NEJM: Seriously consider VV116+Paxlovid combination

On December 29, 2022, The New England Journal of Medicine published a Phase 3 clinical trial paper on the Junshi Biologics/Wangshan Wangshui VV116 head-to-head single-blind control against Pfizer Paxlovid.

VV116 vs. Paxlovid head-to-head comparison

——The difficult exploration of high-standard clinical trials for emerging infectious diseases

This is the first time that a new crown drug in China has entered NEJM.

Following the publication of the paper, on January 5, 2023, the New England Journal of Medicine published a 17-minute interview online with VV116 titled: "The Expanding Arsenal of Oral Agents to Treat Covid-19."

NEJM: The continued spread of the novel coronavirus remains a public health emergency of international concern. What doctors need to know about the spread, diagnosis, and treatment of Covid-19 is a topic that is constantly updated by the journal's infectious disease experts. In an audio interview conducted on January 3, 2023, the editor discussed oral medications for Covid-19, including Paxlovid and the new drug VV116.

The following is a transcript of the interview.

This is the New England Journal of Medicine Covid-19 update, January 4, 2023, and I'm Stephen Morrissey, Editor-in-Chief of the journal. I'm talking to editor-in-chief Eri Krubin and associate editor Lindsey Baden.

The most common oral drug for early Covid-19 is nematevir-ritonavir (Paxlovid), and while this drug has clearly been successful in reducing hospitalizations for severe illness, its uptake has been more limited than one might hope. Unfortunately, ritonavir can interfere with the metabolism of many drugs, which limits its use in people receiving certain medications.

In addition, nematevir-ritonavir (Paxlovid) has clearly had many viral rebounds (recurrent symptoms) and recurrent symptoms, making some people reluctant to take the drug.

Is this an inherent problem with this drug (Paxlovid), or is it simply because the Covid-19 disease has not been observed long enough?

It is not clear whether the viral rebound we see in clinical practice is an attribute of drug treatment? Perhaps the duration of the treatment is too short, or perhaps it is a property of the virus itself.

As far as we know, the dynamics of viral replication weakens over time, which contradicts known data because there is no rebound from natural remedies. You need all this spatial data, but I think we have to balance speed with perfection because the treatment has evolved to the clinic. In the face of the global pandemic we have seen over the past three years, we rarely test the treatment time of any drug. At the same time, (Paxlovid) is a very widespread use of this drug, and I think (Fuyang) this is a very important issue.

Of course, as we will talk about, there are new drugs (VV116) that could change the whole situation.

How best to use medications to clear the (Covid-19) virus? We have another drug (remdesivir injection) that has been shown to be effective in outpatients. Originally used in hospitalized patients with more advanced disease, remdesivir injection was relatively less effective, but it significantly reduced hospitalization rates when studied in outpatients.

The problem is that remdesivir injection is given intravenously, which severely limits its outpatient use.

So, why can't we directly use the mouth and administer it orally?

Somewhat ironically, the gut is designed for oral absorption, whereas most of the medications we use in outpatient settings are oral. However, in fact, oral medications have to overcome many obstacles. It must be sufficiently soluble to reach intestinal epithelial cells. It is designed to degrade complex molecules, it must be absorbed under a wide variety of conditions, and it is likely to be encountered in people who eat on an empty stomach and those who are taking drugs that reduce stomach acid production. It must not be destroyed after the first passage through the liver (first-pass effect).

Changing the absorption and metabolism of molecules through their basic structure is one way to turn (remdesivir injection) into an oral drug (VV116).

VV116 is not remdesivir but a remdesivir derivative that has been tested in an animal model and proven effective in clinical trials.

The new drug was named VV116 (V V sixteen). So, what is this compound?

An unusual feature of VV116 is that it contains a deuterium atom instead of a hydrogen atom, and replacing hydrogen atoms with deuterium can most likely slow down the metabolism of the compound.

The difference between intravenous drugs and oral drugs is that we (US) need to treat patients, treat patients early, and treat patients 24 hours a day.

For most infections, oral treatment is more important because it can be prescribed to patients as early as possible. We have already discussed the limitations of intravenous preparations.

How was the clinical trial of VV116 conducted? This was a single-blind trial conducted in China, and participants were randomly divided into VV116 and Paxlovid groups. Participants had mild to moderate Covid-19 nucleic acid positivity and disease progression with at least one risk factor. This is a (sustainable clinical recovery time) non-inferior clinical trial.

The study included more than 800 patients, about a quarter of whom were not vaccinated. Treatment was started late, with a median of 4 days after symptom onset, and most participants had milder symptoms of nucleic acid-positive disease.

The result?

VV116 is comparable to Paxlovid with a median recovery time of 4 to 5 days.

The public is most concerned about whether to avoid severe illness. It seemed that the risk was low enough and the number of participants small enough that we didn't see any incidents occurring. In addition, I suspect that these two drugs (VV116 and Paxlovid) would be better if they were started early in the course of the disease.

Our primary concern is the prevention of serious disease, which in this study was limited by the sample size as well as by the nature of the subjects studied.

I think the challenge with this non-inferiority or comparative design is that in this case, there is no comparison of the level of efficacy in this population in a natural state.

Here, the placebo group would be very helpful in better defining the new drug VV116.

However, the ethics of placebo-controlled treatment in at-risk populations are complex, although there may be significant differences in efficacy between the two groups.

The design of placebos is important because it is essentially an assessment of the absolute efficacy of a new drug, and is more limited when the sample size is relatively small.

What to do?

Very attractive high-quality double-blind trials were randomised trials conducted with placebo.

However, Pfizer Paxlovid This was conducted in the context of a largely non-immunized population.

Immunocompromised people, unvaccinated, limited natural infections need to consider drug interactions. These patients at highest risk of progression often have complex conditions that require the use of drugs that may interact with ritonavir.

Therefore, this is a huge challenge in the outpatient field and very unmanageable, but due to concerns about drug interactions, a significant proportion of these patients are prone to cardiovascular disease, especially high-risk patients.

Another factor worth mentioning is the idea of combination therapy, perhaps just to quickly eliminate it. Remdesivir and VV116 target viral polymerase.

So as you can imagine, they (VV116 and Paxlovid) might be synergistic with each other. This synergistic effect is very important in chronic infections, but less pronounced in acute viral infections such as Covid-19, where the virus disappears relatively quickly with or without treatment.

However, this is something to keep in mind, especially for patients who are less common and whose immune system cannot clear the virus and whose virus can be chronically shed over time.

Eric, I think that's a very important point. And, you know, as a doctor, take care of immunocompromised patients, both in cancer centers, and those who have received organ transplants, who are undergoing chronic immunosuppressive therapy. Sadly, too many of these patients prolong the shedding of the virus for weeks to months.

I think in this case, you are absolutely right. We need to think very carefully about how these oral drugs (VV116 combination) can be used to try and help these patients.

Chronic infections, currently mainly using Paxlovid in a continuous way, we need to consider using it in a combined way (VV116 + Paxlovid). As you hinted, successive epidemics may provide more opportunities for viral escape and viral mutation.

Well, this is a very small number of patients, this is less than 1% of patients are chronically infected with covid. But in this group of people with severely weakened immune systems, we need to think about how to use these drugs in combination, and how to do this in more limited circumstances than our current routine medication data.

Steve, what do you think?

There are a lot of potential drugs out there. I think that's true. I think it's likely just because these small molecules take a long time to form. But I think there's a lot of hope for finding better antivirals.

I guess that means we're going to have a better drug in the drug bank.

Thank you, Eric. Thank you, Lindsay.