactly? 

The approach taken by both sides is lethal. Both need to change. 

To ivermectin’s supporters and the FLCCC:  we advise you to stop making overconfident claims on specific drugs. Bold claims such as these may cause people to ignore other effective treatments and they stake all the credibility of a balanced, probabilistic approach on one drug. If that drug turns out to be ineffective, the whole project is undermined. Instead, focus on the strong benefit of a protocol that uses multiple, promising low-risk drugs. 

To the skeptics: finding flaws in clinical trials is important and necessary work. But it’s more important to help fix the system so that conducting high quality trials on cheap, repurposed treatments becomes highly profitable. And in the meantime, remember not every flaw means a trial is useless. Help identify promising signals within imperfect trials that indicate the probable efficacy of low-risk treatments, and push for their immediate adoption, so the Fluvoxamine disaster is not repeated. 

The ever-present culture war around who is right and the rigid approach maintained by each side is killing people. Please stop. 

 

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