COVID-19 vaccines were developed and are being delivered by way of a herculean effort from medical professionals around the world. But while vaccinations mark a life-saving milestone in the pandemic response, they don’t mark the end of COVID-19.
Scientists with Halifax-based Appili Therapeutics have been immersed, working on a possible complementary tool. As part of a global consortium, the company is testing to see if an already existing drug is both safe and effective for treating coronavirus in outpatients.
Appili (app-ill-eye) is sponsoring the North American trials for a drug called favipiravir, also known as reeqonus (rick-own-us), carrying the common trade name Avigan.
The now late-stage trials are expected to show if it can help in cases of COVID-19, where symptoms are mild to moderate. If proven out, regulators like Health Canada can approve it to be available for prescriptions in managing COVID-19 going forward, keeping more people out of hospital and more comfortable while their body fights off the virus – if it’s proven.
Avigan is part of a group called broad spectrum anti-virals and it targets the virus’ genetic material (its RNA), and how it makes copies of itself. Basically, it interferes in that process.
Appili CEO Dr. Armand Balboni was recently reached by Atlantic Business Magazine in Washington, D.C. He said Avigan is approved to treat influenza in Japan. Appili was looking at the drug before COVID-19, working with Japan’s FUJIFILM Toyama Chemical Co. to investigate if Avigan could also be a possible treatment for a disease called lassa fever.
“There wasn’t a lot of interest in that disease. It’s an emerging, infectious disease. It’s usually in sub-Saharan Africa so we don’t hear about it much in the West, but (…) we target lots of diseases that may not rise to the level of people hearing about them every day, but we believe that there’s an opportunity to bring drugs to market, and as I like to say we do good and do well,” Balboni said.
Immediate plans changed around January 2020, when company scientists took note of the viral outbreak in China. “We very quickly pivoted as a team to see whether or not we could generate data against COVID-19,” he said.
The new investigation of Avigan has led to the more recently clinical trials, serving a partnership of India-based Dr. Reddy’s Laboratories Ltd., Global Response Aid and FUJIFILM Toyama Chemical.
“(Avigan) has never been approved in Canada by the way for anything, or in the U.S. It’s only been approved in Japan and a few other jurisdictions because people hadn’t done the work (to bring into use elsewhere, or for COVID) and that’s what we’re doing,” Balboni said.
Appili gathered pre-clinical work and developed the paperwork necessary for regulatory authorities. It signed investigators on principle and ultimately obtained its trial approvals.
Moving through trials
There are four phases of clinical trials. Phase one trials are meant to demonstrate a drug is generally safe for use and involve a small group of people. Phase two involves a larger group of people (usually testing on 100 or more) to gather more data on how the drug works and address dosage. Phase three trials move up to groups of 1,000 people or more, where there is closer examination of any side effects and comparison to any existing treatments. Phase four trials follow approval, to gather more information on the best way to use the drug and further evaluate identified benefits or risks.
“These are the studies that are really important to demonstrate that it’s both safe and efficacious – it works and it works as intended for the disease you’re going after.”
“The phase three studies are really the ones that are called pivotal for approval. These are the studies that are really important to demonstrate that it’s both safe and efficacious – it works and it works as intended for the disease you’re going after,” Balboni said, echoing Health Canada’s own descriptions.
Once through phase three, companies can make a submission to regulatory agencies for a label. Essentially, a drug is approved for the use identified.
Appili is currently running multiple trials for Avigan and is in a phase three trial, an international study, on patients with mild to moderate symptoms, where it began enrollment shortly after getting green lights in December 2020.
“This will be the one that’s built or designed to demonstrate conclusively whether or not this drug Avigan works for COVID-19 in patients that are not hospitalized,” Balboni said. “Right now you get sent home. There’s no drugs available for you. At least, not that are given easily. And so this is the first time that someone will have shown an oral drug, a tablet or a pill, can work in this setting. And so that’s the study that we’re running.”
“This is the first time that someone will have shown an oral drug, a tablet or a pill, can work in this setting. And so that’s the study that we’re running.”
An interim result from the phase three trials, a mid-point look at the data, is expected in about four weeks. Top-line data, or the final data from the patients, is expected some time in May.
“We will get a lot of information in the next three or four weeks. It’s really important,” Balboni said.
There is no guarantee any drug developer will get the trial results they desire. Early trials of a drug called remdesivir (another broad-spectrum anti-viral), for example, showed early promise against COVID-19, but the World Health Organization later found further data ultimately showed the drug did not prove to have significant benefits or offer enough in reduced recovery time.
And as reported in late January, Reddy’s cancelled a separate trial of Avigan ongoing in Kuwait, one targeting its use for patients with moderate to severe symptoms. The decision was made to continue on the trials in North America with Appili on use for COVID-19 outpatients with milder symptoms.
Interested in good information
Balboni is open about Appili’s work and his own desire to raise the level of public understanding in Canada of viruses and drug development. He has started outreach events online, bringing together medical professionals to offer their views on COVID-19. He has plans for more beyond COVID.
“I think part of that is it’s our responsibility as a company to ensure that we are putting good information out into the world.”
“My inch of the world is infectious diseases. I feel very passionate about it. I’ve spent a lot of time both as an academic and in the private sector. And so I think it’s really important for me, for this company, to own the intellectual high ground,” he said.
“We want to and we will be around for a long time talking about emerging, infectious diseases. Not just COVID-19. And I think part of that is it’s our responsibility as a company to ensure that we are putting good information out into the world.”
Balboni is a physician who spent 18 years total in active duty and reserves with the U.S. Army and was a faculty member at West Point. He became part of the ebola response as part of his service and then later while working with the U.S. FDA, before moving into the private sector and helping to found Appili.
Work on ebola outbreaks in Africa would lead to 2014 and the first use of genomic sequencing for the purpose of profiling strains and tracking viral spread and mutations. It’s one of the advancements in use today, as part of the public health response to COVID-19 (and one effort Balboni thinks could be ramped up, to closely track new variants).
It was through Balboni’s own time working on ebola response that he met several scientists who would eventually land with FUJIFILM Toyama Chemical, and launch the relationship there.
Tools in the toolbox
The latest online “fireside chat” hosted by Appili featured former commissioner of the U.S. FDA, Dr. Scott Gottlieb; Biotech Equity analyst Dr. David Schimmer and Dr. Syra Madad, the senior director of the System-wide Special Pathogens Program at New York City Health and Hospitals.
The experts lamented the “noise” around COVID-19 in the media. Madad in particular advocated for consistent and clear messaging around vaccines, saying the essential message is patients shouldn’t be overly concerned with what vaccine they’re offered, but focus on gaining what protections they can, as they can.
“We’ve sort of focused a lot on prevalence and number of infections, but we also need to start looking at the vulnerability of the population and the population isn’t nearly as vulnerable as it was a year ago.”
As for what’s changing, Gottlieb said there should also be recognition of the overall improved position for the public right now compared to the start of the pandemic.
“We’ve sort of focused a lot on prevalence and number of infections, but we also need to start looking at the vulnerability of the population and the population isn’t nearly as vulnerable as it was a year ago,” he said, noting the same infection rate today compared to a year ago would not carry the same risk for serious illness and deaths, given vaccines rolling out to the most vulnerable and recognition now of the virus in those people previously infected.
The doctors agreed there should be continued focus on being ready for flare ups, as summer comes, as more people are vaccinated and travel restrictions eased, and particularly as new variants may emerge.
They also agreed in looking beyond COVID-19, to invest in all of the pieces required to prepare for the next, big public health response, down to the secure supply for enough personal protective equipment or pipette heads for laboratory work and regularly updated plans for operations and meeting frontline demands.
There was mention of the improving toolbox. It refers essentially to all the things available to push back against infections, spread and severity of symptoms. In responding to COVID-19, there were few tools available when the World Health Organization declared a global pandemic a year ago. One was public health guidelines – pleas for handwashing, physical distancing. Mask recommendations followed, particularly as more was learned about COVID-19 and its transmission. Public health orders were another tool, including border restrictions and stay-at-home orders. They were needed as cases mounted.
Vaccines were essential in speeding our ‘return to normal’ and any move from a pandemic emergency to a world where COVID-19 is a manageable, endemic virus.
A pill to use in the case of infection would be another tool.
“As long as we’re seeing a progressive decline in severe infections and hospitalizations, I think we’re still on track for a second half of the year (business) recovery and then some have described what comes next as the roaring 20s and hopefully that starts in 2022,” Schimmer said.