APEXXNAR Suspension for injection Ref.[49639] Active ingredients: Pneumococcus, purified polysaccharides antigen

Pharmacotherapeutic group: vaccines, pneumococcal vaccines
ATC code: J07AL02

Mechanism of action

Apexxnar contains 20 pneumococcal capsular polysaccharides all conjugated to a CRM197 carrier protein, which modifies the immune response to the polysaccharide from a T-cell independent response to a T-cell dependent response. The T-cell dependent response leads to both an enhanced antibody response and generation of memory B-cells, allowing for an anamnestic (booster) response on re-exposure to the bacterium.

Vaccination with Apexxnar induces serum antibody production and immunologic memory against the serotypes contained within the vaccine. In adults, the levels of circulating antibodies that correlate with protection against pneumococcal disease have not been clearly defined.

Clinical efficacy

No efficacy studies have been performed with Apexxnar.

Immunogenicity data

Apexxnar clinical trials in adults

Three Phase 3 clinical trials, B7471006, B7471007 and B7471008 (Study 1006, Study 1007, and Study 1008), were conducted in the United States and Sweden evaluating the immunogenicity of Apexxnar in different adult age groups, and in participants who were either pneumococcal vaccine-naïve, or previously vaccinated with Prevenar 13, PPSV23, or both.

Each study included participants who were healthy or immunocompetent with stable underlying conditions, including chronic cardiovascular disease, chronic pulmonary disease, renal disorders, diabetes mellitus, chronic liver disease, and medical risk conditions and behaviours (e.g., smoking) that are known to increase the risk of serious pneumococcal pneumonia and IPD. In the pivotal study (Study 1007), these risk factors were identified in 34%, 32%, and 26% of participants 60 years of age and over, 50 to 59 years of age, and 18 to 49 years of age, respectively. A stable medical condition was defined as a medical condition not requiring significant change in therapy in the previous 6 weeks (i.e., change to new therapy category due to worsening disease), or any hospitalization for worsening disease within 12 weeks before receiving the study vaccine.

In each study, immune responses elicited by Apexxnar and the control pneumococcal vaccines were measured by an opsonophagocytic activity (OPA) assay. OPA assays measure functional antibodies to S. pneumoniae.

Comparison of immune responses of Apexxnar to Prevenar 13 and PPSV23

In a randomised, active-controlled, double-blind, non-inferiority clinical trial (Pivotal Study 1007) of Apexxnar in the United States and Sweden, pneumococcal vaccine-naïve participants 18 years of age and older were enrolled into 1 of 3 cohorts based on their age at enrollment (18 to 49, 50 to 59, and ≥60 years of age), and randomised to receive Apexxnar or control. Participants 60 years of age and older were randomised in a 1:1 ratio to receive Apexxnar (n=1,507) followed 1 month later with the administration of saline placebo or Prevenar 13 (n=1,490), and with the administration of PPSV23 1 month later. Participants 18 to 49 years of age and 50 to 59 years of age were randomly assigned (3:1 ratio); they received a dose of Apexxnar (18 to 49 years of age: n=335; 50 to 59 years of age: n=334) or Prevenar 13 (18 to 49 years of age: n=112; 50 to 59 years of age: n=111).

Serotype-specific OPA geometric mean titres (GMTs) were measured before the first vaccination and 1 month after each vaccination. Non-inferiority of immune responses, OPA GMTs 1 month after vaccination, with Apexxnar to a control vaccine for a serotype was declared if the lower bound of the 2-sided 95% confidence interval (CI) for the GMT ratio (Apexxnar/Prevenar 13; Apexxnar/PPSV23) for that serotype was greater than 0.5.

In participants 60 years of age and older, the immune responses to all 13 matched serotypes elicited by Apexxnar were non-inferior to those elicited by Prevenar 13 for the same serotypes 1 month after vaccination. In general, numerically lower geometric mean titres were observed with Apexxnar in the matched serotypes compared to Prevenar 13 (Table 3), however the clinical relevance of these findings is unknown.

The immune responses induced by Apexxnar to 6/7 additional serotypes were non-inferior to those induced by PPSV23 to the same serotypes 1 month after vaccination. The response to serotype 8 missed the pre-specified statistical non-inferiority criterion (the lower bound of the 2-sided 95% CI for the GMT ratio is 0.49 instead of >0.50) (Table 3). The clinical relevance of this observation is unknown. Supportive analyses for other serotype 8 endpoints in the Apexxnar group showed favourable outcomes. These include a geometric mean fold rise (GMFR) of 22.1 from before vaccination to 1 month post-vaccination, 77.8% of participants achieved a ≥4-fold rise in OPA titres from before vaccination to 1 month after vaccination, and 92.9% of participants achieved OPA titres ≥ LLOQ 1 month after vaccination.

Table 3. OPA GMTs 1 Month After Vaccination in Participants 60 Years of Age and Older Given Apexxnar Compared to Prevenar 13 for the 13 Matched Serotypes and to PPSV23 for the 7 Additional Serotypes (Study 1007)^a,b,c,d:

Abbreviations: CI = confidence interval; GMT = geometric mean titre; LLOQ = lower limit of quantitation; N = number of participants; OPA = opsonophagocytic activity; PPSV23 = pneumococcal polysaccharide vaccine (23-valent).
^a Study 1007 was conducted in the United States and in Sweden.
^b Non-inferiority for a serotype was met if the lower bound of the 2-sided 95% CI for the GMT ratio (ratio of Apexxnar/comparator) was greater than 0.5 (2-fold criterion for non-inferiority).
^c Assay results below the LLOQ were set to 0.5 × LLOQ in the analysis.
^d Evaluable immunogenicity population.
^e GMTs and GMT ratios as well as the associated 2-sided CIs were based on analysis of log-transformed OPA titres using a regression model with vaccine group, sex, smoking status, age at vaccination in years, and baseline log transformed OPA titres.

Immunogenicity in participants 18 through 59 years of age

In Study 1007, participants 50 through 59 years of age and participants 18 through 49 years of age were randomly assigned (3:1 ratio) to receive 1 vaccination with Apexxnar or Prevenar 13. Serotype-specific OPA GMTs were measured before vaccination and 1 month after vaccination. With both vaccines, higher immune responses were observed in younger participants compared with older participants. A non-inferiority analysis of Apexxnar in the younger age group versus Apexxnar in participants 60 through 64 years of age per serotype was performed to support the indication in adults 18 through 49 years of age and 50 through 59 years of age. Non-inferiority was declared if the lower bound of the 2-sided 95% CI for the GMT ratio (Apexxnar in participants 18 through 49 years of age / 60 through 64 years of age and in 50 through 59 years of age / 60 through 64 years of age) for each of the 20 serotypes was >0.5. Apexxnar elicited immune responses to all 20 vaccine serotypes in the two of the younger age groups that were non-inferior to responses in participants 60 through 64 years of age 1 month after vaccination (Table 4).

While not planned as an active control for immunogenicity evaluations in the study, a post hoc descriptive analysis showed generally numerically lower OPA geometric mean titres 1 month after Apexxnar for the matched serotypes compared to Prevenar 13 in participants 18 through 59 years of age, however the clinical relevance of these findings is unknown.

As noted above, individuals with risk factors were included in this study. Across all the age groups studied, in general, a numerically lower immune response was observed in participants with risk factors compared to participants without risk factors. The clinical relevance of this observation is unknown.

Table 4. Comparisons of OPA GMTs 1 Month After Apexxnar in Participants 18 Through 49 or 50 Through 59 Years of Age to Participants 60 Through 64 Years of Age (Study 1007)^a,b,c,d:

Abbreviations: CI = confidence interval; GMT = geometric mean titre; LLOQ = lower limit of quantitation; N = number of participants; OPA = opsonophagocytic activity; PPSV23 = pneumococcal polysaccharide vaccine (23-valent).
^a Study 1007 was conducted in the United States and in Sweden.
^b Non-inferiority for a serotype was met if the lower bound of the 2-sided 95% CI for the GMT ratio (ratio of younger age group/60 through 64 years of age group) was greater than 0.5 (2-fold criterion for non-inferiority).
^c Assay results below the LLOQ were set to 0.5 × LLOQ in the analysis.
^d Evaluable immunogenicity population.
^e GMTs, GMT ratios, and the associated 2-sided CIs were based on analysis of log-transformed OPA titres using a regression model with age group, sex, smoking status, and baseline log transformed OPA titres. The comparisons between participants 18 through 49 years of age and participants 60 through 64 years of age and between participants 50 through 59 years of age and participants 60 through 64 years of age were based on separate regression models.

Immunogenicity of Apexxnar in adults previously vaccinated with pneumococcal vaccine

A Phase 3 randomised, open-label clinical trial (Study 1006) described immune responses to Apexxnar in participants 65 years of age and older previously vaccinated with PPSV23, with Prevenar 13, or with Prevenar 13 followed by PPSV23. Participants previously vaccinated with Prevenar 13 (Prevenar 13 only or followed by PPSV23) were enrolled at sites in the United States, whereas participants and previously vaccinated with PPSV23 only were also enrolled from Swedish sites (35.5% in that category).

Apexxnar elicited immune responses to all 20 vaccine serotypes in participants 65 years of age and older with prior pneumococcal vaccination (Table 5). Immune responses were lower in participants in both groups who received prior PPSV23 vaccinations.

Table 5. Pneumococcal OPA GMTs Before and 1 Month After Apexxnar in Participants 65 Years of Age and Older With Prior Pneumococcal Vaccination (Study 1006)^a,b,c,d:

Abbreviations: CI = confidence interval; GMT = geometric mean titre; LLOQ = lower limit of quantitation; N = number of participants; OPA = opsonophagocytic activity; PPSV23 = pneumococcal polysaccharide vaccine (23-valent).
^a Study 1006 was conducted in the United States and in Sweden.
^b Assay results below the LLOQ were set to 0.5 × LLOQ in the analysis.
^c Evaluable immunogenicity population.
^d Open-label administration of Apexxnar.
^e 2-sided CIs based on the Student t distribution.

Immune responses in special populations

Individuals with the conditions described below have an increased risk of pneumococcal disease.

Studies in HIV and bone marrow transplant participants have not been conducted with Apexxnar.

Limited experience from clinical studies with Prevenar 13 (a pneumococcal conjugate vaccine consisting of 13 polysaccharide conjugates that are also in Apexxnar) are available in adults with HIV infection, and adults following a bone marrow transplant.

Participants who were healthy, or with stable non-immunocompromising chronic medical conditions, in all the age groups analysed had a lower immune response with Apexxnar compared with Prevenar 13 in spite of meeting the predefined non-inferiority margins. The clinical relevance of this observation is unknown.

HIV infection

Adults not previously vaccinated with a pneumococcal vaccine

In Study 6115A1-3002 (B1851021), 152 HIV-infected participants 18 years of age and older (CD4 ≥200 cells/µL, viral load <50,000 copies/mL and free of active acquired immunodeficiency syndrome [AIDS]-related illness) not previously vaccinated with a pneumococcal vaccine were enrolled to receive 3 doses of Prevenar 13. As per the general recommendations, a single dose of PPSV23 was subsequently administered. The vaccines were administered at 1-month intervals. Immune responses were assessed in 131 to 137 evaluable participants approximately 1 month after each dose of the vaccine. After the first dose, Prevenar 13 elicited antibody levels, measured by immunoglobulin G (IgG) geometric mean concentrations (GMCs) and OPA GMTs, that were statistically significantly higher compared with levels prior to vaccination. After the second and third dose of Prevenar 13, immune responses were similar to or higher than those after the first dose.

Adults previously vaccinated with PPSV23

In Study 6115A1-3017 (B1851028), immune responses were assessed in 329 HIV-infected participants 18 years of age and older (CD4+ T-cell count ≥200 cells/µL and viral load <50,000 copies/mL) previously vaccinated with PPSV23 administered at least 6 months prior to enrollment. Participants received 3 doses of Prevenar 13: at enrollment, 6 months, and 12 months after the first dose of Prevenar 13. After the first vaccination, Prevenar 13 elicited antibody levels measured by IgG GMCs and OPA GMTs that were statistically significantly higher compared with levels prior to vaccination. After the second and third dose of Prevenar 13, immune responses were comparable to or higher than those after the first dose. Participants who received previously 2 or more doses of PPSV23 showed a similar immune response compared to participants who previously received a single dose.

Hematopoietic stem cell transplant (HSCT)

In Study 6115A1-3003 (B1851022), 190 participants 18 years of age and older with an allogeneic HSCT were enrolled to receive 3 doses of Prevenar 13 with an interval of at least 1 month between doses. The first dose was administered at 3 to 6 months after HSCT. A fourth (booster) dose of Prevenar 13 was administered 6 months after the third dose. As per the general recommendations, a single dose of PPSV23 was administered 1 month after the fourth dose of Prevenar 13. Immune responses as measured by IgG GMCs were assessed in 130 to 159 evaluable participants approximately 1 month after vaccination. Prevenar 13 elicited increased antibody levels after each dose. Immune responses after the fourth dose of Prevenar 13 were significantly increased for all serotypes compared with those after the third dose.

This study demonstrated that 4 doses of Prevenar 13 elicited serum IgG concentrations similar to those induced by a single dose in healthy participants of the same age group.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Apexxnar in one or more subsets of the paediatric population for the condition of prevention of disease caused by Streptococcus pneumoniae (see section 4.2 for information on paediatric use).