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Janita Good looks at some of the therapeutics currently under investigation and the issues they have highlighted in the context of a pandemic.
COVID-19 is highly contagious and has a relatively long incubation period, which has resulted in a devastating pattern of spread that has overwhelmed healthcare systems around the world. With whole societies in lockdown, a global recession now seems inevitable. The virus spreads quickly yet clinical research is slow and cumbersome. Industry, regulators, government and healthcare workers have had to adapt in order to respond rapidly to this global threat.
Although the genetic sequence of the virus is new, its biology is well-understood as it comes from a family of viruses that includes severe acute respiratory syndrome (SARS) and Middle Eastern respiratory syndrome (MERS). This has allowed scientists to focus on repurposing existing therapeutics in the search for an effective drug therapy. As of 28 February, China’s Clinical Trial Registry listed 105 trials of drugs and vaccines against the virus and as of 11 March, the National Library of Medicine, the American equivalent, listed 84.
This article looks at some of the therapeutics currently under investigation and the issues those investigations have highlighted in the approach to pharmaceutical research in the context of a pandemic.
Gilead Sciences initially developed the antiviral remdesivir for use against Ebola. Original trials confirmed the drug was safe for use in humans but development stopped when research showed antibody therapy was proving more effective. Laboratory tests have shown that it works against a range of similar viruses, including SARS, and an in vitro study published in early February concluded that remdesivir was effective in the control of COVID-19.
On January 31, 2020, a case study in the New England Journal of Medicine reported that a US patient had recovered after receiving remdesivir. Within a week, the Chinese Health Authorities began a phase III clinical trial and Gilead is expediting the laboratory testing of remdesivir against virus samples alongside it. There are now two phase III trials ongoing in the Hubei province of China, with Gilead providing the drug free of charge and providing input on the study design and conduct. Results are expected next month.
Following the FDA’s rapid review and acceptance of Gilead’s investigational new drug (IND) filing, Gilead has initiated two further phase III, randomized, open-label, multi-center studies primarily across Asian countries and other countries globally with high infection rates. These began in early March and are expected to read out in April.
The U.S. National Institute of Allergy and Infectious Diseases (NIAID) has also initiated a phase II adaptive, randomized, double-blind, placebo-controlled trial into remdesivir as a potential treatment for hospitalized adult patients diagnosed with COVID-19. As in the Hubei-based studies, Gilead is providing the drug free of charge.
In anticipation of future need, Gilead has accelerated manufacturing timelines and expanded its network of manufacturing partners in order to ensure sufficient supply will be available and as rapidly as possible. This is before trial results have been reported and before Gilead knows whether the drug will be approved as safe and effective against COVID-19. Gilead is also collaborating with government agencies and regulators, sharing updates of its manufacturing efforts and ensuring that, if the trials are positive, the drug will be approved as quickly as possible.
Gilead have recently announced that it will stop granting individual access to the drug, citing an “exponential increase” in compassionate use requests. Instead, the company plans to transition to an expanded access programmed that it says will speed the process for severely ill patients while allowing for better data collection.
In a global emergency, a cross-organizational collaborative approach is vital. The speed at which remdesivir has moved into clinical development in the current pandemic is evidence of the ability of industry, governments, global health organizations and health providers to adapt in order to respond urgently to a public health threat.
Accelerated drug development is not without risks. Expedited off-label use of a drug without empirical evidence of efficacy may cause harm. Since January, the Chinese government and medical experts have been publicly backing the off-label use of AbbVie's combination HIV drug Kaletra (ritonavir and lopinavir). In February, the China International Exchange and Promotive Association for Medical and Health Care (CPAM) issued a new COVID-19 guideline, which included a recommendation for the therapeutic use of the drug, in combination with nebulized alpha-interferon.
However, on March 18, a study published in the New England Journal of Medicine concluded that no benefit was observed with using the combination drug in adult patients with severe COVID-19 beyond standard care. (Note the authors suggested it may work better if combined with other antiviral agents.)
Whilst the use of off-label drugs as part of a compassionate use programmed can be justified in emergencies where there is no licensed treatment and a death rate that is rising by the day, industry and governments must be wary of recommending therapeutics at the risk of overlooking potentially more effective drugs.
Abbvie have just announced that it is giving up its patents on Kaletra, becoming the first major pharmaceutical company to drop its rights to make money from a drug that might be used during the pandemic. Abbvie will no longer enforce patents relating to Kaletra anywhere in the world for all formulations.
Chloroquine has been used since the Second World War as an antimalarial. On March 16, a French study reported that chloroquine was effective against COVID-19 and three days later, Donald Trump announced that the US was fast-tracking the drug for use as a treatment against COVID-19. The FDA Commissioner later indicated that, while the drug had not been formally approved for testing, access was being expanded so that the authorities could gather more data but the drug would be available only for “compassionate use.” Some medical experts have advised caution with regard to the use of chloroquine due to the fact that the French study was small, lacked randomization and some patients received the drug in conjunction with an antibiotic.
Larger, randomized controlled trials of chloroquine in COVID-19 are currently being launched, the results of which are needed before chloroquine can be considered a safe and effective treatment of COVID-19. The drug is potentially dangerous when used at high doses or for prolonged periods, causing permanent blindness and even death. As such, public statements based on anecdotal evidence or small-scale preliminary trials must be made with extreme caution.
While many trials are under way in China, the decline in new cases means that establishing new trials is becoming difficult. In Italy, where the epidemic is raging, the over-burdened healthcare system does not have the luxury of organizing trials. Further, the number of ongoing studies means that many eligible patients are excluded by virtue of being on alternative therapies under other trial regimes or compassionate use programmed.
Scientists are therefore rushing to set up protocols for new trials in countries expecting a mass rise in new cases and Britain is one of these. Relaxing inclusions or exclusion criteria could be key to resolving the issues surrounding recruitment, especially given the pressing timelines. This would, however, have implications in study design which must be outlined fully in the study limitations.
International trials are a high priority. The World Health Organization (WHO) have recently finalized an international “master protocol” to study the safety and efficacy of drugs used to treat hospitalized patients with COVID-19. This will allow researchers from all countries to pool their results over time and allow for the global standardization of trial design to improve reliability. The initial treatment arms are:
The race for a cure for COVID-19 has shown how important it is for the pharmaceutical industry to be able to adapt in public health emergencies and to cooperate with government, regulators and healthcare workers to ensure a rapid response whilst producing results that are reliable with patient safety in mind. FDA recently made a statement that, while working closely with drug developers and partners for expedited development of targeted drug therapies, it will ensure that any drug put forward meets the agency’s gold standard. As such, it will only approve treatment if the data supports widespread use and shows clear efficacy.
• Consider providing drugs free of charge to facilitate trials where funding is currently limited.
• Expedite trial reporting.
• Instigate discussions with manufacturing partners to expand network of manufacturers and ensure drugs are being produced in sufficient quantities.
• Consider relaxing inclusion or exclusion criteria for studies to improve patient recruitment for new trials.
• Attempt to fast-track approvals of investigational new drug filings to allow for the rapid kick starting of new trials.
• Consider Emergency Use Authorization and Compassionate Use programmed for off-label drugs that have been shown to be safe and effective in patients with COVID-19.
• Prioritize enrolment of patients onto trials for drugs that are showing the most promising results.
Janita Good is Head of UK Life Sciences at Fieldfisher.