Invivyd's VYD2311 Beats mRNA COVID-19 Vaccine on Safety in LIBERTY Phase 3, BLA Planned
核心洞察
Invivyd reported that VYD2311 met all primary and secondary endpoints in the LIBERTY Phase 3 study, with safety and tolerability clinically and statistically superior to an mRNA COVID-19 (搜索) vaccine.
TEAE rates over six days were 56.5% with VYD2311 versus 91.4% with the mRNA vaccine (P<0.0001), and systemic adverse events were 44.1% versus 68.1% (P=0.008).
Co-administration of VYD2311 with the mRNA vaccine produced no immunologic interference and raised neutralizing titers roughly 2.5-fold over vaccine alone across 56 days.
Invivyd, Inc. reported positive topline results from the LIBERTY Phase 3 study showing that its investigational COVID-directed monoclonal antibody VYD2311 has safety and tolerability that is clinically and statistically superior to an mRNA-based COVID-19 (搜索) vaccine. The randomized, double-blind, active-controlled trial also evaluated VYD2311 co-administered with the vaccine and found no immunologic interference between the two agents.
LIBERTY is a companion study to DECLARATION, the ongoing placebo-controlled pivotal trial of VYD2311 for pre-exposure prophylaxis of symptomatic COVID-19 (搜索). Invivyd said it plans to use the two studies as the basis of a Biologics License Application for VYD2311 to the U.S. Food and Drug Administration (搜索) under the Accelerated Approval Program, following a recent Type C meeting with the agency.
Trial Design and Endpoints
LIBERTY enrolled 210 healthy adults aged 18 to 49 and randomized them 1:1:1 to a single intramuscular dose of 250 mg VYD2311, COMIRNATY (COVID-19 (搜索) vaccine, mRNA), or the combination of VYD2311 and the mRNA vaccine. Both single-agent arms were blinded with a concomitant placebo injection so that every participant received two injections regardless of assignment. Placebo injections were volume-matched to either VYD2311 (2 mL) or the COVID-19 vaccine (0.5 mL).
The co-primary endpoints assessed the proportion of subjects experiencing a treatment-emergent adverse event, injection site reaction, or hypersensitivity reaction over the first six days after dosing, and the proportion experiencing a systemic adverse event solicited via an e-diary over the same period. The key secondary endpoint evaluated the proportion with a TEAE, ISR, or hypersensitivity reaction over the full 56 days of the study.
The 250 mg VYD2311 dose studied in LIBERTY is the same dose under evaluation in DECLARATION in both single and multiple-dose arms.
Safety Results
For the six-day co-primary endpoint of any TEAE, ISR, or hypersensitivity reaction, 56.5% of VYD2311 recipients experienced an event versus 91.4% of mRNA vaccine recipients (P<0.0001). In the combination arm, 78.9% experienced such an event versus 91.4% for the vaccine alone (P=0.057).
For solicited systemic adverse events at six days, 44.1% of VYD2311 recipients reported events versus 68.1% with the mRNA vaccine (P=0.008). The combination arm reported 50.0% versus 68.1% (P=0.023).
Over the full 56-day key secondary endpoint, 60.9% of VYD2311 recipients experienced a TEAE, ISR, or hypersensitivity reaction versus 91.4% with the mRNA vaccine (P<0.0001). The combination arm reported 83.1% versus 91.4% (P=0.21).
No adverse events related to VYD2311 were higher than Grade 2, and no hypersensitivity or anaphylaxis was observed with VYD2311 or in any arm of the study.
Neutralizing Titers and Combination Findings
Investigators analyzed vaccine-induced neutralizing antiviral titers to identify any immunologic interference between VYD2311 and the mRNA vaccine. VYD2311 added to the vaccine increased neutralizing titers from vaccine alone by approximately 2.5-fold over the 56-day study. To isolate the vaccine's contribution within the combination, Invivyd removed VYD2311 from combination samples; neutralizing titers from these VYD2311-depleted samples were essentially identical to those observed in the mRNA vaccine monotherapy arm, confirming a lack of immunologic interference.
VYD2311 pharmacokinetics in LIBERTY were consistent with Invivyd's expectations, though the company noted definitive demonstration is pending in DECLARATION. Combined with in vitro potency data against circulating variants, these results allow Invivyd to estimate neutralizing antiviral titers consistent with its target profile for VYD2311 under evaluation in DECLARATION.
The combination arm data suggest that dosing VYD2311 concomitantly with an mRNA COVID-19 (搜索) vaccine may improve the vaccine's safety and tolerability while adding substantially to neutralizing antiviral titers, a finding Invivyd described as a potential area of future clinical study within COVID and other disease areas.
Regulatory Pathway
Invivyd has been in ongoing dialogue with the FDA on regulatory pathways for VYD2311, including a Type C meeting in September and other discussions with FDA leadership. The company intends to submit a BLA under the Accelerated Approval Program pending results from DECLARATION.
Under that plan, Invivyd will unblind and report placebo-controlled safety and neutralizing antiviral titers from DECLARATION while keeping blinded clinical events collected to date. If the data are supportive, the company intends to pursue Accelerated Approval based on DECLARATION and LIBERTY data, along with reference to prior Invivyd monoclonal antibody data. Invivyd then plans to continue accumulating PCR-positive symptomatic COVID-19 (搜索) pooled, blinded events in a post-approval confirmatory randomized cohort to enhance statistical powering of target efficacy, defined as a 70% to 90% relative risk reduction in PCR-positive symptomatic COVID-19 versus placebo.
Invivyd said it believes the evidence base from LIBERTY and the upcoming DECLARATION safety and neutralizing titer data, if positive, combined with data from its previous randomized, placebo-controlled trials EVADE (adintrevimab) and CANOPY (pemivibart), compares favorably to the evidentiary basis routinely used to approve updated COVID vaccines, which also change compositionally to a similar extent as Invivyd monoclonal antibodies. DECLARATION topline safety and immunogenicity data to support the submission are now expected in October 2026, with clinical efficacy data planned to be unblinded post-Accelerated Approval, if granted, subject to clinical event accrual.
Executive Commentary
"We are thrilled to report on this landmark study. LIBERTY has generated the first Phase 3, randomized, blinded, controlled data we are aware of in history that compare different mechanisms for achieving immunization in vulnerable humans: the specific, highly potent investigational monoclonal antibody VYD2311, and an approved mRNA-based COVID-19 (搜索) vaccine currently in wide clinical use," said Marc Elia, Chairman and CEO of Invivyd. "The observed profile of VYD2311 in LIBERTY and measured in vitro potency data of VYD2311 against circulating variants leave us confident and looking forward to the placebo-controlled safety and immunogenicity data we expect shortly in the DECLARATION study."
Michael Mina, M.D., Ph.D., Chief Medical Officer and Chief Epidemiologist of Invivyd, said the LIBERTY data provide high confidence in the VYD2311 profile and offer an important window into its clinical profile ahead of placebo-controlled DECLARATION data. "Today's LIBERTY data alone, even before DECLARATION data, provide more robust contemporary human clinical information than the data associated with recently approved updated COVID-19 (搜索) vaccines," he said. "With regard to the combination of VYD2311 and COVID-19 vaccine, we are intrigued and gratified that the combination may enhance vaccination by reducing unwelcome vaccine-related adverse events, while simultaneously adding the substantial virus neutralizing activity of a highly active monoclonal antibody."
About VYD2311 and DECLARATION
VYD2311 is a novel monoclonal antibody candidate developed for COVID-19 (搜索) to address the need for new prophylactic and therapeutic options. Its pharmacokinetic profile and antiviral potency may allow delivery of clinically meaningful titer levels through more patient-friendly means such as intramuscular administration. The antibody was engineered using Invivyd's proprietary integrated technology platform and is the product of serial molecular evolution designed to generate an antibody optimized for neutralizing contemporary virus lineages. VYD2311 uses the same antibody backbone as pemivibart, Invivyd's investigational monoclonal antibody granted emergency use authorization in the U.S. for pre-exposure prophylaxis of symptomatic COVID-19 in certain immunocompromised patients, and adintrevimab, Invivyd's investigational monoclonal antibody with a safety data package and clinically meaningful results in global Phase 2/3 trials for COVID-19 prevention and treatment.
DECLARATION is a Phase 3, randomized, triple-blind, placebo-controlled trial evaluating VYD2311 efficacy and safety in prevention of symptomatic COVID-19 (搜索) in a broad population of adults and adolescents with and without risk factors for progression to severe disease at three months. Participants receive either a single dose or monthly doses of VYD2311 by intramuscular injection compared with placebo. Total enrollment is approximately 2,400 participants.