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ULTOMIRIS 300 mg/30 ML, concentrate for solution for infusion

ULTOMIRIS 300 MG/3 ML, CONCENTRATE FOR SOLUTION FOR INFUSION

ULTOMIRIS 1100 MG/11 ML, CONCENTRATE FOR SOLUTION FOR INFUSION

Composition

Active substances

Ravulizumab, produced from genetically modified ovarian cells from the Chinese hamster.

Excipients

Sodium dihydrogen phosphate monohydrate

Disodium phosphate heptahydrate

Ultomiris 300 mg/3 mL and 1100 mg/11 mL: L-arginine

Ultomiris 300 mg/3 mL and 1100 mg/11 mL: sucrose

Ultomiris 300 mg/30 mL: sodium chloride

Ultomiris 300 mg/30 mL: 115 mg sodium per 30 mL vial

Ultomiris 300 mg/3 mL: 4.6 mg sodium per 3 mL vial

Ultomiris 1100 mg/11 mL: 16.8 mg sodium per 11 mL vial

Polysorbate 80

Water for injection

Pharmaceutical form and active substance quantity per unit

Concentrate for solution for infusion.

Ultomiris 300 mg/30 mL:

Clear to translucent, slightly whitish solution, pH 7.0.

One 30 mL vial contains 300 mg of ravulizumab (10 mg/mL) and 115 mg of sodium.

After dilution, the final concentration of the solution to be infused is 5 mg/mL.

Ultomiris 300 mg/3 mL:

Translucent, clear to yellowish solution, pH 7.4.

One 3 mL vial contains 300 mg of ravulizumab (100 mg/mL) and 4.6 mg of sodium.

After dilution, the final concentration of the solution to be infused is 50 mg/mL.

Ultomiris 1100 mg/11 mL:

Translucent, clear to yellowish solution, pH 7.4.

One 11 mL vial contains 1100 mg of ravulizumab (100 mg/mL) and 16.8 mg of sodium.

After dilution, the final concentration of the solution to be infused is 50 mg/mL.

Indications/Uses

Paroxysmal nocturnal haemoglobinuria (PNH)

Ultomiris is used in the treatment of adult and paediatric patients with a body weight of 10 kg or above with PNH:

- in patients with haemolysis with one or more clinical symptom(s) indicative of high disease activity,

- in patients who are clinically stable after having been treated with eculizumab for at least the past 6 months.

Atypical haemolytic uraemic syndrome (aHUS)

Ultomiris is used in the treatment of adult and paediatric patients weighing 10 kg and over with aHUS who have not previously been treated with complement inhibitors (complement inhibitor-naïve patients) or have received eculizumab for at least 3 months, with evidence of a response to eculizumab.

Generalised myasthenia gravis (gMG)

Ultomiris is used as an add-on to the standard treatment of adult patients with gMG who are anti-acetylcholine receptor (AChR) antibody-positive.

Neuromyelitis optica spectrum disorder (NMOSD)

Ultomiris is used in the treatment of adult patients with NMOSD who are anti-aquaporin 4 (AQP4) antibody-positive (see “Properties/Effects” section).

Dosage/Administration

Ravulizumab must be administered by healthcare professionals and under the supervision of a physician experienced in the treatment of patients with haematological, renal, neuromuscular or neuroinflammatory disorders.

Before initiating treatment it should be ensured that active meningococcal infection/sepsis is not present and that the patient has been adequately vaccinated against meningococcal disease according to the official vaccination recommendations (see “Contraindications” and “Warnings and precautions”).

To ensure traceability of biotechnological medicinal products, it is recommended that the trade name and batch number should be documented for each treatment.

Adult patients with PNH, aHUS, gMG or NMOSD

The recommended dosing regimen consists of a loading dose followed by maintenance dosing, administered by intravenous infusion. The doses to be administered are based on the patient's body weight, as shown in Table 1. In adult patients (≥ 18 years of age), the maintenance doses should be administered at 8-week intervals, starting 2 weeks after administration of the loading dose. The dosing regimen may occasionally vary by ± 7 days from the scheduled infusion day (except for the first maintenance dose of ravulizumab) but the subsequent dose should be administered according to the original schedule.

For patients being switched from eculizumab to ravulizumab, the loading dose of ravulizumab should be administered 2 weeks after the last eculizumab infusion. Maintenance doses are then administered once every 8 weeks, starting 2 weeks after administration of the loading dose, as shown in Table 1.

Table 1:  Ravulizumab weight-based dosing regimen for adult patients with body weight greater than or equal to 40 kg.

*The first maintenance dose is administered 2 weeks after the loading dose.

Supplemental dosing following plasma exchange (PE), plasmapheresis (PP) or intravenous immunoglobulin (IVIg)

Plasma exchange (PE), plasmapheresis (PP) and intravenous immunoglobulin (IVIg) have been shown to reduce ravulizumab serum levels. A supplemental dose of ravulizumab is required in treatments such as PE, PP or IVIg (Table 2).

Table 2: Supplemental dose of ravulizumab after PP, PE, or IVIg

Abbreviations: IVIg = intravenous immunoglobulin, kg = kilogram, PE = plasma exchange, PP = plasmapheresis

PNH is a chronic disease. It is therefore recommended to continue treatment with ravulizumab for the patient's lifetime, unless discontinuation of ravulizumab is clinically indicated (see "Warnings and precautions" section).

In aHUS, ravulizumab treatment to resolve thrombotic microangiopathy (TMA) manifestations should be for a minimum duration of 6 months. After that, the duration of treatment should be decided individually for each patient. In patients who, in the treating physician’s opinion (or according to the clinical indication), have a higher risk of recurrence of TMA, long-term treatment may be necessary (see “Warnings and precautions” section).

In patients with gMG or NMOSD, treatment with ravulizumab has only been studied in the setting of chronic administration (see “Warnings and precautions” section).

Ravulizumab has not been studied in gMG patients with MGFA Class V.

Patients with hepatic disorders

The safety and efficacy of ravulizumab have not been studied in patients with hepatic impairment; however, pharmacokinetic data suggest that no dose adjustment is required in patients with hepatic impairment.

Patients with renal disorders

No dose adjustment is required in patients with renal impairment (see "Pharmacokinetics" section).

Elderly patients

No dose adjustment is required for patients with PNH, aHUS, gMG or NMOSD aged 65 years and over. There is no evidence indicating that special precautions are required for treating geriatric patients. There is, however, only limited experience with ravulizumab in in elderly patients with PNH, aHUS or NMOSD.

Children and adolescents

Children and adolescents with PNH and aHUS weighing ≥ 40 kg are treated according to the dosage recommendations for adults (Table 1). Table 3 shows the doses and dose intervals calculated by body weight for children and adolescents weighing ≥ 10 kg to < 40 kg.

In patients switching from eculizumab to ravulizumab, the loading dose of ravulizumab should be administered 2 weeks after the last eculizumab infusion. Maintenance doses should then be administered according to a dosing regimen based on body weight, as shown in Table 3, starting 2 weeks after administration of the loading dose.

Table 3: Weight-based ravulizumab dosage regimen in children and adolescents with PNH or aHUS weighing less than 40 kg

*The first maintenance dose is administered 2 weeks after the loading dose.

The safety and efficacy of ravulizumab in children with PNH or aHUS weighing under 10 kg have not yet been studied. The currently available data are described in the “Undesirable effects” section, but no dosage recommendations can be given.

Ravulizumab has not been studied in children and adolescents with PNH who weigh less than 30 kg. The dosage of ravulizumab in children and adolescents under 30 kg is based on the dosage used for children and adolescents with aHUS and on the pharmacokinetic/pharmacodynamic (PK/PD) data available for aHUS and PNH patients treated with ravulizumab.

The safety and efficacy of ravulizumab in children with gMG or NMOSD have not yet been studied. No data are available.

Mode of administration

For intravenous infusion only.

This medicinal product must be administered through a 0.2 µm filter and should not be administered as an intravenous push or bolus injection.

Ultomiris 300 mg/30 mL concentrate for solution for infusion must not be mixed with Ultomiris 300 mg/3 mL or 1100 mg/11 mL concentrate for solution for infusion.

Ultomiris 300 mg/3 mL and 1100 mg/11 mL concentrate for solution for infusion

Ultomiris concentrate for solution for infusion is presented in 3 mL and 11 mL vials (100 mg/mL) and must be diluted to a final concentration of 50 mg/mL. Following dilution, Ultomiris is administered as an intravenous infusion using a syringe pump or infusion pump over a minimum period of 10 to 75 minutes (0.17 to 1.3 hours), depending on body weight (see Tables 4 and 5 below).

Table 4: Infusion rate for doses of Ultomiris 300 mg/3 mL and 1100 mg/11 mL concentrate for solution for infusion

^a Body weight at the time of treatment.

^b For PNH and aHUS indications only.

Table 5: Infusion rate for supplemental doses of Ultomiris 300 mg/3 mL and 1100 mg/11 mL concentrate for solution for infusion

^a Body weight at time of treatment.

^b Refer to Table 2 for selection of ravulizumab supplemental dose

Ultomiris 300 mg/30 mL concentrate for solution for infusion

Ultomiris concentrate for solution for infusion is presented in 30 mL vials (10 mg/mL) and must be diluted to a final concentration of 5 mg/mL. Following dilution, Ultomiris is administered as an intravenous infusion using a syringe pump or infusion pump over a minimum period of 22 to 194 minutes (0.4 to 3.3 hours), depending on body weight (see Tables 6 and 7 below).

Table 6: Infusion rate for doses of Ultomiris 300 mg/30 mL concentrate for solution for infusion

^a Body weight at time of treatment.

^b For PNH and aHUS indications only.

Table 7: Infusion rate for supplemental doses of Ultomiris 300 mg/30 mL concentrate for solution for infusion

^a Body weight at time of treatment.

^b Refer to Table 2 for selection of ravulizumab supplemental dose

For instructions on dilution of the medicinal product before administration, see "Instructions for handling" section.

Contraindications

- Hypersensitivity to the active substance or to any of the substances listed in the "Excipients" section.

- Patients with unresolved Neisseria meningitidis infection at treatment initiation (see "Warnings and precautions" section).

- Patients who are not currently vaccinated against Neisseria meningitidis unless they receive appropriate antibiotic prophylaxis for 2 weeks after vaccination (see "Warnings and precautions" section).

- Patients with hereditary complement deficiencies (see “Warnings and precautions” section).

Warnings and precautions

Serious meningococcal infection

Due to its mechanism of action, ravulizumab increases the patient's susceptibility to meningococcal infection/sepsis (Neisseria meningitidis). Meningococcal disease due to any serogroup may occur (see “Undesirable effects” section). To reduce this risk of infection, all patients must be vaccinated against meningococcal infections at least two weeks prior to starting treatment with ravulizumab, unless the risk of postponing treatment with ravulizumab outweighs the risk of meningococcal infection. Patients who start ravulizumab treatment less than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Vaccines against serogroups A, C, Y, W135 and B, where available, are recommended for prevention of the commonly pathogenic meningococcal serogroups. Patients must be vaccinated or revaccinated according to the official vaccination guidelines. If the patient is being switched from eculizumab treatment, the physician should verify that there is adequate protection against meningococcal disease according to the official vaccination guidelines.

Vaccination may not be sufficient to prevent meningococcal infection. The official guidelines on the appropriate use of antibiotics should be taken into account. Cases of serious or fatal meningococcal infections/sepsis have been reported in patients treated with ravulizumab and in patients treated with other terminal complement inhibitors. All patients should be monitored for early signs of meningococcal infection and sepsis, evaluated immediately if infection is suspected, and treated with appropriate antibiotics. Patients should be informed of these signs and symptoms and seek immediate medical care. Physicians should provide patients with the patient information brochure and patient safety card.

Immunisation

It is recommended that before the start of treatment with ravulizumab, patients start their vaccinations according to the current vaccination guidelines.

Vaccination may further activate the complement. As a result, patients with complement-mediated diseases may experience increased signs and symptoms of their underlying disease. Patients should therefore be closely monitored for disease symptoms after the recommended vaccination.

Patients aged under 18 years must be vaccinated against Haemophilus influenzae and pneumococcal infections, with rigorous adherence to the national vaccination recommendations for each age group.

Other systemic infections

Ravulizumab therapy should be administered with caution to patients with active systemic infections. Ravulizumab blocks terminal complement activation; patients may therefore have increased susceptibility to infections caused by Neisseria species and encapsulated bacteria. Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been observed.

Patients should be informed about potential severe infections and their signs and symptoms. Physicians should advise patients about gonorrhoea prevention.

Infusion-related reactions

Administration of ravulizumab may result in systemic infusion-related reactions and allergic or hypersensitivity reactions including anaphylaxis (see “Undesirable effects” section).

In clinical trials, infusion-related reactions were common (1%). These reactions were mild to moderate in severity and transient, including lower back pain, abdominal pain, muscle cramps, drop in blood pressure, rise in blood pressure, muscle rigidity, limb symptoms, drug sensitivity (allergic reaction), dysgeusia (altered sense of taste) and drowsiness. In the event of a systemic infusion-related reaction, if signs of cardiovascular instability or respiratory compromise occur, the administration of ravulizumab should be interrupted and appropriate supportive measures should be taken.

Discontinuation of treatment in PNH

If patients with PNH discontinue treatment with ravulizumab, they should be closely monitored for signs and symptoms of serious intravascular haemolysis. This is identified by elevated LDH (lactate dehydrogenase) values along with the following: sudden decrease in PNH clone size or sudden fall in haemoglobin, or re-appearance of symptoms such as tiredness/fatigue, haemoglobinuria, abdominal pain, shortness of breath (dyspnoea), major adverse vascular event (including thrombosis), dysphagia or erectile dysfunction. Patients who discontinue ravulizumab therapy should be monitored for at least 16 weeks for haemolysis and other reactions. If signs and symptoms of haemolysis occur after discontinuation, including elevated LDH values, consideration should be given to restarting administration of ravulizumab.

Discontinuation of treatment in aHUS

No specific data on the cessation of ravulizumab are available. In a long-term, prospective observational study, discontinuation of treatment with the complement C5 inhibitor (eculizumab) led to a 13.5 times higher rate of TMA recurrence, and there was a tendency towards a decline in kidney function compared with patients who continued the treatment.

If patients need to discontinue treatment with ravulizumab, they should be continuously and closely monitored for signs and symptoms of TMA. However, it is possible that monitoring is not sufficient for predicting or preventing serious TMA complications.

Complications of TMA after cessation of treatment can be identified by any of the following observations:

(i)At least two of the following laboratory findings are simultaneously present: a decrease of at least 25% in the platelet count from either the baseline count or the highest platelet count during ravulizumab treatment; increase of at least 25% in serum creatinine from the baseline value or from the lowest value during ravulizumab treatment; or increase of at least 25% in serum LDH from the baseline value or from the lowest value during ravulizumab treatment (the results should be confirmed by a second measurement) or

(ii)any of the following symptoms of TMA: change in mental state or seizures or other extrarenal manifestations of TMA, including cardiovascular abnormalities, pericarditis, gastrointestinal symptoms/diarrhoea or thrombosis.

If complications of TMA occur after cessation of ravulizumab, resumption of ravulizumab treatment with the loading and maintenance doses should be considered (see “Dosage/Administration” section).

Treatment discontinuation in gMG

Given that gMG is a chronic disease, patients benefiting from ravulizumab treatment who discontinue treatment should be monitored for symptoms of the underlying disease. If symptoms of gMG occur after discontinuation, consideration should be given to restarting treatment with ravulizumab.

Switching from eculizumab to ravulizumab

In patients with gMG who are not responding to the eculizumab approved dosing regimen, treatment with ravulizumab is not recommended.

Discontinuation of treatment in NMOSD

Ravulizumab for the treatment of NMOSD has only been studied in the context of long-term use and the effect of discontinuing ravulizumab has not been described. Patients in whom Ultomiris treatment has been discontinued should be closely monitored for signs of a possible relapse of the NMOSD.

Patients with Shiga toxin-producing E. coli haemolytic uraemic syndrome (STEC-HUS)

No data are available on the use of Ultomiris in patients with STEC-HUS.

Sodium content

Ultomiris 300 mg/30 mL concentrate for solution for infusion

When diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, the maximum dose of this medicinal product contains 2.65 g sodium per 720 mL, equivalent to 133% of the WHO-recommended maximum daily intake of 2 g sodium for an adult.

Ultomiris 300 mg/3 mL and 1100 mg/11 mL concentrate for solution for infusion

When diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, the maximum dose of this medicinal product contains 0.18 g sodium per 72 mL, equivalent to 9.1% of the WHO-recommended maximum daily intake of 2 g sodium for an adult.

Interactions

No interaction studies have been performed.

Based on the potential inhibitory effect of ravulizumab on the complement-dependent cytotoxicity of rituximab, ravulizumab may reduce the expected pharmacodynamic effects of rituximab.

See “Dosage/Administration” section for guidance in case of concomitant PE, PP or IVIg treatment.

Chronic intravenous human immunoglobulin (IVIg) treatment may interfere with the endosomal neonatal Fc receptor (FcRn) recycling mechanism of monoclonal antibodies such as ravulizumab and thereby decrease serum ravulizumab concentrations.

Pregnancy, lactation

Pregnancy

Women of child-bearing age

Women of childbearing age must use effective contraception methods during treatment and for up to 8 months afterwards.

Pregnancy

No clinical data on the use of ravulizumab in pregnant patients are available.

Non-clinical reproductive toxicology studies were not conducted with ravulizumab (see "Preclinical data" section). Reproductive toxicology studies which assessed the effect of C5 blockade on the reproductive system were conducted in mice using the murine surrogate molecule BB5.1. No specific test article-related reproductive toxicities were identified in these studies. Human IgG is known to cross the human placental barrier, and thus ravulizumab may potentially cause terminal complement inhibition in the foetal circulation. Insufficient data are available from animal studies with respect to reproductive toxicity (see "Preclinical data" section).

The use of ravulizumab may be considered in pregnant women following a benefit-risk analysis.

Lactation

It is unknown whether ravulizumab is excreted in human milk. Non-clinical reproductive toxicology studies conducted in mice with the murine surrogate molecule BB5.1 identified no adverse effects in the young resulting from consuming milk from treated dams.

A risk to the infant cannot be excluded.

Since many medicinal products and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in breast-fed infants, breast-feeding should be discontinued during treatment with ravulizumab and for up to 8 months afterwards.

Fertility

No specific non-clinical studies on fertility have been conducted with ravulizumab.

Non-clinical reproductive toxicology studies conducted in mice with a murine surrogate molecule (BB5.1) identified no adverse effects on the fertility of the treated females or males.

Effects on ability to drive and use machines

Ultomiris has no or negligible influence on the ability to drive and use machines.

Undesirable effects

Summary of the safety profile

The safety profile of Ultomiris is based on ongoing and completed clinical trials involving a total of 804 patients treated with Ultomiris. The most common adverse reactions to ravulizumab are headache (28.2%), upper respiratory tract infection (19.9%), nasopharyngitis (19.5%), diarrhoea (16.9%), fever (16.4%), nausea (13.7%), arthralgia (13.2%), tiredness/fatigue (13.1%), back pain (12.6%), abdominal pain (11.8%) and dizziness (10.1%). The most serious adverse reactions are meningococcal infections (0.7%), including meningococcal sepsis, meningococcal encephalitis and meningococcal infection (see "Warnings and precautions" section), and disseminated gonococcal infection (0.1%).

Tabulated list of adverse reactions

Table 8 gives the adverse reactions observed in clinical trials and during post-marketing surveillance.

Adverse reactions are listed by MedDRA system organ class and frequency using the following convention: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); and not known (frequency cannot be estimated from available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 8: Adverse reactions from clinical trials and post marketing

^a Meningococcal infection includes the Preferred Terms (PT) meningococcal infection, meningococcal sepsis and meningococcal encephalitis

^b Gonococcal infection includes disseminated gonococcal infection

^c Estimated from post-marketing experience

^d Hypersensitivity is an umbrella term for the Preferred Term (PT) drug hypersensitivity with connected causality and the Preferred Term hypersensitivity

Description of selected adverse reactions

Meningococcal infection/sepsis/encephalitis

Vaccination reduces but does not completely eliminate the risk of meningococcal infections. In clinical trials, <1% of patients developed serious meningococcal infections during treatment with ravulizumab. All of these were adults with PNH or NMOSD and had been vaccinated. Please refer to the "Warnings and precautions" section for information on the prevention and treatment of suspected meningococcal infection. Meningococcal infections in patients treated with ravulizumab presented as meningococcal sepsis and encephalitis. Patients should be informed of the signs and symptoms of meningococcal septicaemia and of the need for immediate medical treatment.

Immunogenicity

Treatment with any therapeutic protein may induce an immune response. In adult PNH patient studies (N = 475), in a study in children and adolescents with PNH (N = 13), in aHUS studies (N = 89), in a gMG study (N = 86) and in an NMOSD study (N = 58) only two cases (0.3%) of the development of treatment-related anti-active substance antibodies have been reported with ravulizumab (1 adult patient with PNH and 1 adult patient with aHUS). These anti-active substance antibodies were transient in nature with a low titre and did not correlate with clinical response or adverse events.

Children and adolescents

Paroxysmal nocturnal haemoglobinuria (PNH)

In children and adolescents with PNH (N = 13, aged 9 to 17 years old) enrolled in the paediatric PNH study (ALXN1210-PNH-304), the safety profile appeared similar to that observed in adult PNH patients. The most common adverse reactions reported in children and adolescents with PNH were abdominal pain, nausea, nasopharyngitis and headache, which occurred in 3 patients (23.1%).

Atypical haemolytic uraemic syndrome (aHUS)

In children and adolescents with signs of aHUS (N = 34) (aged 10 months to under 18 years) who took part in the study ALXN1210-aHUS-312, the safety profile of ravulizumab seemed similar to that in adult patients with signs of aHUS. The safety profiles in the different paediatric age groups seem to be similar. The safety data for patients aged under 2 years are limited to four patients. The most commonly reported adverse reaction in paediatric patients was fever (32.3%).

Generalised myasthenia gravis (gMG)

Ravulizumab has not been studied in children and adolescents with gMG.

Neuromyelitis optica spectrum disorder (NMOSD)

Ravulizumab has not been studied in children and adolescents with NMOSD.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is very important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions online via the ElViS portal (Electronic Vigilance System). You can obtain information about this at www.swissmedic.ch.

Overdose

No cases of overdose have been reported. Patients who experience overdose should have their infusion interrupted immediately and be closely monitored.

Properties/Effects

ATC-Code

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA43

Mechanism of action

Ravulizumab is a monoclonal IgG_2/4K antibody that specifically binds to the complement protein C5, 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 generation of C5b-9. Ravulizumab preserves the early components of complement activation that are essential for opsonisation of micro-organisms and clearance of immune complexes.

Pharmacodynamics

Following ravulizumab treatment in adult and paediatric patients with PNH not previously treated with complement inhibitors and patients with PNH previously treated with eculizumab in phase 3 trials, 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, in adult patients with gMG and in adult patients with NMOSD 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, aHUS, gMG or NMOSD were exposure-dependent with ravulizumab. Free C5 concentrations less than 0.5 µg/mL were correlated with maximal intravascular haemolysis control and complete terminal complement inhibition. In gMG, terminal complement activation leads to MAC deposition at the neuromuscular junction and impairment of neuromuscular transmission. In NMOSD, uncontrolled terminal complement activation caused by anti-AQP4 autoantibodies leads to MAC- and C5a-dependent inflammation, which results in astrocyte necrosis, increased permeability of the blood-brain barrier and damage to surrounding glial cells and neurons.

Clinical efficacy

Paroxysmal nocturnal haemoglobinuria (PNH)

The safety and efficacy of ravulizumab in adult patients with PNH were assessed in two open-label, randomised, active-controlled phase 3 trials:

- a trial in adult patients with PNH who had not previously received complement inhibitor treatment,

- a trial in adult patients with PNH who were clinically stable after having been treated with eculizumab for at least the previous 6 months.

Ravulizumab was administered in accordance with the recommended dosing regimen described in the "Dosage/Administration" section (4 infusions of ravulizumab over 26 weeks) while eculizumab was administered according to the approved dosing regimen for 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 start of treatment with ravulizumab or eculizumab, or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination.

There were no noteworthy differences in demographics or in characteristics present at start of the trial between the ravulizumab and eculizumab treatment groups in either of the phase 3 trials. The 12-month transfusion history was similar between the ravulizumab and eculizumab treatment groups within each of the phase 3 trials.

Study in adult patients with PNH who had not previously received complement inhibitor treatment (ALXN1210-PNH-301)

The study in patients not previously treated with complement inhibitors was a 26-week multicentre open-label randomised active-controlled phase 3 study, conducted in 246 patients who had not received complement inhibitor treatment prior to study entry, followed by a long-term extension phase in which all patients received ravulizumab. Patients eligible for this study had to demonstrate high disease activity, defined as an LDH value ≥1.5 × upper limit of normal (ULN) at screening along with the presence of one or more of the following PNH-related signs or symptoms in the 3 months prior to screening: tiredness/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 transfusion due to PNH.

More than 80% of patients in both treatment groups had a history of transfusion in the 12 months prior to study entry. The majority of the study population from the study with patients not previously treated with complement inhibitors were highly haemolytic at baseline; 86.2% of enrolled patients had, in association with PNH, an elevated LDH value ≥3 × ULN, a direct measure of intravascular haemolysis.

Table 9 presents the baseline characteristics of the PNH patients enrolled in the study of patients not previously treated with complement inhibitors. No apparent clinically meaningful differences were observed between the treatment arms.

Table 9:  Baseline characteristics in the study of patients not previously treated with complement inhibitors

^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 symptoms and disorders.

The coprimary endpoints were transfusion avoidance, and haemolysis as directly measured by normalisation of LDH values (LDH values ≤1 × ULN; the ULN for LDH is 246 U/L). Key secondary endpoints included the percentage change from baseline in LDH values, change in quality of life (FACIT Fatigue Score), the proportion of patients with breakthrough haemolysis and the proportion of patients with a stabilised haemoglobin level.

Ravulizumab was non-inferior compared to eculizumab for both coprimary endpoints, avoidance of packed red blood cell transfusion in accordance with 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 (study with patients not previously treated with complement inhibitors)

Note: Black triangles indicate the non-inferiority margins; grey dots indicate point estimates.

Note: LDH = lactate dehydrogenase; CI = confidence interval; FACIT = Functional Assessment of Chronic Illness Therapy.

The concluding efficacy analysis in the study included all patients who had ever been treated with ravulizumab (n = 244), and the median duration of treatment was 1423 days. The concluding analysis confirmed that the response to ravulizumab treatment observed in the primary evaluation period was sustained throughout the study.

Study in adult PNH patients previously treated with eculizumab (ALXN1210-PNH-302)

The study in patients previously treated with eculizumab was a 26-week multicentre open-label randomised active-controlled phase 3 study conducted with 195 patients with PNH who were clinically stable (LDH ≤1.5 × ULN) after having been treated with eculizumab for at least the past 6 months, followed by a long-term extension phase in which all patients received ravulizumab.

The PNH medical history was similar for the ravulizumab and eculizumab treatment groups. The 12-month transfusion history was similar for the ravulizumab and eculizumab treatment groups, and more than 87% of patients in both treatment groups had not received a transfusion in the 12 months prior to study entry. The mean total PNH red blood cell 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 10 presents the baseline characteristics of the PNH patients enrolled in the study of patients previously treated with eculizumab. No apparent clinically meaningful differences were observed between the treatment arms.

Table 10:  Baseline characteristics in the study of patients previously treated with eculizumab

^a Based on medical history.

^b “Other” category included neutropenia, renal dysfunction and thrombocytopenia, as well as a number of other symptoms and disorders.

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

Ravulizumab was non-inferior compared to eculizumab for the primary endpoint, percentage change in LDH from baseline to day 183, and for all 4 key secondary endpoints (Figure 2).

Figure 2: Analysis of coprimary and secondary endpoints – full analysis set (study with patients previously treated with eculizumab)

Note: Black triangles indicate the non-inferiority margins; grey dots indicate point estimates.

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

The concluding efficacy analysis in the study included all patients who had ever been treated with ravulizumab (n = 192) and had a mean duration of treatment of 968 days. The concluding analysis confirmed that the response to ravulizumab treatment observed in the primary evaluation period was sustained throughout the study.

Atypical haemolytic uraemic syndrome (aHUS)

Study in adult patients with aHUS (ALXN1210-aHUS-311)

The study in adults was a multicentre, single-arm, phase 3 clinical study in patients with documented aHUS who had not had any treatment with a complement inhibitor prior to enrolment in this study and showed signs of thrombotic microangiopathy (TMA). The study consisted of a 26-week initial evaluation period and the patients had the option of participating in an extension of up to 4.5 years.

A total of 58 patients with documented aHUS were enrolled. The inclusion criteria excluded patients who had TMA resulting from thrombotic thrombocytopenic purpura (TTP) or Shiga toxin-producing Escherichia coli haemolytic uraemic syndrome (STEC-HUS). Two patients were excluded from the complete analysis set because of a confirmed diagnosis of STEC-HUS. At the start of the study, 93% of the patients showed extrarenal (cardiovascular, pulmonary, central nervous, gastrointestinal, cutaneous or musculoskeletal) signs or symptoms of aHUS.

Table 11 shows the demographic characteristics and baseline characteristics of 56 adult patients who were included in study ALXN1210-aHUS-311 and formed the complete analysis set.

Table 11: Baseline characteristics in the study in adults

Note: the percentages are based on the total number of patients.

Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; Max. = maximum; Min. = minimum.

The primary endpoint was the complete response of the TMA during the 26-week period for the first assessment, demonstrated by normalisation of the haematological parameters (platelet count ≥150 × 10⁹/L and LDH ≤246 U/L) and an improvement in serum creatinine by ≥25% compared with the baseline value. Patients had to fulfil each criterion for a complete response of the TMA at 2 different assessments separated by an interval of at least 4 weeks (28 days) and at each measurement in between.

A complete response of the TMA was observed in 30 of the 56 patients (53.6%) during the 26-week period for the first assessment, as shown in Table 12.

Table 12: Analysis of the complete response of the TMA and the components of the complete response of the TMA during the 26-week period for the first assessment (ALXN1210-aHUS-311)

^a The 95% CIs for the fraction were based on the asymptotic Gaussian approximation method with continuity correction.

Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy.

Four further patients showed a complete response of the TMA, which was confirmed after the 26-week period for the first assessment (the complete response of the TMA was observed on days 169, 302, 401 and 407). Thus, a total of 34 out of 56 patients showed a complete response of the TMA (60.7%; 95% CI: 47.0%, 74.4%). The number for the response of individual components increased to 48 patients (85.7%; 95% CI: 75.7%, 95.8%) for the normalisation of the platelet count, to 47 patients (83.9%; 95% CI: 73.4%, 94.4%) for the normalisation of LDH, and to 35 patients (62.5%; 95% CI: 48.9%, 76.1%) for improvement in kidney function.

A complete response of the TMA was achieved within a median period of 86 days (7 to 169 days). An increase in the mean platelet count was observed soon after the start of ravulizumab treatment, with a rise from 118.52 × 10⁹/L at the start of the study to 240.34 × 10⁹/L on day 8 being observed. The value remained above 227 × 10⁹/L at all subsequent visits during the period for the first assessment (26 weeks). Similarly, the mean LDH value decreased from the baseline value during the first 2 months of treatment, and the decrease was maintained throughout the period for the first assessment (26 weeks).

Of the patients who presented with stage 5 chronic kidney disease, 67.6% (23/34) showed an improvement in the chronic kidney disease of 1 or more stages. The stage of the chronic kidney disease continued to improve in many patients (19/30) after a complete response of the TMA was achieved during the 26-week period for the first assessment. Of the 29 patients who were dialysis-dependent at the time of enrolment in the study, 17 were able to discontinue dialysis treatment by the end of the available follow-up period, while 6 out of 27 patients who were not receiving any dialysis treatment at the start of the study were receiving dialysis treatment at the last available follow-up examination. Table 13 summarises the secondary efficacy results from study ALXN1210-aHUS-311.

Table 13: Secondary efficacy result for study ALXN1210-aHUS-311

Note: n: number of patients with available data for a defined examination at the visit on day 183. m: number of patients who fulfil a defined criterion. The stage of the chronic kidney disease (CKD) is determined using the chronic kidney disease stage classification of the National Kidney Foundation. Stage 5 is the worst category, whereas stage 1 is the best category. The baseline value is determined using the last available eGFR before the start of treatment. Improvement/deterioration: compared with the CKD stage at the start of the study. *The 95% confidence intervals (95% CI) are based on the exact Clopper-Pearson confidence interval. ^aExcludes patients with stage 1 CKD at the start of the study, because no improvement is possible in them. ^bExcludes patients with stage 5 at the start of the study, as no deterioration is possible in them.

Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy.

Generalised Myasthenia Gravis (gMG)

Study in adult patients with gMG

The efficacy and safety of ravulizumab in adult patients with gMG was assessed in a phase 3, randomised, double-blind, placebo-controlled, multicentre study (ALXN1210-MG-306). Patients participating in this study were subsequently allowed to enter an open-label extension phase during which all patients received ravulizumab.

Patients with gMG (diagnosed at least 6 months previously) and a positive serum test for anti-acetylcholine receptor (AChR) antibodies, MGFA (Myasthenia Gravis Foundation of America) clinical classification Class II to IV and residual symptomatology as evidenced by a Myasthenia Gravis Activities of Daily Living (MG-ADL) total score ≥6 were randomised to treatment with either ravulizumab (N = 86) or placebo (N = 89). Patients on immunosuppressant therapies (corticosteroids, azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate mofetil or tacrolimus) were permitted to continue on this previous therapy throughout the course of the study. In addition, a rescue therapy (including high-dose corticosteroids, 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 randomised, controlled period of study ALXN1210-MG-306. The characteristics of patients at baseline are presented in Table 14. The overwhelming majority of patients enrolled in the study (97%) had been treated with at least one immunomodulatory therapy, including immunosuppressant therapies, PE/PP or IVIg, in the last two years prior to study enrolment.

Table 14: Baseline characteristics in study ALXN1210-MG-306