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Wonder Drugs, Safe and Effective, and Proof of Concept

Introduction

There are few drugs that can seriously lay claim to the title of ‘Wonder drug’, penicillin and aspirin being two that have perhaps had greatest beneficial impact on the health and wellbeing of Mankind. But ivermectin can also be considered alongside those worthy contenders, based on its versatility, safety and the beneficial impact that it has had, and continues to have, worldwide—especially on hundreds of millions of the world’s poorest people. Several extensive reports, including reviews authored by us, have been published detailing the events behind the discovery, development and commercialization of the avermectins and ivermectin (22,23-dihydroavermectin B), as well as the donation of ivermectin and its use in combating Onchocerciasis and lymphatic filariasis.^1–6) However, none have concentrated in detail on the interacting sequence of events involved in the passage of the drug into human use.

When it first appeared in the late-1970s, ivermectin, a derivative of avermectin (Fig. 1 ) was a truly revolutionary drug, unprecedented in many ways. It was the world’s first endectocide, forerunner of a completely new class of antiparasitic agents, potently active against a wide range of internal and external nematodes and arthropods. In the early-1970s, a novel international Public Sector–Private Sector partnership was initiated by one of us (Ōmura, then head of the Antibiotics Research Group at Tokyo’s Kitasato Institute), forming a collaboration with the US-based Merck, Sharp and Dohme (MSD) pharmaceutical company. Under the terms of the research agreement, researchers at the Kitasato Institute isolated organisms from soil samples and carried out preliminary in vitro evaluation of their bioactivity. Promising bioactive samples were then sent to the MSD laboratories for further in vivo testing where a potent and promising novel bioactivity was found, subsequently identified as being caused by a new compound, which was named ‘avermectin’.⁷⁾ Despite decades of searching around the world, the Japanese microorganism remains the only source of avermectin ever found.¹⁾ Originating from a single Japanese soil sample and the outcome of the innovative, international collaborative research partnership to find new antiparasitics, the extremely safe and more effective avermectin derivative, ivermectin, was initially introduced as a commercial product for Animal Health in 1981. It is effective against a wide range of parasites, including gastrointestinal roundworms, lungworms, mites, lice and hornflies.^7–12) Ivermectin is also highly effective against ticks, for example, the ixodid tick Rhipicephalus (Boophilus) microplus, one of the most important cattle parasites in the tropics and subtropics, which causes enormous economic damage. Indicative of the impact, in Brazil, where some 80% of the bovine herd is infested, losses total about $2 billion annually.¹³⁾ Today, ivermectin is being used to treat billions of livestock and pets around the world, helping to boost production of food and leather products, as well as keep billions of companion animals, particularly dogs and horses, healthy. The ‘Blockbuster’ drug in the Animal Health sector, meaning that it achieved annual sales in excess of over US$1 billion, maintained that status for over 20 years. It is so useful and adaptable that it is also being used off-label, sometimes, illegally, for example to treat fish lice in the aquaculture industry, where it can have a negative impact on non-target organisms. It also has extensive uses in agriculture.²⁾

https://pmc.ncbi.nlm.nih.gov/articles/PMC3043740/

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Remdesivir is a prodrug of a nucleotide analogue that is intracellularly metabolized to an analogue of adenosine triphosphate that inhibits viral RNA polymerases. Remdesivir has broad-spectrum activity against members of several virus families, including filoviruses (e.g., Ebola) and coronaviruses (e.g., SARS-CoV and Middle East respiratory syndrome coronavirus [MERS-CoV]) and has shown prophylactic and therapeutic efficacy in nonclinical models of these coronaviruses.^14-17 In vitro testing has also shown that remdesivir has activity against SARS-CoV-2. Remdesivir appears to have a favorable clinical safety profile, as reported on the basis of experience in approximately 500 persons, including healthy volunteers and patients treated for acute Ebola virus infection,^18,19 and supported by our data (on file and shared with the World Health Organization [WHO]). In this report, we describe outcomes in a cohort of patients hospitalized for severe Covid-19 who were treated with remdesivir on a compassionate-use basis.

https://www.nejm.org/doi/full/10.1056/NEJMoa2007016

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The favorable safety profile observed during phase 1 testing of BNT162b2^4,8 was confirmed in the phase 2/3 portion of the trial. As in phase 1, reactogenicity was generally mild or moderate, and reactions were less common and milder in older adults than in younger adults. Systemic reactogenicity was more common and severe after the second dose than after the first dose, although local reactogenicity was similar after the two doses. Severe fatigue was observed in approximately 4% of BNT162b2 recipients, which is higher than that observed in recipients of some vaccines recommended for older adults.¹² This rate of severe fatigue is also lower than that observed in recipients of another approved viral vaccine for older adults.¹³ Overall, reactogenicity events were transient and resolved within a couple of days after onset. Lymphadenopathy, which generally resolved within 10 days, is likely to have resulted from a robust vaccine-elicited immune response. The incidence of serious adverse events was similar in the vaccine and placebo groups (0.6% and 0.5%, respectively).

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The data presented in this report have significance beyond the performance of this vaccine candidate. The results demonstrate that Covid-19 can be prevented by immunization, provide proof of concept that RNA-based vaccines are a promising new approach for protecting humans against infectious diseases, and demonstrate the speed with which an RNA-based vaccine can be developed with a sufficient investment of resources. The development of BNT162b2 was initiated on January 10, 2020, when the SARS-CoV-2 genetic sequence was released by the Chinese Center for Disease Control and Prevention and disseminated globally by the GISAID (Global Initiative on Sharing All Influenza Data) initiative. This rigorous demonstration of safety and efficacy less than 11 months later provides a practical demonstration that RNA-based vaccines, which require only viral genetic sequence information to initiate development, are a major new tool to combat pandemics and other infectious disease outbreaks. The continuous phase 1/2/3 trial design may provide a model to reduce the protracted development timelines that have delayed the availability of vaccines against other infectious diseases of medical importance. In the context of the current, still expanding pandemic, the BNT162b2 vaccine, if approved, can contribute, together with other public health measures, to reducing the devastating loss of health, life, and economic and social well-being that has resulted from the global spread of Covid-19.

https://www.nejm.org/doi/full/10.1056/nejmoa2034577

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Thank you, Big Pharm and Medical Science!

For keeping us safe from the Rogue Koronavirus.