Heavy! NEJM: The efficacy of domestic new crown oral drugs is not inferior to Paxlovid and the safety is better

With the introduction of new epidemic prevention policies, more and more people have zero contact
with the new crown.
People's symptoms are severe or mild, but almost all of them have the experience of rushing to buy drugs and materials such as ibuprofen, antigen tests, canned yellow peaches, etc.
, and Paxlovid, known as the "new crown special drug", has even speculated on some channels at sky-high prices and is difficult to find
.
This also reflects the huge demand for new crown treatment drugs
.

Pfizer-developed nematevir-ritonavir (trade name: Paxlovid) has received emergency use authorization
for the treatment of Covid-19 in several countries and regions.
But the supply is far below demand, so more treatments
need to be developed.
VV116, jointly developed by Junshi Biologics and a number of others, is an oral antiviral drug with strong activity against SARS-CoV-2 and is a small molecule inhibitor
of RNA replicase of the new coronavirus.
At the same time, this is also the first clinical trial
of a new crown innovative drug independently developed in China published by the global authoritative journal New England Journal of Medicine (NEJM).

Led by Professor Zhao Ren and Academician Ning Guang of Shanghai Ruijin Hospital and Professor Gao Yuan of Shanghai Renji Hospital, the first domestic oral antiviral drug "head-to-head" non-inferiority phase 3 clinical trial
for Covid-19 patients during the epidemic of the omicron variant was carried out in 7 Shanghai hospitals.
On December 28, the clinical trial was published in NEJM as VV116 versus Nirmatrelvir–Ritonavir for Oral Treatment of Covid-19
.
The results showed that for adult patients with mild to moderate Covid-19 with high-risk factors, domestic VV116 was not inferior to Paxlovid in terms of duration of clinical recovery (4 versus 5 days; Risk ratio, 1.
17; 95% confidence interval, 1.
02~1.
36), and fewer
adverse events.

Researchers conducted a phase 3 randomized clinical trial
with non-inferiority and blinding of observers during the outbreak.
Symptomatic adults with mild to moderate Covid-19 at high risk of progression were randomly assigned to receive a 5-day course
of VV116 or nirmatvir-ritonavir.
The primary endpoint was time to sustained clinical recovery by day 28
.
"Sustained clinical recovery" is defined as the reduction of all Covid-19-related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, higher scores indicate more severe; The total score for 11 indicators for 2 consecutive days ranges from 0 to 33).

The experiment flowchart is shown in the figure below
.

Illustration: Screening, randomization and follow-up
of clinical trials.
Participants were recruited from seven research centers in Shanghai, China, between 4 April and 2 May 2022, when the B.
1.
1.
529 (omicron) strain was predominantly
during the Covid-19 outbreak.
The data for the final analysis is as of August 18
, 2022.
(Source: Cao Z, et al.
2022)

In the primary analysis of the whole analysis population, 377 participants in the VV116 group and 378 participants in the nimatevir-ritonavir group experienced sustained clinical recovery
.
The hazard ratio from randomization to sustained clinical recovery time was 1.
17, indicating that VV116 was not inferior to nematevir-ritonavir
.
Demographic information and baseline statistics show that only 24.
3% have not been vaccinated against the new crown, and 92.
1% are mild
.
The primary endpoint (time to clinical symptom recovery) results are shown in the figure below, with a median symptom recovery time of 4 days in the VV116 group and 5 days
in the nematevir-ritonavir group.
Subgroup analysis by different factors was consistent with the FAS-wide analysis set (FAS) results, i.
e.
, VV116 was comparable
to nematevir-ritonavir in terms of clinical symptom recovery time.
Moreover, virological results were a secondary clinical endpoint important for evaluating antivirals, and both groups also maintained comparable levels
in terms of coronavirus (nasopharyngeal swab) conversion negative.

Illustration: Time
to sustained clinical recovery.
The lower bound of the bilateral 95% confidence interval with a hazard ratio greater than 0.
8 was considered to indicate non-inferiority (hazard ratio >1 indicates a shorter sustained clinical recovery time in participants receiving VV116 than participants receiving nimatevir-ritonavir).

(Source: Cao Z, et al.
2022)

At 28 days follow-up, participants receiving VV116 reported fewer adverse events than participants receiving nimatevir-ritonavir (67.
4% vs 77.
3%), and participants receiving VV116 reported fewer grade 3 or 4 adverse events (2.
6% vs 5.
7%), as shown in
the table below 。 The most commonly reported adverse events (≥5% of participants in either group) were dysgulose (3.
6% VV116 vs.
25.
8% nematevir-ritonavir), hypertriglyceridemia (10.
7% and 20.
9% in both groups), and hyperlipidemia (3.
1% and 9.
6%), all of which were not serious
.

Caption: Reporting of adverse events in the VV116 group and the nimatevir-ritonavir group at 28-day follow-up (Source: Cao Z, et al.
2022)

This clinical trial shows the non-inferiority and better safety of domestic new crown drugs, but it needs to be verified
in the future in the more diverse and more complex virus strains and in more heterogeneous populations.
Under the great pressure of the epidemic, researchers in Shanghai still insist on promoting high-standard new drug clinical trials, thanks to their efforts to fight the new crown!

Reference source:

Cao Z, Gao W, Bao H, et al.
VV116 versus nirmatrelvir–ritonavir for oral treatment of Covid-19.
N Engl J Med 2022 December 28.