Ivermectin and COVID19

 The huge personal and economic cost of COVID 19 has led to a desperate search for a treatment. As previously described here at Medoratorio, one route is to repurpose medicines approved for other illnesses, which has the obvious advantages of a pre-existing safety profile and manufacturing base. The best known example is perhaps chloroquine. This has unfortunately become politicised, and there are concerns over side effects in seriously ill patients, but in Brazil, for example, it is considered worth prescribing in the very earliest stages of infection.

 

Another less known example is ivermectin. Ivermectin is a well established anti-parasitic drug, used in the treatment of River Blindness (onchocerciasis) and Lymphatic Filariasis in humans for example, and various parasitic infections in animals. It is also used against arthropods, for example ivermectin is an FDA approved treatment for headlice.

 

There is also interest in ivermectin as a useful treatment for COVID-19. This is supported by a recently published paper (1) showing a 5,000 fold reduction in virus replication following ivermectin treatment, though it should be stressed that this was in vitro, not in a living animal. However, ivermectin has been shown in an animal model to reduce infection of another virus, Pseudorabies virus (2). It apparently works by blocking import of the virus into the cell nucleus. COVID-19 cannot replicate itself, it needs to use the nucleus of it's host, and so if access to the host nucleus is reduced, virus replication is reduced as well (3).

 

So far so good, but the situation grew more complicated in April. As described in an article in The Scientist (4) a pre-print of an article using proprietary clinical data from the company Surgisphere appeared to show a clear clinical advantage in patient survival from ivermectin treatment. This data was taken up by the well respected medical journals The Lancet, and New England Journal of Medicine, and was understandably seized upon by governments desperate for a treatment for their citizens. In May, Peru included ivermectin as a COVID-19 treatment in official clinical guidelines, quickly followed by other countries. Bolivia approved ivermectin use and later started handing out hundreds of thousands of doses to residents (4).

 

Unfortunately, serious concerns about the Surgisphere data soon emerged, and The Lancet, and New England Journal of Medicine both retracted their articles.

 

The current situation with ivermectin is unclear. It is regarded as a safe drug, but there are concerns. Perhaps the most important at this stage is that ivermectin intended for animal treatment may be used as a form of self treatment by people without access to a vaccine or cure for virus infection. Animal drugs should never be used for human use, the formulations and doses are different and potentially very toxic. This was recently stressed in an open letter from the FDA (5). Use of veterinary ivermectin has already been associated with skin blistering and stomach complaints (4). Even when properly administered, care should be taken. Ivermectin can interfere with drug transport by MDR proteins, and therefore can potentially disturb the pharmacology of co-administered drugs (6).

 

It should be stressed that, when properly used, ivermectin is regarded as a safe drug. A recent retrospective study from Florida does suggest that ivermectin use can possibly reduce COVID-19 mortality (7), and ClinicalTrials.gov (U.S. National Library of Medicine) lists 37 clinical trials ongoing or planned around the world. It may turn out to be a very useful treatment for COVID-19 and other viruses, but at the moment it's efficacy is unproven.

 

 

1. Caly et al (2020). The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research, 178, 104787.

2. Lv et al (2018). Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antiviral Research, 159, 55-62.

3. Wagstaff et al (2012). Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem. J., 443, 851-856.

4. Offord (2020). https://www.the-scientist.com/news-opinion/surgisphere-sows-confusion-about-another-unproven-covid19-drug-67635

5. https://www.fda.gov/animal-veterinary/product-safety-information/fda-letter-stakeholders-do-not-use-ivermectin-intended-animals-treatment-covid-19-humans

6. Didier & Loor (1996). The abamectin derivative ivermectin is a potent P-glycoprotein inhibitor. Anticancer Drugs, 7, 745-51.

7. Rajter et al (2020). https://www.medrxiv.org/content/10.1101/2020.06.06.20124461v2

Adequate safety testing of experimental treatments paramount even in a pandemic setting

Although there could be an extreme impulse to fast forward treatments in a pandemic setting, it is very important to conduct adequate safety checks on investigational drugs and vaccines. The treatment cannot be worse than the disease itself.

This is where repurposed drugs (existing drugs that are investigated for new therapeutic purposes) have an advantage as they often have extensive safety date backing them and are amenable to being fast-tracked. This is also, where biologics (vaccines and antibodies) have their limitations. Just because a biologic is safe in a primate model, by no means proves that it is going to be safe in humans.

Let us not forget the PAREXEL trial that went catastrophically wrong more than 14 years ago, when eight healthy young men took part in a clinical trial of an experimental leukaemia drug, TGN1412. The drug that had been shown to be safe in monkeys however led to the men fighting for their lives soon after treatment and has left some with permanent immune issues.

Having a safe treatment is especially vital in COVID-19 management when approximately 80% of people testing positive for SARS-CoV-2 may only get a mild disease.

Reference

https://pubmed.ncbi.nlm.nih.gov/17256444/

Gilead’s Remdesivir shows exceptional promise in the treatment of severely ill COVID-19 patients

''Certainly, Remdesivir appears to have come a full circle.''

Hot on the heels of the disappointing clinical trial from China in patients treated with Remdesivir as reported  in the journal Lancet, comes superbly encouraging results from a trial sponsored by the United States National Institute of Allergy and Infectious Diseases (NIAID).

In the NIAD trial, over a thousand hospitalized patients with severe COVID-19 were randomly chosen to receive either Remdesivir or a placebo. Those who received Remdesivir recovered faster than those who received the placebo (dummy) showing 31% faster time to recovery. Remdesivir also increased survival, with a mortality rate of 8% for those who received the drug and 11.6% for those on the placebo.

The Chinese trial was small, and comprised of 237 severe COVID-19 hospitalised patients who randomly received either Remdesivir or a placebo. Although the drug showed a good safety profile, Remdesivir treatment did not cause significant clinical or antiviral effects. However, interestingly the study showed that patients receiving Remdesivir had a numerically faster time to clinical improvement than those receiving placebo, though not statistically significant.

Earlier in February of this year, researchers in Wuhan had shown that Remdesivir and another drug chloroquine are highly effective in cell culture models of 2019 nCOV  the virus that causes COVID-19. In their paper, they had made a strong case for the testing of these drugs in patients saying  “Since these compounds have been used in human patients with a safety track record and shown to be effective against various ailments, we suggest that they should be assessed in human patients suffering from the novel coronavirus disease.” Certainly, Remdesivir appears to have come a full circle.

Remdesivir which began its life in Gilead Sciences under the leadership of the Czechoslovakia born Tomáš Cihlář as a treatment for Ebola virus disease and Marburg virus infections, has now proved its mettle against COVID-19. Though not a  completed cure for COVID-19, until a better drug arrives Remdesivir may well be the gold standard in the  treatment of COVID-19.

References

https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19

https://www.niaid.nih.gov/news-events/nih-clinical-trial-remdesivir-treat-covid-19-begins

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext

https://www.nature.com/articles/s41422-020-0282-0

Could a drug trialled by University of Dundee researchers clampdown COVID-19?

“…we hope that brensocatib can put a brake on the devastation this disease causes, to literally stop COVID-19 when it begins attacking the lungs.” -  Professor James Chalmers

The Tay Bridge- The iconic gateway to Dundee

Dundee, the beautiful ‘city of Discovery’ in Scotland has many firsts to its role in the field of medicine. One of the early noted examples in its innovation history is the nineteenth century pivotal discovery by Thomas Maclagan, a Physician at the Dundee Royal Infirmary. Maclagan was the first to recognize the value of thermometers during a major fever epidemic, which led to reducing death rates. Today, thermometers are the bedrock of medicine and essential tools in clinical examination.

Now, Dundee may again play a crucial role in medicine, this time in the management of COVID-19 pandemic. In a major collaborative venture between researchers from Dundee University School of Medicine and Insmed, a biopharmaceutical company, the effectiveness of the drug brensocatib as a potential treatment for COVID-19  will be evaluated in clinical trials at Ninewells hospital and other sites in the country.

Brensocatib is a novel oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), an enzyme that catalyses the activation of neutrophil serine proteases in neutrophils. In a study of 300 patients receiving standard hospital care, half will be treated with Brensocatib, and the other half will receive a placebo.

About 20% of COVID-19 patients develop inflammation of the lungs, which may necessitate ventilation. Research shows that in severe cases of COVID-19, the body’s own inflammatory response meant to clear the virus goes on an ‘overdrive’ leading to lung damage, respiratory failure, and death in severe cases.

Previous studies in patients with underlying lung disease show reduction of lung inflammation by  brensocatib. The researchers hypothesise that the drug will confer similar beneficial effects in COVID-19 patients and will explore whether it can reduce the incidence of acute lung injury and prevent mechanical ventilation. They are hopeful that the treatment could reduce the patients’ dependency on oxygen support and reduce hospital stays thereby reducing the burden on an already overstretched healthcare system.

Professor  James Chalmers, a Consultant Physician at the University who leads the trial says-

 “High rates of patients requiring ventilation and overwhelming intensive care unit capacity has been a major cause of excess deaths around the world and we hope that brensocatib can put a brake on the devastation this disease causes, to literally stop COVID-19 when it begins attacking the lungs.”

https://investor.insmed.com/2020-04-23-Brensocatib-Formerly-INS1007-to-be-Studied-in-Patients-with-Severe-COVID-19-in-Investigator-Initiated-Trial

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Could Remdesivir be Gilead’s balm against COVID-19

As COVID-19 (novel coronavirus) continues to spread across the world, Gilead Sciences the Californian pharmaceutical company is testing Remdesivir, an investigational nucleotide analog against this deadly disease. This unlicensed drug shows broad-spectrum antiviral activity against Ebola, MERS, and SARS in cell culture and animal models. Gilead’s investigational new drug (IND) application for COVID-19 was accepted by USFDA following rapid review (2). Clinical trials are underway - two in China’s Hubei province (one in patients with severe disease and another in those with moderate disease) and another trial in University of Nebraska Medical Center in Omaha, USA, to evaluate the safety and efficacy of Remdesivir in adults diagnosed with COVID-19 (3,4). The world eagerly awaits the first trial results from China in April.

References

1. Jeremiah 8:22, The Bible

2. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-remdesivir-treat-covid-19-begins

3. https://www.gilead.com/news-and-press/press-room/press-releases/2020/2/gilead-sciences-initiates-two-phase-3-studies-of-investigational-antiviral-remdesivir-for-the-treatment-of-covid-19

4. https://www.gilead.com/purpose/advancing-global-health/covid-19

Locusts and human health

Recent reports of immense locust swarms in East Africa (and to a lesser extent in Pakistan), have led to comparisons with Biblical plagues. The numbers are extraordinary. Swarms can cover several square kilometres, with up to 80 million adult locusts per km2. With a following wind they can travel up to 130 km per day (FAO 2020). Kenya has it’s worst infestation for 25 years, Ethiopia it’s worst for 70.

Simply being in a swarm is dangerous, not from the insects themselves, but the asthma sensitisation they cause (Soparkar et al 1993).

But of course there is a much worse problem than that.

Even a very small, one-square-kilometre locust swarm can eat the same amount of food in one day as about 35,000 people (FAO, 2020). Farms can be wiped out in hours. And the locusts are not just eating and flying - with enough food each female locust can lay approximately 200 eggs, which emerge to augment the swarms.

The immediate loss of such vast quantities of food has obvious implications for health, and over 13 million people in Djibouti, Eritrea, Ethiopia, Kenya, and Somalia will experience “severe acute food insecurity,” according to the FAO, whilst another 20 million are at risk.

But the implications, economic and medical, go beyond that. Farmers in East Africa would normally plant most crops to coincide with the first rainy season, in March or April. Exactly the right conditions to boost new generations of locusts, not just from the fresh new crops, but the new growth across the countryside. And even once the swarms have passed, new crops need seeds. Many farmers use this year’s harvest for seeds for the next, except that there is no harvest.

A recent paper by Conte, Piemontese and Tapsoba (2020) focussed on the effect on child health of locust swarms in Mali, West Africa. This starts even before the locusts arrive, as food prices invariably rise due to speculative hoarding by suppliers. Then there is the, potentially devastating arrival of the locusts themselves, leading to acute food shortages. Both these effects have significant effects on child growth, especially if the child is in utero at the time, but perhaps surprisingly, there is little difference between those children exposed to the “speculative” phase and those exposed to the actual invasion. A factor that maybe should be borne in mind during disaster planning.

Whilst there are definite economic consequences for farmers post invasion, ranging from loss of seed stock to starvation of livestock, which are often also economic assets, there seems to be no strong effect on children born in the years afterwards, perhaps because the harvests were good.

The locust swarms this year are going to get worse before they get better. The rebuilding of agriculture will be a huge task in many countries, and a temporary one, the locusts will return.



Further reading

Conte, Bruno, Piemontese, Lavinia and Tapsoba, Augustin (2020). Ancient Plagues in Modern Times: The Impact of Desert Locust Invasions on Child Health. TSE Working Paper, n. 20-1069, Toulouse

Food and Agricultural Organisation of the United Nations (2020). http://www.fao.org/ag/locusts/en/info/info/faq/index.html

Soparkar GR, Patel PC, Cockcroft DW. (1993). Inhalant atopic sensitivity to grasshoppers in research laboratories. J Allergy Clin Immunol., 92(1 Pt 1), 61-5.

Niraparib shows significant promise in the treatment of advanced ovarian cancer patients with poor treatment options

Encouraging results have emerged from a Phase3 clinical trial that investigated the efficacy of Niraparib, an orally administered poly ADP ribose polymerase (PARP) inhibitor, in patients with newly diagnosed advanced ovarian cancer who were at high risk for relapse (González-Martín et al, 2019). In such patients, Niraparib maintenance treatment resulted in significantly increasing progression-free survival (the time when the cancer did not progress further in the patient), compared to those treated with a placebo. Niraparib could consequently become an integral part in the arsenal against advanced ovarian cancer.

Ovarian cancer is characterised with the poorest survival rate among all gynaecological cancers resulting in 152,000 deaths worldwide each year. The main treatments for ovarian cancer are surgery, and combination chemotherapy with platinum and paclitaxel. However, up to 85% of the patients with advanced ovarian cancer have a relapse on completing chemotherapy. Even when treatments exist, there are safety concerns, or only a subset of patients is targeted. Therefore, there remains an unmet medical need for the vast majority of patients with advanced ovarian cancer.

The protein, poly ADP ribose polymerase (PARP), plays a crucial role in DNA repair. PARP helps repair damaged cells by mending single-strand breaks in the DNA. PARP inhibitors halt DNA repair in cancer cells leading to cell death. Previous clinical studies have focussed on PARP inhibitors in tumours with BRCA mutations as fault in this gene too results in impaired DNA repair. The rationale is that blocking PARP with a PARP inhibitor in such a context would prevent the cells from repairing themselves leading to cell death. Therefore, clinical trials had been conducted in selected patient populations. Niraparib, had been previously shown to be significantly effective in ovarian cancer patients with BRCA mutations leading to its regulatory approval. However, recent studies as evident in the PRIMA trial show that Niraparib is effective in ovarian cancer patients regardless of BRCA mutations.

The latest clinical trial involved 733 ovarian cancer patients. Patients were at  Stages III or IV who have advanced disease and  considered to have incurable disease with chemotherapy alone, including those who had tumors with homologous-recombination deficiency (with either mutated or unmutated BRCA) and those with homologous-recombination proficiency. All patients had been previously treated with platinum-based chemotherapy and had shown response to it. Patients were randomised and treated with Niprarib or a placebo.

-The median progression-free survival in patients having tumours with homologous-recombination deficiency, was 21.9 months in the Niraparib group which was significantly longer than in the placebo group (10.4 months).

Within the population with homologous-recombination deficiency, the median duration of progression-free survival in the subgroup with BRCA mutations was 22.1 months in the niraparib group and 10.9 months in the placebo group. In the subgroup without BRCA mutations progression-free survival was  19.6 months with niraprib and 8.2 months on placebo

-In the subgroup of patients with homologous-recombination proficiency, the median duration of progression-free survival was 8.1 months in the niraparib group and 5.4 months in the placebo group.

In patients with advanced ovarian cancer in other subgroups with a poor prognosis, including in those who received neoadjuvant chemotherapy, the median duration of progression-free survival 13.9 (Niraparib) vs. 8.2 months (placebo).

In the overall population, the progression-free survival was 13.8 months in niraparib group and 8.2 months with placebo.

References: González-Martín A et al, Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer,  N Engl J Med. 2019 Sep 28.