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Pharmacology: Ravulizumab is a humanized monoclonal antibody (mAb) consisting of 2 identical 448 amino acid heavy chains and 2 identical 214 amino acid light chains and has a molecular weight of approximately 148kDa. The constant regions of ravulizumab include the human kappa light chain constant region, and the protein engineered "IgG2/4" heavy chain constant region.
The heavy chain CH1 domain, hinge region, and the first 5 amino acids of the CH2 domain match the human IgG2 amino acid sequence, residues 6 to 36 in the CH2 region (common to both human IgG2 and IgG4 amino acid sequences), while the remainder of the CH2 domain and the CH3 domain match the human IgG4 amino acid sequence. The heavy and light chain variable regions that form the human C5 binding site consist of human framework regions grafted to murine complementarity-determining regions.
Pharmacodynamics: Mechanism of Action: Ravulizumab is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the membrane attack complex [MAC or C5b-9]) and preventing the generation of the C5b-9. By binding specifically to C5, ravulizumab antagonizes terminal complement-mediated inflammation, and cell lysis while preserving the early components of complement activation that are essential for opsonization of microorganisms and clearance of immune complexes.
This mechanism of action provides the therapeutic rationale for the use of ULTOMIRIS in PNH, complement-mediated TMA, gMG in which uncontrolled complement activation is involved. In patients with PNH, complement-mediated intravascular hemolysis is blocked with ULTOMIRIS treatment. ULTOMIRIS resolves complement-mediated TMA. In gMG patients, ULTOMIRIS inhibits terminal complement activation, which otherwise leads to MAC deposition at the neuromuscular junction resulting in impairment of neuromuscular transmission.
Ravulizumab was specifically engineered to dissociate from C5 and associate with human neonatal Fc receptor (FcRn) at pH 6.0 (with minimal impact in binding to C5 in intravascular space where the normal pH is 7.4). As a result, dissociation of antibody: C5 complexes in the acidified environment of the early endosome after pinocytosis is increased. Therefore, free antibody is recycled from the early endosome back into the vascular compartment by FcRn, resulting in an extended ravulizumab terminal elimination half-life (see Pharmacokinetics as follows).
ULTOMIRIS dosing has been optimized to achieve therapeutic steady state concentrations following the first dose, resulting in immediate onset of action and complete terminal complement inhibition by the end of infusion, that is sustained throughout the dosing interval.
This dosing regimen provides prolonged pharmacologic activity, based on the half-life of ravulizumab in serum, and allows dosing once every 8 weeks (or once every 4 weeks for patients weighing less than 20 kg).
Pharmacodynamic Effects: Following ULTOMIRIS treatment in both adult and pediatric complement-inhibitor naïve patients and SOLIRIS-experienced patients with PNH in Phase 3 studies, immediate and complete inhibition of serum free C5 (concentration of < 0.5 μg/mL) was observed by the end of the first infusion and sustained throughout the entire 26-week treatment period in all patients. In contrast, serum free C5 concentrations did not consistently remain < 0.5 μg/mL following SOLIRIS treatment.
Following ULTOMIRIS treatment, immediate and complete inhibition of serum free C5 was also observed in adult and pediatric patients with complement-mediated TMA and adult patients with gMG by the end of the first infusion and was sustained throughout the primary treatment period.
The extent and duration of the pharmacodynamic response were exposure-dependent in patients with PNH, complement-mediated TMA, gMG, following ULTOMIRIS treatment. Free C5 levels of < 0.5 μg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition.
Clinical Efficacy and Safety: Paroxysmal Nocturnal Hemoglobinuria (PNH): The safety and efficacy of ULTOMIRIS in adult patients with PNH were assessed in two open-label, randomised, active-controlled Phase 3 trials: a complement-inhibitor naïve study in adult patients with PNH who were naïve to complement inhibitor treatment, a SOLIRIS-experienced study in adult patients with PNH who were clinically stable after having been treated with SOLIRIS (eculizumab) for at least the previous 6 months.
ULTOMIRIS was dosed in accordance with the recommended dosing described in Dosage & Administration (4 infusions of ULTOMIRIS over 26 weeks) while SOLIRIS was administered according to the approved dosing regimen of SOLIRIS of 600 mg every week for the first 4 weeks and 900 mg every 2 weeks (15 infusions over 26 weeks).
Patients were vaccinated against meningococcal infection prior to or at the time of initiating treatment with ULTOMIRIS or SOLIRIS, or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination.
There were no noteworthy differences in the demographic or baseline characteristics between the ULTOMIRIS and SOLIRIS treatment groups in either of the Phase 3 studies. The 12-month transfusion history was similar between ULTOMIRIS and SOLIRIS treatment groups within each of the Phase 3 studies.
Study in Complement-Inhibitor Naïve Adult Patients with PNH: The Complement-Inhibitor Naïve Study was a 26-week, multicenter, open-label, randomized, active-controlled, Phase 3 study conducted in 246 patients who were naïve to complement inhibitor treatment prior to study entry. Eligible patients to enter this trial had to demonstrate high disease activity, defined as LDH level ≥ 1.5 × upper limit of normal (ULN) at screening along with the presence of 1 or more of the following PNH-related signs or symptoms within 3 months of screening: fatigue, haemoglobinuria, abdominal pain, shortness of breath (dyspnoea), anaemia (haemoglobin < 10 g/dL), history of a major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction; or history of packed red blood cell (pRBC) transfusion due to PNH.
More than 80% of patients in both treatment groups had a history of transfusion within 12 months of study entry. The majority of the complement inhibitor-naïve study population was highly haemolytic at baseline; 86.2% of enrolled patients presented with elevated LDH ≥ 3 × ULN, which is a direct measurement of intravascular haemolysis, in the setting of PNH.
Table 1 presents the baseline characteristics of the PNH patients enrolled in the Complement-Inhibitor Naïve Study, with no apparent clinically meaningful differences observed between the treatment arms. (See Table 1.)
Click on icon to see table/diagram/imageThe coprimary endpoints were transfusion avoidance, and hemolysis as directly measured by normalization of LDH levels (LDH levels ≤ 1 × ULN; the ULN for LDH is 246 U/L). Key secondary endpoints included the percent change from baseline in LDH levels, change in quality of life (FACIT-Fatigue), the proportion of patients with breakthrough hemolysis, and proportion of patients with stabilized hemoglobin.
ULTOMIRIS was non-inferior compared to eculizumab for both coprimary endpoints, avoidance of pRBC transfusion per protocol-specified guidelines and LDH normalisation from day 29 to day 183, and for all 4 key secondary endpoints (see Figure 1).
Click on icon to see table/diagram/imageStudy in Adult PNH Patients Previously Treated with SOLIRIS: The SOLIRIS-Experienced Study was a 26-week, multicenter, open-label, randomized, active-controlled Phase 3 study conducted in 195 patients with PNH who were clinically stable (LDH ≤ 1.5 x ULN) after having been treated with SOLIRIS for at least the past 6 months.
PNH medical history was similar between ULTOMIRIS and SOLIRIS treatment groups. The 12-month transfusion history was similar between ULTOMIRIS and SOLIRIS treatment groups and more than 87% of patients in both treatment groups had not received a transfusion within 12 months of study entry. The mean total PNH RBC clone size was 60.05%, mean total PNH granulocyte clone size was 83.30%, and the mean total PNH monocyte clone size was 85.86%.
Table 2 presents the baseline characteristics of the PNH patients enrolled in the SOLIRIS-Experienced Study, with no apparent clinically meaningful differences observed between the treatment arms. (See Table 2.)
Click on icon to see table/diagram/imageThe primary endpoint was hemolysis as measured by LDH percent change from baseline. Secondary endpoint included the proportion of patients with breakthrough hemolysis, quality-of-life (FACIT-Fatigue), transfusion avoidance (TA), and proportion of patients with stabilized hemoglobin.
ULTOMIRIS was non-inferior compared to eculizumab for the primary endpoint, percent change in LDH from baseline to day 183, and for all 4 key secondary endpoints (see Figure 2).
Click on icon to see table/diagram/imageAtypical Hemolytic Uremic Syndrome (aHUS): Study in Adult Patients with aHUS: The adult study was a multicenter, single arm, Phase 3 study conducted in patients with documented aHUS who were naïve to complement inhibitor treatment prior to study entry and had evidence of thrombotic microangiopathy (TMA). The study consisted of a 26-week Initial Evaluation Period and patients were allowed to enter an extension period for up to 4.5 years.
A total of 58 patients with documented aHUS were enrolled. Enrolment criteria excluded patient presenting with TMA due to a thrombotic thrombocytopenic purpura (TTP), Shiga toxin Escherichia coli related hemolytic uremic syndrome (STEC-HUS). Two patients were excluded from the Full Analysis Set due to a confirmed diagnosis of STEC-HUS. Ninety-three percent of patients had extra renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline.
Table 3 presents the demographics and baseline characteristics of the 56 adult patients enrolled in Study ALXN1210-aHUS-311 that constituted the Full Analysis Set. (See Table 3.)
Click on icon to see table/diagram/imageThe primary endpoint was Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count ≥ 150 x 109/L and LDH ≤ 246 U/L) and ≥ 25% improvement in serum creatinine from baseline. Patients had to meet each Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between.
Complete TMA Response was observed in 30 of the 56 patients (53.6%) during the 26-week Initial Evaluation Period as shown in Table 4. (See Table 4.)
Click on icon to see table/diagram/imageFour additional patients had a Complete TMA Response that was confirmed after the 26-week Initial Evaluation Period (with a Complete TMA Response occurring at Days 169, 302, 401 and 407) resulting in an overall Complete TMA Response in 34 of 56 patients (60.7%; 95% CI: 47.0%, 74.4%). Individual component response increased to 48 (85.7%; 95% CI: 75.7%, 95.8%) patients for platelet count normalization, 47 (83.9%; 95% CI: 73.4%, 94.4%) patients for LDH normalization, and 35 (62.5%; 95% CI: 48.9%, 76.1%) patients for renal function improvement.
Complete TMA Response was achieved at a median time of 86 days (7 to 169 days). An increase in mean platelet count was observed rapidly after commencement of ravulizumab, increasing from 118.52 × 109/L at baseline to 240.34 ×109/L at Day 8 and remaining above 227 × 109/L at all subsequent visits in the Initial Evaluation Period (26 weeks). Similarly, mean LDH value decreased from baseline over the first 2 months of treatment and was sustained over the duration of the Initial Evaluation Period (26 weeks).
Of the patients who presented at CKD Stage 5, 67.6% (23/34) showed an improvement of 1 or more CKD Stages. Chronic kidney disease stage continued to improve for many patients (19/30) after achieving Complete TMA Response during the 26-week Initial Evaluation Period. 17 of the 29 patients who required dialysis at study entry were able to discontinue dialysis by the end of the available follow-up while 6 of 27 patients who were off dialysis at baseline were on dialysis at last available follow-up. Table 5 summarizes the secondary efficacy outcomes for Study ALXN1210-aHUS-311. (See Table 5.)
Click on icon to see table/diagram/imageGeneralized Myasthenia Gravis (gMG): Study in Adult Patients with gMG: The efficacy and safety of ULTOMIRIS in adult patients with gMG was assessed in a Phase 3, randomized, double-blind, placebo-controlled, multicenter study (ALXN1210-MG-306). Patients participating in this study were subsequently allowed to enter an Open-Label Extension (OLE) Period during which all patients received ULTOMIRIS.
Patients with gMG (diagnosed for at least 6 months) with a positive serologic test for anti-acetylcholine receptor (AChR) antibodies, MGFA (Myasthenia Gravis Foundation of America) clinical classification Class II to IV and remaining symptomatology as evidenced by a Myasthenia Gravis Activities of Daily Living (MG-ADL) total score ≥ 6 were randomized to receive either ULTOMIRIS (N = 86) or placebo (N = 89). Patients on immunosuppressant therapies (corticosteroids, azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate mofetil, or tacrolimus) were permitted to continue on therapy throughout the course of the study. In addition, rescue therapy (including high-dose corticosteroid, PE/PP, or IVIg) was allowed if a patient experienced clinical deterioration, as defined by the study protocol.
A total of 162 (92.6%) patients completed the 26-week RCP of Study ALXN1210-MG-306. The baseline characteristics of patients are presented in Table 6. The majority (97%) of patients included in the study had been treated with at least one immunomodulatory therapy including immunosuppressant therapies, PE/PP, or IVIg in the last two years prior to enrolment. (See Table 6.)
Click on icon to see table/diagram/imageThe primary endpoint was the change from baseline to Week 26 in the MG-ADL total score.
The secondary endpoints, also assessed changes from baseline to Week 26, included the change in the Quantitative Myasthenia Gravis (QMG) total score, the proportion of patients with improvements of at least 5 and 3 points in the QMG and MG-ADL total scores, respectively, as well as changes in quality-of-life assessments.
ULTOMIRIS demonstrated a statistically significant change in the MG-ADL total score as compared to placebo. Primary and secondary endpoint results are presented in Table 7. (See Table 7.)
Click on icon to see table/diagram/imageIn Study ALXN1210-MG-306, a clinical responder in the MG-ADL total score was defined as having at least a 3-point improvement. The proportion of clinical responders at Week 26 was 56.7% on ravulizumab compared with 34.1% on placebo (nominal p=0.0049). A clinical responder in the QMG total score was defined as having at least a 5-point improvement. The proportion of clinical responders at Week 26 was 30.0% on ravulizumab compared with 11.3% on placebo (p=0.0052).
Table 8 presents an overview of the patients with clinical deterioration and patients requiring rescue therapy over the 26-week RCP. (See Table 8.)
Click on icon to see table/diagram/imageAt the time of the analysis, 150 of the 158 patients who entered the Open-Label Extension Period were ongoing in the study.
In patients who initially received ULTOMIRIS during the RCP and continued to receive ULTOMIRIS during the first 26 weeks of the OLE, the treatment effect was sustained (Figure 3). In patients who initially received placebo during the 26-week RCP and initiated treatment with ULTOMIRIS during the OLE, a rapid and sustained treatment response (Figure 3), was observed. (See Figure 3.)
Click on icon to see table/diagram/imageIn the OLE of the study, clinicians had the option to adjust immunosuppressant therapies. In patients followed for 34 weeks in the OLE, 28.0% of patients decreased their daily dose of corticosteroid therapy and 6.2% of patients stopped corticosteroid therapy. The most common reason for change in corticosteroid therapies was improvement in MG symptoms while on ULTOMIRIS treatment.
Pediatric Population: Paroxysmal Nocturnal Hemoglobinuria (PNH): Study in Pediatric Patients with PNH: The pediatric study (ALXN1210-PNH-304) is a multi-center, open-label, Phase 3 study conducted in SOLIRIS-experienced and complement inhibitor-naïve pediatric patients with PNH.
From interim results, a total of 13 PNH pediatric patients completed ULTOMIRIS treatment during the Primary Evaluation Period (26 weeks) of Study ALXN1210-PNH-304. Five of the 13 patients had never been treated with complement inhibitor and 8 patients received treatment with SOLIRIS prior to study entry.
Most of the patients were between 12 and 17 years of age at first infusion (mean: 14.4 years), with 2 patients under 12 years old (11 and 9 years old). Eight of the 13 patients were female. Mean weight at baseline was 56 kg, ranging from 37 to 72 kg. Table 9 presents the baseline disease history and characteristics of the paediatric patients enrolled in Study ALXN1210 PNH-304. (See Table 9.)
Click on icon to see table/diagram/imageBased on body weight, patients received a loading dose of ULTOMIRIS on Day 1, followed by maintenance treatment on Day 15 and once every 8 weeks (q8w) thereafter for patients weighing ≥ 20 kg, or once every 4 weeks (q4w) for patients weighing < 20 kg. For patients who entered the study on SOLIRIS therapy, Day 1 of study treatment was planned to occur 2 weeks from the patient's last dose of SOLIRIS.
The weight-based dose regimen of ULTOMIRIS provided immediate, complete, and sustained inhibition of terminal complement throughout the entire 26-week primary evaluation period regardless of prior experience with SOLIRIS. Following initiation of ULTOMIRIS treatment, steady-state therapeutic serum concentrations of ULTOMIRIS were achieved immediatelyafter the first dose and maintained throughout the 26-week Primary Evaluation Period in both cohorts. There were no breakthrough hemolysis events in the study and no patients had post-baseline free C5 levels above 0.5 μg/mL. Mean percent change from baseline in LDH was -47.91% on Day 183 in the complement inhibitor-naïve cohort and remained stable in the SOLIRIS-experienced cohort during the 26-week Primary Evaluation Period. Sixty percent (3/5) of complement inhibitor-naïve patients and 75% (6/8) of eculizumab-experienced patients achieved haemoglobin stabilisation by Week 26 respectively. Transfusion-avoidance was reached for 84.6% (11/13) of patients during the 26-week Primary Evaluation Period.
These interim efficacy results are presented in Table 10 as follows. (See Table 10.)
Click on icon to see table/diagram/imageBased on these data from these interim results, the efficacy of ULTOMIRIS in pediatric PNH patients appears to be similar to that observed in adult PNH patients.
Atypical Hemolytic Uremic Syndrome (aHUS): Study in Pediatric Patients with aHUS: The pediatric study is a 26-week ongoing, multicenter, single arm, Phase 3 study conducted in pediatric patients.
A total of 21 SOLIRIS-naïve patients with documented diagnosis of aHUS and evidence of TMA were enrolled, of whom 18 were included in the full analysis set. Enrolment criteria excluded patients presenting with TMA due to TTP and STEC-HUS. Two patients were given a single dose, and one patient received 2 doses, but then discontinued and were excluded from the Full Analysis Set because aHUS was not confirmed. The overall mean weight at baseline was 22.2 kg; majority of the patients were in the baseline weight category ≥ 10 to < 20 kg. The majority of patients (72.2%) had pretreatment extra renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 33.3% (n = 6) of patients had CKD Stage 5.
A total of 10 patients who switched from SOLIRIS to ULTOMIRIS with documented diagnosis of aHUS and evidence of TMA were enrolled. Patients had to have clinical response to SOLIRIS prior to enrolment (i.e LDH < 1.5 X ULN and platelet count ≥ 150,000/μL, and eGFR > 30 mL/min/1.73m2). Consequently, there is no information on the use of ravulizumab in patient refractory to eculizumab.
Table 11 presents the baseline characteristics of the pediatric patients enrolled in Study ALXN1210-aHUS-312. (See Table 11.)
Click on icon to see table/diagram/imageThe primary endpoint was Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count ≥ 150 x 109/L and LDH ≤ 246 U/L) and ≥ 25% improvement in serum creatinine from baseline. Patients had to meet all Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between.
Complete TMA Response was observed in 14 of the 18 naïve patients (77.8%) during the 26-week Initial Evaluation Period as shown in Table 12. (See Table 12.)
Click on icon to see table/diagram/imageComplete TMA Response during the Initial Evaluation Period was achieved at a median time of 30 days (15 to 97 days). All patients with Complete TMA Response maintained it through the Initial Evaluation Period with continuous improvements seen in renal function. An increase in mean platelet count was observed rapidly after commencement of ravulizumab, increasing from 60.50 × 109/L at baseline to 296.67 × 109/L at Day 8 and remained above 296 × 109/L at all subsequent visits in the Initial Evaluation Period (26 weeks).
Three additional patients had a Complete TMA Response that was confirmed after the 26-week Initial Evaluation Period (with a Complete TMA Response occurring at Days 291, 297 and 353); thus, 17 of 18 (94.4%) pediatric patients (95% CI: 72.7%, 99.9%) had a Complete TMA Response. Individual component response increased to 17 of 18 (94.4%; 95% CI: 72.7%, 99.9%) patients for each platelet count normalization, 17 of 18 (94.4%; 95% CI: 72.7%, 99.9%) patients for LDH normalization, and 17 of 18 (94.4%; 95% CI: 72.7%, 99.9%) patients for renal function improvement.
All 6 patients who required dialysis at study entry were able to discontinue dialysis; 5 of which had already done so by Day 43. No patient started dialysis during the study. The majority of the patient population (15/17) improved by 1 or more CKD stages by Day 183; 14 patients improved by 2 or more stages. Table 13 summarizes the secondary efficacy results for Study ALXN1210-aHUS-312. (See Table 13.)
Click on icon to see table/diagram/imageIn SOLIRIS-experienced patients, switching to ULTOMIRIS maintained disease control as evidenced by stable hematologic and renal parameters, with no apparent impact on safety.
The efficacy of ravulizumab for the treatment of aHUS appears similar in paediatric and adult patients.
Pharmacokinetics: Absorption: ULTOMIRIS doses are 100% bioavailable resulting from intravenous administration. The time to maximum observed concentration (tmax) is expected at the end of infusion (EOI) or soon after EOI. Over the studied dose and regimen range, ravulizumab exhibited dose proportional and time linear pharmacokinetics (PK).
Distribution: The mean (standard deviation [SD]) central volume and volume of distribution at steady state in adult and pediatric patients with PNH or complement mediated-TMA treated with ravulizumab IV, adult patients with gMG treated with ravulizumab IV, are presented in Table 14.
Biotransformation and Elimination: As an immunoglobulin gamma (IgG) monoclonal antibody, ravulizumab is expected to be metabolized in the same manner as any endogenous IgG (degraded into small peptides and amino acids via catabolic pathways) and is subject to similar elimination. Ravulizumab contains only natural occurring amino acids and has no known active metabolites. The mean (SD) terminal elimination half-life and clearance of ravulizumab in adult and pediatric patients with PNH or complement-mediated TMA treated with ravulizumab IV, adult patients with gMG treated with ravulizumab IV are presented in Table 14.
Pharmacokinetic Parameters: A linear, 2-compartment PK model was developed that adequately described the observed ravulizumab PK following intravenous and subcutaneous administration. The estimated mean (SD) clearance, central volume, volume at steady state and terminal elimination half-life following multiple dosing of ravulizumab in adult and pediatric patients with PNH or complement-mediated TMA treated with ravulizumab IV, adult patients with gMG treated with ravulizumab IV are presented in Table 14. (See Table 14.)
Click on icon to see table/diagram/imageTherapeutic concentrations are achieved immediately following the first dose of ULTOMIRIS. In patients with PNH, complement-mediated TMA, gMG pharmacodynamic activity correlates directly with ravulizumab serum concentrations above the target exposure level and results in free C5 levels < 0.5 μg/mL, achieving immediate, complete and sustained terminal complement inhibition in all patients.
PK parameters for ULTOMIRIS are consistent across PNH, complement-mediated TMA, gMG patient populations.
Special Populations: No formal trial of the effect of sex, race, age (geriatric), hepatic or renal impairment on the pharmacokinetics of ravulizumab was conducted. However, based on population-PK assessment, no impact of sex, age, race and hepatic or renal function on ravulizumab PK was identified in patients with PNH, complement-mediated TMA, or gMG and as a result, no dosing adjustment is considered necessary.
The pharmacokinetics of ravulizumab have been studied in complement-mediated TMA patients with a range of renal impairment and age including patients receiving dialysis. There have been no observed differences in pharmacokinetic parameters noted in these subpopulations including patients with proteinuria.
Body weight is a clinically significant covariate on the pharmacokinetics of ravulizumab.
Toxicology: Preclinical safety data: The tissue cross-reactivity of ravulizumab was evaluated by assessing binding to a panel of human tissues. C5 expression in the human tissue panel examined in this study is consistent with published reports of C5 expression. No unexpected tissue cross-reactivity was observed.
In a 26-week toxicity study performed in mice with a surrogate antibody directed against murine C5, treatment did not affect any of the toxicity parameters examined. C5-induced hemolytic activity in an ex vivo assay was effectively blocked throughout the course of the study in both female and male mice.
Animal reproductive toxicology studies have not been conducted with ravulizumab, but were conducted in mice with a murine surrogate complement inhibitory antibody, BB5.1. No clear treatment-related effects or adverse effects were observed in the murine surrogate reproductive toxicology studies in mice. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose (approximately 4 times the maximum recommended human ravulizumab dose, based on a body weight comparison); however, the exposure did not increase fetal loss or neonatal death.
No animal studies have been conducted to evaluate the genotoxic and carcinogenic potential of ravulizumab.
Non-clinical data reveal no special hazard for humans based on nonclinical studies using a murine surrogate molecule, BB5.1, in mice.
