ULTOMIRIS Concentrate for solution for infusion Ref.[50087] Active ingredients: Ravulizumab

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants
ATC code: L04AA43

Mechanism of action

Ravulizumab is a monoclonal antibody IgG2/4K that specifically binds to the complement protein C5, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal complement complex [C5b-9]) and preventing the generation of the C5b-9. Ravulizumab preserves the early components of complement activation that are essential for opsonisation of microorganisms and clearance of immune complexes.

Pharmacodynamic effects

Following ravulizumab treatment in both adult and paediatric complement inhibitor-naïve patients and eculizumab-experienced patients with PNH in Phase 3 studies, immediate, complete and sustained 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. Immediate and complete inhibition of serum free C5 was also observed in adult and paediatric patients with aHUS by the end of the first infusion and throughout the 26-week treatment period.

The extent and duration of the pharmacodynamic response in patients with PNH and aHUS were exposure dependent for ravulizumab. Free C5 levels less than 0.5 µg/mL were correlated with maximal intravascular haemolysis control and complete terminal complement inhibition.

Clinical efficacy and safety

Paroxysmal nocturnal haemoglobinuria

The safety and efficacy of ravulizumab 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,
• an eculizumab-experienced study in adult patients with PNH who were clinically stable after having been treated with eculizumab for at least the previous 6 months.

Ravulizumab was dosed in accordance with the recommended dosing described in section 4.2 (4 infusions of ravulizumab over 26 weeks) while eculizumab was administered according to the approved dosing regimen of eculizumab 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 ravulizumab or eculizumab, 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 ravulizumab and eculizumab treatment groups in either of the Phase 3 studies. The 12-month transfusion history was similar between ravulizumab and eculizumab 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, multicentre, open-label, randomised, 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 6 presents the baseline characteristics of the PNH patients enrolled in the complement inhibitornaïve study, with no apparent clinically meaningful differences observed between the treatment arms.

Table 6. Baseline characteristics in the complement inhibitor-naïve study:

^a Based on medical history.
^b “Other” as specified on case report form included thrombocytopenia, chronic kidney disease, and pancytopenia, as well as a number of other conditions.

The coprimary endpoints were transfusion avoidance, and haemolysis as directly measured by normalisation 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 haemolysis and proportion of patients with stabilized haemoglobin.

Ravulizumab 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 (Figure 1).

Figure 1. Analysis of coprimary and secondary endpoints – full analysis set (complement inhibitor-naïve study):

Note: The black triangle indicates the non-inferiority margins, and grey dots indicates point estimates.
Note: LDH = lactate dehydrogenase; CI = confidence interval; FACIT = Functional Assessment of Chronic Illness Therapy

Study in adult PNH patients previously treated with eculizumab

The eculizumab-experienced study was a 26-week, multicentre, open-label, randomised, 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 eculizumab for at least the past 6 months.

PNH medical history was similar between ravulizumab and eculizumab treatment groups. The 12-month transfusion history was similar between ravulizumab and eculizumab 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 7 presents the baseline characteristics of the PNH patients enrolled in the eculizumabexperienced study, with no apparent clinically meaningful differences observed between the treatment arms.

Table 7. Baseline characteristics in the eculizumab-experienced study:

^a Based on medical history.
^b “Other” category included neutropenia, renal dysfunction, and thrombopenia, as well as a number of other conditions.

The primary endpoint was haemolysis as measured by LDH percent change from baseline. Secondary endpoints included the proportion of patients with breakthrough haemolysis, quality-of-life (FACIT-Fatigue), transfusion avoidance (TA), and proportion of patients with stabilised haemoglobin.

Ravulizumab 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 (Figure 2).

Figure 2. Analysis of primary and secondary endpoints – full analysis set (eculizumab-experienced study):

Note: The black triangle indicates the non-inferiority margins, and grey dot indicates point estimates.

Note: LDH = lactate dehydrogenase; CI = confidence interval.

Atypical haemolytic uremic syndrome (aHUS)

Study in adult patients with aHUS

The adult study was a multicentre, 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 patients presenting with TMA due to thrombotic thrombocytopenic purpura (TTP) or Shiga toxin Escherichia coli related haemolytic 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 8 presents the demographics and baseline characteristics of the 56 adult patients enrolled in Study ALXN1210-aHUS-311 that constituted the full analysis set.

Table 8. Baseline characteristics in the adult study:

Note: Percentages are based on the total number of patients.
Abbreviations: aHUS = atypical haemolytic uremic syndrome; eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum.

The primary endpoint was Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalisation of haematological parameters (platelet count ≥150 × 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 9.

Table 9. Complete TMA response and complete TMA response components analysis during the 26-week initial evaluation period (ALXN1210-aHUS-311):

^a 95% CIs for the proportion were based on the asymptotic Gaussian approximation method with a continuity correction.
Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy.

Four 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 normalisation, 47 (83.9%; 95% CI: 73.4%, 94.4%) patients for LDH normalisation, 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 10 summarises the secondary efficacy outcomes for Study ALXN1210-aHUS-311.

Table 10. Secondary efficacy outcome for study ALXN1210-aHUS-311:

Note: n: number of patients with available data for specific assessment at Day 183 visit. m: number of patients meeting specific criterion. Chronic kidney disease (CKD) stage is classified based on the National Kidney Foundation Chronic Kidney Disease Stage. Stage 5 is considered the worst category, while Stage 1 is considered the best category. Baseline is derived based on the last available eGFR before starting treatment.
Improved/Worsened: compared to CKD stage at baseline. *95% confidence intervals (95% CIs) are based on exact confidence limits using the Clopper-Pearson method.
^a Excludes those with CKD Stage 1 at baseline as they cannot improve.
^b Excludes patients with Stage 5 at baseline as they cannot worsen.
Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy

Paediatric population

Paroxysmal nocturnal haemoglobinuria (PNH)

Study in paediatric patients with PNH

The paediatric study (ALXN1210-PNH-304) is a multicentre, open-label, Phase 3 study conducted in eculizumab-experienced and complement inhibitor-naïve paediatric patients with PNH. From interim results, a total of 13 PNH paediatric patients completed ravulizumab treatment during the primary evaluation period (26 weeks) of Study ALXN1210-PNH-304. Five of the 13 patients had never been treated with a complement inhibitor and 8 patients received treatment with eculizumab prior to study entry.

Most of the patients were between 12 years and 17 years of age at first infusion (mean: 14.4 years), with 2 patients under 12 years old (11 years 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 11 presents the baseline disease history and characteristics of the paediatric patients enrolled in Study ALXN1210-PNH-304.

Table 11. Disease History and Characteristics at Baseline (Full Analysis Set):

^a Other PNH-associated conditions were reported as “renal and splenic infarcts” and “multiple lesions concerning for embolic process”.
Note: Percentages were based on the total number of patients in each cohort.
Abbreviations: LDH = lactate dehydrogenase; max = maximum; min = minimum; PNH = paroxysmal nocturnal hemoglobinuria; pRBC = packed red blood cell; RBC = red blood cell.

Based on body weight, patients received a loading dose of ravulizumab 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 eculizumab therapy, Day 1 of study treatment was planned to occur 2 weeks from the patient’s last dose of eculizumab.

The weight-based dose regimen of ravulizumab provided immediate, complete, and sustained inhibition of terminal complement throughout the 26-week primary evaluation period regardless of prior experience with eculizumab. Following initiation of ravulizumab treatment, steady-state therapeutic serum concentrations of ravulizumab were achieved immediately after the first dose and maintained throughout the 26-week primary evaluation period in both cohorts. There were no breakthrough haemolysis 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 eculizumab-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 by 84.6% (11/13) of patients during the 26-week primary evaluation period.

These interim efficacy results are presented in table 12 below.

Table 12. Interim efficacy outcomes from the Paediatric study in PNH patients (ALXN1210-PNH304) - 26-week primary evaluation period:

Abbreviations: LDH = lactate dehydrogenase

Based on data from these interim results, the efficacy of ravulizumab in paediatric PNH patients appears to be similar to that observed in adult PNH patients.

Atypical haemolytic uremic syndrome (aHUS)

Use of Ultomiris in paediatric patients for treatment of aHUS is supported by evidence from one paediatric clinical study (a total of 31 patients with documented aHUS were enrolled; 28 patients aged 10 months to 17 years were included in the full analysis set).

Study in paediatric patients with aHUS

The paediatric study is a 26-week ongoing, multicentre, single arm, Phase 3 study conducted in paediatric patients.

A total of 21 eculizumab-naïve patients with documented diagnosis of aHUS and evidence of TMA were enrolled, of which 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 eculizumab to ravulizumab, had documented diagnosis of aHUS and evidence of TMA were enrolled. Patients had to have clinical response to eculizumab 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 13 presents the baseline characteristics of the paediatric patients enrolled in Study ALXN1210-aHUS-312.

Table 13. Demographics and baseline characteristics in study ALXN1210-aHUS-312:

Note: Percentages are based on the total number of patients.
^a Patients can have multiple races selected.
Abbreviations: aHUS = atypical haemolytic uremic syndrome; eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum.

The primary endpoint was Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalisation of haematological parameters (platelet ≥150 × 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 14.

Table 14. Complete TMA response and complete TMA response components analysis during the 26-week initial evaluation period (ALXN1210-aHUS-312):

Note: 1 patient withdrew from study after receiving 2 doses of ravulizumab.
^a 95% CIs for the proportion were based on the asymptotic Gaussian approximation method with a continuity correction.
Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy.

Complete 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%) paediatric 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 platelet count normalisation, 17 of 18 (94.4%; 95% CI: 72.7%, 99.9%) patients for LDH normalisation, and 17 of 18 (94.4%; 95% CI: 72.7%, 99.9%) patients for renal function improvement.

All 6 of the 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 15 summarises the secondary efficacy results for Study ALXN1210-aHUS-312.

Table 15. Secondary efficacy outcome for study ALXN1210-aHUS-312:

Note: n: number of patients with available data for specific assessment at Day 183 visit. m: number of patients meeting specific criterion. Chronic kidney disease (CKD) stage is classified based on the National Kidney Foundation Chronic Kidney Disease Stage. Stage 1 is considered the best category, while Stage 5 is considered the worst category. Baseline is derived based on the last available eGFR before starting treatment.
Improved/Worsened: Compared to CKD stage at baseline.
^* 95% confidence intervals (95% CIs) are based on exact confidence limits using the Clopper Pearson method.
^a Improved excludes patients with Stage 1 at baseline, as they cannot improve
^b worsened excludes patients with Stage 5 at baseline as they cannot worsen.
Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy.

In eculizumab-experienced patients, switching to ravulizumab 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.