Junshi’s COVID Antiviral Superior To Paxlovid?
Unexpected protocol changes and a single-blind design for a Phase III head-to-head trial seem to have played to the advantage of Junshi’s oral derivative of Gilead’s antiviral remdesivir in COVID-19.
Mounting concerns over protocol changes and trial design have shrouded Shanghai Junshi Biosciences Co., Ltd.’s claim of superiority for its COVID-19 oral antiviral VV116 over Pfizer Inc.’s Paxlovid (nirmatrelvir plus ritonavir).
On 25 May, the Hong Kong- and Shanghai-listed Chinese biotech reported positive outcomes from a Phase III registrational head-to-head study versus Paxlovid in China for the early treatment of mild-to-moderate COVID-19. The trial was conducted in patients at high risk of progression to severe disease including death.
The announcement came only three months after Paxlovid was authorized in China for conditional emergency use for the treatment of mild-to-moderate disease in adults.
VV116 is an oral derivative of the RNA-dependent RNA polymerase inhibitor remdesivir, originally developed by Gilead Sciences, Inc. and marketed as Veklury in injection form. VV116 was originally developed by Suzhou, China-based Vigonvita Life Sciences Co., Ltd and Junshi gained rights in October 2021 for territories worldwide excluding Central Asia, Russia, North Africa and the Middle East.
The 822-patient study reached its pre-specified primary endpoint and secondary efficacy endpoint, Junshi said on 25 May, adding that the results showed that VV116 provided patients with a shorter median time to sustained clinical recovery (up to day 28) versus Paxlovid, achieving statistical superiority.
However, the Chinese firm relegated the other primary endpoint in the original study protocol - percentage of subjects progressing to severe or critical COVID-19 or all-cause death as of day 28 - to one of the secondary endpoints, raising concerns among investors.
With all the enrolment having taken place in Shanghai during a spike in new cases of the Omicron variant, “we expect in both arms of the trial the rate of disease progression or death would be quite low, making it practically impossible to make a conclusion of non-inferiority in a finite sample size,” cautioned Credit Suisse in a 25 May research note, quoting what Junshi had shared with the brokerage.
The Shanghai-based bioventure noted that Paxlovid’s EPIC-HR trial enrolled only patients without immunization against COVID-19, while VV116’s head-to-head trial enrolled vaccinated patients.
“Though we believe changing primary endpoint in a running Phase III trial is not a good practice, we still believe it makes sense to change one of the co-primary endpoints of disease progression or death to a secondary endpoint, which also avoids wasting alpha,” the company explained, as quoted in the Credit Suisse note.
The biotech’s surprise manoeuvre seems to have paid off, as it revealed in its press release that no COVID-19 disease progression or death were reported in the VV116 or Paxlovid arm in the head-to-head study.
As to the secondary efficacy endpoints, VV116 showed a trend toward superiority over Paxlovid in time to sustained disappearance of clinical symptoms and the time to patients testing negative for SARS-CoV-2 for the first time.
The single-blind design of the trial also appeared to be unconvincing to investors, as it only concealed the distribution of VV116 and Paxlovid to both the investigators (including the endpoint evaluator) and Junshi.
The adoption of the design was aimed to quickly complete patient enrolment, the company explained to the Credit Suisse analysts. Had the trial been double-blinded, Junshi would have had to make VV116 and Paxlovid look the same, which could have required months of manufacturing and quality control work and consequently may have substantially delayed patient enrolment.
Additionally, Junshi said in its release that the oral antiviral has a good safety profile, with an overall adverse event occurrence lower than for Paxlovid. Further detailed numerical findings will be published later in a medical journal later, the biotech added, which may throw further light on the findings.
Apart from the head-to-head trial, Junshi has also enrolled the first patients in two separate international Phase III trials of VV116 versus standard of care, in patient groups with mild-to-moderate and moderate-to-severe infections, respectively.
Due to a recent surge in Omicron cases in China, enrolment in both groups has “achieved relatively rapid progress,” Ning Li, Junshi’s general manager, said during a 22 April online investor event.
Simcere And Others
Besides Junshi, an increasing number of Chinese biotechs have joined the race to develop me-too drugs of Paxlovid.
On 10 April, Hong Kong-listed Simcere Pharmaceutical Group kick-started a Phase I study of SIM0417, its same-class candidate, after striking a co-development deal with Shanghai Institute of Materia Medica in November 2011. The molecule is China’s first home-grown oral 3CL protease inhibitor for COVID-19 to move into the clinical stage.
Guangzhou-based Guangdong Raynovent Biotech announced on 23 May that it had completed the first patient enrolment in a placebo-controlled Phase I trial with its 3CL protease inhibitor RAY1216 in healthy subjects.
Similarly, Hong Kong-listed Ascletis Pharma, Inc. is expected to file an investigational new drug application for ASC11 in the second half of 2022, with the Phase I trial in healthy subjects due to be completed by the end of 2022, the company said in a stock market disclosure on 19 April.
Junshi also has another oral antiviral candidate, VV993, in the 3CL protease inhibitor class, which is still in preclinical development without a timeline for moving in the clinic at present.