I wrote down this post on April 13th and updated til September 1st, 2020 and then abandoned that post due to several issues with Blogger format, and therefore this is the new post.
New Year Times COVID-19 Vaccine Tracker:
https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html
https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html
Before I jump into the list of drugs which may be the treatment of C19, I would like to add general regime being used in India - for severe disease. General considerations are to add steroids (dexamethasone/methyl prednisolone), anticoagulants (heparin/aspirin - must if D-Dimer is high → oral Aspirin/Clopidogrel or Apixaban), Doxy+Iver, IV fluids if needed. Vitamin C 1g, Zinc 50mg, Statins, Vitamin D etc are also adviced.
- Hydroxy-chloroquine (HCQS)
This old antimalarial and DMARD drug saw massive support from ICMR and US President Trump. People started taking it as prophylaxis without any proven benefit in prophylaxis. Trials in China also showed no proven benefit i.e. faster recovery with HCQS. In vitro studies showed that HCQS kills the virus.
In June, 2020 WHO says it is not working, and then again says they are continuing the trials to confirm it can reduce Covid-19 symptoms.
I am not going to write down the dose how Indian doctors are prescribing it to patients, as it would create self prescribing but it is given as pre-exposure prophylaxis and some data says those on PrEP are often asymptomatic. Those patients with contact history are also given a short course of HCQS.
A ICMR data showed HCQ may be beneficial for HCPs (media report).
- Ivermectin
Ivermectin is approved for parasitic infections, and it's is repurposed for COVID-19 treatment, as it is shown to cause ~ 5000 fold reduction in SARS-CoV2 at 48h in cell culture. Dr Md Tarek Alam of Bangladesh is conducting trial with antiprotozoal Ivermectin and antibiotic Doxycycline in COVID-19 patients.
In Australia there is a trial of Ivermectin, Doxycycline and Zinc for treatment of COVID-19.
In India the use of Ivermection for prophylaxis and treatment against COVID-19 has been started. Though ICMR is yet to approve it in its COVID care guideline, many state government guidelines have started to include Ivermectin in Covid-19 treatment protocol. Being one of the cheapest drug, Ivermectin is getting popular in India for mild to moderate cases of Covid-19.
Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19 - on American Journal of Therapeutics.
To get data on worldwide trials of IVM in C-19 visit: https://ivmmeta.com/
- Remdesivir
This Gilead-made antiviral drug (GS-5734) was actually made against Ebola virus. It inhibits viral RNA polymerases by activating nucleoside triphosphate metabolite. It prevents the replication of viral RNA in vitro. Remdesivir is a broad spectrum antiviral drug. It is basically a prodrug, it's active metabolite GS-441524 does the main work to stop the viral replication.
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In India initially Remdesivir was available through black market. But soon Indian pharma companies had started to launch their own branded Remdesivir. Zydus remains to be the company to offer cheapest Remdesivir as of now.
⇒ Hetero's remdesivir of 100mg Covifor at Rs 5400
⇒ Mylan's DesRem (100mg) at Rs 4800
⇒ Jubilant Generics Ltd - Jubi-R (100mg) at Rs 4700
⇒ Cipla - CipRemi at Rs 4000
⇒ Zydus Cadila - Remdac at Rs 2800
⇒ Mylan's DesRem (100mg) at Rs 4800
⇒ Jubilant Generics Ltd - Jubi-R (100mg) at Rs 4700
⇒ Cipla - CipRemi at Rs 4000
⇒ Zydus Cadila - Remdac at Rs 2800
⇒ Dr Reddy's - Redyx at Rs ??
FDA has approved Remdesivir for hospitalised COVID-19 patients (age >12 y, weight > 40 kg) on October 22, 2020.
However WHO, with its SOLIDARITY trial is not backing Remdesivir for C19 treatment. But experts believe WHO's trial has several drawbacks.
- GS-441524
GS-441524 is the nucleoside of the prodrug remdesivir, is developed by Gilead Sciences. Interestingly this drug is widely popular before this pandemic hit the world, but not for human use. It has been shown that GS-441524 is a cure for feline infectious peritonitis (caused by Feline Coronavirus), which was like near 100% mortality rate among cats.
However Gilead will not pursue this drug for veterinary approval, as it might jumble up human approval.
- Favipiravir (brand name Avigan)
This antiviral drug was developed by Toyama Chemical of Fujifilm group, and got approval of use in Japan in 2014. It became a generic drug in 2019.
Since April 2020, Favipiravir is being used for nCoV-19 infection in China. Favipiravir, a purine nucleic acid analog and potent RdRp (RNA-dependent RNA polymerase) inhibitor was approved for use in influenza (similar to Oseltamivir). Researches have showed that Favipiravir may able to control symptoms i.e. faster remission in mild to moderate COVID-19 cases.
In June end, 2020, Glenmark launched it in India at Rs 103 per tablet of 200mg.
Soon after Glenmark's launch of favipiravir in India, several pharma companies launched their favipiravir at reduced prices. Glenmark too reduced price to Rs 75 per 200mg tablet.
⇒ Glenmark - Flaviflu @Rs 75 per 200 mg tablet
⇒ Brinton - Flaviton @Rs 59
⇒ Jenburkt - Flavivent @Rs 39
⇒ Cipla - Ciplenza @Rs 68
⇒ Hetero - Favivir @Rs 59
⇒ MSN - Favilow @ Rs 33
⇒ FDC - PiFLU/Favenza @ Rs 55
⇒ Brinton - Flaviton @Rs 59
⇒ Jenburkt - Flavivent @Rs 39
⇒ Cipla - Ciplenza @Rs 68
⇒ Hetero - Favivir @Rs 59
⇒ MSN - Favilow @ Rs 33
⇒ FDC - PiFLU/Favenza @ Rs 55
⇒ Lupin - CoviHalt @ Rs 49
⇒ Abbott - Fapvir @ Rs 42 - 400mg tab also available now
In mild to moderate cases of COVID-19, Favipiravir is given in huge dose - 1800mg BID on D1 and then, 800mg BID from D2 to upto D14. As it is available in 200mg tablet, one has to consume 18 tablets on day 01. Therefore BDR Pharmaceuticals is going to launch 800mg version of Favipiravir under BDFAVI brand name.
- Tocilizumab
Tocilizumab is an IL-6 inhibitor, is on phase III trial by Roche (Actemra | COVACTA trial) - to counteract cytokine release syndrome in severe lung damage cases which has worst prognosis. Tocilizumab is currently indicated for the treatment of various Rheumatological disorders like Rheumatoid Arthritis, Systemic and Polyarticular Juvenile Idiopathic Arthritis.
Severe form of COVID-19 is often associated with IL-6 mediated Cytokine Release Syndrome (CRS), causing symptoms like high fever and hypoxic pneumonitis.
In India Tocilizumab is yet to be approved for COVID-19 in India, therefore the use of Tocilizumab in severe COVID-19 is restricted and must be done after weighing risks and benefits. In India, Roche Products (India) Pvt. Ltd. is importing Actemra and Cipla is marketing and distributing Actemra.
On 29 July, 2020 Roche has announced that the COVACTA trial did not meet its primary endpoint of improved clinical status in patients with COVID-19 associated pneumonia, or the key secondary endpoint of reduced patient mortality. The study was the first global, randomised, double-blind, placebo-controlled phase III trial investigating Actemra/RoActemra in this setting. Roche remains committed to continuing the Actemra/RoActemra clinical trial programme in COVID-19 to further explore Actemra/RoActemra in other treatment settings, including in combination with an antiviral. In addition to COVACTA, Roche has initiated several studies to further investigate Actemra/RoActemra as a potential treatment for patients with COVID-19 associated pneumonia, including two phase III clinical trials, REMDACTA and EMPACTA, as well as the phase II MARIPOSA trial.
Update from April end, 2021: In India it is COVID-hell, and like many times before, there is scarcity of oxygen, hospital beds and the drugs like Remdesivir, Flavipiravir, Ivermectin, Doxycyline, Tocilizumab etc. The health system got to be collapsed ('or it has been collapsed for long, this time it got exposed)
Instead of anti IL-6 - Tocilizumab, doctors started prescribing anti-CD6 Itolizumab and VEGF-A targeting mAb Bevacizumab.
Approved for moderate to severe chronic plaque psoriasis in 2013, Itolizumab is another repurposed drug against COVID-19 as it can reduce T-cell proliferation alongwith substantial downregulation of cytokines production.
Countering C19 Cytokine storm
Apart from controlling IL-6, scientists are also targeting IL-1. IL-1 is produced by damaged cells, also by macrophages and neutrophils upon the detection of the virus. It seems IL-1 plays a critical role during the early pathogenesis of the disease, however it is dificult to detect by cytokine assays, may be detected using an RNA profile. It seems this proinflammatory mediator may be the reason of thrombosis and disease severity.
Anti- IL therapy:
Anti IL-1beta therapy - Canakinumab
IL-1 Receptor antagonist - Anakinra
- Umifenovir (Arbidol)
This antiviral is used against influenza in China and Russia. By mid-June '20, Umifenovir is in clinical trials in India.
In October, 2020 Glenmark Pharma announced that the addition of antiviral Umifenovir did not demonstrate any significant clinical benefit over Favipiravir alone in moderate COVID-19 patients.
- Tilarone
This broad spectrum antiviral, is being used in Russia and other federation countries against multiple viruses, including acute respiratory viral infection, influenza, and hepatitis. Based on earlier research, Tilarone is also active against chikungunya and MERS-CoV viruses. Available as Amixin® in some countries, Tilarone is an inducer of interferon.
Researchers from North Carolina State University and Collaborations Pharmaceuticals has found that three commonly used antiviral and antimalarial drugs are effective in vitro at preventing replication of SARS-CoV-2. The medicines are: tilorone, quinacrine and pyronaridine.
- Tofacitinib (Xeljanz)
A JAK 1 / 3 inhibitor from the house of Pfizer, Tofacitinib is being used as an anti-RA drug, approved by FDA in 2012 is also a possible candidate against Covid-19.
- Human convalescent plasma
There has been update that plasmapheresis also tried to counteract cytokine storm. Human convalescent plasma with a SARS-CoV-2–specific antibody (IgG) binding titer greater than 1:1000 (end point dilution titer, by enzyme-linked immunosorbent assay [ELISA]) and a neutralization titer greater than 40 (end point dilution titer) that had been obtained from 5 patients who recovered from COVID-19 and transfused in 5 critically ill patients after 10-22 days of admission and all are recovered. (Source)
- Hyperimmune Globulin
Best of convalescent plasma, hyperimmune Globulin will provide purified and enriched preparation of COVID-19 specific neutralizing antibodies in high concentration, free from blood transmitted viruses and other plasma proteins. The solution is like a vaccine to be used in prophylaxis too. India's Intas Pharma developed it, and got a nod from DCGI to conduct clinial trial against moderate to severe COVID-19 pneumonia.
- AZD7442
AZD7442 is the combination of two antibodies, that are being developed to both treat and prevent coronavirus infections. The two antibodies (AZD8895 + AZD1061) were discovered by Vanderbilt University Medical Center from the convalescent plasma (taken from recovered COVID-19 patients) and licensed to AstraZeneca in June. In animal and human cell models, the cocktail has been shown to block the binding of the SARS-CoV-2 virus to host cells and protect against infection.
Phase I trial was announced in August end 2020, funded by US government. This mab is developed using half life extension technology, that would give atleast 6 months of protection.
- REGN-COV2
Similar to AZD7442, REG-COV2 is another cocktail of 2 antibodies - casirivimab (REGN10933) and imdevimab (REGN10987), from the house of Regeneron. It is currently in late-stage clinical trials for the treatment and prevention of COVID-19 infection.
The two potent, virus-neutralizing antibodies that form REGN-COV2 bind non-competitively to the critical receptor binding domain of the virus's spike protein, which diminishes the ability of mutant viruses to escape treatment and protects against spike variants that have arisen in the human population.
In India Cipla has launched 2-dose vials of the mab cocktail as partnering with Roche, who is taking care of Regeneron in international markets. It is available as RONAPREVE since May 2021, and a second batch will be available by mid June 2021. The antibody cocktail (Casirivimab and Imdevimab) is to be administered for the treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age or older, weighing at least 40 kg) who are confirmed to be infected with SARS-COV2 and who are at high risk of developing severe COVID-19 disease and do not require oxygen. It has been shown to help these high-risk patients before their condition worsens, reducing the risk of hospitalisation and fatality by 70% and shortening the duration of symptoms by four days.
Each pack of Antibody Cocktail (Casirivimab and Imdevimab) contains one vial of Casirivimab and one vial of Imdevimab totaling 2400 mg of the antibody cocktail (one vial of Casirivimab (1200 mg) and one vial of Imdevimab (1200 mg)). Each pack can treat two patients as the dosage per patient is a combined dose of 1200 mg (600 mg of Casirivimab and 600 mg of Imdevimab) administered by intravenous infusion or subcutaneous route. The vials need to be stored at 2°C to 8°C. If opened for the first patients’ dose, a vial can be used for the second patients’ dose within 48 hours if stored at 2°C to 8°C.
The price for each patient dose [a combined dose of 1200 mg (600 mg of Casirivimab and 600 mg of Imdevimab)] will be INR 59,750 inclusive of all taxes. The maximum retail price for the multidose pack (each pack can treat two patients) is INR 119,500 inclusive of all taxes.
✘ Ruxolitinib (Jakafi)
There is another way to block IL-6 via inhibiting receptor signal transduction by JAK (Janus Kinases 1/2). Example is Ruxolitinib, but it can affect the host’s antiviral immunity mediators such as natural killer cells, dendritic cells, and beneficial cytotoxic T lymphocytes as well as deleterious effects on cytokines such as IL-2, IL-7, and IL-15. It is now approved for use in myelofibrosis and polycythemia vera.
RUXCOVID study shows no benefit of Ruxolitinib in COVID-19 associated cytokine storm.
- Baricitinib
Another JAK Inhibitor (JAK 1/2), Baricitinib also neutralizes protein AAK1, which can facilitate entry of SARS-CoV-2. BenevolentAI, the UK-based AI drug discovery company initially identified baricitinib as a potential treatment using its machine learning system. Lilly is offering this drug as Olumiant as anti-inflammatory in rheumatoid arthritis (2mg once daily pill) and initial use under trial shows it can shorten recovery time if used with Remdesivir.
FDA approves emergency use of Baricitinib with Remdesivir in severe C19 infection.
Other JAK inhibitors - Fedratinib, Pacritinib
- Mavrilimumab
A single-centre prospective cohort study, based on San Raffaele Hospital, Milan, Italy shows mavrilimumab may be another choice in treating severe COVID-19 pneumonia and systemic hyperinflammation. Mavrilimumab is an anti-granulocyte–macrophage colony-stimulating factor (GM-CSF) receptor-α monoclonal antibody. It was given as single IV dose of 6 mg/kg on top of standard care.
Given its cardinal role in innate inflammation, GM-CSF may be a potential mediator of the cytokine storm. Atypical pathogenic T helper 1-cells expressing GM-CSF have been identified in patients with more severe COVID-19, but not in those with less symptomatic patterns and in healthy controls.
Update: At the end of December, 2021 Bermuda-based Kiniksa Pharmaceuticals announced that the Phase III portion of the Phase II/III trial of mavrilimumab in COVID-19-related acute respiratory syndrome (ARDS) did not meet the primary efficacy endpoint.
- Lenzilumab
It is another investigational humanized granulocyte macrophage-colony stimulating factor monoclonal antibody. It is being tested along with steroids + Remdesivir.
Mavrilimumab targets the GM-CSF α receptor; whereas otilimab, namilumab, and lenzilumab bind directly to GM-CSF.
- Remestemcel-L
Remestemcel-L (Ryoncil, Mesoblast) is an investigational allogeneic cell therapy consisting of culture-expanded mesenchymal stem cells derived from the bone marrow of an unrelated donor. FDA is yet to approve its use in children with steroid-refractory acute graft vs host disease (SR-aGvHD) following allogeneic bone marrow transplant.
It is believed to work by downregulating the production of proinflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues. Therefore Mesoblast had already begun testing the allogeneic cell therapy in COVID-19 patients with acute respiratory distress syndrome (ARDS). Novartis has obtained a global license to Mesoblast’s cell therapy remestemcel-L in the treatment of COVID-19.
- APN01 or rhACE2 APN01
Developed by Austria based Apeiron Biologics, APN01 is a recombinant human ACE 2, which is under Phase-2 clinical development in Acute Lung Injury and Pulmonal arterial hypertension. Recently, ACE2 has been shown to be the cellular entry receptor for the novel coronavirus SARS-CoV-2. Apeiron initiated a clinical Phase II study in several European countries with patients severly infected with SARS-CoV-2 in April 2020.
APN01 has a unique effect as it blocks infection (by directly binding viral particles) and reduces inflammation (reducing disease mediated organ pathology). It has enzymatic activity that normalizes the COVID-19 induced Renin Angiotensin System deregulation, which is a key driver in Acute Lung Injury.
- Baladol
Kochi based Indian pharma company PNB Vesper Life Science Private Limited has launched a new proprietary molecule - GPP-Baladol (PNB-001) against COVID-19 disease. By its mechanism of action it is a CCK2 (cholecystokinin) antagonist. On 11st September, 2020 Drug Controller General of India (DCGI) approved the pharma company to conduct clinical trials with the new drug. Preclinical studies show the promising result with Baladol, nearly 4 times better result to reduce inflammation as compared with Dexamethasone. The trial will be run at BMJ Medical College, Pune. More details: https://pnbvesper.com/pnb001_and_covid19.html
- Merimepodib
It is a broad spectrum antiviral. It is being tested with Remdesivir, the trial is in phase II.
- Bamlanivimab (LY-COV555)
Neutralizing Antibody from Eli Lilly - Bamlanivimab (LY-COV555)
It is a potent neutralizing IgG1 monoclonal antibody directed against the spike protein of SARS-COV2. It is expected to block viral attachment and entry into human cells. Canadian antibody-drug discovery platform AbCellera Biologics Inc. has screened out LY-CoV555 out of more than 500 Ab and scientists at Eli Lilly have developed it.
In the BLAZE-1, phase 2 trial Bamlnivimab is being tested as monotherapy and in combination with Etesevimab (LY-CoV016, also known as JS016).
- ZRC-3308
Zydus Cadilla's mAb cocktail against the spike proteins of SARS-Cov2. ZRC-3308 has demonstrated the ability to neutralize SARS-CoV-2 both in vitro and in animal studies. In animal studies ZRC-3308 reduced damage to the lungs in both prophylactic and therapeutic settings. ZRC-3308 has been found to be safe and well tolerated in animal toxicology studies.
The company is applied for permission for human trial from DCGI in May 27, 2021- Regdanvimab (CT-P59)
mab therapy for C19
Celltrion has already presented the results from phase I clinical trial as 44% reduced mean clinical recovery time in comparison to the average placebo recovery time and no patients treated with CT-P59 required hospitalisation or antiviral therapy.
- Inhaled interferon
UK based Synairgen has developed inhaled formulations of interferon β1a, SNG001, and small clinical trial with nebulized SNG001 showed positive results.
Interferon against COVID-19
Interferons (IFNs) are widely used against viral diseases. In the early days of COVID-19 pandemic there was news coming from Cuba that the scientists over there having good results with IFN-α2b (given 3 doses IM/week x 2 weeks). A prospective observational study can be found at PubMed.
Cuba has long history with IFNs, as in 1981 Cuba had manufactured its first interferon to use against the haemorrhagic dengue epidemic. Cuba later manufactured ‘recombinant’ human interferon Alfa-2b in 1986. Considered one of the stars of the Cuban biotechnology boom, IFN has reportedly been effective in the treatment of HIV, human papilloma virus, Hepatitis B and C.
Iran did a comparative study of Interferon-β1a and Interferon-β1b. The result is pending.
NIH (US) strongly recommends not to use IFN (α & β) in COVID-19 disease.
IFN α2a is used in treatment of chronic hepatitis C & hepatitis B, but efficacy was limited due to short in-vivo half life. While IFN α2b is used in hepatitis B and melanoma and facing similar issues. Therefore IFN is conjugated with a polyethylene glycol moiety. Pegylation increases its half life and efficacy.
Drugs Controller General of India (DGCI) announced EUA to Zydus Cadila for Virafin (PEG-IFN α2b) use in COVID-19 on 23rd April, 2021. This EUA approval for use in moderate C-19 disease is based on a phase II randomized study. Press release can be found here.
- Hanfangchin A (tetrandrine) - a chloroquine dervivative, currently on phase III trials.
- Astemizole - An antihistamine was withdrawn from market due to fatal side effects, now again being testing against COVID-19.
- Clofazamine - An anti-leprosy drug.
- Molnupiravir (MK-4482/EIDD-2801)
Originally developed by Emory University's drug innovation company, Drug Innovation Ventures at Emory or simply DRIVE, MK-4482 was acquired by Miami-based company Ridgeback Biotherapeutics, is now under Merck by some business deal. It is an experimental oral antiviral drug, initially meant to work against influenza. It is a prodrug of the synthetic nucleoside derivative N4-hydroxycytidine, and exerts its antiviral action through introduction of copying errors during viral RNA replication. Phase 2 trial is set to be completed soon, and phase III trial may be started from September 2020.
Interim results of a phase IIa study have shown that Molnupiravir eliminated SARS-CoV2 in the nasopharynx of C19 patients in 5 days. Though the data is very promising, experts say it is too early to tell if molnupiravir can keep COVID-19 patients out of the ICU. Most significant dosing is probably 800mg twice daily orally.
On April 28, 2021 Merck signed non-exclusive voluntary licensing agreements with 5 Indian pharma companies - Sun Pharmaceutical Industries, Cipla, Dr Reddy’s Laboratories, Emcure Pharmaceuticals and Hetero Labs to ontract manufacture molnupiravir.More details here.
- Nitazoxanide
This is another antiparasitic and antiviral agent. Pharma company Romark has started a phase 3 trial of its extended formulation.
Super Computer driven potential anti-COVID-19 drugs:
Summit supercomputer at Oak Ridge National Lab in Tennessee analysed data (more than 40,000 genes from 17,000 genetic samples) and offers new prospective to COVID-19. The data analysis supports the Bradikinin hypothesis against COVID-19 pneumonia. (source)
Potential drugs found from the data
- Danazol, Stanozolol, and Ecallantide - reduce bradykinin production and could potentially stop a deadly bradykinin storm
- Icatibant - reduce bradykinin signaling and could blunt its effects
- Vitamin D - can reduce bradykinin storm
- Hymecromone - reduce hyaluronic acid levels, potentially stopping deadly hydrogels from forming in the lungs
- Tetracycline ointment (APT T3X)
The brand came in the highlight, as Virology Research Services evaluated the anti-viral impact of the APT T3X, against coronavirus (NL63) and Influenza A virus and concluded that it is a highly effective formulation against coronavirus. They claim, “As per the lab report states, no infectious virus was detected after 30 seconds of T3X treatment." This ointment can be used intranasally post exposure to reduce the viral load.
- Biovista AI - Proposed repurposed COVID-19 drugs:
Persidis brothers used Biovista's Project Prodigy AI platform to predict useful drugs in COVID-19. The list includes:
- Antifibrinolytic agent aprotinin and the A2RB irbesartan as having potential for reducing the effects of cytokine storm and high viral load associated with COVID-19.
- Caplacizumab (indicated in acquired Thrombotic Thrombocytopenia Purpura) and ezetimibe/atorvastatin as potential treatments to address blood clotting and inflammation related to COVID-19.
- Two bioactive compounds — lycopene and vitamin D — as potentially useful in treating COVID-19
- AT-527
It's an oral antiviral agent developed by Boston based biotech company Atea Pharmaceuticals. Roche seems very much interested into it, as they will pay a lumpsum in cash for partial rights of it. AT-527 is a prodrug of a guanosine nucleotide analog is shown to be highly efficacious and well tolerated in HCV-infected subjects. The study shows potent in vitro activity of AT-511, the free base form of AT-527 - to inhibit replication of SARS COV2.
Current status: Phase II trial
- PF-07304814
Pfizer is conducting a phase 1b trial of this IV drug against COVID-19. This small novel molecule is found to target 3CL protease enzyme, that SARS COV2 uses to organize and multiply. This investigestional antiviral is the first in class to target this enzyme.
PF-07304814 contains a phosphate group that makes the compound soluble and gets cleaved by alkaline phosphatase enzymes in tissue, releasing the active antiviral PF-00835231. The molecule was discovered by Pfizer chemists in 2002-03 during SARS outbreak but as it was not a pandemic, the research around the molecule was shelved.
- Fluvoxamine
In a study, a collaboration between the university’s Department of Psychiatry and Division of Infectious Diseases, this anti-depressant (SSRI by molecule) is found to be an effective drug to prevent severe COVID-19 or pulmonary manifestations.
- ADG2 - Ab against SARSCOV2
Massachusetts based Adagio Therapeutics announced the company's lead Ab candidate - ADG2 shows similar or higher potency against SARS-CoV-2 compared to monoclonal antibodies (mAbs) in clinical development (in vitro and in vivo), while also uniquely offering broad neutralization against a range of sarbecoviruses that pose a threat to humans. The company expects its half-life engineered version of ADG2, called ADG20, to enter clinical studies in early 2021. Many put this antibody in the category of broadly neutralising antibodies.
- Bucillamine
It is an anti-rheumatic agent, being used for Rx of RA in Japan and South Korea over 30 years. It is a cysteine derivative with 2 thiol groups that is 16-fold more potent than acetylcysteine (NAC) as a thiol donor in vivo, giving it vastly superior function in restoring glutathione and therefore greater potential to prevent acute lung injury during influenza infection. Bucillamine has also been shown to prevent oxidative and reperfusion injury in heart and liver tissues. It is now repurposed for COVID-19 treatment.
- 2-Deoxy-D-Glucose (2-DG)
2-DG oral powder is being tested as anti cancer drug and now repurposed against COVID-19. The King George Hospital (KGH) and Andhra Medical College (AMC) have successfully completed the trial (probably phase II) in India. Dr. Reddy's Pharma is planning to do the phase III trial of 2-DG.
The 2-DG has, according to DRDO, been jointly developed by Institute of Nuclear Medicine and Allied Sciences (INMAS), and Dr Reddy’s Laboratories (DRL), Hyderabad.
As we are going through the tail of 2nd wave, 2-DG is yet to be available in market. Dr Reddy's have plan to launch in mid-June, and it could be delayed. However many doctors in India already have expressed their skeptical mindset towards 2-DG against COVID-19 virus.
- Imatinib
If you have worked in a COVID ICU, you already knew the fact that ARDS is killing the patients. The hypoxaemic respiratory failure from capillary leak and alveolar oedema is the main pathology behind C-ARDS. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak.
Imatinib has been used as 800mg orally on D1 and 400mg orally on D2 to D10. The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings.
- Colchicine
Colchicine is an oral anti-inflammatory drug being used in Covid-19. The COLCORONA trial used colchicine 0.5 mg twice daily for three days, then once daily for the next 27 days.
Colchicine was shown to be ineffective in individuals hospitalised with COVID-19 in the RECOVERY study. But the medicine has demonstrated promise in lowering hospital admissions in patients with COVID-19 in Canada's COLCORONA study, nothing is known about its usefulness in lowering recovery time or disease burden.
- Aprotinin
German researchers have found that the approved protease inhibitor aprotinin displayed activity against SARS-CoV-2. An antifibrinolytic molecule, Aprotinin inhibits the entry of SARS-CoV-2 into host cells and may compensate for the loss of host cell protease inhibitors that are downregulated upon SARS-CoV-2 infection.
Aprotinin aerosols are approved in Russia for the treatment of influenza and could be readily tested for the treatment of COVID-19.
- RSLV-132
Resolve Therapeutics has brought RSLV-132, an investigational drug to treat long COVID. It is a novel targeted biologic drug designed to remove pro-inflammatory nucleic acids from the circulation of patients. These acids are thought to be one of the key triggers of multiple pro-inflammatory cascades. The compound consists of a catalytically active human RNase moiety fused to a human IgG1 Fc domain that digests RNA circulating in the blood, thereby decreasing inflammation.
- Dornase alfa (Pulmozyme - Genentech)
It is a highly purified solution of rhDNase I, an enzyme which selectively cleaves DNA. It is approved for use in cystic fibrosis - as it hydrolyzes the DNA present in sputum/mucus of cystic fibrosis patients and reduces viscosity in the lungs, promoting improved clearance of secretions.
In COVID-19 the lungs get filled up with immune broth - neutrophil extracellular traps (NETs) during the innate immune response - all leads to ARDS. A study suggests the use of inhaled dornase alfa (in Nebulizated form), a recombinant DNAse I that lyses NETs, to reduce ventilatory requirements and improve oxygenation status, as well as outcomes in critically ill patients with ARDS subsequent to confirmed or highly suspected COVID-19 infection.
- Brilacidin (PMX-30063)
Brilacidin is a new class of broad spectrum antibiotics, host defense protein mimetics (HDPM)that works by disrupting bacterial cell membranes, mimicking defensins that play a role in innate immunity. It is a non peptide synthetic molecules modeled after HDPs.
It has been found that Brilacidin is another drug candidate to show demostrate antiviral activity against SARS COV2. Its main mechanism appears to disrupt viral integrity and impact viral entry. In August 2020 Innovation Pharmaceuticals has reported promising data from ongoing in-vitro testing of its Brilacidin at a US Regional Biocontainment Laboratory (RBL) to treat Covid-19. In December 2020, the drugmaker received Investigational New Drug (IND) approval from the FDA to start a Phase 2 clinical trial.
- Desidustat
Desidustat is a molecule from Zydus Cadila, which is a Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitor. It is being tested to treat anaemia in CKD (DREAM-ND phase III trial is going on in CKD patients not on HD. It improves iron mobilization to the bone marrow and protects against acute and chronic kidney injury by reducing inflammatory cytokines like IL-6 and oxidative stress.
This molecule is repurposed in the treatment of COVID-19 pneumonia and ARDS. In the phase 2b studies run in Mexico, "None of the hospitalised patients required mechanical ventilator in the Desidustat arm, while 25 per cent of COVID-19 patients on the standard of care arm required mechanical ventilation." It seems Desidustat controls ARDS, by reducing inflammatory processes and hypoxia by increased hemoglobin synthesis.
- Aviptadil/RLF-100
It is a synthetic human Vasoactive Intestinal Polypeptide (VIP). VIP is released throughout the body, but remains mostly concentrated in lungs. It is produced by immune cells and nerve endings and acts as a neurotransmitter. It helps improve muscle activity and blood flow in gastrointestinal tract. Studies have shown VIP has anti-inflammatory and anti-cytokine activity properties. RLF-100 protects alveolar type II cells that are responsible for oxygen exchange in lungs.
Aviptadil can be delivered using Senetek's novel and patented autoinjector (Reliaject), which renders the self-injection process exceptionally easy, unobtrusive to perform and helps ensure accurate, safe delivery of the medication.
In India Aviptadil will be launched soon by Zuventus (under brand name of Oxyptadil - Inj of 150 mcg/10ml). (Updated, July 2021)- Camostat mesylate
Al Ain Hospital, Abu Dhabi, United Arabs Emirates has used Camostat mesylate (pdf) as 600mg daily and the prelimininary observation suggests camostat mesylate may be also effective to treat the most advanced cases of COVID-19 with organ dysfunction. It should be noted that randomized clinical trials are ongoing.
- Olokizumab
Another drug used for RA, Olokizumab is being repurposed against COVID-19. It is of Russian in origin, made by R Pharma. Belgium’s UCB, the initial developer of olokizumab, sold a development and marketing license for the drug to R-Pharm in 2013. In Russia it was approved for use in RA in May '20. Since February '20 when SARS-CoV2 became the cause behind COVID 19 pandemic R-Pharm is working with Olokizumab as it can inhibit IL-6, the immune molecule to cause cytokine storm syndrome in severe COVID-19 disease. Chief Medical Officer, R-Pharma Mikhail Samsonov told Reuters in an interview in October '20 that final results of a 372-person placebo-controlled, randomised clinical trial with Olokizumab will be published soon.
Indian pharma company Dr Reddy's Laboratories had planning to launch in the country. However GoI has rejected Dr Reddy's proposal to grant EUA to this monoclonal antibody on 30th Jan '21. - Budesonide
The Principle Trial of UK has shown that common inhaled steroid Budesonide may be a choice among patients of 50+ age with moderate COVID disease who are on home treatment. Budesonide is helping to shorten recovery time.
Doctors are already prescribing this medicine to ICU/HDU patients to combat the lung inflammation. So this cheap medicine could do wonder for home COVID patients.
- Inhaled Pulmonary Vasodialators
Inhaled pulmonary vasodilators have been a valuable adjunctive treatment for outpatient management of pulmonary arterial hypertension.
Examples are Treprostinil, Iloprost, Epoprostenol, Nitric Oxide
American College of Cardiology has run a trial of these among in-patients. You can read more about them - here.
- FP-025
Foresee Pharmaceuticals has a drug candidate - FP-025 (previously FP-003) which is matrix metalloproteinase 12 inhibitor. It is being tested as a drug candidate against asthma. It is now repurposed for lung injury in COVID-19.
- Narsoplimab
Narsoplimab (OMS721 from Omeros Pharma) is an IgG-4 hmAb targeting mannan-binding lectin-associated serine protease-2 (MASP-2), the effector enzyme of the lectin pathway of the complement system. The lectin pathway is one of the principal pathways of complement and is activated primarily by tissue damage and microbial infection. Importantly, inhibition of MASP-2 does not appear to interfere with the classical complement pathway, a critical component of the acquired immune response to infection. This novel, proprietary drug is designed to prevent complement-mediated inflammation and endothelial damage while leaving intact the respective functions of the other pathways of innate immunity.
Narsoplimab is being tested against HSCT-TMA (Hematopoietic stem cell transplant-associated thrombotic microangiopathy), IgA Nephropathy, Atypical Hemolytic Uremic Syndrome (aHUS).
In Italy Narsoplimab has been used in critical COVID-19 patients where the drug is targeted to reverse endothelial damage, which can play an early and central pathogenic role in ARDS and thrombosis. All narsoplimab-treated patients recovered and survived, without any adverse reaction.
Narsoplimab is being assessed in the I-SPY COVID-19 Trial, an adaptive platform for critically ill Covid-19 patients.
I-SPY trial includes Remdesivir, Pulmozyme, IC14, Celecoxib+Famotidine, Narsoplimab, Aviptadil Acetate and Cyclosporine. More molecules may be added later on.
- IC-14/Atibuclimab
Implicit Bioscience's IC-14 is a mAb against CD-14. CD14 is a pattern recognition receptor for the bacterial cell wall components from Gram-positive and Gram-negative bacteria as well as mycobacteria. Binding of lipopolysaccharide (LPS) or other cell wall constituents to CD14 initiates signal transduction through the Toll-like receptors resulting in the release of pro-inflammatory cytokines and the initiation of the systemic inflammatory response. IC14 inhibited the release of TNF-alpha, IL-6, and IL-10 and delayed the release of sTNFR(I) and IL-1ra.
Under I-SPY trial IC-14 has been tested against COVID-19. It should be noted that IC-14 trial on sepsis has been discontinued.
- ARDS-003
Canada based Tetra Bio-Pharma has two investigational medications against hyperinflammation. One of them ARDS-003 shows an anti-inflammatory effect in pre-clinical studies using a mouse model of pulmonary fibrosis (PF) and could be considered for the treatment of COVID-19, the company announced.
A synthetic compound, ARDS-003 acts on the body’s endocannabinoid system, a widespread neuromodulatory system that plays important roles in the central nervous system. The medication binds to CB2 receptors, which are responsible for modulating inflammation and the activity of cytokines.
On April 5, 2021 Tetra Bio-Pharma announced US-FDA has favorably reviewed the preclinical data package and clinical development plan of ARDS-003 to treat COVID-19 patients.
siRNA-NP Technology
viral genome and form RNA-induced silencing complex (RISC) and disrupt viral genome.
Researchers at City of Hope, a research center based in California, and Griffith University in Australia have collaborated to create a new experimental anti-viral therapy based on this technology.
siRNA approved in other diseases (all made by Alnylam Pharma)
Read more about the drugs of such technology which are in pipeline: https://www.alnylam.com/alnylam-rnai-pipeline/
- Patisiran- the first siRNA - in Rx of hereditary transthyretin amyloidosis (hATTR) (2018)
- Givosiran was approved to treat acute hepatic porphyria (2019)
- Lumasiran was approved to treat primary hyperoxaluria type 1 (2020)
Alnylam Pharma has a specific candidate for COVID-19 - ALN-COV (also referred to as VIR-2307), an investigational RNAi therapeutic targeting the SARS-CoV-2 genome. Vir Biotechnology is the main collaborator with Alnylam. Both companies are working together from earlier days - mostly towards a treatment of hepatitis B viral infection.
Vir Biotech has two other molecules (mAb candidate) - Sotrovimab (VIR-7831/ GSK4182136) (for early treatment, in phase III trials) and VIR-7832 with collaboration with GSK.
Sotrovimab is a recombinant human IgG1-kappa monoclonal antibody that binds to a conserved epitope on the spike protein receptor binding domain of SARS-CoV-2. The Fc domain of sotrovimab includes M428L and N434S amino acid substitutions (LS modification) that extend antibody half-life.
In the end of May, 2021 US-FDA granted EUA to sotrovimab to use against COVID-19 based on an interim analysis from the randomized, double-blind, placebo-controlled phase 1/2/3 COMET-ICE trial. The authorized dosage of sotrovimab is a single intravenous infusion of 500mg administered as soon as possible after a positive SARS-CoV-2 test and within 10 days of symptom onset.
- AR-712
Developed by Aridis Pharma, AR-712 is a cocktail of fully human mAbs (AR-711 and AR-713) that are directed against the receptor binding domain of the SARS-CoV-2 virus. It is formulated for delivery via inhalation using a nebulizer, effective against the Delta and Delta Plus variants, and is expected to provide broad coverage of all known high-risk variants.
The animal efficacy data reported by the Coronavirus Immunotherapeutics Consortium (CoVIC) showed that the Company's COVID-19 monoclonal antibody (mAb) AR-711, one of two mAbs in the AR-712 cocktail, ranks among the top 5 most potent mAbs that the CoVIC consortium have studied to date.
Aridis has other hmAbs against COVID-19, for eg, AR-701 is a cocktail of fully human mAbs discovered from convalescent COVID-19 patients that are directed at multiple surface proteins of the SARS-CoV-2 virus.
- Proxalutamide
In some observational and interventional studies antiandrogens have demonstrated a protective effect for COVOD-19 patients. Proxalutamide, an androgen receptor antagonist, could be an effective treatment for men with COVID-19 in an outpatient setting. The inital report came in July 2021 (link).
However as updated at the end of December, 2021 Kintor Pharmaceutical has reported interim assessment data where its nonsteroidal antiandrogen, proxalutamide, failed to meet statistical significance in Phase III clinical trial to treat Covid-19 in the outpatient setting. The data was collected from 348 subjects with mild-to-moderate disease. With the latest development, the company plans to seek approval from regulatory authorities to modify the trial protocol and enrol infected people at greater risk with several comorbidities and/or unvaccinated. In the interim findings, no safety concerns and treatment-associated serious adverse events were observed.
------- Drugs found to be NOT effective against COVID 19----------
✘ Lopinavir/ritonavir (Kaletra)
The combo is generally used as anti-retroviral therapy among HIV+ patients. In some trials it shows promising results against Covid-19 [Primary outcome - time to clinical improvement; Secondary outcome - mortality, ICU stay, viral load]. It has proteolysis activity. During the initial days Kaletra was used in COVID-19 in many countries (Dose: Lopinavir/Ritonavir (400/100 mg) twice daily x 14 days) as but later it is found ineffective against SARS-CoV2. Chinese trial says no benefit was observed with lopinavir-ritonavir treatment beyond standard care (Link)
✘ Selinexor
It is a first in class, selective inhibitor of nuclear export (SINE) used as an anti-cancer medication. Developed by Karyopharm Therapeutics, Selinexor functions by binding with, and inhibiting, the nuclear export protein, XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. XPO1 is a karyopherin which performs nuclear transport of several proteins, including tumor suppressors, oncogenes, and proteins involved in governing cell growth, from the cell nucleus to the cytoplasm; it is often overexpressed and its function misregulated in several types of cancer. By inhibiting the XPO1 protein, SINEs lead to a buildup of tumor suppressors in the nucleus of malignant cells and reduce levels of oncogene products which drive cell proliferation. This ultimately leads to cell cycle arrest and death of cancer cells by apoptosis.
It is approved in 2019 for use in relapsed refractory multiple myeloma in combination with dexamethasone & bortezomib. Karyopharm started a phase II randomized trial with low dose oral Selinexor in COVID-19 but discontinued the study in August, 2020.
✘ Ravulizumab-cwvz
Ravulizumab-cwvz binds and prevents the activation of Complement component 5 (C5) in the terminal complement cascade. Available as Ultomiris, this humanized monoclonal antibody complement inhibitor medication (first in class) designed for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.
It was being used by the innovator Alexion Pharma in severe C19 patients on IPPV (invasive mechanical ventilation) support along with best supportive care. However Alexion has paused further enrollment in a phase 3 study evaluating ravulizumab-cwvz (Ultomiris®) in adults with severe coronavirus disease 2019 (COVID-19) requiring mechanical ventilation due to a lack of efficacy.
✘? Sarilumab
Regeneron and Sanofi also initiated trial for Sarilumab (Kevzara), another IL-6 inhibitor. On September 1, 2020, Sanofi announced they are to stop conducting further clinical studies for Kevzara in COVID-19, as it fails to reach primary and secondary key endpoint. (Press release).
However in July, 2021, WHO have said Sarilumab may be used as an alternative to Tocilizumab in C-19 patients with cytokine storm.
✘ Leronlimab
CytoDyn's lead investigational mAb against COVID-19 did not meet the primary endpoint for clinical improvement as assessed by change in total symptom score. Moreover, the trial did not meet any of the secondary endpoints including mortality, time to symptom resolution, and time to return to normal activity. (PR at FDA.gov)
✘ Avdoralimab
Avdoralimab (also known as IPH-5401; NN-8210; NNC-0215-0384) is new investigational monoclonal antibody from Innate Pharma. It specifically binds and blocks C5a receptors (C5aR1) expressed on subsets of myeloid-derived suppressor cells (MDSC) and neutrophils. Targeting C5a/C5aR1 has been demonstrated scientifically and through positive clinical trials in some complement-driven inflammatory diseases.
The company started FORCE trial based on pre-clinical data showing that patients who progress towards severe COVID-19 disease exhibit activation of the C5a/C5aR1 pathway. However phase II FORCE trial evaluating avdoralimab in COVID-19 patients with severe pneumonia did not meet its primary endpoints in all three cohorts trial.
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