COVID-19 oral antivirals

AH: The second you've got this sort of stuff done, COVID mutates and there's a new mutation and the drugs don't work. So there has to be some middle ground between real-world studies that can provide useful data, as opposed to just an active-arm group, but also keeping up with this really dynamic COVID landscape.

[Music] Welcome to the Australian Prescriber Podcast. Australian Prescriber: independent, peer-reviewed, and free.

Critical to our current COVID-19 strategy is the concept that we are better at treating COVID-19 than we were two years ago. While widespread vaccination has been critical, COVID-19 antiviral therapies have been a cornerstone of our approach to mild and moderate COVID-19 in at-risk individuals. In the last six months, there's been a frame shift in our approach, urgent efforts in the face of major waves of COVID. With such urgency though comes questions about how to maintain rational prescribing and to ensure real-world best outcomes. So where do we stand with this?

I'm David Liew, a clinical pharmacologist and rheumatologist from Melbourne, and your host for today. Today I'm speaking with two authors of an editorial in Australian Prescriber which asks questions about how we maintain equitable access and the quality use of medicines with COVID-19 antivirals, especially oral ones.

Amy Legg is a research and clinical pharmacist at Royal Brisbane and Women's Hospital, and Andrew Henderson is an infectious diseases physician and microbiologist at the PA Hospital in Brisbane, and the chair of Queensland Health's COVID-19 Clinical Therapeutic Guidelines Working Group. Amy and Andrew, welcome to the program.

AH: Thank you, David. Thank you for having us.

Amy what's the COVID-19 antiviral situation at the moment, and how do we get to the stage where we have the TGA-approved options that we do going to the people that they're going to?

AL: In the context of mild to moderate COVID where we have patients that have fairly mild symptoms, and we know that they might be at risk of progressing to more severe outcomes, such as requiring hospitalisation or even dying, we have three antivirals in our arsenal which do provide us a nice armamentarium for treating patients with mild to moderate COVID.

So we have IV remedesivir, which can be used in a three-day regimen, but isn't all that practical given that it's IV and given three days in a row. It might be useful in some hospitalised patients but, by and large, what we're talking about in this setting is the oral antivirals.

The first is Paxlovid. The drug name is nirmatrelvir/ritonavir. Nirmatrelvir is doing the bulk of the heavy lifting in terms of the antiviral. It's boosted by ritonavir to give it a nice, long half-life in the body. It has shown benefit in terms of reduction in hospitalisations and death, particularly if started within five days of symptom onset.

We also have another antiviral called molnupiravir. It has a similar role in therapy in that we use it early in the first five days of symptom onset, and maybe a reduced efficacy profile compared to nirmatrelvir/ritonavir. They've been supplied to hospitals as part of the National Medication Stockpile, meaning that they are free of charge. We are shifting into a space now where molnupiravir has PBS access and that may change the way patients are accessing it in the community.

I guess when we looked before at certainly remdesivir, but also in that mild to moderate space looking at neutralising monoclonal antibodies such as sotrovimab being the one which was used perhaps more, they were perhaps a little bit easier to regulate in terms of access, although maybe that wasn't entirely perfect as well.

AL: Yeah. I definitely think sometimes the beauty of a restrictive regimen is that it can be restricted, and when you need a lot of health infrastructure to give something, then you can provide a lot of health infrastructure, and when patients are having to present to specialised COVID clinics or fall within certain COVID teams, then that does help us. It's easier obviously with education and communication if you're only communicating with a small cohort of people who all work underneath the same governance structure. Once that sort of balloons out into the community, all those resources that go into communicating with everyone, ensuring the messaging is the same, and ensuring health equity is applied systemically, is quite difficult.

So how does that work now? How do we decide who gets the therapies that they do, Amy?

AL: At the moment, what has happened is a little bit of a two-tiered system. Within Queensland, particularly in the hospital setting, what happened 100% of the time until just recently, was people with COVID who were unwell enough or met criteria for therapeutics would really come under a COVID virtual ward where that team would then be able to work out what the most effective therapy was for that patient, really choosing between sotrovimab, nirmatrelvir/ritonavir, molnupiravir, and potentially even the IV remdesivir regimen.

Now the only access that the community prescribers have outside of those COVID virtual wards is molnupiravir which, as you can imagine, somewhat elevates it above the others once you have access to one and not the others.

How did those criteria come about? Andrew, Amy, you've both been involved in shaping that in Queensland. Were they easy to put together? Did you have much in terms of direction? Do you think that they reflect the best use of medicine?

AH: The putting together of guidelines is not a simple process. We're fortunate in Australia that we could leverage off the Australian National Taskforce guidelines. Outside of that, there were international guidelines already available through the NIH and NICE in the United Kingdom.

We obviously look at the clinical trials to begin with, and then we formulate as best as we can evidence-based approaches to which patients should be eligible for therapy.

I suppose one of the key things to mention just around sotrovimab is that in January we were pretty worried that we were going to run short. I think the Omicron wave caught everyone by surprise in terms of how quickly it took off and, in Queensland, we didn't have a huge amount of experience using sotrovimab up until late December because most of the outbreaks had been in New South Wales and Victoria.

We had fairly broad criteria for accessing sotrovimab, broader than what was used in the clinical trials, and that's one of the challenges that we're now facing with molnupiravir and Paxlovid.

We were so concerned that we were going to run short on sotrovimab that we actually brought together an expert group of clinicians across Queensland, and we put together a tiered-access approach to sotrovimab. Fortunately, as more stock became available, we were able to open up a little bit more on the request of clinicians who felt that some of their patients may benefit.

So there's always a balance between supply and clinical evidence. I suppose with drugs like molnupiravir, the group that was represented in the clinical trial only makes up a small proportion now of who we're looking at treating in Australia, and one of the concerns about that is that obviously the MOVe-OUT trial included patients who weren't vaccinated, whereas our vaccinated cohort is very large, and the immunosuppressed cohort weren't represented in the only trial for this drug to have been approved and then granted PBS availability.

Because we've obviously been very lucky in this country. We've had the COVID-19 Living Guidelines, which have been able to synthesise the evidence that does exist well, but I guess you and your authors are arguing in this editorial that it's hard to know the benefits of these agents, how they apply beyond the trials in real life. Where do you think that comes about?

AH: I think the Living Taskforce Guidelines have been very open and upfront in saying that they're unsure about the clinical benefit of some of these therapies in the immunosuppressed cohort group, in addition to that, the patients who have now had third doses to bring them up to date, in terms of their definitions according to ATAGI for vaccination status.

For a drug like molnupiravir, which had a relative risk reduction of about 30% for your risk of hospitalisation in an unvaccinated group compared to nirmatrelvir/ritonavir, which had an efficacy of around 70 to 80%, when you present that to a patient and ask, "Which therapy would you prefer to have?", most of us would prefer to have the one that had the higher efficacy, and that may not always be true because these weren't head-to-head studies.

The guidelines obviously provide a framework, but we also need to educate our clinicians about how to have that risk-based discussion and approach to the individual patient and actually say that, "Perhaps some of these therapies, although they are listed for treatment of COVID, well, your COVID is unlikely to actually cause too many problems for you."

Amy, I'm interested to know what you think about the education that went out to clinicians, to prescribers and to pharmacists about these medications in practice.

AL: In the hospital setting, we're very lucky, we had the National Society of Hospital Pharmacists that was able to provide education. But certainly the use of these medications does require a certain amount of risk–benefit analysis and risk profiling to ensure that we are all following the same flowcharts to get to the best therapies for our patients.

There has been a lot of talk about the fact that for a long time COVID was managed within specialised settings, and we don't know a lot of information that we would like as COVID shifts and changes so readily. And we do really want to light a fire in people's bellies about contributing to postmarketing surveillance, and what that looks like in the community just seems harder for us to be able to capture that real-world data that we think will really help drive where the benefits are once we take those fairly small, highly specialised clinical trials and try and apply them to the implementation of these drugs, such that it is in Australia.

Perhaps you can tell us a little bit about what postmarketing surveillance has occurred with intravenous agents so far, as far as the neutralising monoclonal antibodies are concerned? What do you think the advantages of having done that kind of work are and where the gaps are?

AL: The benefit in implementing sotrovimab as part of our mild to moderate therapy is that it is aimed to prevent hospitalisations and deaths. In the COMET-ICE trial that sotrovimab gained its provisional approval on, in the sotrovimab group there were 291 patients and only three of those patients then got readmitted for longer than 24 hours in a 28-day follow-up period.

Our hospitalisation rate after sotrovimab is much higher. In fact, it's higher than the placebo group. But, similarly we have used it in a cohort of patients who not only are unvaccinated with risk factors but also are immunocompromised. And those immunocompromised patients really weren't included in the COMET-ICE trial, but it's sort of unpalatable not to treat a cohort of patients that you think are biologically plausible to have a poor response to vaccination and potentially not be able to fight the infection themselves. So we want to treat them, but they also have a high rate of being re-hospitalised within 28 days.

We've seen a real dilution of the effect when we've tried to look at it within our cohort. But without control groups and without head-to-head studies, there may still be a benefit there. What we would need is to compare ourselves to Australia, ideally compare ourselves to patients with similar comorbidities who weren't treated, but also to compare our patients to patients with similar comorbidities who didn't get COVID, and that would really help provide a landscape where we would have a much better idea of what benefit we were getting, what we were prepared to pay for it, and which patients we should be prioritising therapy to.

The other thing I'll just quickly add is, the second you've got this sort of stuff done, COVID mutates and there's a new mutation and the drugs don't work. So there has to be some middle ground between real-world studies that can provide useful data, as opposed to just an active-arm group, but also keeping up with this really dynamic COVID landscape.

Well, Andrew, what I'm hearing is that now in the form of oral antivirals, we've got newer agents which we've had less experience with, evidence is still evolving. We know that there are patients who we're worried about, like my rheumatology patients, many of whom we strongly suspect have a poor vaccination response, are at risk. So, once we go out into the community where we don't have things captured quite as well, how are we going to deal with that kind of postmarketing surveillance? How are we going to deal with the education that's required to prescribers and to pharmacists?

AH: Yeah. It's a really important area of any therapeutic, be it in the area of COVID therapeutics or, I guess, other antimicrobial therapies that Amy and I would commonly deal with. In Australia, our process for bringing new medications through is typically a lot slower than through the EMA or FDA process and so, typically, we have that data available to inform us beforehand. So usually that information can then be used to generate education, provide to hospital staff as well as primary care in terms of its widespread use.

I think with these new therapies that have come through, I think we have to bear in mind that it's such a quick-changing landscape, and this is absolutely no criticism of the decisions that have been made, but we, as a nation, purchased 300,000 doses of molnupiravir before it was TGA-approved.

So we have to look at this process, whereby there was a pre-purchase agreement, things move so quickly and, in the current climate, you can be criticised for not actually purchasing therapies that may then turn out to be useful in practice. But on the basis of that, I think the TGA approvals and other approvals around therapies have often been made before there's been publications and peer-reviewed assessment of data.

So I guess on top of that then, without having a huge amount of clinical data, we need to look at the postmarketing surveillance to inform us around both efficacy and the side-effects profile. There's certainly a number of medications which have made it into an approval process which were then found out later on that actually have a more adverse side-effect profile than what was seen in clinical trials.

We need additional data to be reported. There's obviously processes available for that, for reporting adverse events to the TGA, but there's not typically a process for reporting on clinical efficacy once a drug is registered.

The important point around this is, I think, as a group of clinicians that are going to be putting together guidelines for this, was that we want to work with companies or we want to work with other clinicians. We certainly want to work within our framework to put together quality assurance projects that allow us to inform efficacy over time and then it allows us then to inform for ongoing clinical practice.

It has necessarily moved so quickly. Acting in a space where it's been, like you said, damned if you do, damned if you don't, and that we've really been having to act in the absence of clear data, now we're at this point where we want to collect more data, like you say. How are we going to try and implement these kind of things when prescribers are dispersed and dispensing pharmacists are dispersed, as far as these medicines potentially are?

AH: I'd say the process is fairly robust in hospitals and healthcare facilities. I'd say that the process is less robust in primary care, and that's where the prescribing is moving.

So what we may well see is that if we just collect data on hospitalised patients, then we are going to have a skewed effect if we don't collect data on a control group of patients who are given molnupiravir or Paxlovid who are not admitted to hospital.

While the medications are within the National Medical Stockpile and prescribing is occurring through healthcare facilities, this data is challenging to get, but it's doable. Once it goes into primary care, we certainly have limited availability to get that data.

And things change so quickly. We think back to casirivimab/imdevimab, which the government, again, purchased, and we hit the Omicron wave and it was sidelined because of a lack of neutralisation to that. So, sometimes we get it right and sometimes we don't get it right, but I think we need to have a very flexible approach to treating COVID because who knows what may come up next? We should be keeping our options open in terms of what therapeutics we have available to patients.

Absolutely.

AL: David, just one thing to add to that. One of the things we're doing within Queensland Health is trying to develop an online electronic portal, which was really the brainchild of Andrew and one of our other colleagues, Tina Patterson.

So, with the National Medical Stockpile, there are spreadsheets that get sent back to the Government which does enable some data collection but, unfortunately, when you look at that data, it's not going to be ever enough to help us really make decisions around effectiveness.

What would potentially be useful, if we're going to be asking pharmacists and clinicians to be collecting this data for the NMS anyway, would be to design something that could be Australia-wide that people are routinely entering information into. I actually think there's a lot of people who would be interested in contributing to this because all, community, hospital alike, we all want to know where the benefits are for our patients.

And if there was a national portal where a group of people could look at and say, "This is the data that we'll need to assess real-world outcomes," and developed an online portal that could be intermittently used to extract data and run these sort of reports, even at a governmental level or at least at a highly specialised clinical level or data analysis level, that would be fantastic.

Amy, you've worked in antimicrobial stewardship in the Top End. You've seen the challenges in those kind of settings where trying to balance service delivery in a stretched environment versus trying to do some things which have a broader view. Are there lessons that you think we can learn from that?

AL: Yeah. You've got to show people what the data's being used for. I could not agree more. If you ask people to collect data and they don't understand or they're not getting the data fed back to them in a useful way, you can absolutely agree that they're going to get pretty sick of filling that out.

But when I really think there's a real investment of health professionals' time into COVID now, and we want to know where the benefits are, I think the data that's been used to get these drugs to the market is not necessarily going to be what we see in practice. Data collection for the sake of data collection is an unpalatable refrain.

Absolutely. Andrew, we all can see that this COVID-19 thing isn't entirely over yet. We may well see more variants. We may see new therapies. How do you think the challenges are going to play out from here, and do you think we've learned some lessons now from this rapid rollout in the last six?

AH: Look, it's exciting to be in a situation where we're not talking lockdowns and we're not talking about closing the borders. So I think that's a real positive.

We would be naïve if we think that we are at the tail end of this pandemic. However, I think we're also coming to the point where we start thinking about how COVID starts to become a bit more like other respiratory tract infection or viruses in that it sort of generally causes a mild disease amongst patients, particularly amongst our vaccinated patients who have had booster doses. However, we recognise that COVID is a little bit different to some of our other respiratory infections such as influenza, and that it seems to cause a more severe illness, and particularly our immunocompromised patients remain very vulnerable towards COVID.

I suppose one of the keys towards managing the pandemic has been vaccination, but there's also patients that don't respond to vaccination and remain vulnerable.

Moving forward, there will be therapies such as Evusheld which will perhaps provide passive immunity to those who are unvaccinated. On top of that, I think we are always going to need to think about new therapies, and there are a number of ongoing Phase III clinical trials that are continuing in novel COVID therapeutics.

There's also a number of adaptor platform studies which continue to look at remodelled or repurposed therapies, and one of those is fluvoxamine, which is an antidepressant, which has hadmixed encouraging results so far. So, from the TOGETHER study, although it was a placebo-controlled trial, it showed a benefit. Internationally we've been a little bit more hesitant than these newer antivirals just in terms of recommending it. So I think more data to support whether fluvoxamine works or doesn't work will be good. If it is effective, then what a great drug for $4, compared to the thousands of dollars that we are expending on some of these novel antivirals. That's not to say that we'll put all our money into fluvoxamine. I think what we need to do is have a balanced approach.

We've talked a lot today about the equipoise, about the balance required, and thank you so much to both of you for really illustrating the kind of pathways that we need to look at going forward. Thanks for your time today.

AH: Thank you very much.

AL: Thanks, David.

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Dr Henderson declares participation on advisory board meetings for MSD, and Amy Legg has no disclosures. I am on the Drug Utilisation Sub Committee of the PBAC but do not represent them here. The views of the guests and the host on this podcast are their own and may not represent Australian Prescriber or NPS MedicineWise.

I'm David Liew. Thanks for joining us, and stay safe.