One is remdesivir, the Gilead antiviral developed for use against Ebola and Marburg, both exotic filoviruses with case fatality rates of about 50% (vs. about 0.7% for COVID19). The National Institute of Allergy and Infectious Diseases (NIAID), the division of NIH that funds research on infectious diseases, is sponsoring its own randomized clinical trial using remdesivir against COVID-19 that has been given to 250 patients already.
The other is chloroquine, used since 1949 as an anti-malarial. It has long been known to work against SARS coronavirus, the closest prior pathogen to COVID-19. It works against a wide range of viral and bacterial pathogens — including Ebola — by inhibiting cellular entry. With remdesivir, it has already been tested in China against COVID-19.
Mikhail Shilman, my coworker (at KGI) and cofounder (at our startup) issued a statement about these two approvals:
The FDA decision this morning to fast-track approval chloroquine for treatment of COVID-19 coronavirus shows the potential for previously approved drugs to be deployed quickly to treat emerging infectious diseases that can rapidly infect an entire community or nation.
Chloroquine, an anti-malarial, has been safely used for 70 years around the world. The FDA has policies to encourage the repurposing existing drugs because it is quicker and lowers the risk of unexpected adverse effects. It is also a drug that is already being mass produced and is simple to manufacture, and thus can be quickly scaled up unlike complex large-molecule therapies.
Coronaviruses attack epithelial cells within the lungs. It can be life threatening because once it is inhaled, the infection inflames and swells the lungs in a way that makes it increasingly hard to breath. We thus need an orally administered drug that can be distributed in our system to reach and protect organs like lungs.
As we showed in our 2015 paper in Nature Scientific Reports, chloroquine is one of only two quinoline drugs that protects cells against certain types of viral and bacterial pathogens. It blocks the entry of these pathogens into the cell, including Ebola and SARS coronavirus, by binding to and inhibiting the function of the host Cathepsin protein, which mediates the uptake of these pathogenic agents into human cells. While we have not tested COVID-19 coronavirus, it is believed to work the same way as SARS and MERS coronaviruses.
Of the two drugs, chloroquine is the weaker of the two, better tolerated and better suited for treatment for the several weeks necessary for the body’s immune system to clear a virus such as COVID-19. The other drug, amodiaquine, is much stronger and better for immediate threats but has the potential for side effects if taken for longer periods; that is why I’ve been working to develop amodiaquine for inhaled anthrax, which kills the majority of patients in a matter of days.
Recent research has shown that chloroquine is effective against COVID-19 samples in the lab. Bayer said today they are donating three million chloroquine tablets for use as a COVID-19 treatment. Given the urgency of the pandemic and the proven safety of this drug, it is now appropriate to test chloroquine as a way to protect or treat high-risk populations.
Market RealitiesSome of the coverage of the COVID-19 crisis has asked why the US doesn’t have a treatment for this coronavirus and why the government is taking so long to bring one to market. The two reasons are the regulatory process, and the perception of market demand.
Well, the reason is that it typically 7-10 years after discovery of a drug to get it approved. DiMasi, Hansen, & Grabowski (2003) estimate the mean duration of a Phase 1 safety study as 1.8 years, a Phase 2 efficacy study as 2.1 years, and a larger scale Phase 3 study at 2.5 years. So that is 6.4 years, not counting the 2-3 years before that to justify getting into humans, and the 12-21 month delay (depending on therapeutic area) waiting for FDA approval (DiMasi, Grabowski & Vernon, 2004).
While the FDA allows off-label use of approved drugs, and compassionate use access when there is no standard of care, our society (like any other) expects a rigorous, multi-year process to prevent sale of unsafe or ineffective products.
The other issue is the commercial reality. The DiMasi et al (2004) study estimated that on average, clinical trials for an antiinfective drug took $362 million and lasted 10.3 years.
As the CEO of a (tiny) pharma company, it’s hard to make a case for pursuing a scientifically feasible drug unless a) it’s a big market or b) someone else (government, foundation) bears the risk. I know for sure that I won’t get venture capital to fund my trials unless investors think there is a good chance of achieving sizable revenues — particularly given the 11% clinical success rate for all human therapeutics (DiMasi et al 2016).
So when there’s an epidemic, under normal circumstances firms will have something approved long after it’s over. If no one (or almost no one) is sick any more, there’s no market for treatment. However, insurers and public health authorities are willing to buy a vaccine so the disease doesn’t come back again.
Finally, even if approvals are accelerated, it takes time to be able to manufacture a drug at scale with FDA-approved quality standards. Repurposing existing drugs are the only ones likely to be ready for widespread usage this year. Thus, we should be excited by this good news, and the increased sense of urgency by the government to encourage further investment in deploying these therapies.