KAVIGALE Solution for injection/infusion Ref.[114761] Active ingredients: Sipavibart

Pharmacotherapeutic group: Immune sera and immunoglobulins, antiviral monoclonal antibodies
ATC code: J06BD09

Mechanism of action

Sipavibart is a recombinant human IgG1 monoclonal antibody that provides passive immunisation by binding the SARS-CoV-2 spike protein receptor binding domain (RBD). Sipavibart is long-acting, with amino acid substitutions to extend antibody half-life (YTE) and to reduce antibody effector function and potential risk of antibody-dependent enhancement of disease (TM). Sipavibart binds to the spike protein RBD of SARS-CoV-2 (BA.2) with equilibrium dissociation constant of KD = 20.95 pM, blocking RBD binding to the human ACE2 receptor. This results in a blockade of virus entry.

Antiviral activity

In a SARS-CoV-2 pseudovirus neutralisation assay, sipavibart had antiviral activity through direct neutralisation.

Antiviral resistance

Evaluation of neutralisation susceptibility of variants identified through global surveillance and in participants who received sipavibart is ongoing.

Neutralisation activity of sipavibart against pseudovirus SARS-CoV-2 variants are shown in Table 2.

Table 2. Sipavibart pseudovirus neutralisation data against SARS-CoV-2 variants:

^a Range of reduced in vitro potency across multiple sets of co-occurring substitutions and/or testing labs using research-grade assays; mean fold change in half maximal inhibitory concentration (IC₅₀) of monoclonal antibody required for a 50% reduction in infection compared to ancestral reference strain (Wuhan D614G).
^b Pseudoviruses expressing the entire SARS-CoV-2 spike variant protein and individual characteristic spike substitutions.
^c Sipavibart is not deemed active against this variant.
^d BA.2.86 includes BA.2.86, BA.2.86.1, JN.2, and JN.3, which have the same SARS-CoV-2 spike protein sequence.
^e Presumed IC₅₀ based on presence of F456L mutation in the variant.

Immunogenicity

Treatment-emergent anti-drug antibodies (ADA) were uncommonly (0.8% (5/604)) detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed. However, data are still limited.

Clinical efficacy

SUPERNOVA parent study, main cohort

The SUPERNOVA parent study, main cohort is a Phase III, randomised (1:1), double-blind, comparator-controlled clinical trial studying sipavibart for the pre-exposure prophylaxis of COVID-19 in immunocompromised adults and adolescents ≥ 12 years of age. This study started in March 2023 and the primary analysis is dated March 2024 during a period in which mixed variants, including both susceptible and non-susceptible variants, were circulating.

A total of 1 669 adults and adolescents ≥12 years of age and weighing at least 40 kg were randomised to receive a single dose of sipavibart 300 mg via intramuscular injection, and 1 666 were randomised to receive a comparator (tixagevimab 300 mg + cilgavimab 300 mg or placebo). Participants received a second dose of sipavibart 300 mg or placebo 6 months after the initial dose. The study excluded participants who received COVID-19 vaccine or those with a history of laboratory-confirmed or rapid-test confirmed SARS-CoV-2 infection within 3 months prior to the first visit. At interim analysis, the median follow-up time post-second dose was 61 days (range 1 to 180 days).

The baseline demographics were balanced across the sipavibart and comparator treatment arms. The median age was 60 years [36.3% 65 years of age or older, 15 participants 12 years to less than 18 years (including 8 who received sipavibart)], 56.8% of participants were female, 74.1% were Caucasian, 6.5% were Asian, 12.1% were Black/African American, and 21.5% were Hispanic/Latino. All participants had at least one immunocompromising clinical condition, including but not limited to:

• taking immunosuppressive medication (74.3%)
• haematologic malignancy (15.3%)
• moderate/severe secondary immunodeficiencies (predominantly haemodialysis) (15.1%)
• solid organ transplant (14.2%)
• within one year of receiving B-cell depleting therapies (13.3%)
• solid tumour cancer and on treatment (3.4%)
• haematopoietic stem-cell transplantation (2.0%)
• moderate/severe primary immunodeficiencies (1.6%)
• advanced or untreated HIV infection (1.1%), and
• received chimeric antigen receptor T-cell therapy (0.3%)

The study included dual primary efficacy endpoints, comparing the efficacy of sipavibart to a comparator in the prevention of symptomatic COVID-19 (1) caused by any SARS-CoV-2 variant up to 181 days post last dose confirmed by RT-PCR and (2) attributable to matched variants (variants that do not contain the F456L mutation based on viral sequencing data and are expected to be susceptible to sipavibart) up to 181 days post last dose confirmed by RT-PCR. For each of the dual primary endpoints, a superiority test was performed to compare the relative risk of symptomatic COVID-19 between treatment arms.

Relative risk reduction where events were counted regardless of receipt of COVID-19 vaccinations/medicinal products or unblinding is presented in Table 3.

Table 3. Relative risk reduction of symptomatic COVID-19:

CI = Confidence Interval, N = number of participants in the analysis.
^a The comparator was either tixagevimab + cilgavimab or placebo.
^b Not multiplicity controlled.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with sipavibart in one or more subset of the paediatric population in the pre-exposure prophylaxis of COVID-19 (see section 4.2 for information on paediatric use).