Has the Real Game-Changer to Halt COVID-19 Devastation Arrived?

CME INDIA Presentation by Dr. S. K. Gupta, MD (Med), FICP, CFM (France) Clinical Asst. Professor GS Medical College, CCSU, Uttar Pradesh, India. Visiting Consultant, Max Super Specialty Hospital, New Delhi.

Paxlovid® (PF-07321332; ritonavir), new anti-viral combination pill from Pfizer has surfaced and hope swells.

Has the Real Game-Changer to Halt COVID-19 Devastation Arrived?

Hope on horizon

New drug combo has shown to cut the chances of hospitalization or death for adults at risk of developing severe disease by 89%.
The trial of Pfizer Inc’s experimental antiviral pill for Covid-19 was stopped early once it showed robust benefits.
The results appear to surpass those seen with Merck & Co Inc’s pill molnupiravir, which was shown last month to halve the likelihood of dying or being hospitalized for Covid-19 patients also at high risk of serious illness.

PAXLOVID™ (PF-07321332; ritonavir) was found to reduce the risk of hospitalization or death by 89% compared to placebo in non-hospitalized high-risk adults with COVID-19.

In the overall study population through Day 28, no deaths were reported in patients who received PAXLOVID™ as compared to 10 deaths in patients who received placebo.

Pfizer plans to submit the data as part of its ongoing rolling submission to the U.S. FDA for Emergency Use Authorization (EUA) as soon as possible.

(Courtsey:https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate)

New Drug, a protease inhibitor, is given in combination with an older antiviral called ritonavir. The combination treatment, which will have the brand name Paxlovid, consists of three pills given twice daily.
(The combination is different from Lopinavir+Ritonavir which failed in Solidarity trials in 2020). (Trial was done with a code name, generic name not yet disclosed).
Pfizer’s drug, part of a class known as protease inhibitors, blocks an enzyme the coronavirus needs in order to multiply. So, it stops multiplication of Virus.
Pfizer plans to submit trial results to the US food and drug administration as part of the emergency use application it opened in October.

Trial

An interim analysis of the Phase 2/3 EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) randomized, double-blind study of non-hospitalized adult patients with COVID-19, who are at high risk of progressing to severe illness.
Trial was done in 1,219 patients. Study looked at hospitalizations or deaths among people diagnosed with mild to moderate Covid-19 with at least one risk factor for developing severe disease, such as obesity or older age. But company didn’t clarify if it works the same way in patients with multiple co-morbidities like Diabetes and Obesity.
It found that 0.8% of those given Pfizer’s drug within three days of symptom onset were hospitalized and none had died by 28 days after treatment. That compared with a hospitalization rate of 7% for placebo patients. There were also seven deaths in the placebo group.
Rates were similar for patients treated within five days of symptoms – 1% of the treatment group was hospitalized, compared with 6.7% for the placebo group, which included 10 deaths.

Drug is effective only if given early

Antivirals need to be given as early as possible, before an infection takes hold, in order to be most effective. Merck tested its drug within five days of symptom onset.
Once the virus takes hold, the inflammatory effects drive the course of disease and then only anti-inflammatory drugs like corticosteroids work.
In SARS too, Oseltamivir works only if given early in course of infection.
Works even after Five days.
Combo has high efficacy, even if it was five days after a patient has been infected was treated, as people might wait a couple of days before getting a test or something, and this means that we have time to treat people and really provide a benefit from a public health perspective.

Primary End Point:

Reduction in risk of COVID -19 related hospitalization or death from any cause in patient treated within 3 days vs Placebo: 89%.

0.8% of patients who received PAXLOVID™ were hospitalized through Day 28 following randomization (3/389 hospitalized with no deaths), compared to 7.0% of patients who received placebo and were hospitalized or died (27/385 hospitalized with 7 subsequent deaths).

The statistical significance of these results was high (p<0.0001).

In the overall study population through Day 28, no deaths were reported in patients who received PAXLOVID™ as compared to 10 (1.6%) deaths in patients who received placebo.

Side effects

Treatment-emergent adverse events were comparable between PAXLOVID™ (19%) and placebo (21%), most of which were mild in intensity.

Comparison with Molnupiravir

Merck’s molnupiravir has a different mechanism of action designed to introduce errors into the genetic code of the virus.
It had shown 50% efficacy in reducing death or hospitalization when given early in high risk individuals.
Merck has already sold millions of courses of the treatment, which was approved this week by UK regulators, to the United States, the UK and others.
MSN Pharma and Aurobindo Pharma has withdrawn from trial of Molnupiravir in moderately ill patients
While Pfizer trial was closed early, the robust benefits show. It seems more to do with trial design than affectivity of drug in moderately sick patients.

	Paxlovid	Molnupiravir
Efficacy in high risk	89%	50%
Reduction of hospitalization/deaths in 28 days	8.2 vs 0.7%	14.1 vs 7.3%
Death in placebo vs drug	7 vs 0	8 vs 0
Combination or single	PF-07321332+ Ritonavir	Single
Repurposed	No	Yes
Mechanism	Blocks the activity of the SARS-CoV-2-3CL protease, Not Mutagenic	Nucleoside Analog; induces mutations
Variant of concern efficacy	Yes	Yes
Estimated cost	Unknown	May be >$700

Way Ahead

Britain also has secured 250,000 courses of Pfizer’s antiviral.
Yet to be seen if needed in mild disease?
Pfizer is also studying whether its pill could be used by people without risk factors for serious Covid-19 as well as to prevent coronavirus infection in people exposed to the virus.
Two other trials – one in people without underlying risk factors and another in people who have been exposed to the virus but asymptomatic – are continuing, with those results likely be available in the first quarter of 2022.

CME INDIA Learning Points

PAXLOVID™ is an investigational SARS-CoV-2 protease inhibitor antiviral therapy, specifically designed to be administered orally so that it can be prescribed at the first sign of infection or at first awareness of an exposure, potentially helping patients avoid severe illness which can lead to hospitalization and death.
PF-07321332 has been designed to block the activity of the SARS-CoV-2-3CL protease, an enzyme that the coronavirus needs to replicate.
Co-administration with a low dose of ritonavir helps slow the metabolism, or breakdown, of PF-07321332 in order for it to remain active in the body for longer periods of time at higher concentrations to help combat the virus.
PF-07321332 inhibits viral replication at a stage known as proteolysis, which occurs before viral RNA replication.
In preclinical studies, PF-07321332 did not demonstrate evidence of mutagenic DNA interactions.
The Phase 2/3 EPIC-SR (Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients) and EPIC-PEP (Evaluation of Protease Inhibition for COVID-19 in Post-Exposure Prophylaxis) studies, began in August and September 2021 respectively has not been included in the present interim analysis.
Enrolled individuals had a laboratory-confirmed diagnosis of SARS-CoV-2 infection within a five-day period with mild to moderate symptoms.
All were required to have at least one characteristic or underlying medical condition associated with an increased risk of developing severe illness from COVID-19.
Each patient was randomized (1:1) to receive PAXLOVID™ or placebo orally every 12 hours for five days.
EPIC-SR includes a cohort of vaccinated patients who have an acute breakthrough symptomatic COVID-19 infection and who have risk factors for severe illness.
The interim results are exciting but we need to wait for peer-reviewed data. This study has not been published till date.

CME INDIA Tail Piece

More Hype to counter the Molnupiravir?

Dr. Shashank Joshi, DM Endo, Mumbai:

Both the antivirals have been similar to other antivirals, though have built more narrative than real science.

Dr. H D Sharan, Cardiologist, Ranchi:

In trial , this drug was started between 3 to 5 days of onset of symptoms. All anti-viral drugs will only work in the early phase when the virus is replicating. Favipiravir did not help irrespective of when it was started.
Let us wait and see how it works in real life before either hyping it or junking it.