WHO prioritizing Gilead’s remdesivir, designing master protocol for 2019-nCoV outbreak

WHO plans to establish master protocol for 2019-nCoV outbreak

Gilead’s remdesivir is the most promising candidate for treating 2019-nCoV acute respiratory disease, according to a draft report of WHO’s R&D Blueprint Clinical Trials expert group.

The group agreed in principle to design a randomized, controlled master protocol that can compare multiple investigational therapies in parallel.

The report, circulated to the group on Jan. 29, states: “Among the different therapeutic options, Remdesivir was considered the most promising candidate based on the broad antiviral spectrum, the in vitro and in vivo data available for coronaviruses and the extensive clinical safety database (in particular coming from the Ebola virus disease clinical trial and MEURI) in eastern Congo).” MEURI is Monitored Emergency Use of Unregistered and Investigational Interventions.

The report states that in studies conducted in mice, “Remdesivir showed superior efficacy” over the combination of the protease inhibitor Kaletra lopinavir/ritonavir from AbbVie Inc. (NYSE:ABBV) and IFNβ.

Gilead Sciences Inc. (NASDAQ:GILD) plans to begin enrolling 2019-nCoV patients in two Chinese trials in mid-February. The company said on its earnings call Tuesday that it is “investing pretty heavily” in manufacturing of the therapy “to make sure we’re prepared as best as we can” (see “Gilead Prepares for Chinese Trials Of Antiviral After Treating U.S. Patient”; "Gilead Working 'Night and Day' on Coronavirus Response").

The WHO group decided the HIV protease inhibitors, lopinavir and ritonavir, either alone or in combination with IFNβ1b, is a “suitable second option for rapid implementation in clinical trials.” Preclinical data and limited clinical experience in treating MERS, another coronavirus, suggest that the protease inhibitors “could provide some degree of clinical benefit and would be worth investigating particularly in severe cases.” It noted that a protocol assessing lopinavir/ritonavir as monotherapy is under way in China.

It is not likely that monoclonal and polyclonal antibodies under development to treat MERS will be effective against 2019-nCoV, the group concluded. It does recommend, however, the exploration and possible development of immunotherapies targeted specifically at 2019-nCoV. “Monoclonal antibodies could be promising and kept in view, but the focus currently should be on candidates that could be evaluated immediately.”

The report states that the use of convalescent sera -- serum obtained from individuals who have recovered from a 2019-nCoV infection -- “could also be an option for consideration, but it remains to be defined if sufficient amounts of sera with high antibodies titres could be feasibly collected, using concentration and purification processes.”

The group also identified products that should not be prioritized for treating 2019-nCoV, including ribavirin, immunosuppressants and immunostimulators such as corticosteroids and steroids, and chloroquine.

Master protocol

There is “strong agreement” among expert group members that a master protocol should be designed to evaluate potential 2019-nCoV therapies.

The group agreed that the master protocol should be a randomized, multicenter, multi-arm trial that can accommodate the drugs prioritized by the WHO’s Working Group on Treatment Prioritization.

The 2019-nCoV master protocol “should be initiated as soon as possible with a pilot phase designed to learn more on the natural history of the disease,” the draft report stated.

The primary endpoint for the master protocol, according to the expert group, should be a composite endpoint of “mortality and clinical improvement” from the time of first dose in eligible and consenting participants. Therapies that show a significant effect on either mortality or clinical improvement would be deemed successful.

Inclusion criteria should allow participation in the master protocol of all hospitalized, symptomatic patients with confirmed 2019-nCoV, the expert group recommended.

It also suggested that a separate study could be conducted of hospitalized, asymptomatic patients “for drugs with reasonable safety profile and sufficient availability to assess their effect on clinical progression and virologic outcomes, such as viral shedding.”

The comparator arm for the master protocol should be standard of care, “particularly if the standard of care can be optimized and harmonized across sites,” the expert group stated.

WHO plans to establish a Working Group on Protocol Writing to formulate a master protocol.

Other steps for research, innovation

In a draft Strategic Preparedness and Response Plan released on Feb. 3, WHO outlined other steps the global research community should take to address the 2019-nCoV outbreak.

The plan calls for the international community to agree on “common standards for clinical trials, specimen sharing, and data sharing during this and other outbreaks.”

WHO said it is “bringing together stakeholders to agree on standardized protocols for biological sampling, sample storage, shipment and transport, testing, record taking and data entry. Shared platforms will include common repositories for data, research outcomes and findings, and dissemination strategies will be put in place to enable the sharing of preliminary research findings and data.”

Further analysis of the coronavirus crisis can be found at https://www.biocentury.com/coronavirus. The 2019-nCoV content is free to all who visit the site.

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