Why Vir, Brii believe their mAbs may succeed where others have failed
NIH testing mAbs from Vir, Brii in hospitalized COVID-19 patients
NIH is testing mAbs from Vir and Brii in hospitalized COVID-19 patients.
NIH has added two investigational mAb therapies to its ACTIV-3 Phase III master protocol of hospitalized COVID-19 patients, hoping to succeed in a setting where two other mAbs failed.
Headlines about record-breaking death statistics in the U.S., as well as widespread failure to deploy mAbs that have been authorized for outpatient use, point to the urgent need for safe, effective treatments that can save the lives of hospitalized COVID-19 patients.
The two new ACTIV-3 arms will test VIR-7831, a mAb that Vir Biotechnology Inc. (NASDAQ:VIR) is developing in partnership with GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), and a cocktail that combines BRII-196 and BRII-198, two mAbs from Brii Biosciences.
Vir and Brii, which have been shunned by the Trump administration’s Operation Warp Speed over their ties to China, believe their mAbs can succeed despite the failure of mAbs from Regeneron Pharmaceuticals Inc. (NASDAQ:REGN) and Eli Lilly and Co. (NYSE:LLY) in the hospital setting.
In October, ACTIV-3 halted a sub-study of bamlanivimab from Lilly and AbCellera Biologics Inc. (NASDAQ:ABCL) based on a DSMB finding that it was unlikely to help hospitalized patients. Regeneron also halted a study of its casirivimab/imdevimab mAb cocktail in hospitalized patients in October based on a determination by a DSMB that they may cause more harm than benefit.
FDA has granted emergency use authorizations for the two products in the outpatient setting, but predictions of a slow uptake have so far proven correct as governments and healthcare systems have failed to create effective systems for administering them.
Challenges include identifying locations where infusions of COVID-19-positive patients can be safely administered, as well as identifying patients and arranging for them to travel to an infusion center within days of their diagnosis.
Only 5-20% of the mAbs distributed have been administered, Operation Warp Speed’s scientific adviser Moncef Slaoui told CNBC television Dec. 16. An HHS spokesperson confirmed the figures and told BioCentury that “Operation Warp Speed looks forward to working with healthcare systems to increase utilization of this therapeutic.”
Patients in the ACTIV-3 mAb sub-studies will be randomized to a placebo arm, VIR-7831 or the Brii combination.
The trial will start by enrolling about 450 hospitalized volunteers with mild-to-moderate COVID-19 with fewer than 13 days of symptoms.
Efficacy will be assessed after five days of treatment based on a composite endpoint consisting of two seven-point ordinal scales, each ranging from being able to undertake usual activities with minimal or no symptoms, to death.
Following an assessment of results from the initial cohort, expected in January, the trial could be expanded to include an additional 1,050 participants.
The second group of patients “may include participants with more severe illness, so that researchers can evaluate the primary endpoint of sustained recovery,” NIH’s National Institute of Allergy and Infectious Diseases reported. “Participants will have met this endpoint when they have been discharged from the hospital and lived at home for 14 consecutive days, prior to 90 days of follow-up. “
Vir is developing VIR-7831 in partnership with GSK.
“VIR-7831, which has a high barrier to resistance and has the potential to neutralize the virus and kill infected cells, could allow this treatment to be effective for patients in hospital settings, where other antibodies have so far not shown an impact,” Hal Barron, CSO and president of R&D at GSK, told BioCentury.
The company “has properties that conceivably could make it more effective in hospitalized patients” than the Lilly-AbCellera and Regeneron mAbs, George Scangos, president and CEO of Vir, told BioCentury. “Everybody with antibodies talks about neutralization potential. That’s table stakes, an antibody has to have that, but some antibodies can do other things.”
Vir is developing a single mAB derived from a SARS patient, in part because it believes an antibody that is conserved between SARS and SARS-CoV-2 is more likely to remain effective if the virus mutates, Scangos said.
The Fc domain of VIR-7831 was engineered, using Xencor’s Xtend Fc technology, to have an extended half-life via stronger binding to FcRn. Through FcRn, the mAb can also recruit NK cells and macrophages to activate the killing of infected cells, while protecting uninfected cells.
Another difference, Scangos said, is that while other COVID-19 mAbs bind to the receptor binding motif, “ours binds to a different epitope that is more difficult to mutate.” This difference could reduce the number of resistant mutations.
“In a hospitalized patient, the viral titers are high, there are many infected cells, and having an antibody that can not only block infection of new cells but also kill infected cells potentially has an advantage,” Scangos said. “That’s one of the key differentiators for our antibody.”
ACTIV-3 is testing a 500 mg dose of VIR-7831, and Vir is testing the same dose in the outpatient setting in its COMET-ICE study.
The dose is substantially lower than those Lilly and Regeneron have tested and that FDA authorized.
“Our interpretation of the data is that Lilly and Regeneron over-dosed — that in an abundance of caution, they tested very high doses and those high doses are probably not needed,” Scangos told BioCentury.
While both studies of VIR-7831 are administering the mAb through an IV infusion, the 500 mg dose could be delivered in an IM injection, Scangos said. This would reduce many of the barriers that have limited deployment of the Lilly and Regeneron outpatient COVID-19 mAbs.
Vir and GSK have lined up capacity to manufacture about two million doses of Vir-7831 in 2021, more in 2022, and is “constantly working to see if we can increase capacity,” Scangos said.
Brii’s mAb cocktail
The journey to BRII-196 and BRII-198 started in January at Shenzhen 3rd People’s Hospital where researchers worked with colleagues at Tsinghua University to isolate hundreds of antibodies from COVID-19 patients.
Brii characterized two non-competing antibodies from the collection. It started with a combination because “we knew that you need a cocktail to provide better efficacy and more importantly, delay the development of resistance,” Zhi Hong, president and CEO of Brii, told BioCentury.
In addition, Hong said he was concerned about the potential for a mAb to cause antibody-dependent enhancement (ADE).
To minimize the potential for ADE and extend its mAbs’ half-life, Brii modified the Fc region of its two COVID-19 mAb candidates.
Hong said that Brii has designed two molecules in what it believes is a “balanced approach” that comprises a “very potent” antibody that interferes with the life cycle of SARS-CoV-2 and modifies any potential immune enhancement to minimize the potential harm, Hong said.
Brii’s cocktail consists of 1,000 mg of each mAb.
The company has reserved capacity to make 400,000 doses through June 2021. If its product is approved, Brii could produce 1 million doses per year, Hong said.
In addition to the ACTIV-3 study in hospitalized patients, Brii said it is preparing to study the BRII-196 and BRII-198 combination in non-hospitalized COVID-19 patients who are at high risk of disease progression.
The company declined to provide details of the planned outpatient study, but it could be added to NIH’s ACTIV-2 trial, a Phase II/III master protocol that is studying Lilly’s bamlanivimab as a treatment for non-hospitalized patients with mild to moderate COVID-19.
Brii has also submitted an IND for the BRII-196 and BRII-198 combination to the Department of Health in Hong Kong to study the cocktail in Asian populations with COVID-19. That study is expected to begin in early 2021, the company said.