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Recent vaccine news from Pfizer (PFE) and Moderna (MRNA) provide some optimism to a world suffering from disease, death, and lockdown, and desperately looking for a solution to the COVID-19 pandemic for a return to normal life and work. Safe and effective vaccines will help contain the spread of COVID-19, but history tells us they are unlikely to serve as a silver bullet or eliminate the need for therapeutics to treat those people who still become infected. Coronaviruses are typically seasonal, do not induce long-term immunity, and can be subject to mutational escape. This virus is endemic in the population, which means it is not going away any time soon, and we still need better ways to treat the infected.
It is important to clarify what these vaccine trials have shown – and what they have not shown. The primary endpoint in each of these trials was achieved predominantly by preventing mild symptomatic infections. Several things remain to be seen: will the efficacy numbers hold up as more cases occur in the trial, and for how long will this protection from infection last? More importantly, we need to find out whether these vaccines will prevent the worst outcomes of this disease and its severe complications leading to hospitalizations and death. So far the trend points in that direction, but there were too few severe cases in the trials to have statistical certainty. The last point of concern is that PCR testing was not regularly performed on all trial participants to assess the prevention of asymptomatic cases of infection. The worst 2020 nightmare for young people is to carry an infection without knowing it, show up at a family gathering and infect Grandparents. We have no idea if the vaccines are preventing all infections (and thus preventing further asymptomatic spread), or only preventing mild symptoms, based on these trial results. The 95% primary endpoint result is promising but only tells us so much information.
Getting even 100 million people across the US vaccinated would be a monumental achievement of industry and would probably take a year to achieve in a best-case scenario. If we generously assume this happens next year, and assuming the 95% efficacy number holds up, this means providing 100 million people with vaccinations would still leave 5 million of those people susceptible to the infection. This is in addition to all those who will not be vaccinated and remain susceptible as they are now, such as the immunocompromised. While efficacy of the vaccines looks good so far in the elderly, the numbers are far too small to truly evaluate that question. In addition, some of the population will refuse vaccination, either due to antivax conspiracy theories, or out of abundance of caution because these are new products which were developed quickly and don’t yet have long-term safety follow-up. It is clear that developing COVID-19 therapeutics to treat infections remains extremely important.
We expect vaccination will only benefit some of the population, and any protective benefit may wane over time. As a result, we anticipate a durable need for therapeutics, in particular to treat elderly and immunosuppressed individuals that simultaneously are least responsive to vaccines and at greatest risk for COVID-19 complications. The rollout of these vaccines is likely to be uneven and leave openings for outbreaks throughout the western world. Once an outbreak occurs, it is too late for vaccination, and infected people need to be treated with therapeutics. An effective prophylactic is needed for fellow household members of those who test positive and quarantine at home. In the most detailed and methodologically sound household transmission study to date, the CDC recently found 53% transmission rates among household members from index cases. (https://www.cdc.gov/mmwr/volumes/69/wr/mm6944e1.htm). An effective prophylactic can also help the vulnerable elderly populations in long-term care facilities where the highest COVID-19 death toll has occurred so far. Appili is testing Favipiravir (Avigan) precisely in this setting as a prophylactic to help prevent this disaster from happening again. Multiple approaches are needed for the toolkit to defeat the pandemic, and effective treatments remain a high priority to go together with vaccines in this fight.
There is a growing body of evidence that early intervention in the disease progression is key for acute antiviral treatment approaches. Based on mechanism of action, antivirals need to be administered quickly before a virus has time to spread throughout the body and while the body is slowly turning on its adaptive immunity. Once the virus is already widespread, it is too late to shut off its replication or neutralize it with antibodies. If we can treat newly infected patients early, by keeping a lid on viral replication as the body slowly turns on its B-Cell and T-Cell responses to catch up with the virus, we can prevent these downstream sequelae and keep people out of the hospital. This can ease the pressure currently on hospital systems which in some regions are on the verge of collapse in the chaos of treating so many patients at once.
Currently the only FDA-approved antiviral drug is Remdesivir, which blocks the RNA-dependent RNA polymerase (RDRP), which SARS-Cov2 uses to replicate itself within a cell and to spread throughout the body. Avigan (Favipiravir) is an antiviral drug inhibiting the same target. Remdesivir was approved based on a US trial that found its administration shortens the time to clinical improvement in hospitalized patients but without demonstrating unambiguous reduction in mortality. It was an important proof of concept for the RDRP target against COVID-19, but it pointed to the importance of earlier treatment, which Remdesivir is incapable of. Given that Remdesivir is administered as an IV, doctors provide it only during hospitalization. By the time hospitalization is needed, patients typically already have advanced disease, and it is largely too late for an antiviral to act, as the virus has already replicated and spread. Those same hospitalized patients waited without a viable treatment until their symptoms got so bad that they needed to visit the emergency room. If we could instead provide the antiviral immediately in the form of a pill when early mild symptoms have not yet gotten worse, this could attack the virus before it is widespread in the body and prevent the hospitalization from happening in the first place. As a pill, Avigan enables early antiviral treatment at the first sign of symptoms and would provide better outcomes with reduction in hospitalizations and an unambiguous prevention of deaths, unlike Remdesivir. As an oral drug, Avigan would also be less expensive and easier to mass distribute to the population than Remdesivir, which today is an expensive specialty treatment used in a setting where it is least likely to help. By giving the Avigan pill more immediately within the first 72 hours of testing positive and showing symptoms, it can reach a much broader patient population and prevent severe cases.
Gilead (GILD) (the makers of Remdesivir) clearly understands the value proposition of an oral antiviral for SARS-Cov2 infection and why that would be a superior approach as they stated their intention to reformulate Remdesivir into an oral drug, but this is a very long process with no guarantee of success. Avigan already exists as an equivalent to an oral Remdesivir, hitting the same target with a different compound, and Appili can seize this opportunity for itself.
Asymptomatic spread, the contagion window, and how Avigan can reduce duration
The spread of COVID-19 has been driven in part by long periods of infectiousness including in patients without overt symptoms, either in the pre-symptomatic stage or during asymptomatic infections. As an antiviral pill, Avigan has the potential for widespread use in the community to block transmission. This may be achieved through treatment of COVID-19 patients as described above, reducing viral load and transmission potential, or through administration as post-exposure prophylaxis, preventing the virus from taking hold in subjects recently exposed to a confirmed COVID-19 case. Use of chemoprophylaxis is well established for prevention of other infections.
Seasonal influenza: (Uyeki et al., 2019; Jefferson et al., 2014; Doll et al., 2017; Okoli et al., 2014)
HIV: (Stanley et al., 2017; Tan et al., 2017)
Group A Streptococcus: (Arnold et al., 2006)
Observational data also suggests potential benefits from post-exposure chemoprophylaxis against another coronavirus, MERS-CoV, the causative agent of MERS.
Appili trials in nursing facilities will both directly and indirectly assess the role of Avigan in controlling the spread of COVID-19 and address the question of asymptomatic spread not examined in the vaccine trials.
Early intervention versus late stage hospital intervention
The importance of early antiviral treatment has been demonstrated for other viruses, especially influenza. For example, delaying treatment with oseltamivir in influenza patients is associated with increased disease severity and death (Kumar 2011, Lee 2010, Hiba 2011), and earlier treatment is associated with quicker hospital discharge rates (Lee 2007).
In the case of COVID-19, high viral loads early in the course of infection followed by inflammatory disease and organ dysfunction is now an established paradigm, and it suggests that the benefit from antivirals would be greater early in the infection. Appili believes that signals of benefit from trials of Avigan in the hospital setting are encouraging but likely underestimate the potential utility of the drug and its broader applicability. Appili’s ongoing studies are designed to assess Avigan in settings where it is most likely to show benefit – early and in the community –precisely where Remdesivir cannot be used.
One last important point on this subject is the relevance of RDRP as a target for many viruses including all RNA viruses, such as MERS, SARS, and other coronaviruses. Since symptoms of these viruses usually start off similarly and diagnostic testing doesn’t always provide immediate answers on the cause of these symptoms, Avigan could be initiated immediately upon the emergence any cold/flu-like symptoms, before finding out precisely what virus is responsible. This means that once Appili demonstrates proof of concept in SARS-Cov2 infection, Avigan will remain relevant to deploy quickly in future pandemics. It also means that in the current pandemic, it can be used more broadly against all current causes of cold/flu-like symptoms with the knowledge that in some of those cases these mild early symptoms will develop into severe disease, and Avigan can prevent that from happening. In this scenario, Avigan is relevant for early treatment even in locations where Covid testing is not ideal, and it has broad application potentially to influenza and other viruses without reliable or aggressive diagnostic efforts attached to them.
Appili timeline and near-term catalysts
- Working with the larger consortium of global partners, Appili has shortened the time to study start, finish, and achievement of potential regulatory milestones. Appili will also benefit from significant news flow and catalysts from their own work and those of their partners.
- Appili has a Phase 2 trial ongoing in Canada in long-term care homes, and through its consortium, expects data readouts from a US inpatient Phase 2 trial before the end of 2020, as well as a US outpatient Phase 2 and a Middle East inpatient Phase 3 trial in 1Q-2021.
- Appili also expects the first patient enrolled for their Phase 3 treatment trial in US + Latin America within the month, and the first patient enrolled in their Phase 3 post-exposure prophylaxis trial before year-end. The Phase 3 treatment study is expected to read out in 2Q-2021, and the post-exposure prophylaxis study in 3Q-2021.
- With each data readout, Appili will explore the potential for regulatory submissions and approvals which may become an important milestone. EUA’s have been granted efficiently by FDA for any treatments showing benefit against COVID-19.
Disclosure: Author is Long APLIF & APLI