Vaccine Information: Trumenba (Page 2 of 3)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Trumenba. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

Immune System Disorders: Hypersensitivity reactions, including anaphylactic reactions.

Nervous system disorder: Syncope (fainting).

7 DRUG INTERACTIONS

In clinical trials, Trumenba was administered concomitantly with HPV4 in adolescents 11 through 17 years of age and with MenACWY and Tdap in adolescents 10 through 12 years of age [see Clinical Studies (14) and Adverse Reactions (6)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There are no adequate and well-controlled studies of Trumenba in pregnant women. Available human data on Trumenba administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

Two developmental toxicity studies were performed in female rabbits administered Trumenba prior to mating and during gestation. The dose was 0.5 mL at each occasion (a single human dose is 0.5 mL). These studies revealed no evidence of harm to the fetus or offspring (until weaning) due to Trumenba [see Animal Data].

Animal Data

Two developmental toxicity studies were performed in female rabbits. Animals were administered Trumenba by intramuscular injection 17 days and 4 days prior to mating and on gestation Days 10 and 24. The dose was 0.5 mL at each occasion (a single human dose is 0.5 mL). No adverse effects on pre-weaning development up to post-natal day 21 were observed. There were no fetal malformations or variations observed due to the vaccine.

8.2 Lactation

Risk Summary

Available data are not sufficient to assess the effects of Trumenba on the breastfed infant or on milk production/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Trumenba and any potential adverse effects on the breastfed child from Trumenba or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

Safety and effectiveness have not been established in children <10 years of age. In a clinical study, 90% of infants <12 months of age who were vaccinated with a reduced dosage formulation had fever.

8.5 Geriatric Use

Safety and effectiveness of Trumenba in adults >65 years of age have not been established.

11 DESCRIPTION

Trumenba is a sterile suspension composed of two recombinant lipidated factor H binding protein (fHbp) variants from N. meningitidis serogroup B, one from fHbp subfamily A and one from subfamily B (A05 and B01, respectively).¹ The proteins are individually produced in E. coli. Production strains are grown in defined fermentation growth media to a specific density. The recombinant proteins are extracted from the production strains and purified through a series of column chromatography steps. Polysorbate 80 (PS80) is added to the drug substances and is present in the final drug product.

Each 0.5 mL dose contains 60 micrograms of each fHbp variant (total of 120 micrograms of protein), 0.018 mg of PS80 and 0.25 mg of Al ³⁺ as AlPO₄ in 10 mM histidine buffered saline at pH 6.0.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Protection against invasive meningococcal disease is conferred mainly by complement-mediated antibody-dependent killing of N. meningitidis. The effectiveness of Trumenba was assessed by measuring serum bactericidal activity using human complement (hSBA).

fHbp is one of many proteins found on the surface of meningococci and contributes to the ability of the bacterium to avoid host defenses. fHbps can be categorized into two immunologically distinct subfamilies, A and B.¹ The susceptibility of serogroup B meningococci to complement-mediated antibody-dependent killing following vaccination with Trumenba is dependent on both the antigenic similarity of the bacterial and vaccine fHbps, as well as the amount of fHbp expressed on the surface of the invading meningococci.

13 NONCLINICAL TOXICOLOGY

Trumenba has not been evaluated for carcinogenic or mutagenic potential or impairment of fertility in males. Vaccination of female rabbits with Trumenba had no effect on fertility [see Pregnancy (8.1)].

14 CLINICAL STUDIES

The immunogenicity of Trumenba described in this section is based on results from four clinical studies:

•

Following the two-dose schedule (0 and 6 months) in subjects 10 through 25 years of age in the U.S. and Europe (Study 1057);

•

Following the three-dose schedule (0, 2, and 6 months) in subjects 10 through 25 years of age in the U.S., Canada, and Europe (Studies 1009 and 1016); and

•

Following the two-dose (0 and 6 months) and three-dose schedules (0, 1–2, and 6 months) in subjects 11 through 18 years of age in Europe (Study 1012).

Serum bactericidal antibodies were measured with hSBA assays that used each of four meningococcal serogroup B strains. These four primary test strains express fHbp variants representing the two subfamilies (A and B) of meningococcal serogroup B strains causing invasive disease in the U.S. and Europe. The studies assessed the proportions of subjects with a 4-fold or greater increase in hSBA titer for each of the four primary strains. The studies also assessed the composite response to the four primary strains combined (proportion of subjects who achieved a hSBA titer greater than or equal to 1:8 [three strains] and 1:16 [one strain]). To assess the effectiveness of the two- and three-dose schedules of Trumenba against diverse meningococcal serogroup B strains, the proportion of subjects achieving a defined hSBA titer (≥LLOQ) following completion of the two- or three-dose series was evaluated against a panel of 10 additional strains, each expressing a different fHbp variant.

14.1 Immunogenicity

The hSBA responses to each of the primary strains observed after the second dose of Trumenba in Study 1057 are presented in Table 7.

Table 7: Percentages of Subjects 10 through 25 Years of Age With ≥4-fold Rise in hSBA Titer and Composite Response Following Administration of Trumenba on a 0-and 6-Month Schedule for Four Primary Strains (Study 1057)*^, †

fHbp Variant ‡		N §	% (95% CI) ¶
Abbreviations: CI=confidence interval; fHbp=factor H binding protein; hSBA=serum bactericidal assay using human complement; LLOQ=lower limit of quantitation; LOD=limit of detection.Note: LLOQ = 1:16 for A22; 1:8 for A56, B24, and B44.Note: The 4-fold increase is defined as follows: (1) For subjects with a baseline hSBA titer <1:4, a response is defined as an hSBA titer ≥1:16. (2) For subjects with a baseline hSBA titer ≥ LOD and < LLOQ, a response is defined as an hSBA titer ≥4 times the LLOQ. (3) For subjects with a baseline hSBA titer ≥ LLOQ, a response is defined as an hSBA titer ≥4 times the baseline titer.Note: Pre-specified criteria for assessment of hSBA responses (4-fold rise in titer to each primary test strain, and titer above LLOQ for all four primary test strains) among subjects in the U.S. and Europe were met in this study for all test strains except strain A22. Pre-specified criteria for the lower bound of the 95% CI for 4-fold rise in titer were set at 75%, 85%, 55%, and 60%, respectively, for A22, A56, B24, and B44, and 65% for the composite hSBA response for all four primary test strains.
* Evaluable immunogenicity population. † Study 1057: NCT03135834. ‡ For the second dose, serum was obtained approximately 1 month after vaccination. § For ≥ 4-fold increase, N=number of subjects with valid and determinate hSBA titers for the given strain at both the specified time point and baseline. For composite hSBA response, N=number of subjects with valid and determinate hSBA results on all 4 strains at the given time point. U.S. subjects constituted approximately 80% of the total subjects evaluated for immunogenicity. ¶ Exact 2-sided confidence interval (Clopper-Pearson method) based upon the observed proportion of subjects. # Composite response = hSBA ≥ LLOQ for all 4 primary meningococcal B strains.
≥4-Fold Increase
PMB80 (A22)	Dose 2	827	73.8(70.6, 76.7)
PMB2001 (A56)	Dose 2	823	95.0(93.3, 96.4)
PMB2948 (B24)	Dose 2	835	67.4(64.1, 70.6)
PMB2707 (B44)	Dose 2	850	86.4(83.9, 88.6)
Composite hSBA Response #
	Before Dose 1	799	1.8(1.0, 2.9)
	Dose 2	814	74.3(71.2, 77.3)

The hSBA responses after the second dose of Trumenba in Study 1057 against a panel of 10 additional strains representing the diversity of meningococcal fHbp types prevalent among strains circulating in the US are presented in Table 8.

Table 8. Percentages of Subjects 10 through 25 Years of Age With a hSBA Titer ≥ LLOQ Against 10 Additional Strains Following Administration of Trumenba on a 0- and 6-Month Schedule (Study 1057)*^, †

fHbp Variant ‡		N §	% (95% CI) ¶
Abbreviations: CI=confidence interval; fHbp=factor H binding protein; hSBA=serum bactericidal assay using human complement; LLOQ=lower limit of quantitation.Note: LLOQ = 1:16 for A06, A12, and A19; 1:8 for A07, A15, A29, B03, B09, B15, and B16.
* The evaluable immunogenicity population was used for the analysis. † Study 1057: NCT03135834. ‡ For the second dose, serum was obtained approximately 1 month after vaccination. § N=number of subjects with valid and determinate hSBA titers for the given strain. U.S. subjects constituted approximately 80% of the total subjects evaluated for immunogenicity. ¶ Exact 2-sided confidence interval (Clopper and Pearson) based upon the observed proportion of subjects.
PMB3175 (A29)	Before Dose 1	166	4.8(2.1, 9.3)
	Dose 2	166	95.2(90.7, 97.9)
PMB3010 (A06)	Before Dose 1	157	5.7(2.7, 10.6)
	Dose 2	159	89.3(83.4, 93.6)
PMB3040 (A07)	Before Dose 1	150	32.0(24.6, 40.1)
	Dose 2	157	96.8(92.7, 99.0)
PMB824 (A12)	Before Dose 1	154	5.2(2.3, 10.0)
	Dose 2	157	83.4(76.7, 88.9)
PMB1672 (A15)	Before Dose 1	166	22.9(16.7, 30.0)
	Dose 2	165	89.1(83.3, 93.4)
PMB1989 (A19)	Before Dose 1	167	5.4(2.5, 10.0)
	Dose 2	167	90.4(84.9, 94.4)
PMB1256 (B03)	Before Dose 1	172	3.5(1.3, 7.4)
	Dose 2	164	74.4(67.0, 80.9)
PMB866 (B09)	Before Dose 1	171	9.9(5.9, 15.4)
	Dose 2	166	71.1(63.6, 77.8)
PMB431 (B15)	Before Dose 1	172	6.4(3.2, 11.2)
	Dose 2	167	85.0(78.7, 90.1)
PMB648 (B16)	Before Dose 1	172	8.1(4.5, 13.3)
	Dose 2	164	77.4(70.3, 83.6)

The hSBA responses to each of the primary strains observed in U.S. subjects after the third dose of Trumenba are presented for Study 1009 and Study 1016 in Table 9.

Table 9: Percentages of U.S. Subjects 10 through 25 Years of Age With ≥4-fold Rise in hSBA Titer and Composite Response Following Administration of Trumenba on a 0-, 2-, and 6-Month Schedule for Four Primary Strains (Studies 1009 and 1016)*^, †^, ‡^, §

		Study 1009		Study 1016
		(10 through 18 Years of Age)		(18 through 25 Years of Age)
		N ¶	% (95% CI) #	N ¶	% (95% CI) #
fHbp Variant Þ
Abbreviations: CI=confidence interval; fHbp=factor H binding protein; hSBA=serum bactericidal assay using human complement; LLOQ=lower limit of quantitation; LOD=limit of detection.
Note: LLOQ = 1:16 for A22; 1:8 for A56, B24, and B44.
Note: The 4-fold increase is defined as follows: (1) For subjects with a baseline hSBA titer <1:4, a response is defined as an hSBA titer ≥1:16. (2) For subjects with a baseline hSBA titer ≥ LOD and < LLOQ, a response is defined as an hSBA titer ≥4 times the LLOQ. (3) For subjects with a baseline hSBA titer ≥ LLOQ, a response is defined as an hSBA titer ≥4 times the baseline titer.
Note: Pre-specified criteria for assessment of hSBA responses (4-fold rise in titer to each primary test strain, and titer above LLOQ for all four primary test strains) among U.S. subjects were met in these studies. For Study 1009 pre-specified criteria for the lower bound of the 95% CI for 4-fold rise in titer were set at 75%, 85%, 65%, and 60%, respectively, for A22, A56, B24 and B44, and 75% for the composite hSBA response for all four primary test strains. For Study 1016 pre-specified criteria for the lower bound of the 95% CI for 4-fold rise in titer were set at 55%, 85%, 50%, and 60%, respectively, for A22, A56, B24, and B44, and 60% for the composite hSBA response for all four primary test strains.
* Evaluable immunogenicity population. † Study 1009: NCT01830855, and Study 1016: NCT01352845. ‡ Study 1009: Group 1 (0, 2, and 6 months). § Study 1016: Group 1 (0, 2, and 6 months). ¶ For ≥ 4-fold increase, N=number of subjects with valid and determinate hSBA titers for the given strain at both the specified time point and baseline. For composite hSBA response, N=number of subjects with valid and determinate hSBA results on all 4 strains at the given time point. # Exact 2-sided confidence interval (Clopper-Pearson method) based upon the observed proportion of subjects. Þ For the third dose, serum was obtained approximately 1 month after vaccination. ß Composite response = hSBA ≥ LLOQ for all 4 primary meningococcal B strains.
≥4-Fold Increase
PMB80 (A22)	Dose 3	587	86.2(83.1, 88.9)	644	81.1(77.8, 84.0)
PMB2001 (A56)	Dose 3	526	92.0(89.4, 94.2)	621	90.7(88.1, 92.8)
PMB2948 (B24)	Dose 3	585	81.9(78.5, 84.9)	634	83.9(80.8, 86.7)
PMB2707 (B44)	Dose 3	555	88.3(85.3, 90.8)	643	79.3(76.0, 82.4)
Composite hSBA Response ß
	Before Dose 1	507	0.6(0.1, 1.7)	610	3.3(2.0, 5.0)
	Dose 3	537	85.7(82.4, 88.5)	625	82.4(79.2, 85.3)

The hSBA responses after the third dose of Trumenba against a panel of 10 additional strains representing the diversity of meningococcal fHbp types prevalent among strains circulating in the U.S. are presented for Study 1009, and Study 1016 in Table10.

Table 10. Percentages of U.S. Subjects 10 through 25 Years of Age With a hSBA Titer ≥ LLOQ Against 10 Additional Strains Following Administration of Trumenba on a 0-, 2-, and 6-Month Schedule (Study 1009 and Study 1016)*^, †

		Study 1009		Study 1016
		(10 through 18 Years of Age)		(18 through 25 Years of Age)
fHbp Variant ‡		N §	% (95% CI) ¶	N §	% (95% CI) ¶
Abbreviations: CI=confidence interval; fHbp=factor H binding protein; hSBA=serum bactericidal assay using human complement; LLOQ=lower limit of quantitation.
Note: LLOQ = 1:16 for A06, A12, and A19; 1:8 for A07, A15, A29, B03, B09, B15, and B16.
* The evaluable immunogenicity population was used for the analysis. † Study 1009: NCT01830855 and Study 1016 NCT01352845. ‡ For the third dose, serum was obtained approximately 1 month after vaccination. § N=number of subjects with valid and determinate hSBA titers for the given strain. ¶ Exact 2-sided confidence interval (Clopper and Pearson) based upon the observed proportion of subjects.
PMB3175 (A29)	Before Dose 1	169	11.2(6.9, 17.0)	160	23.8(17.4, 31.1)
	Dose 3	176	98.9(96.0, 99.9)	162	98.8(95.6, 99.9)
PMB3010 (A06)	Before Dose 1	178	7.9(4.4, 12.8)	166	10.8(6.6, 16.6)
	Dose 3	179	97.8(94.4, 99.4)	164	89.0(83.2, 93.4)
PMB3040 (A07)	Before Dose 1	170	37.6(30.3, 45.4)	165	55.8(47.8, 63.5)
	Dose 3	178	96.1(92.1, 98.4)	165	95.2(90.7, 97.9)
PMB824 (A12)	Before Dose 1	180	5.0(2.3, 9.3)	166	4.8(2.1, 9.3)
	Dose 3	180	76.1(69.2, 82.1)	165	66.7(58.9, 73.8)
PMB1672 (A15)	Before Dose 1	170	15.9(10.7, 22.3)	159	30.2(23.2, 38.0)
	Dose 3	166	86.7(80.6, 91.5)	159	89.9(84.2, 94.1)
PMB1989 (A19)	Before Dose 1	174	5.7(2.8, 10.3)	158	23.4(17.1, 30.8)
	Dose 3	173	91.9(86.8, 95.5)	163	94.5(89.8, 97.4)
PMB1256 (B03)	Before Dose 1	183	2.2(0.6, 5.5)	164	5.5(2.5, 10.2)
	Dose 3	181	92.3(87.4, 95.7)	161	84.5(77.9, 89.7)
PMB866 (B09)	Before Dose 1	180	12.2(7.8, 17.9)	165	13.9(9.0, 20.2)
	Dose 3	182	85.7(79.8, 90.5)	162	72.2(64.7, 79.0)
PMB431 (B15)	Before Dose 1	180	27.8(21.4, 34.9)	163	33.1(26.0, 40.9)
	Dose 3	183	97.3(93.7, 99.1)	163	95.7(91.4, 98.3)
PMB648 (B16)	Before Dose 1	180	6.7(3.5, 11.4)	161	11.8(7.3, 17.8)
	Dose 3	180	83.9(77.7, 88.9)	159	72.3(64.7, 79.1)

In Study 1012, Trumenba was administered according to different schedules, including Group 1 (0, 1, and 6 months), Group 2 (0, 2, and 6 months) and Group 3 (0 and 6 months). The hSBA responses observed after the second dose in Groups 1, 2, and 3 and completion of the three-dose series in Group 1 and 2 are presented in Table 11.

Table 11: Percentages of European Subjects 11 through 18 Years of Age With a ≥4-Fold Increase in hSBA Titer and Composite Response *^, † (Study 1012)

	Group 1	Group 2	Group 3
	3-Dose Schedule (0, 1, and 6 Months) ‡	3-Dose Schedule (0, 2, and 6 Months) §	2-Dose Schedule (0 and 6 Months) ¶
fHbp Variant #	% (95% CI) Þ	% (95% CI) Þ	% (95% CI) Þ
Abbreviations: CI=confidence interval; fHbp=factor H binding protein; hSBA=serum bactericidal assay using human complement; LLOQ=lower limit of quantitation; NA=not applicable.
Note: LLOQ = 1:16 for PMB80 (A22) and 1:8 for PMB2001 (A56), PMB2948 (B24), and PMB2707 (B44).
Note: The ≥4-fold increase is defined as follows: (1) For subjects with a baseline hSBA titer <1:4, a ≥4-fold increase was defined as an hSBA titer ≥1:16. (2) For subjects with a baseline hSBA titer ≥ LOD and < LLOQ, a response is defined as an hSBA titer ≥4 times the LLOQ. (3) For subjects with a baseline hSBA titer ≥ LLOQ, a response is defined as an hSBA titer ≥4 times the baseline titer.
* Per-schedule Evaluable populations. Dose 2 data include subjects who received two doses, irrespective of whether they received the third dose. † Study1012: NCT01299480. ‡ Group 1 (0, 1, and 6 months). The denominators ranged from 173 to 187 after Dose 2 and 178 to 188 after Dose 3, depending on the strain. § Group 2 (0, 2, and 6 months). The denominators ranged from 229 to 240 after Dose 2 and 159 to 162 after Dose 3, depending on the strain. ¶ Group 3 (0 and 6 months). The denominators ranged from 188 to 203 after Dose 2, depending on the strain. # For the second and third doses, serum was obtained approximately 1 month after vaccination. Þ Exact 2-sided confidence interval (Clopper and Pearson) based upon the observed proportion of subjects. ß Composite response = hSBA ≥LLOQ for all 4 primary meningococcal B strains.
≥4-Fold Increase
PMB80 (A22)
Dose 2	58.8(51.4, 66.0)	72.5(66.4, 78.0)	82.3(76.3, 87.3)
Dose 3	77.6(70.9, 83.4)	87.7(81.6, 92.3)	NA
PMB2001 (A56)
Dose 2	87.8(82.2, 92.2)	90.7(86.2, 94.1)	90.1(85.1, 93.8)
Dose 3	91.2(86.1, 94.9)	93.8(88.8, 97.0)	NA
PMB2948 (B24)
Dose 2	51.1(43.6, 58.5)	54.2(47.7, 60.7)	64.5(57.4, 71.1)
Dose 3	74.1(67.1, 80.2)	78.3(71.1, 84.4)	NA
PMB2707 (B44)
Dose 2	48.1(40.7, 55.6)	53.4(46.8, 59.9)	66.0(58.9, 72.6)
Dose 3	80.9(74.5, 86.2)	78.6(71.4, 84.7)	NA
Composite Response ß
Before Dose 1	4.6(2.0, 8.8)	2.2(0.7, 5.0)	1.5(0.3, 4.4)
Dose 2	52.0(44.3, 59.7)	52.0(45.3, 58.6)	72.9(65.9, 79.1)
Dose 3	80.3(73.7, 85.9)	81.8(74.9, 87.4)	NA