There Was No New Needle in the COVID Therapeutic Haystack A COVID-19 Therapeutics Analysis

Background

Introduction

Treatment/Therapeutic Strategy

The treatment/therapeutic strategy is summarized in the second bar below the disease progression image.

COVID-19 Progression and Treatment/Therapeutic Strategy

The four treatment/therapeutic phases are:

	Damage Being Addressed
Treatment/Therapeutic Phase	Direct Viral Damage	Hyper- Inflammation	Blood Clots	Lack of Oxygen
Prevent infection.	X
Suppress viral replication and inflammation.	X	X	X
Suppress hyperinflammation.		X	X	X
Suppress organ damage.			X	X

It is discouraging to note:

• Many diseases, especially those that are rare, genetic, or complex lack definitive cures.
• No respiratory disease has ever been cured.

National Institute of Health Guidelines

The NIH produced 72 versions of very comprehensive treatment guidelines. They grew from 90 pages long to 278 pages after 12 months, and finally to 478 pages. The final update, Last NIH COVID Treatment Guidelines, was on February 29, 2024.

Therapeutic Flood

With the pandemic, pharmaceutical companies and academic researchers pursued new therapeutics with World War II-like urgency and focus. Several websites tracked global therapeutic trials:

• No longer operational, The Global Coronavirus COVID-19 Clinical Trial Tracker listed 2,533 trials on December 31, 2020.
• No longer being updated, the World Health Organization Treatment Tacker listed 4,634 trials in August 2023.
• The FDA Clinical Trial Tracker is still operational.

A May 2021, Nature paper [1] reported that there were multiple trials of the same drug, most too small to draw definitive conclusions. As will be seen, therapeutics discussed here had many papers whose results were often contradictory.

Trials of the Same Drug   Drug Trial Size

For perspective, the Pfizer mRNA vaccine phase 3 trial had 43,448 participants, and its first PAXLOVID phase 3 trial had 2,246 adult participants.

A July 2024, Heliyon paper [2] summarized COVID clinical trials through April 23, 2023.

Global Clinical Trials

The following summarizes the FDA Clinical Trials and The Mouse That Roared therapeutic paper statistics as of November 1, 2024. It excludes 1,686 COVID-19 vaccine trials.

FDA COVID-19 Therapeutic Clinical Trials				Google Scholar	Mouse papers
Total	Completed	Terminated	Results
4,855	2,222	427	528	~3,000,0001	3,065

• Google Scholar reported 5,550,000 papers for COVID. COVID scholar reported 143,711, the NIH 374,733, and PubMed 53,165.

For perspective, there were 1,107 FDA clinical trials for triple negative breast cancer, 720 for the flu, 193 for RSV, and 18 for Addison’s disease.

For the high-impact therapeutics, I used Google Scholar to find the paper with the most citations and/or impact. Even there, there is a sample bias as the prestigious journals’ papers and older papers often get the most citations. For example, of the 20 therapeutics with referenced papers in this article, the highest cited papers on 8 of them was the New England Journal of Medicine. Further, many of the early, highly cited papers suggested a therapeutic, e.g., probiotics, should be investigated or were the first to trial it often with only a few people.

A therapeutic goes through three trial phases and a Regulatory Review, Phase 1 - safety with a small group, Phase 2 - effectiveness with a larger group, Phase 3 - effectiveness and safety with a very large group.

Clinical trial costs and failure rates are significant barriers to drug development. Costs were reported in a July 2014, Office of the Assistant Secretary for Planning and Evaluation paper [3].

2012 Drug Trial Costs

Further, the paper reported 12% odds of making it all the way through regulatory approval.

Cost, success rates, and therapeutic differential advantage are factors behind how few therapeutics are approved by the FDA each year as shown in the next image from a January 2024, Nature paper [4].

Yearly FDA Drug Approval

(New molecular entities (NMEs) and biologics license applications (BLAs). Vaccines and gene therapies are not included.)

As an example of a drug that has not made it to market because a “good enough drug” is available might be masitinib. A July 2021 Science paper [5], which has been cited 208 times, reported masitinib (MPRO) reduced the SARS-CoV-2 viral load by more than 99% and reduced inflammatory cytokine levels in mice. Since early 2023, it has been attempting to recruit people for a clinical trial.

Testing and Targets

There are many potential therapeutic targets including the viral proteins, cytokines, immune system cells, and organs.

Therapeutic Targets

Viral proteins are juicy therapeutic targets. Antiviral, anti-inflammatory and specialized therapeutics were used as weapons against them.

	Antiviral	Anti-inflammatory	Specialized
Structural Proteins
S	X	X
N	X	X	Heart, amyloidosis
M	X	X
E	X	X	Kidney, lung
Nonstructural Proteins
Nsp1	X	X
Nsp2
Nsp3 (PLpro)	X
Nsp5 (Mpro)	X	X
Nsp6		X	mRNA transport
Nsp7	X
Nsp8	X
Nsp9	X	X
Nsp10	X	X
Nsp11
Nsp12 (RdRp)	X
Nsp13	X
Nsp14(Exon)	X	X
Nsp15	X	X
Nsp16	X	X
Accessory Proteins
ORF3a	X	X	Mitochondrial function
ORF3b		X
ORF3c
ORF6		X
ORF7a	X
ORF7b	X
ORF 8		X	Cholesterol formation
ORF9b
ORF9c			Mitochondrial functionHeart cellsCholesterol formation
ORF10		X

Squeakinstein

Therapeutic testing first involves animals. While COVID-19 has been reported in wild mice, their ACE2 receptors aren’t good matches for SARS-CoV-2. In 2000, mice were genetically engineered to have human-like ACE2 receptors. Recent tricks improved this genetic engineering and even made mice for Long COVID studies. The resulting transgenic mouse would have made Mary Shelly proud - a Squeakinstein. All kinds of therapeutics were tried on them.

Squeakinstein – A Transgenic, COVID-19 Infected K18-hACE2 Mouse

One study had mice do three months of swim training to test exercise immune system impact.

Mouse That Roared Papers

The following chart shows the distribution of all The Mouse That Roared Therapeutics and indicates how many were FDA approved. Notice 75% of the papers were on antivirals.

The Mouse That Roared COVID-19 Therapeutic Papers

Prevent Infection

We are here:

Prevent Infection

These are FDA Clinical Trials and The Mouse That Roared prevent infection papers’ statistics.

	FDA Clinical Trials			Google Scholar	Mouse Papers
	Total	Completed	Results
Prevention1	326	145	53
Nasal sprays	53	35	4	23,200	78
BCG Vaccination	9	5	0	31,000	26
Vitamin D	89	52	4	1,370,000	49
Probiotics	22	12	2	51,800	7
Pemgarda	1	0	0	38	1

• Some drugs here are also in treatment categories

Nasal Sprays

Since muscularly administered COVID-19 vaccines don’t provide good upper respiratory protection, nasal sprays and gargles are appealing therapeutics. In fact, an engineered lama nanobodies nasal spray protected Squeakinsteins or fully cured them if infected.

0.5 - 1% Povidone Iodine Nasal Spray or Gargle

Several pre-pandemic studies reported iodine nasal spray or gargle killed all viruses in the nose or mouth. A September 2020, Ear Nose and Throat paper [6] with 102 citations reported all evaluated concentrations of nasal antiseptics and oral rinse antiseptics completely inactivated SARS-CoV-2 after 60 seconds. A September 2022, Ear Nose & Throat paper [7] reported povidone iodine nasal spray resulted in an 8.57 reduction of COVID-19 hospitalization or death rates. The NIH Guidelines are silent on nasal sprays.

Bacille Calmette-Guérin Vaccination

The 80-year-old Bacille Calmette-Guérin (BCG) tuberculous vaccination is one of the world’s most widely used vaccines. An April 2020 Lancet paper [8], which was cited 389 times, reported it was believed BCG stimulated “trained immunity” to respiratory infections.

Early in the pandemic, African countries with extensive BCG vaccination had 65% of the case rates of neighboring countries with less extensive BCG vaccination. However, a September 2022, PLOS ONE paper [9] reported that the differences in COVID-19 burden associated with BCG vaccination rates generally diminished in magnitude and usually lost statistical significance as the pandemic progressed. Though a few subsequent papers reported some minor protective effect, most reported no effect. The NIH Guidelines are silent on it.

Vitamin D

Researchers assessed vitamins A, C, D or K’s preventative effects. Most of the action was in vitamin D, which had wide ranging assessments on its effectiveness. The NIH Guidelines said there was insufficient evidence to recommend for or against vitamin C or D.

Probiotics

A November 2020, medRxiv preprint [10] reported that in an analysis of 327,720 UK participants, some dietary supplements lowered SARS-CoV-2 infection risk. Probiotics provided a 14% reduced infection chance (95%CI: [8%,19%]). No The Mouse That Roared paper reported negative results. The NIH Guidelines are silent on probiotics.

Pemgarda

The company who makes Pemgarda reported phase three trial results:

• Through month 6, 84% relative infection risk reduction.
• In months 7-12, 64% risk reduction of symptomatic COVID-19 in an immunocompetent adult population.

However, a November 2024, bioRxiv preprint [11] reported variants KP.3.1.1 and XEC significantly impacted its neutralization rates. Subsequent New England Journal of Medicine papers reported the same impacts.

Suppress Viral Replication and Inflammation

We are here:

Suppress Viral Replication and Inflammation

The biggest take away from this review is that it is better to keep the barbarians at the gate than to battle them in the courtyard.

Keep the Barbarians at the Gate

The following image is an update of one from an October 2020, Nature paper [12] which was cited 1,878 times. The red and pick boxes show what parts of the viral life cycle can be impacted by antivirals. The pink boxes were as of October 2020. The red boxes represent viral impact subsequently discovered. The circled boxes correspond to FDA approved antivirals.

Viral Lifecycle and Antiviral Targets

Following are the number of the FDA Clinical Trials and The Mouse That Roared antiviral papers’ statistics. Included are therapeutics that will receive special attention. As will become clear, almost all antivirals targeted the spike protein or two nonstructural proteins – nsp5 (Mpro also called 3CL^pro) or nsp12 (RdRp). Even though disabling other structural, e.g. the Nucleocapsid, or nonstructural, e.g., nsp1, proteins would have disabled the virus, there were relatively few papers and no approved therapeutics that addressed them.

These three targets were discovered early in 2020!

• A February 2020, Nature paper [13] investigated drugs that had worked on other viruses, e.g. SARS-CoV-1, MERS and Ebola. It reported Remdesivir was likely to be effective.
• A March 2020, Science paper [14] reported the development of an MPRO inhibitor.
• A February 2020, Nature paper [15] reported the spike protein was an ideal target for vaccines and therapeutics.

	FDA Clinical Trials			Google Scholar	Mouse Papers
	Total	Completed	Results
Antiviral	736	304	102	3,200,000	2331
Spike Protein Monoclonal Antibody1	99	39	18	24,400	497
Casirivimab/imdevimab2	25	8	11	6,830	38
Sotrovimab2	24	9	10	5,720	53
Tixagevimab/cilgavimab2	18	12	6	4,230	39
MPRO				18,900	502
PAXLOVID	45	14	7	9,780	176
RdRp3				23,300	193
Molnupiravir3	20	7	5	11,000	107
Remdesivir4	108	51	26	41,200	73
Innate Immunity
Interferon	68	36	0	491,000	37
Other Types
Renin-Angiotensin System Inhibitors	9	2	0	38,000	4
ACE2	31	10	2	63,700	102
Simvastatin	4	1	0	16,900	8
Promising But Generally Ineffectual
Convalescent Plasma	175	87	30	42,300	48
Favipiravir	65	36	9	23,100	26

• There were 71 nanobody The Mouse That Roared papers and none with an FDA match.
• Many papers discussed multiple monoclonal antibodies.
• Many papers discussed RdRp therapeutics with other therapeutics, e.g., PAXLOVID and monoclonal antibodies.
• About 20 The Mouse That Roared Molnupiravir papers were co-studies with PAXLOVID.

Monoclonal Antibodies and Nanobodies

Monoclonal antibodies and nanobodies bind to various targets, e.g., cancer cells or a viral protein.

The FDA approved its first monoclonal antibody in 1986. It helped prevent kidney transplant rejection. According to a June 2022, Antibody Therapeutics paper [16], 162 had been approved around the world by June 30, 2022.

Biosimilar, diagnostic, and veterinary antibodies are not included.

Monoclonal antibodies address transplants, cancers, sepsis, multiple sclerosis, arthritis, blood clotting, stroke, bacterial infection, autoimmune diseases, RSV, degenerative myopia, diabetes, macular degeneration, and many obscure diseases. The flu has no monoclonal antibody drugs because of its rapid mutation rate. In March 2024, a Cell Immunity paper [17] reported a promising new approach. Time will tell.

Monoclonal antibodies were highly effective until Variants of Concern emerged.

Interestingly, a November 2024, Cell paper [18] reported several non-neutralizing antibodies provided protection against SARS-CoV-2 in different animal models.

On March 22, 2024, the FDA approved Pemgarda (pemivibart) as a preventative monoclonal antibody for immunocompromised people. It was effective against the JN.1 variant but as will be discussed later lost some of its effectiveness against KP3.1.1 and XEC.

The FDA-approved monoclonal antibodies were quite effective if taken early and could be taken by pregnant women. Once taken, the FDA recommended delaying vaccination by 90 days as they could interfere with the COVID-19 vaccines. Here is data on their effectiveness.

• Casirivimab with imdevimab – a February 2022, Lancet paper [19] which was cited 223 times reported in seronegative patients, 396 (24%) of 1633 patients allocated to casirivimab and imdevimab versus 452 (30%) of 1520 patients allocated to usual care died within 28 days (rate ratio [RR] 0.79, 95% CI 0.69–0.91;).
• Bamlanivimab plus etesevimab – A July 2021, New England Journal of Medicine paper [20] which was cited 701 times reported that by day 29, 11 of 518 patients (2.1%) in the bamlanivimab–etesevimab group had a COVID-19–related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, −4.8 percentage points; 95% confidence interval [CI], −7.4 to −2.3; relative risk difference, 70%; P<0.001). No deaths occurred in the bamlanivimab–etesevimab group; 10 deaths occurred in the placebo group. Beta and Gamma wiped it out.
• Sotrovimab - An October 2021, New England Journal of Medicine paper [21] which was cited 1,136 times reported that it had hospitalization or death 85%relative risk reduction, 97.24% confidence interval, 44 to 96. Though it had some effectiveness in Omicron BA.1 and BA.2, later Omicron subvariants wiped it out.
• Evusheld (tixagevimab and cilgavimab) – An April 2022, New England Journal of Medicine paper [22] which was cited 700 times reported that follow-up at a median of 6 months showed a relative infection risk reduction of 82.8% (95% CI, 65.8 to 91.4). Though it had some effectiveness in Omicron BA.1 and BA.2, later Omicron subvariants wiped it out. It was extensively used for infection protection.

The NIH Guidelines noted these monoclonal antibodies are no longer effective.

Llama, hamster, or ferret monoclonal antibodies and nanobodies were developed for:

• The neuropilin-1 binding domain
• The furin/TMPRSS2 cleavage site
• Several structural and nonstructural proteins

• Disable Viral Replication Proteins

Several viral proteins and protein complexes are essential for the viral replication. Here is an image of the SARS-CoV-2 proteins.

SARS-CoV-2 Viral Proteins

• NSP5 - MPRO/3CL

The virus replicates by hijacking our replication machinery and material. It produces two long polyproteins called ORF1a and ORF1b which are cleaved into individual nonstructural proteins. Two viral enzymes do this cleaving after the replication process is jumpstarted by our less efficient cleaving enzymes. MPRO (nsp5), the main protease, cleaves the ORF1a polyprotein. Disabling MPRO, disables viral replication. Likewise, disabling Plpro (nsp3), the papain-like protease, disabled viral replication. There are no approved nsp3 drugs.

PAXLOVID

PAXLOVID, nirmatrelvir plus ritonavir, is the most effective FDA-approved COVID-19 antiviral. Nirmatrelvir was tested against MERS in 2012. It disables MPRO by cleaving it. Though used for treating HIV/AIDS, Ritonavir is seldom employed for its own antiviral activity but instead boosts other protease inhibitors. The FDA granted early use authorization on December 21, 2021, and full approval on May 23, 2023. No MPRO mutation has disabled it.

China developed a PAXLOVID look-alike called Azvudine and developed another MPRO drug called leritrelvir which they claim is as effective as PAXLOVID.

• Who Can Take it?

Some people can’t take PAXLOVID because of ritonavir drug interactions. FDA PAXLOVID Drug Interactions and University of Liverpool Drug Interactions websites assess these interactions. The assessments include when not to take various COVID-19 drugs, take them with careful monitoring, or take them only after pausing their medications, e.g., simvastatin in the case of PAXLOVID. PAXLOVID is safe for pregnant women.

• Effectiveness

There have been many studies reporting slightly different results. A June 2022, New England Journal of Medicine [23] which was cited 2023 times on the PAXLOVID phase three, adult trial reported:

• 89.1% hospitalization risk reduction. No one died while 1% in the placebo group died.
• 3.1% of the people taking PAXLOVID reported diarrhea compared to 1.6% in the placebo group.
• 5.6% of the people taking PAXLOVID reported a very bitter, metallic taste later called PAXLOVID mouth. Sucking on sweets or taking saccharin helped reduce the bitter taste. Only .03% of the patients reported a very bitter taste in the placebo group.

A July 2023, Lancet paper [24] reported that PAXLOVID’s effectiveness in preventing hospital admission or death differed greatly by when it was taken.

• within 30 days of a positive test for SARS-CoV-2, 53.6% (95% CI 6.6-77.0),
• within 5 days of symptom onset, 79.6% (95% CI 33.9-93.8)
• on first day of symptom onset, 89.6% (95% CI 50.2-97.8).

The NIH recommends “treatment should be initiated as soon as possible and within 5 days of symptom onset.”

• Viral Rebound

Viral rebound happens in about 2%-5% of those who took PAXLOVID. Viral rebound is not understood, and studies reported wildly differing results. The CDC [25] reported that with a virologic response through day 5, viral rebound occurred in 6.4%-8.4% of PAXLOVID recipients and 5.9%-6.5% of placebo recipients during the 2021 pre-Omicron and 2022 Omicron periods.

• Who Takes it?

Because of cost, rebound fear, and side effects, PAXLOVID is significantly underutilized. A November 2022, CDC report [26] reported that among 699,848 adults aged ≥18 years eligible for PAXLOVID during April–August 2022, 28.4% received a PAXLOVID prescription within 5 days of COVID-19 diagnosis. Further, usage dropped precipitously in lower socioeconomic groups even when the government was paying for it.

In October 2022, the NY Times [27] reported use by political party.

100 PAXLOVID Courses per 100 COVID-19 Cases

• NSP12 - RdRp

Unlike many viruses including the flu, SARS-CoV-2 replication has error correction which improves its replication rates. Two approved therapeutics reduced its error correction effectiveness by interfering with the nsp12 nonstructural protein called RdRp.

• Remdesivir is an intravenous, hospital-administered therapeutic. It was effective against Hepatitis C and RSV in 2009, Ebola in 2014 and Marburg in 2015. The FDA approved it for COVID-19 use on Oct 22, 2020.
• Lagevrio (Molnupiravir) is a tablet therapeutic. It was used against influenza, Ebola, chikungunya, and various coronaviruses including MERS. The FDA approved it for COVID-19 use on December 23, 2021.

Lagevrio (Molnupiravir)

A December 2021, New England Journal of Medicine [30] paper which was cited 1,852 times reported its effectiveness was:

	Molnupiravir	Placebo
Hospitalization or death - 29th day	6.9%	9.7%
Serious adverse events	30.4%	31.6%

A July 2022, medR_xiv [31] preprint reported a retrospective study of 92 million patients with PAXLOVID (n =11,270) or Molnupiravir (n =2,374) taken within 5 days of COVID-19 symptoms.

	PAXLOVID		Molnupiravir
	7 Days	30 Days	7 Days	30 Days
Symptoms	2.31%	5.87%	3.75%	8.21%
Hospitalization	0.44%	0.77%	0.84%	1.39%
Rebound1	3.53%	5.40%	5.86%	8.59%

• Patients with COVID-19 rebound had significantly higher prevalence of underlying medical conditions than those without.

All joint studies reported greater PAXLOVID effectiveness. However, Molnupiravir can be taken by more people.

The NIH Guidelines recommended Molnupiravir after PAXLOVID and remdesivir.

• Created Mutations

A January 2023, medR_xiv [30] preprint reported Molnupiravir induced SARS-CoV-2 mutations.

Molnupiravir Created Mutation Rates

Molnupiravir potentially could change to our DNA. However, the FDA reported that the genotoxicity data after treatment implied Molnupiravir has a low risk for damaging our DNA. Nonetheless, the FDA recommended:

• Against pregnant patients use unless therapy is indicated and there are no options.
• The use of effective contraception during and following Molnupiravir treatment.
• Only people ages 18 or greater use it.

Other Antivirals

In addition to the antivirals already discussed, about 550 additional ones were discussed in The Mouse That Roared. The remaining 550 papers addressed every pink and red box in the above figure titled Viral Lifecycle and Antiviral Targets. The therapeutics used many different tricks, e.g., used amino acids, peptides, aptamers, short-RNA, micro-RNA, ultra-violet light in lungs, plasma activated water, to disrupt a biochemical process either by just changing molecules’ shapes or damaging them, e.g., through proteases or kinases. Many therapeutics addressed disrupting the N-protein’s glycans. There were extensive drug and compound searches, e.g., 350,000, 33,590, 22,000, 18,000, 6,710, 6,218, 2100, 1,900, 1796, and 850. They were administered by chewing gum, nasal spray, mouth wash, table and needle.

The drug compounds and sources included - H₂ Sulfur compounds, NaCl, ZnO, CeO_2, hydrophobic C60, copper, gold, silver, ClO2, CuFe204, boron, NO, Se, vitamin B-a and B-12 supplements, TMPRSS2 inhibitor, phosphatidic acid, nucleic acid, antiandrogen, human breast milk, pluripotent stem cell, earthworms, chewing gum, shark immune cells, mesenchymal stem cells, fungi, bacteria such as e-coli, marine sponges, scorpion venom, interferons, NK cells, sea cucumbers, mink lung epithelial cell, CRISPR to find or modify, cow milk, monoclonal antibodies, coffee, bee venom, electric fields, mouth wash, purified IgG, anti-protozoal, induce vomiting, spider hemocytes, salamandra, sweet potato roots, oriental wasp, human defensins, bile acids, antibiotics, hen egg yolks, bovine herpesvirus, male contraceptive, cardiac imaging, and inhaled heparin.

Many drugs that had effectiveness against other diseases showed some effectiveness against COVID-19. The diseases included gas, leprosy, irritable bowel syndrome, tapeworms, anti-epileptic, gout, vaginal infection, hepatitis, HIV/AIDS, parasites, sleeping sickness, Prozac, anticonvulsants, laxatives, hyponatremia, over active bladder, circadian rhythm, cystinosis, influenza, anti-fungal, anti-biotic, macular degeneration, asthma, malaria, RSV, cardiac imaging, ring stage parasites, antipsychotic, diuretic, kidney damage, HPV, bipolar, epilepsy, schizophrenia, anxiety, migraine, tranquilizers, cholesterol, hepatitis C, pulmonary fibrosis, gall stones, liver disease, type I Gaucher, Fabry disease, anemia and hypovolemia, herpes, pancreatitis, reflux esophagitis, weight loss, hypertension, ectopic pregnancies, abnormal hemoglobin, allergy, hay fever, common cold, rheumatoid arthritis, rapid heartbeats, shortness of breath, pale skin, cold hands and feet, dark urine, jaundice, mitochondrial antioxidant, lung transplantation, antiandrogen, lactate-lowering, viral hemorrhagic fevers, throat and tonsils infections, ulcerative colitis, gallstones, diabetic kidney disease, lupus, and methemoglobinemia.

Cancer drugs against many different types of diseases were: leprosy, irritable bowel syndrome, tapeworms, anti-epileptic, gout drug, vaginal infection, hepatitis, HIV/AIDS, antiparasitic; sleeping sickness, anticonvulsants, laxatives, hyponatremia, over active bladder, circadian rhythm, cystinosis, influenza, anti-fungal, anti-biotic, macular degeneration, asthma, malaria, RSV, ring stage parasites, antipsychotic, diuretic, kidney damage, HPV, depression, bipolar, epilepsy, schizophrenia, anxiety, migraine, tranquilizers, cholesterol, hepatitis C, hydrophobic C60, pulmonary fibrosis, gall stones, liver disease, type I Gaucher, Fabry disease, anemia and hypovolemia, herpes, pancreatitis, reflux esophagitis, weight loss, hypertension, ectopic pregnancies, abnormal hemoglobin, allergy, hay fever, common cold, rheumatoid arthritis, rapid heartbeats, shortness of breath, pale skin, cold hands and feet, dark urine, jaundice, mitochondrial antioxidant, lung transplantation, lactate-lowering, viral hemorrhagic fevers, ulcerative colitis, gallstones, diabetic kidney disease, lupus, methemoglobinemia.

Suppress Hyperinflammation

We are here:

Suppress Hyperinflammation

Sadly, the barbarians have broached the gate and are winning the fight. Either there will be:

• Mild or moderate COVID-19 which will require no further treatment.
• Severe COVID-19 which could result in hospitalization and potentially death.

More likely in severe cases, Long COVID can follow either outcome.

Inflammation

Inflammation is a natural response to injury to eliminate its cause, to remove damaged cells, and to start healing. Inflammation:

• Recognizes the harmful stimuli like injury or pathogens, e.g. SARS-Co-2.
• Releases signaling molecules like histamines and cytokines.
• Recruits immune cells: White blood cells, particularly neutrophils and macrophages, to neutralize pathogens and remove debris.

Hyperinflammation is excessive inflammation. COVID hyperinflammation damages many parts of the body as shown by this image from a December 2020, New England Journal of Medicine paper [37] which has been cited 2,889 times.

Cytokine Storm Damage

Causes

Hyperinflammation has two causes.

• When SARS-CoV-2 binds to the ACE2 receptor, it dysregulates the renin-angiotensin-aldosterone system (RAAS) which has important roles in inflammation and blood pressure control. Through a complex process, this results in an overproduction of cytokines which are small proteins that act as signaling molecules in the immune system. This over production is called the cytokine storm. There are hundreds of cytokines, of which most proinflammatory cytokines are tumor necrosis factor-alpha (TNF-α):Interleukin-1 (IL-1), (IL-6), IL-17, (IL-12), (IL-23) and interferon IFN-γ.

Cytokines work together to amplify inflammation and coordinate immune responses, but when overproduced, they can lead to excessive inflammation and tissue damage, as seen in autoimmune diseases, cancer, infections and physical damage.

2.

In addition, the innate immune system’s workhorses, the effector cells, are damaged and release cytokines. This damage also promotes viral replication as it takes 4-6 days for our adaptive immune system to kick in.

If hospitalized, the fight for one’s life is now very serious. Hyper inflammation is very hard to treat because treating inflammation risks impairing the body's defense mechanisms, the biology is complex, it has several causes, it is self-sustaining, there is individual variability, and the treatments have side effects.

Many of the hyperinflammation drugs also treat COVID-19 comorbidities such as cancer, obesity, diabetes, or the gut’s microbiology. Thus, there is a confusing interplay of the drugs’ targets and the reasons for their outcomes.

The FDA Clinical Trial and The Mouse That Roared anti-inflammatory therapeutics statistics are:

	FDA Clinical Trials			Google Scholar	Mouse Papers1
	Total	Completed	Results
Anti-Inflammatory	241	97	22	214,000	457
Tocilizumab	75	31	7	38,600	43
Anakinra	25	13	3	14,600	16
Baricitinib	27	8	3	13,400	24
Corticosteroid	79	34	3	127,000	65
Dexamethasone	93	40	7	131,000	56
Metformin	9	2	1	42,600	24

• Many papers discussed several drugs.

The two therapeutic approaches to hyperinflammation are:

• Address the cause, i.e., protect the renin-angiotensin and innate immune systems.
• Address the result, i.e., reduce inflammation.

Other Anti-inflammatory Therapeutics

What follows is a characterization of the 275 The Mouse That Roared ant-inflammatory papers that haven’t already been discussed. They addressed:

• Cytokines - IL-6 (main target), IL-2, TNF-αi, I-17 IL-23, interleukin 7, IFNγ, TNFα, IL-1β, IL-18, TGF-β1, IFN-α and β , ANG2, NLRP3.
• Effector Cells – macrophages, cytotoxic T cells, neutrophils, and mast cells
• Kinases, an enzyme that catalyzes the transfer of a phosphate group from ATP to a specified molecule - Janus and Casein kinase 2, TANK-binding kinase 1, spleen tyrosine kinase.
• Miscellaneous others, e.g. transcription factors, a gene that encodes a protein that detects products of damaged cells and triggers an immune response, GSDMD inhibitors exosomes, adenine dinucleotide metabolism, NETS.

The drugs had many ingredients: cluster of differentiation 24, N-Protein antibodies, monoclonal antibodies for selected cytokines, interferon, genes, gene expression, CRISPR modified T cells, stem cell transplants, hydrogen, immunoglobulins, molecules that cause cell death, bacteria, blood purification, plasma exchange, algae, synthetic angiotensin (1-7) (TXA-127) or an angiotensin II type1 receptor–biased ligand, low dose radiation, low-intensity pulsed ultrasound, pharmacologic stress agent used in cardiac perfusion imaging studies, drugs to maintain general anesthesia, hyperimmune plasma from sheep, mesenchymal stromal sells from many sources, injectable porous silicon particles, silver, selenium, lithium, sodium nitrate, hydrogen rich water, cytotoxic T lymphocytes, cellular human amniotic fluid, degalactosylated bovine glycoproteins, activated protein C, vitamin E, peptide angiotensin-(1-7) [Ang-(1-7)], blood filter, antioxidant enzymes.

They addressed many different diseases.

Autoimmune Diseases: rheumatoid arthritis, ankylosing spondylitis, psoriasis (including plaque psoriasis), Crohn's disease, inflammatory bowel disease, ulcerative colitis, ankylosing spondylitis, alopecia areata, multiple sclerosis, chronic immune thrombocytopenia, Behçet's disease, eczema, atopic dermatitis, seborrheic dermatitis, gout, plaque psoriasis, and keratoconjunctivitis sicca associated with Sjögren's syndrome.

Many human diseases, particularly immunosuppressed diseases like inflammatory bowel syndrome are associated with inflammation. From a 2013 national estimate provided in a December 2016, JAMA paper [46], US adults’ immunosuppression prevalence from health conditions and medication use was 2.7%. Selected autoimmune drugs are useful with COVID because they attack cytokines, autoantibodies, and interfere with cell signaling pathways that drive inflammation

Cancer: bone marrow, small cell lung cancer, leukemias (chronic myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia), multiple myeloma, prostate cancer, castration-resistant prostate cancer, high-risk primary or secondary myelofibrosis, testicular, and ovarian cancer, glioblastoma multiforme and myelodysplastic syndromes.

Selected cancer drugs are useful with COVID because they attack cytokines, have strong anti-inflammatory effects, and shrink tumors would release pro-inflammatory mediators.

Other Lung Diseases - chronic obstructive pulmonary disease (COPD), chronic bronchopulmonary disorders, idiopathic pulmonary fibrosis, acute lung injury, bleomycin lung injury, ARDS (acute respiratory distress syndrome), and TB (tuberculosis).

Others - abnormal blood lipid levels, acute pancreatitis, alcohol use disorder, Alzheimer’s, ALS, angina pectoris, chronic hepatitis, chronic kidney disease, diabetes, diabetic kidney disease, disseminated intravascular coagulation and pancreatitis, epilepsy, gastroesophageal reflux disease, graft/host diseases, heart problems, hemophagocytic lymphohistiocytosis, high blood pressure, hyperlipidemia, hypertriglyceridemia, lactobezoar, malaria, migraines, nausea, nephrotic syndrome, neuropathic pain, osteoporosis in postmenopausal women, peptic ulcer disease, prion diseases, depression, psychosis and anxiety, schizophrenia, sepsis, solid organ transplant, superficial mycoses, tapeworm, viscid or excessive mucus, Zollinger-Ellison syndrome

Suppress Organ Damage

We are here.

Suppress Organ Damage

One is very, very ill, and there is no silver bullet. These are the FDA clinical trial and The Mouse that Roared papers that addressed two key areas of organ treatment.

	FDA Clinical Trials	Google Scholar	Mouse papers
	Lungs
Oxygen	25	1,570,000	71
ECMO	3	40,800	52
Vilobelimab	1	446	6
	Cardiovascular
Anti-coagulants1			54
Heparin	12	133,000	32

• Interpreting FDA clinical trial searches must be done with extreme care. For example, these were the number trials for different, highly related terms.
  • Anti-coagulant or anti coagulant - 34
  • Anti coagulant therapy - 31
  • Anti-coagulants - 1

Lungs

As previously noted, lungs can be damaged by direct viral damage, inflammation, blood clots, and/or lack of oxygen. Oxygenation will be assessed here. Yet again, a key message is to act quickly. Following are the increasingly aggressive oxygen treatments.

• Conventional oxygen.
• High-Flow Nasal Cannula, the nasal delivery of an adjustable mixture of heated and humidified air and oxygen at rates that exceed spontaneous inspiratory flow.
• Mechanical ventilation.
• Extracorporeal Membrane Oxygenation.

• Extracorporeal Membrane Oxygenation (ECMO)

ECMO is a mechanically supported ventilation system that is used on average 15 days with an interquartile range of 8-17 days for COVID-19 patients. It is the predominate form of mechanical ventilation with one meta study reporting 98.6% use. A May 2024, BMC Journal paper [47] reported 54% of the patients experienced hemorrhagic complications. Even with it, lung transplantation may be proposed. These are the ECMO outcome statistics from a September 2020, Lancet paper [49].

ECMO Outcome Rates

An August 2023, Journal of Clinical Medicine paper [51] reported selected study ARDS patient mortality with and without ECMO.

Characteristic	Follow-Up	ECMO	Conventional
ARDS-H1N1	6 months	37%	53%
ARDS	60 days	35%	46%
ARDS	60 days	34%	47%
ARDS	90 days	36%	48%
COVID ARDS	60 days	26%	33%
COVID ARDS	60 days	35%	47%

The NIH Guidelines recommend starting with high-flow nasal cannula oxygen followed by noninvasive ventilation or intubation and mechanical ventilation. Though ECMO was referenced on 51 pages in the NIH guidelines regarding the use of other therapeutics with it, there were no explicit discussion of it.

• Vilobelimab

The monoclonal antibody Vilobelimab was trialed for septic shock in 2012. A December 2022, Lancet paper [52] which was cited 88 times reported all-cause mortality rate at 28 days was 32% (95% CI 25–39) in the vilobelimab group and 42% (35–49) in the placebo group (hazard ratio 0.73, 95% CI 0.50–1.06; p=0.094). The FDA granted early use authorization on April 4, 2023.

The NIH Guidelines stated that though vilobelimab received a COVID-19 FDA EUA, there was insufficient evidence to recommend either for or against its use.

• Other Treatments

The Mouse That Roared papers reported that other oxygenation treatments were attempted without much success - hyperbaric chamber along with a cytokine therapeutic (erythropoietin), repurposed drugs imatinib (cancer), methylthioninium chloride and nebulized recombinant tissue plasminogen activator (stroke).

References

1. Helen Pearson, How COVID broke the evidence pipeline, Nature News, May 2021.
2. Débora Dummer Meira, et al, Bioinformatics and molecular biology tools for diagnosis, prevention, treatment and prognosis of COVID-19, Cell Heliyon, July 2024.
3. Aylin Sertkaya et al, Examination of Clinical Trial Costs and Barriers for Drug Development, Assistant Secretary for Planning and Evaluation, July 2014.
4. 2023 FDA approvals, Nature, January 2024.
5. Nir Drayman et al, Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2, Science, August 2021.
6. Jesse S. Pelletier, MD, et al, Efficacy of Povidone-Iodine Nasal and Oral Antiseptic Preparations Against Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2), Ear, Nose & Throat Journal, September 2020.
7. Amy L Baxter, MD et al, Rapid initiation of nasal saline irrigation to reduce severity in high-risk COVID+ outpatients, Ear, Nose & Throat Journal, August 2022.
8. Nigel Curtis et al, Considering BCG vaccination to reduce the impact of COVID-19 Lancet, April 2020.
9. Jorge R. Ledesma et al, Spurious early ecological association suggesting BCG vaccination effectiveness for COVID-19, PLOS ONE, September 2022.
10. Panayiotis Louca, et al Dietary supplements during the COVID-19 pandemic: insights from 1.4M users of the COVID Symptom Study app - a longitudinal app-based community survey, medRxiv, November 2020.
11. Tianjiao Yao et ai, Neutralizing Activity and Viral Escape of Pemivibart by SARS-CoV-2 JN.1 sublineages, bioRxiv, November 2024.
12. Philip V’kovski et al, Coronavirus biology and replication: implications for SARS-CoV-2, Nature October 2020.
13. Manli Wang, et al, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Nature, February 2020.
14. Linlin Zhang et al, Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors, Science, March 2020.
15. Lanying Du et al, The spike protein of SARS-CoV — a target for vaccine and therapeutic development, Nature, February 2020.
16. Xiaochen Lyu, et al, The global landscape of approved antibody therapies. Antibody Therapeutics, June 2022.
17. Julia Lederhofer et al, Protective human monoclonal antibodies target conserved sites of vulnerability on the underside of influenza virus neuraminidase, Cell Immunity, March 2024.
18. Jordan J. Clark et al, Protective effect and molecular mechanisms of human non-neutralizing cross-reactive spike antibodies elicited by SARS-CoV-2 mRNA vaccination, cell Reports, November 2024.
19. Recovery Collaborative Group, Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial, Lancet February 2023.
20. Michael Dougan, M.D., et al, Bamlanivimab plus Etesevimab in Mild or Moderate COVID-19, New England Journal of medicine, July 2021.
21. Anil Gupt, Early Treatment for COVID-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab, New England Journal of Medicine, October 2021.
22. Myron J. Levin Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of COVID-19, New England Journal of Medicine, April 2022.
23. Jennifer Hammond, Ph.D., et al, Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with COVID-19, New England Journal of Medicine, February 2022.
24. Joseph A Lewnard, PhD, et al, Effectiveness of nirmatrelvir–ritonavir in preventing hospital admissions and deaths in people with COVID-19: a cohort study in a large US health-care system, Lancet July 2023.
25. Dallas J Smith et al, SARS-CoV-2 Rebound With and Without Use of COVID-19 Oral Antivirals, CDC Morbidity and Mortality Weekly Report, December 2023.
26. Melisa M. Shah, MD, et al PAXLOVID Associated with Decreased Hospitalization Rate Among Adults with COVID-19 — United States, April–September 2022, CDC Morbidity and Mortality Weekly Report, November 2022.
27. David Leonhardt, The Power of PAXLOVID, NY Times, October 2022.
28. John H. Beigel, M.D. et al, Remdesivir for the Treatment of COVID-19 — Final Report, New England Journal of Medicine, May 2020.
29. Sandra Rajme-López, et al, Nirmatrelvir/ritonavir and remdesivir against symptomatic treatment in high-risk COVID-19 outpatients to prevent hospitalization or death during the Omicron era: a propensity score-matched study, Therapeutic Advances in Infectious Diseases, March 2024.
30. Angélica Jayk Bernal, M.D, et al, Molnupiravir for Oral Treatment of COVID-19 in Nonhospitalized Patients, New England Journal of Medicine, December 2021.
31. Lindsey Wang et al, COVID-19 Rebound after PAXLOVID and Molnupiravir during January-June 2022, medRxiv, June 2022.
32. Theo Sanderson et al, Identification of a molnupiravir-associated mutational signature in SARS-CoV-2 sequencing databases, medRxiv, January 2023.
33. The REMAP-CAP Investigators, Simvastatin in Critically Ill Patients with COVID-19, New England Journal of Medicine, October 2023.
34. Nora Mehalek, et al, Convalescent plasma and all-cause mortality of COVID-19 patients: systematic review and meta-analysis Nature, August 2023.
35. Qingxian Cai et al, Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study, Engineering October 2020.
36. Dr. Oleksandr Kamyshnyi et al, Therapeutic Effectiveness of Interferon-α2b against COVID-19 with Community-Acquired Pneumonia: The Ukrainian Experience, International Journal of Molecular Sciences, April 2023.
37. David C. Feigenbaum, M.D. et al, Cytokine Storm, New England Journal of Medicine, December 2023.
38. Rafael Venegas-Rodríguez et al, Jusvinza, an anti-inflammatory drug derived from the human heat-shock protein 60, for critically ill COVID-19 patients. An observational study, PLOS ONE, February 2023.
39. Dolores Grosso et al, Safety and feasibility of third-party cytotoxic T lymphocytes for high-risk patients with COVID-19, Blood Advances, June 2024.
40. F. La Rosée et al, The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation, Nature June 2020.
41. Xavier Mariette, MD, PhD et al, Effectiveness of Tocilizumab in Patients Hospitalized With COVID-19A Follow-up of the CORIMUNO-TOCI-1 Randomized Clinical Trial, JAMA May 2021.
42. Carlos Salama et al, Tocilizumab in Patients Hospitalized with COVID-19 Pneumonia, New England Journal of Medicine, December 2020.
43. John H. Stone et al, M.D Efficacy of Tocilizumab in Patients Hospitalized with COVID-19, New England Journal of Medicine, October 2020.
44. Evdoxia Kyriakopoulos, MD, et al, Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis, Lancet, October 2021.
45. Andre C. Kalil et al, Baricitinib plus Remdesivir for Hospitalized Adults with COVID-19,New England Journal of Medicine, December 2020.
46. The RECOVERY Collaborative Group, Dexamethasone in Hospitalized Patients with COVID-19, The New England Journal of Medicine, July 2020.
47. Mohammad Reza Aghasadeghi, et al, Effect of high dose Spirulina supplementation on hospitalized adults with COVID-19: a randomized controlled trial, Frontiers in Immunology, April 2024.
48. Carolyn T Bramante et al, Metformin reduces SARS-CoV-2 in a Phase 3 Randomized Placebo Controlled Clinical Trial, medRxiv, June 2023.
49. Maximilian Feth et al, Hemorrhage and thrombosis in COVID-19-patients supported with extracorporeal membrane oxygenation: an international study based on the COVID-19 critical care consortium, BMC Journal of Intensive Care, May 2024.
50. Ryan P Barbaro, MD, et al, Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry, Lancet Sept 2020.
51. Filip Burša, Long-Term Outcomes of Extracorporeal Life Support in Respiratory Failure, Journal of Clinical Medicine, August 2023.
52. Prof Alexander P J Vlaar, MD, et al, Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicenter, double-blind, randomized, placebo-controlled, phase 3 trial, Lancet 2022.
53. The REMAP, ACTIV-4a, NS ATTACC investigators, Therapeutic Anticoagulation with Heparin in Critically Ill Patients with COVID-19, New England Journal Of Medicine Paper, August 2021.
54. Xinwang Chen, et al, Effect of anticoagulation on the incidence of venous thromboembolism, major bleeding, and mortality among hospitalized COVID-19 patients: an updated meta-analysis, Frontiers in Cardiovascular Medicine, April 2024.