Favipiravir, A Potential COVID-19 Treatment

Drug Topics®: Hi, this is Gabrielle Ientile with Drug Topics®. Today I'm going to be talking to Armand Balboni, MD, PhD, chief executive officer of Appili Therapeutics, about favipiravir, a potential COVID-19 treatment for elderly and long-term care populations.

Before we get started, here's the latest news from drugtopics.com. A recent analysis showed a surge in prescription pills for hydroxychloroquine and chloroquine, likely due to off-label prescribing. The JAMA study analyzed prescription patterns and found that hydroxychloroquine/chloroquine fills increased by 1977% since last year.

States are slowly easing their barriers to pharmacists-provided COVID-19 testing. In early April, the US Department of Health and Human Services (HHS) authorized licensed pharmacists to order and administer COVID-19 tests approved by the FDA. By mid-May, about two-thirds of states had adjusted regulations for pharmacists-provided testing, but just a handful of pharmacies have managed to navigate the maze of federal, state, and supply-chain practicalities. And that's the latest news from drugtopics.com.

Drug Topics®: Dr. Balboni, thank you so much for joining me today.

Balboni: I'm glad to be here.

Drug Topics®: You’re the CEO of Appili Therapeutics. Can you talk a little bit about what the company does and your-day-to-day at the company during the pandemic as well?

Balboni: The company was founded in 2015 as a singly focused company, and the idea was to tackle infectious diseases in a way that others don't or can't. What we do is we look for unmet need first. So, is there a disease out there in the infectious disease world where folks are not able to readily find a solution, and we really try and match programs then with the disease, and we do that in a way that's agnostic to where something was created. And I think that's what's a little bit different here. We're all scientists, either by training, or experience, or both. We don't necessarily make the things in-house. Instead, we go and find solutions to problems, which means that we have antifungals, 2 antibiotics, and now an antiviral program. For me, the daily mission is one of trying to keep the team moving forward with the portfolio of products which really touches on a number of really important diseases. I like to say that we're a socially conscious biotech. We both do good and we do well, and I know people roll their eyes when they hear that you need to be a socially conscious biotech company. But we really are. We really try and find those tough problems and then we really relish the challenge to go find solutions.

Drug Topics®: What do you see as the significance of Appili’s approach and focus on elderly and long-term-care settings?

Balboni: So that's specifically looking at the antiviral program that we have been working with Fujifilm Toyama Chemical. It's a drug called favipiravir. It's a broad-spectrum antiviral. The long-term-care setting, as many of us have seen and know, even though the pandemic has not been going on for really that long, has disproportionately affected those in the long-term-care setting-the elderly. It doesn't mean that others can't get it, but we see a particular real serious problem there, and in fact, in many places, including Ontario, where our first clinical trial is being run for favipiravir in the long-term-care setting, 80% of the morbidity and mortality has been associated with the elderly, and so that that is really an unmet need, and it really fits into our wheelhouse.

I think the other reason we're focusing on that group is just the properties of the of the drug. Favipiravir is particularly well-suited for that population based on its properties, which are: it's oral, it's a tablet, unlike remdesivir, which is injected in an IV. And also, in the elderly, even when a vaccine becomes available, and we all certainly hope one will and I'm confident there will be one, the elderly don't necessarily respond to vaccines in the same way that everyone else does. Their immune system tends to be a bit more challenged. We think that there will be a place for this drug. And then finally, we focused on this group because nobody else was. We have the only randomized control trial, looking at this population for prophylaxis, meaning we're giving it soon-after infection as soon as possible, very early on in course of the disease. And, you know, it’s the only trial in the world to look at this really important population. So for all those reasons, we thought that it was a good fit for us.

Drug Topics®: Before we go into the phase 2 trials, can you talk a little bit about your professional background and your interest in infectious disease research?

Balboni: Sure. I've been doing this for a while now. I did my graduate work in the MD, PhD program at Mount Sinai School of Medicine. I guess now it's called the Icahn School of Medicine at Mount Sinai in New York. And then I've spent over 17 years in the US military as an officer, and in infectious diseases, which means that I've spent my time at both infectious disease labs like USAMRIID. I was at FDA for a while during the Ebola outbreak in 2014, helping to forward new drugs. And then I was the Director of Clinical and Regulatory Affairs, for DOD, where we ran about 110 clinical trials around the world. And that's really where I started to develop this passion about unmet need. Because as you as you probably know, most of the diseases that you're going after for DOD are rather esoteric. Things like Ebola, HIV, malaria, lassa fever, and dengue-I mean neglected diseases that folks don't really think about too much. But in the military, of course, you send troops everywhere. And so those diseases, largely fall on the government to try and fix. And then, the rest of our team-really what keeps me interested is that we have a great team of infectious disease specialists, from our chief medical officer, to the scientists, to our program managers. It really is a great environment to work in. I think it blends some of the professional passions that I've had with kind of the personal, everyday working environment where everybody is focused on the same types of diseases.

Drug Topics®: So in the age of COVID-19, there have been several sort of buzzword drugs like hydroxychloroquine and remdesivir being the most prominent, of course. Can you talk a little bit about favipiravir, what it is and what it does? Why hasn't it yet gained the same amount of traction that these other potential treatments have?

Balboni: I'll certainly give you my opinion about that. I think if you do look at a broad spectrum antivirals there really are only two right now that are at this stage of development. And that's the remdesivir, the Gilead’s drug that you talked about, and favipiravir, which is the Fujifilm Toyama Chemical, is the innovator but there are other folks working on it, I think-Heissen Pharmaceuticals, Glenmark out of India, and then Chemrar out of Russia. And I think it's a bit slower because it was a little bit further behind. The mechanism of action, however, is the same as remdesivir. I worked on both remdesivir and favipiravir when I was at FDA, looking at them for Ebola. There’s a lot of data around them. I think, early on, it didn't capture their attention because frankly, remdesivir did. And I think that that's okay. Favipiravir, after the splash of Gilead’s drug, people then in the field wait for the gold standard, which is the randomized control trial. There have been tantalizing hints that the peer reviewer is working, most notably two clinical trials run by Heissen Pharmaceuticals in China, and now the Russian study, which has been reporting positive data as well. These are, again, preliminary studies and not the randomized control trials. I think after the splash is made with remdesivir, everyone waits for the RCTs. That's what we're waiting for. There is now beginning to be some attention paid to favipiravir, particularly because it is differentiated from remdesivir, and importantly, the drugs like hydroxychloroquine that you talked about really gained a lot of attention because of publication by press. It's a bit of a sore spot with me and many others, that it can derail trials, like we see with hydroxychloroquine in the in the retracted studies out of the Lancet. It really does have the potential to derail large-scale randomized controlled trials, and then we won't know if it works. And so I like to say that favipiravir is probably one RCT away from just really becoming part of the everyday discussion around these drugs.

Drug Topics®: So what can you tell us about the phase 2 study with favipiravir?

Balboni: So favipiravir is an already approved drug in Japan for influenza. There have been two phase 3 trials run in the US and a number of phase threes in other locations. Now there are a couple of phase threes running in Europe and one in Russia. But the Fujifilm studies really set the tone here, which means that it's been extensively studied, it's been in over 3000 people. The safety profile is really well understood with this with this drug. And it is, again, approved for pandemic flu in Japan and China. It's been recently approved for COVID-19 in Russia. And I expect that India will also end up with the COVID-19 approval, at least for emergency use-sort of the equivalent-in the next couple of days. I think this is really moving forward.

I think the other thing we know about this drug is the mechanism of action. We know how it works. It targets the RNA-dependent RNA polymerase, which is a protein important for maturation packaging, and then subsequent reinfection of other cells. So it's really important to get it on board early. Remdesivir, by the way, works the same way. And so I think scientifically, we know how it works. And again, we have a very good understanding of the side effects profile. If I had to say there's one knock on this drug, and there is, it's the fact that in the preclinical studies, it was noted that there may be some teratogenic or fetal embryonic kind of effects in animals. We haven't seen that in people, but we have noted that in animals, and I suspect that that's a concern for folks going forward. It is, by the way, another reason that we thought that the long-term-care setting was probably the most appropriate for this drug, the profile of the drug, if there are concerns about potential teratogenicity, the best way to deal with that is to simply not give it to people who may be at risk of getting pregnant or having children. This population is fairly low risk in terms of that. Favipiravir, scientifically, is very well understood. Lots of people have seen it, and it is moving forward in randomized control trials, which is incredibly important. For all of those reasons it's a very solid program at this point, not speculative and certainly not a science project.

Drug Topics®: Dr. Balboni, thank you so much for joining me today.

Balboni: Thanks for having me.

Editor’s note: This interview transcription has been lightly edited for style and clarity.

Check back to drugtopics.com for part 2 of this interview, and more expert interviews on COVID-19.