Early COVID-19 drug studies: what have we learned?

The past week has seen first results from studies of existing antiviral drugs and repurposed agents in those hospitalised with COVID-19, raising at least as many questions as answers. A combination of two antivirals (lopinavir–ritonavir: Kaletra®) used to treat HIV infection did not reduce mortality in a randomised study conducted in almost 200 severely-ill Chinese patients[1], although with a hint that earlier treatment might just be of some benefit[2].

Avigan® (avilavir/ favipiravir), an influenza drug approved in Japan and China has been reported as clearing the COVID-19 virus in four days, versus those treated with another antiviral agents. However, this was not a randomised study and involved less severely ill subjects, with benefit confined to those receiving early treatment. Although while broadly hailed as “highly effective in media reports, Avigan’s developer (Fujifilm) has been cautious in making claims around efficacy. Avigan® has been associated with severe adverse events, limiting its use as an influenza treatment.

An investigational antiviral with a similar mechanism of action, remdesivir (GS-5734; Gilead Sciences, Inc), and which is known to be active against the SARS and MERS coronaviruses is in late-stage testing in China, the US and South Korea. Anecdotal findings from a small number of severely ill patients infected while aboard a cruise ship have suggested remdesivir may have reduced reliance on ventilator support. Despite an absence of hard evidence, the drug was approved for compassionate use in the US on March 19^th. As of today (Sunday 22^nd March), Gilead was forced to temporarily limit patient access to remdesivir due to “overwhelming demand”[3].

Similarly, chloroquine, a decades old antimalarial drug, has also been approved for compassionate use on the back of anecdotal evidence, with the hope that it may also have a prophylactic effect. A related drug, hydroxychloroquine, in combination with the antibiotic azithromycin, has been reported as reducing viral burden in a small study[4]. Both drugs have been reported to be in short supply through high demand in the US, leading to problems for autoimmune disease patients dependent on the same drugs.

Actemra®, a biologic developed for rheumatoid arthritis targets the cytokine IL-6, an immune system component responsible for the “cytokine storm” observed in CAR-T therapy and apparently a contributor to the pathology of severe COVID-10 infection has been observed to be of benefit in a small and uncontrolled study in China. A similar anti-IL-6 biologic, Kevzara® (Regeneron) is moving towards Phase III studies in COVID-19 infection.

No big wins, but, and perhaps the most you can hope for from early, essentially empirical interventions and anecdote are hints and glimmers of possible ways forward. More such early and empirical, will light the way, with China, not surprisingly, ahead of the curve with over thirty medicines (including traditional Chinese medicines) identified as having an anti-COVID-19 effect in the laboratory.

[In case you missed it in my Favourites sidebar, check out Derek Lowe's blog: 
https://blogs.sciencemag.org/pipeline/archives/2020/03/24/the-latest-coronavirus-clinical-trials#comment-314221]

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[1] A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. Cao B et al. NEJM

Online March 18^th 2020 March 18, 2020 DOI: 10.1056/NEJMoa2001282 https://tinyurl.com/ulpek4c

[2] Covid-19 — The Search for Effective Therapy. Baden LR et al. NEJM online March 18^th 2020 DOI: 10.1056/NEJMe2005477 https://tinyurl.com/yx6jrrxe

[3] Gilead pauses access to experimental Covid-19 drug due to ‘overwhelming demand’. Herper M. STAT online March 22^nd 2020 https://tinyurl.com/tum92s6

[4] Information for Clinicians on Therapeutic Options for COVID-19 Patients. CDC website accessed 22^nd March 2020. https://tinyurl.com/rx7ujpz

Life During Wartime

As you may have noticed, there’s a lot happening on this small planet of ours. One small personal bright spot is that, having spent years involved in infectious disease, from diagnostic test design through vaccine and drug development, I’ve been able to help family, friends and colleagues make sense of the pandemic and have been fortunate to engage with those whose knowledge and experience goes well beyond mine.

Let’s start with the good news. While in no way underplaying the threat posed by COVID-19, the biopharma industry has been quick off the mark, with both well-trodden and new paths to treatment and prevention under very active exploration. Experience gained from past SARS and MERS epidemics (and seasonal influenza) mean that industry and public health and regulatory agencies are not starting from scratch.

That’s not to imply that treatments and vaccines will be here a week come Tuesday. Problems encountered in early SARS vaccine studies are a reminder of just how steep the learning curve might prove to be, and, at the time of writing, early clinical data for studies of repurposed drugs in ameliorating the effect of COVID-19 infection is equivocal at best. But, every hint of potential benefit will assist in identify strategies with a higher probability of success.

My white coat-days are long gone, and my battle against COVID-19 is essentially confined to taking the obvious practical measures to keep family, friends and myself at low-risk for infection. Lord, how I miss the pub already….

The only small additional effort I can make is in using this (very) modestly visited blog to pull together what’s relevant and important in controlling COVID-19, with the hope that it just might assist in developing a sense of perspective for anyone interested in the how and why of the science and industry effort.

So, until the world has adjusted to the new normal, this blog will be mainly dedicated to selected COVID-19 news, with at least a once a day update. Comments and questions, all and any feedback more welcome than ever.

The pain paradox

Pain, whether short, sharp and temporary, or a constant misery, affects all of us. Around 20% of the adult population of Europe and the US lives with chronic pain (defined as "localised or widespread pain lasting three months or longer"), most commonly  arising from low back problems, osteoarthritis or rheumatoid arthritis, and from nerve damage (neuropathic pain), a common consequence of diabetes and surgery.

Pain medication is a daily and essential  part of life for millions of individuals but we remain heavily reliant on a relatively small number of drug types, several of which were introduced into common use over a century ago. The origins of aspirin and purified opiates, both available commercially since the start of the 20^th century, go back thousands of years,  to the use of willow leaf or bark teas and extracts of poppy seeds and juices.

Paracetamol (acetaminophen), was introduced in the 1950s (some 50 years after its discovery) and “non steroidal anti-inflammatory drugs” (NSAIDS), a mainstay for arthritis sufferers, during the 1970s and 1980s. Synthetic opioids and opioid reformulations, such as  fentanyl and extended release oxycodone,  have acquired notoriety through their association with epidemic levels of abuse and dependence but these drugs remain invaluable in the relief of otherwise intractable pain (blame the system, not the product).

An analysis published by the Biotechnology Innovation Organization (BIO) highlights a surprising lack of innovation in pain drug development. While the BIO report focuses on the US, the picture is not radically different in Europe and Japan.

Almost all pain medications approved for sale in the  US during the past decade have been either reformulations of previously marketed drugs or have involved drugs previously approved for other indications. Only two novel pain medications have been approved since 2009, of which one, milnacipran, had previously received approval  as an antidepressant. Industry’s last great foray in pain drug development ended in the early 2000s,  as a class of anticipated blockbusters, the cyclooxegenase-2 (COX-2) inhibitors such as Celebrex® and Vioxx®,  turned out to be potentially unsafe in a significant subset of patients.

Pain drug development activity is not at a standstill, but is hardly thriving. The BIO analysis identified 220 clinical studies for pain indications, of which over half involve novel drugs. This seems respectable until you consider that, in total,  this clinical development activity is less than one-tenth of the activity devoted to cancer drug development, and that the majority of cancer studies involve novel agents.

Investment serves as a rough and ready barometer of relative commercial attractiveness. Novel pain drug development pulled in $576 million in venture funding during the period 2007 to 2016: in comparison, $10.3 billion was showered on novel cancer drug development during the same period. As an aside, despite the uncontested economic and societal impact of drug addiction, novel substance abuse treatments have attracted only $16 million in venture investment in a decade. 

Given the number of individuals in dire need of safer and more effective pain medication, why is industry and the investment community apparently disengaged from pain drug development? Perceived risk would appear to be a major factor, with the probability of FDA approval of a novel pain drug being around 2%, well below the 10% or better for drugs addressing other indications.

Reimbursement is another key issue. The pain drug market is largely generic and healthcare payers demand hard evidence of superiority or cost-effectiveness of new treatments over established medications, something that’s not easy to establish given  the difficulty in capturing and quantifying the subjective impact of pain in clinical studies.

Even when there is a clear basis for potential advantage over existing drugs, such as with the close to market calcitonin gene-related peptide (CGRP) inhibitors which have been shown to be highly effective in migraine prevention, the inability to predict which patients are likely to respond to treatment could make payers reluctant to meet the expected $8,500 per patient drug cost.  

Pain is biologically complex  and novel targets amenable to drug discovery are, to date, few and far between. As in oncology drug development, across the board innovation, combining AI analytics, population-based studies, biomarkers, predictive animal models and better means of patient data capture will be needed to find more prospective winners and to tempt industry and investors back to pain drug development.   

Photo credit: Trying2