ULTOMIRIS is indicated for:

·       The treatment of adult and pediatric patients with a body weight of 10 kg or above with paroxysmal nocturnal hemoglobinuria (PNH).

·       The treatment of adults and pediatric patients with a body weight of 10 kg or above with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).

·       The treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive.

·       The treatment of adult patients with anti-aquaporin 4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD).

Adult and pediatric patients with PNH and aHUS with body weight greater than or equal to 5 kg:

The recommended ULTOMIRIS intravenous (IV) maintenance dosing in adult and pediatric patients with PNH or aHUS with a body weight greater than or equal to 5 kg is based on the patient’s body weight, as shown in Table 1, with maintenance doses administered every 4 or 8 weeks, starting 2 weeks after loading dose.

Refer to Table 2 for treatment initiation instructions in patients who are complement inhibitor treatment-naïve or switching treatment from SOLIRIS^®.

Dosing schedule is allowed to occasionally vary by ± 7 days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS), but the subsequent dose should be administered according to the original schedule.

Adult patients with gMG or NMOSD with body weight greater than or equal 40 kg

The recommended ULTOMIRIS IV maintenance dosing in adult patients with gMG or NMOSD with a body weight greater than or equal to 40 kg is based on the patient’s body weight, as shown in Table 1, with maintenance doses administered every 8 weeks, starting 2 weeks after loading dose.

Refer to Table 2 for treatment initiation instructions in patients who are complement inhibitor treatment-naïve or switching treatment from SOLIRIS.

Dosing schedule is allowed to occasionally vary by ± 7 days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS IV) but the subsequent dose should be administered according to the original schedule.

Table 1:        ULTOMIRIS Weight-Based Dosing Regimen

*See Table 2 for ULTOMIRIS IV loading dose instructions prior to maintenance dosing.

**For PNH and aHUS indications only.

Abbreviations: aHUS = atypical hemolytic uremic syndrome; IV = intravenous; PNH = paroxysmal nocturnal hemoglobinuria

Table 2:        ULTOMIRIS IV Treatment Initiation Instructions

Abbreviations: aHUS = atypical hemolytic uremic syndrome; IV = intravenous; PNH = paroxysmal nocturnal hemoglobinuria; SC = subcutaneous

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

Plasma exchange (PE), plasmapheresis (PP), and intravenous immunoglobulin (IVIg) have been shown to reduce ULTOMIRIS serum levels. A supplemental dose of ULTOMIRIS is required in the setting of PE, PP, or IVIg (Table 3).

Table 3:        Supplemental Dose of ULTOMIRIS IV Dose after PE, PP, or IVIg 

Abbreviations: IVIg = intravenous immunoglobulin; PE = plasma exchange; PP = plasmapheresis

Home Infusion

Home infusion may be considered for patients who have tolerated infusions well in the clinic. The decision of a patient to receive home infusions should be made after evaluation and recommendation from the treating physician. Home infusions should be performed by a qualified healthcare professional.

There is limited safety data supporting home-based infusions. Additional precautions in the home setting such as availability of emergency treatment of infusion reactions or anaphylaxis are recommended.

1.1.1       Method of Administration

ULTOMIRIS 10 mg/mL must be diluted to a final concentration of 5 mg/mL.

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 10 mg/mL must be diluted, prior to administration by intravenous infusion depending on body weight, see Table 4 below.

Table 4:        Loading and Maintenance Dose Administration Rate for ULTOMIRIS 10 mg/mL

^* For PNH and aHUS indications only.

^a Body weight at time of treatment.

Abbreviations: aHUS = atypical hemolytic uremic syndrome; IV = intravenous; PNH = paroxysmal nocturnal hemoglobinuria

Table 5:        Supplemental Dose Administration Rate for ULTOMIRIS 10 mg/mL

^a Body weight at time of treatment.

Abbreviation: IV = intravenous

ULTOMIRIS 10 mg/mL and 100 mg/mL should not be mixed together.

For instructions on dilution of the medicinal product before administration, see Section 6.6.

1.1.2       Special Populations

Women of Childbearing Potential

Women of childbearing potential should use effective contraception methods during treatment and up to 8 months after treatment.

Pediatric Population/Use in children

Use of ULTOMIRIS in pediatric patients for treatment of PNH is supported by evidence from a pediatric clinical study (13 patients aged 9 to 17 years). The safety and efficacy of ULTOMIRIS IV for the treatment of pediatric and adult patients with PNH appear similar (Section 5.1.3).

Use of ULTOMIRIS in pediatric patients for treatment of aHUS is supported by evidence from a pediatric clinical study (14 patients aged 10 months to 17 years). The safety and efficacy of ULTOMIRIS for the treatment of aHUS is consistent in pediatric and adult patients.

ULTOMIRIS has not been studied in PNH patients below 9 years of age. The posology to be used in pediatric patients with PNH is identical to the weight-based dosing recommendations provided for pediatric patients with aHUS, with maintenance dosing starting 2 weeks after loading dose administration. Based on the PK/PD data available in aHUS and PNH patients treated with ULTOMIRIS, this dosing regimen is expected to result in an efficacy and safety profile similar to that in adults, for all pediatric patients starting at 5 kg.

ULTOMIRIS has not been evaluated in pediatric patients with gMG or NMOSD.

Use in the Elderly

ULTOMIRIS may be administered to patients aged 65 years and over. There is no evidence indicating any special precautions are required for treating a geriatric population.

Patients with Aplastic Anemia

ULTOMIRIS may be administered to patients with PNH treated with concomitant medications for aplastic anemia (including immunosuppressive therapies). There is no evidence indicating any special precautions are required in patients with aplastic anemia.

Renal and Hepatic Impairment

Studies have not been conducted to examine the effects of hepatic impairment; however pharmacokinetic data suggest that no dose adjustment is required in patients with hepatic impairment.

No dose adjustment is required for patients with renal impairment, see Section 5.2.5.

The clinical trials of ULTOMIRIS in patients with aHUS included patients with other complement- mediated TMA conditions (patients with renal impairment, some of whom were receiving dialysis). No dose adjustment is required in this population, see Section 5.2.5.

1.1.1       Serious Meningococcal Infection

Due to its mechanism of action, the use of ULTOMIRIS increases the patient's susceptibility to meningococcal infection/sepsis (Neisseria meningitidis). Meningococcal disease due to any serogroup may occur. To reduce this risk of infection, all patients must be vaccinated against meningococcal infection at least 2 weeks prior to initiating ULTOMIRIS unless the risk of delaying ULTOMIRIS outweighs the risks of developing a meningococcal infection. Patients who initiate ULTOMIRIS 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 in preventing the commonly pathogenic meningococcal serogroups. Patients must be vaccinated or revaccinated according to current national guidelines for vaccination use.

Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given to official guidance on the appropriate use of antibacterial agents. Cases of serious or fatal meningococcal infections/sepsis have been reported in patients treated with ULTOMIRIS and 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 steps should be taken to seek medical care immediately. Physicians should provide patients with a patient information brochure and a Patient safety card.

1.1.2       Immunization

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

1.1.3       Other Systemic Infections

ULTOMIRIS therapy should be administered with caution to patients with active systemic infections. ULTOMIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially infections caused by Neisseria species. Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported in patients treated with ULTOMIRIS and other terminal complement inhibitors.

Patients should be provided with information from the Patient Information Brochure to increase their awareness of potential serious infections and their signs and symptoms. Physicians should advise patients about gonorrhea prevention. Patients below the age of 18 years old must be vaccinated against Haemophilus influenzae and pneumococcal infections and need to adhere strictly to the national vaccination recommendations for their age group.

1.1.4       Infusion Reactions (Infusion-Related Reactions)

Administration of ULTOMIRIS may result in systemic infusion-related reactions that cause allergic or hypersensitivity reactions (including anaphylaxis).

In case of a systemic infusion-related reaction, if signs of cardiovascular instability or respiratory compromise occur, administration of ULTOMIRIS should be interrupted and appropriate supportive measures should be instituted.

1.1.5       Immunogenicity

Treatment with any therapeutic protein may induce an immune response.

In ULTOMIRIS IV studies in PNH (N = 488), aHUS (N = 89), gMG (N = 86), and NMOSD (N = 58), treatment emergent anti-drug antibodies were reported in 2 patients (0.28%), one with PNH and one with aHUS. These anti-drug antibodies were transient in nature with low titer and did not correlate with clinical response or adverse events.

1.1.6       Treatment Discontinuation in PNH

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a chronic disease and treatment with ULTOMIRIS is recommended to continue for the patient’s lifetime.

If patients with PNH discontinue treatment with ULTOMIRIS, they should be closely monitored for signs and symptoms of hemolysis, identified by elevated LDH along with sudden decrease in PNH clone size or hemoglobin, or re-appearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction. Any patient who discontinues ULTOMIRIS should be monitored for at least 16 weeks to detect hemolysisand other reactions. If signs and symptoms of hemolysis occur after discontinuation, including elevated LDH, consider restarting treatment with ULTOMIRIS.

1.1.7       Treatment Discontinuation in aHUS

ULTOMIRIS treatment to resolve aHUS should be a minimum duration of 6 months, beyond which length of treatment needs to be considered for each patient individually. Patients who are at higher risk for TMA recurrence, as determined by the treating healthcare provider (or clinically indicated), may require chronic therapy.

There are no specific data on ravulizumab discontinuation. In a long-term prospective observational study, discontinuation of complement C5 inhibitor treatment (SOLIRIS) resulted in a 13.5-fold higher rate of TMA recurrence and showed a trend toward reduced renal function compared to patients who continued treatment.

If patients must discontinue treatment with ravulizumab, they should be monitored closely for signs and symptoms of TMA on an on-going basis. However, monitoring may be insufficient to predict or prevent severe TMA complications.

TMA complications post-discontinuation can be identified if any of the following is observed:

(i)             At least two of the following laboratory results observed concurrently: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ravulizumab treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during ravulizumab treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during ravulizumab treatment; (results should be confirmed by a second measurement 28 days apart).

Or

(ii)            any one of the following symptoms of TMA: a change in mental status or seizures or other extra renal TMA manifestations including cardiovascular abnormalities, pericarditis, gastrointestinal symptoms/diarrhoea; or thrombosis.

If TMA complications occur after ravulizumab discontinuation, consider reinitiation of ravulizumab treatment beginning with the loading dose and maintenance dose described in Section 4.2.

1.1.8       Treatment Discontinuation in gMG

Considering that gMG is a chronic disease, patients benefiting from ULTOMIRIS treatment who discontinue treatment should be monitored for symptoms of the underlying disease. If symptoms of gMG occur after discontinuation, consider restarting treatment with ULTOMIRIS.

1.1.9       Treatment Discontinuation in NMOSD

Considering that NMOSD is a chronic disease, patients benefiting from ULTOMIRIS treatment who discontinue treatment should be monitored for symptoms of NMOSD relapse. If symptoms of NMOSD relapse occur after discontinuation, consider restarting treatment with ULTOMIRIS.

No interaction studies have been performed.

Concomitant use of ULTOMIRIS with neonatal Fc receptor (FcRn) blockers may lower systemic exposures and reduce effectiveness of ULTOMIRIS. Closely monitor for reduced effectiveness of ULTOMIRIS.

See Section 4.2.1 for guidance in case of concomitant PE, PP, or IVIg treatment.

Pregnancy

No clinical data on exposed pregnancies are available.

Nonclinical reproductive toxicology studies were not conducted with ravulizumab. Reproductive toxicology studies were conducted in mice using the murine surrogate molecule BB5.1, which assessed effect of C5 blockade on the reproductive system. No specific test-article related reproductive toxicities were identified in these studies. Human IgG are known to cross the human placental barrier, and thus ravulizumab may potentially cause terminal complement inhibition in fetal circulation.

Lactation

It is unknown whether ravulizumab is excreted into human milk. Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in nursing infants, breast-feeding should be discontinued during treatment and up to 8 months after treatment.

Nonclinical reproductive toxicology studies conducted in mice with the murine surrogate molecule BB5.1 identified no adverse effect to pups resulting from consuming milk from treated dams.

Fertility

No specific non-clinical study on fertility has been conducted with ravulizumab.

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

No studies on the effects on the ability to drive and use machines have been performed.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via their national reporting system.

a.     Summary of the safety profile

The most common adverse drug reactions (≥ 10%) across all clinical trials are headache, nasopharyngitis, upper respiratory tract infection, diarrhea, pyrexia, nausea, arthralgia, fatigue, back pain and abdominal pain. The most serious adverse reactions in patients in clinical trials are meningococcal infection and meningococcal sepsis.

b.     Tabulated list of adverse reactions

Table 6 lists the adverse reactions observed from clinical trials and post-marketing experience. Adverse reactions with ULTOMIRIS are listed by System Organ Class and preferred term using MedDRA frequency convention very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 6:        Adverse drug reactions from clinical trials & post marketing experience^a

^a Estimated postmarketing experience based on 2020-Dec-31 cutoff from Periodic Safety Update Report (PSUR) (Type II variation submitted for hypersensitivity).

^b Meningococcal infection is a group term that includes Preferred Terms meningococcal infection, meningococcal sepsis, and encephalitis meningococcal.

^c Gonococcal infection includes disseminated gonococcal infection; data based on 2021-Dec-31 cutoff date from Development Safety Update Report (DSUR).

Source: Data on file based on 52-week data cutoff from Phase 3 PNH Studies ALXN1210‑PNH‑301 (2018‑Sep‑04), Final study data from ALXN1210-PNH-302 (CSR dated 08 Nov 2022) and Final study data from Study ALXN1210-PNH-201 (CSR dated 12 Aug 2022); 52-week cutoff from Phase 3 complement-mediated TMA Studies ALXN1210-aHUS-311 (2019-Oct-10) and ALXN1210‑aHUS‑312 (2020-Jan-28); 90-day safety update for Study ALXN1210-PNH-103 (2018-Apr-23) and Study ALXN1210‑PNH-304 (2020-Dec-01); ; 60-week data cutoff from gMG Study ALXN1210‑MG‑306 (2021-Nov-09); Week 108 data from SC Study ALXN1210‑PNH‑303 (2022-Mar-02); and Primary Treatment Period for NMOSD Study ALXN1210‑NMO‑307 (2022‑Apr‑26).

c.      Description of selected adverse reactions

Meningococcal infections/sepsis

In clinical studies, the most serious adverse reactions from ULTOMIRIS were meningococcal infections, which were uncommon in frequency (0.5%) (Section 5.1.3). Meningococcal infections in patients treated with ULTOMIRIS have presented as meningococcal sepsis. Patients should be informed of the signs and symptoms of meningococcal septicemia and advised to seek medical care immediately.

Infusion reactions (Infusion-related reactions)

In clinical trials, infusion-related reactions were common (1.8%). They were mild to moderate in severity and transient (e.g., lower back pain, abdominal pain, muscle spasms, drop in blood pressure, elevation in blood pressure, limb discomfort, drug hypersensitivity [allergic reaction], dysgeusia [bad taste], and drowsiness). These reactions did not require discontinuation of ULTOMIRIS.

d.     Paediatric population

In children and adolescent PNH patients (aged 9 to 17 years old) included in the pediatric PNH Study (ALXN1210-PNH-304), the safety profile of ULTOMIRIS IV was consistent with that observed in adult PNH patients. The most common adverse reaction reported in pediatric PNH patient was abdominal pain and nasopharyngitis.

In pediatric aHUS patients (aged 10 months to 17 years old) included in Study ALXN1210 aHUS 312, the safety profile of ULTOMIRIS IV was consistent with that observed in adult patients with evidence of aHUS. The safety profile was also consistent for pediatric patients in the different age-group subsets. The safety data for patients below 2 years of age are limited to four patients. The most common adverse reaction reported in pediatric patients was pyrexia.

ULTOMIRIS IV has not been evaluated in pediatric patients with gMG or NMOSD.

e.      Geriatric population

No overall differences in safety were reported between elderly (≥ 65 years) and younger patients (< 65 years) with ULTOMIRIS.

To report any side effect(s):

Saudi Arabia:

Other GCC States:

No case of overdose has been reported to date.

Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AA43

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.

5.1          Pharmacodynamic properties

5.1.1    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 terminal complement complex [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 and complement-mediated TMA, gMG and NMOSD 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. In patients with NMOSD, ULTOMIRIS inhibits terminal complement activation, thus preventing MAC formation and C5a-dependent inflammation, and limiting astrocyte necrosis and damage to surrounding glial cells and neurons.

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 Section 5.2).

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; ravulizumab half-life in serum yields prolonged pharmacologic activity, allowing dosing once every 8 weeks (or once every 4 weeks below 20 kg).

5.1.2 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.

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 or NMOSD by the end of the first infusion and throughout the primary treatment period.

The extent and duration of the pharmacodynamic response were exposure-dependent in patients with PNH, complement-mediated TMA, gMG or NMOSD following ULTOMIRIS IV 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 clinical development program was designed to determine whether ULTOMIRIS is noninferior to SOLIRIS in adult patients with PNH regardless of previous treatment status while assessing potential beneficial effects of a longer dosing interval. The safety and efficacy of ULTOMIRIS in patients with PNH were assessed in two distinct and complementary populations: a complement-inhibitor-naïve population of patients with active hemolysis to establish the magnitude of the efficacy response, and a population of patients stable on SOLIRIS therapy that allowed the assessment of the maintenance of efficacy and safety in a population switching to ULTOMIRIS. Accordingly, two adequate and well controlled Phase 3 trials were conducted to cover each population:

·       a Complement-Inhibitor Naïve Study in adult patients with PNH who were naïve to complement inhibitor treatment (ALXN1210-PNH-301),

·       a SOLIRIS-Experienced Study in patients with PNH who were clinically stable after having been treated with SOLIRIS (eculizumab) for at least the previous 6 months (ALXN1210- PNH-302).

ULTOMIRIS was dosed in accordance with the recommended dosing described in Section 4.2 (4 infusions of ULTOMIRIS over 26 weeks) while SOLIRIS was administered according to the approved dosing regimen of SOLIRIS (15 infusions over 26 weeks) which was the standard-of-care for PNH at the time of studies.

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. Twelve-month transfusion history was similar between ULTOMIRIS and SOLIRIS treatment groups within each of the Phase 3 studies.

The safety and efficacy of ULTOMIRIS IV in pediatric patients with PNH was assessed in PNH Study ALXN1210-PNH-304, an open-label, Phase 3 study conducted in eculizumab experienced and complement inhibitor treatment naïve pediatric patients with PNH.

5.1.3.1.1         Study in Complement-Inhibitor Naïve 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.

PNH medical history was similar between ULTOMIRIS and SOLIRIS treatment groups. The twelve- month transfusion history was similar between ULTOMIRIS and SOLIRIS treatment groups. 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 hemolytic at baseline; 86.2% of enrolled patients presented with elevated LDH ≥ 3 x ULN, which is a direct measurement of intravascular hemolysis, in the setting of PNH. The median total RBC clone size was 33.75%, consistent with ongoing active hemolysis of PNH erythrocytes in a patient population with a large median granulocyte clone size (92.55%).

Table 7 presents the baseline characteristics of the PNH patients enrolled in the Complement-Inhibitor Naïve Study.

Table 7:        Baseline Characteristics in the Complement-Inhibitor Naïve Study (ALXN1210-PNH-301)

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

Abbreviations: LDH = lactate dehydrogenase; PNH = paroxysmal nocturnal hemoglobinuria; pRBC = packed red blood cell; SD = standard deviation

The coprimary endpoints were transfusion avoidance, and hemolysis as directly measured by normalization of LDH levels. Transfusion avoidance was considered as achieved only by the patients who did not receive a transfusion and did not meet the protocol specified guidelines for transfusion from baseline to Day 183. 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 the proportion of patients with stabilized hemoglobin.

In the Complement-Inhibitor Naïve Study, both coprimary endpoints, avoidance of pRBC transfusion per protocol-specified guidelines and LDH normalization from Day 29 to Day 183, met the primary objective and showed ULTOMIRIS was statistically significant for noninferiority compared to SOLIRIS. ULTOMIRIS also achieved statistically significant noninferiority compared to SOLIRIS for all 4 key secondary endpoints. Both coprimary endpoints and all key secondary endpoints favored ULTOMIRIS (Figure 1).

Figure 1:  Analysis of Coprimary and Secondary Endpoints – Full Analysis Set         (Complement- Inhibitor Naïve Study) (ALXN1210-PNH-301)

Note: The black triangle indicates the noninferiority margins, and grey dots indicates point estimates Note: LDH = lactate dehydrogenase, CI = confidence interval

Transfusion avoidance through Day 183 was achieved by 73.6% of patients in the ULTOMIRIS group compared to 66.1% in the SOLIRIS group. The difference between the ULTOMIRIS and SOLIRIS treatment groups in the percentage of patients who avoided transfusion was 6.8% (95% CI: -4.66%, 18.14%). Total number of units transfused was also lower for the ULTOMIRIS group (222 for SOLIRIS vs 155 for ULTOMIRIS). The adjusted prevalence of LDH normalization (LDH levels ≤ 1 × ULN from Day 29 through Day 183) was 53,6% for the ULTOMIRIS group and 49,4% for the SOLIRIS group. The adjusted odds ratio for the comparison of ULTOMIRIS to SOLIRIS was 1.187 (95% CI: 0.796, 1.769). The median time to first LDH normalization was 24 days for ULTOMIRIS and 29 days for SOLIRIS.

Mean percent change in LDH from baseline to Day 183 was -76.84% for the ULTOMIRIS group and - 76.02% for the SOLIRIS group. The mean difference between treatment groups was -0.83% (95% CI: - 5.21%, 3.56%).

Mean change in FACIT-Fatigue total score from baseline to Day 183 was 7.07 for the ULTOMIRIS group and 6.40 for the SOLIRIS group, with a 3-point improvement from baseline on this scale considered a clinically meaningful improvement. The mean difference between treatment groups was 0.67 (95% CI: -1.21, 2.55). Both treatment groups showed improvement in fatigue as measured by FACIT- Fatigue overtime, with ULTOMIRIS better than SOLIRIS at all time points for the FACIT-Fatigue.

Breakthrough hemolysis defined as at least one new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥ 2 × ULN, after prior LDH reduction to < 1.5 × ULN on therapy, was experienced by 4.0% of patients in the ULTOMIRIS group and 10.7% of patients in the SOLIRIS group. The difference between treatment groups was -6.7% (95% CI: -14.21%, 0.18%).

Hemoglobin stabilization through Day 183 was achieved by 68.0% of patients in the ULTOMIRIS group and 64.5% of patients in the SOLIRIS group. The difference between treatment groups was 2.9% (95% CI: -8.80%, 14.64%).

Because statistically significant noninferiority was achieved for both coprimary and all 4 key secondary endpoints, superiority was assessed following the prespecified hierarchical testing order that began with breakthrough hemolysis endpoint. The treatment difference for breakthrough hemolysis (p = 0.0558) did not reach the prespecified threshold for superiority (p < 0.05), and no further testing was conducted. The incidence of breakthrough hemolysis was more than 2-fold higher in the SOLIRIS group (13 patients with 15 events) than in the ULTOMIRIS group (5 patients with 5 events). Of the 15 breakthrough hemolysis events seen in the SOLIRIS group, 7 were associated with elevated free C5 above 0.5 µg/mL. No patients in the ULTOMIRIS group had elevations of free C5 levels above 0.5 µg/mL.

5.1.3.1.2         Study in 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 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 twelve- 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. Per study entry criteria, all patients presented with controlled hemolysis at baseline; consistent with a population under continuous treatment with SOLIRIS. 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 8 presents the baseline characteristics of the PNH patients enrolled in the SOLIRIS-Experienced Study.

Table 8:        Baseline Characteristics in the SOLIRIS-Experienced Study (ALXN1210 PNH-302)

a “Other” category included neutropenia, renal dysfunction, and thrombopenia, as well as a number of other conditions.

Abbreviations: LDH = lactate dehydrogenase; PNH = paroxysmal nocturnal hemoglobinuria; pRBC = packed red blood cell; SD = standard deviation

The 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.

In the SOLIRIS-Experienced Study, the primary endpoint, Percent Change in LDH from baseline to Day 183, met the primary objective and showed ULTOMIRIS was statistically significant for noninferiority compared to SOLIRIS. ULTOMIRIS also achieved statistically significant noninferiority compared to SOLIRIS for all 4 key secondary endpoints. Both primary endpoints and all key secondary endpoints favored ULTOMIRIS (Figure 2).

Figure 2: Analysis of Primary and Secondary Endpoints – Full Analysis Set (SOLIRIS- Experienced Study) (ALXN1210-PNH-302)

Note: The black triangle indicates the noninferiority margins, and grey dot indicates point estimates. Note: LDH = lactate dehydrogenase, CI = confidence interval

Mean percent change in LDH from baseline to Day 183 showed a decrease of less than 1% (-0.82%) for the ULTOMIRIS group and an increase of greater than 8% (+8.39%) for the SOLIRIS group with a treatment difference (ULTOMIRIS- SOLIRIS) of -9.21% (95% CI: -18.84%, 0.42%).

Breakthrough hemolysis, using the same definition as the Complement-Inhibitor Naïve Study, was experienced by none of the patients in the ULTOMIRIS group and 5 (5.1%) of the patients in the SOLIRIS group. The difference between treatment groups was -5.1% (95% CI: -18.99%, 8.89%). The incidence of breakthrough hemolysis was higher in the SOLIRIS group (7 events) than in the ULTOMIRIS group (0 events). Of the 7 breakthrough hemolysis events seen in the SOLIRIS group, 4 were associated with elevated free C5 above 0.5 µg/mL. There were no breakthrough hemolysis events in the ULTOMIRIS group and no patients in the ULTOMIRIS group had elevations of free C5 levels above

0.5 µg/mL.

Mean change in FACIT-Fatigue total score from baseline to Day 183 was 2.01 for the ULTOMIRIS group and 0.54 for the SOLIRIS group. The LS mean difference between treatment groups was 1.5 (95% CI: -0.2, 3.2). Both treatment groups showed improvement in fatigue as measured by FACIT-Fatigue over time, with ULTOMIRIS better than SOLIRIS at all time points following Day 8.

Transfusion avoidance was achieved by 87.6% of patients on ULTOMIRIS compared to 82.7% of patients on SOLIRIS by week 26. The difference between the ULTOMIRIS and SOLIRIS treatment groups in the percentage of patients who avoided transfusion was 5.5% (95% CI: -4.27%, 15.68%).

Hemoglobin stabilization through Day 183 was achieved by 76.3% of patients in the ULTOMIRIS group and 75.5% of patients in the SOLIRIS group. The difference between treatment groups was 1.4% (95% CI: -10.41%, 13.31%).

Because statistically significant noninferiority was achieved for the primary endpoint and all 4 key secondary endpoints, the prespecified hierarchical order continued with superiority testing of percent change from baseline in LDH. The assessment of the treatment difference for superiority resulted in p-

value = 0.0583 which did not reach the prespecified significance threshold for superiority (p < 0.05) and therefore no additional testing in the hierarchy was conducted.

Overall, treatment with ULTOMIRIS in both complement-inhibitor naïve and SOLIRIS-experienced patients was associated with clinically meaningful benefits across disease-relevant endpoints and reduction of the overall risk of breakthrough hemolysis through better C5 control and elimination of the risk of pharmacodynamic-associated breakthrough hemolysis.

5.1.3.1.3         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 treatment naïve pediatric patients with PNH. Patients who completed the 26-week primary evaluation period are to be followed for up to 4 years in the long-term Extension Period.

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 inhibition and 8 patients were treated with SOLIRIS. Eleven of the 13 patients were between 12 and 17 years of age at first infusion, with 2 patients under 12 years old (11 and 9 years old). Based 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 treatment period regardless of prior experience with SOLIRIS. Following initiation of ULTOMIRIS treatment, steady-state therapeutic serum concentrations of ULTOMIRIS were achieved immediately after the first dose and maintained throughout the Primary Evaluation Period in both cohorts. There was no breakthrough hemolysis during the 26-week Primary Evaluation Period 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 treatment naïve cohort and remained stable in the SOLIRIS-experienced cohort during the 26-week Primary Evaluation Period. Three (60%) of the 5 complement inhibitor treatment-naïve patients and 6 (75%) of the 8 SOLIRIS-experienced patients achieved hemoglobin stabilization by Week 26, respectively. Transfusion-avoidance was reached for 85% (11/13) of patients during the 26-week Primary Evaluation Period.

A clinically relevant improvement from baseline in QoL as assessed by Pediatric FACIT-Fatigue (ie, mean improvement of > 3 units for Pediatric FACIT-Fatigue scores) was sustained throughout the Primary Evaluation Period in the 5 complement inhibitor treatment-naïve patients. A slight improvement was also observed in SOLIRIS-experienced patients.

Table 9 presents efficacy outcomes for the Primary Evaluation Period.

Table 9:        Efficacy Outcomes from the 26-Week Primary Evaluation Period of Pediatric Study in Patients with PNH (ALXN1210-PNH-304)

a No patients experienced breakthrough hemolysis during the Primary Evaluation Period. One patient experienced breakthrough hemolysis after 1.8 years of treatment during the Extension Period; however, at the time of the breakthrough hemolysis event the patient had adequate C5 inhibition (free C5 < 0.5 µg/mL).

Abbreviations: C5 = complement component 5; CI = confidence interval; FACIT = Functional Assessment of Chronic Illness Therapy; LDH = lactate dehydrogenase; PNH = paroxysmal nocturnal hemoglobinuria; SD = standard deviation

Based on these data, pediatric patients with PNH can be initiated on ULTOMIRIS or switched from SOLIRIS to ULTOMIRIS safely and with no loss of efficacy. The efficacy of ULTOMIRIS in pediatric PNH patients is similar to that observed in adult PNH patients enrolled in pivotal studies (Section 5.1.3.1).

5.1.3.1.4         Long-Term Efficacy and Safety Data in PNH

Long-term safety and efficacy data were obtained from patients with PNH that were initially treated with ULTOMIRIS in Phase 1b/2 (n = 39) studies and continued to be treated in extension periods from studies which demonstrated a sustained effect of ULTOMIRIS on all PNH measures for over 2 years as evidenced by mean LDH values, transfusion avoidance and mean hemoglobin values and safety profile consistent with results from Phase 3 studies (ALXN1210-PNH-301 and ALXN1210-PNH-302).

1.1.3.2                   Complement-mediated TMA Including aHUS (ALXN1210-aHUS-311)

The safety and efficacy of ravulizumab in patients with complement-mediated TMA was assessed in 2 open label, single arm, Phase 3 studies. Study ALXN1210-aHUS-311 enrolled adult patients with complement-mediated TMA. Study ALXN1210-aHUS-312 enrolled pediatric patients with complement-mediated TMA.

5.1.3.2.1         Study in Adult Patients with Complement-Mediated TMA

The adult study was a multicentre, single arm, Phase 3 study conducted in patients who were naïve to complement inhibitor treatment prior to study entry. 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 TMA were enrolled. Enrolment criteria excluded patient presenting with TMA due to a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, Shiga toxin Escherichia coli related hemolytic uremic syndrome (STEC-HUS) and genetic defect in cobalamin C metabolism. Two patients were excluded from the Full Analysis Set due to a confirmed diagnosis of Shiga toxin Escherichia coli-related hemolytic uremic syndrome (STEC-HUS). Consequently, there is no information on the use of ULTOMIRIS in these populations. The majority of patients had extra renal signs or symptoms of aHUS at baseline. At baseline, 71.4% (n = 41) of patients had Stage 5 chronic kidney disease (CKD).

Table 10 presents the demographics and baseline characteristics of the 56 adult patients enrolled in Study ALXN1210-aHUS-311 that constituted the Full Analysis Set.

Table 10:         Baseline Characteristics in the Adult Study (ALXN1210-aHUS-311)

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

Abbreviations: aHUS = atypical hemolytic uremic syndrome; eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum; SD = standard deviation; TMA = thrombotic microangiopathy

The primary endpoint was Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) 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. All serum creatinine values obtained while a patient was on dialysis were excluded from all analyses. When a patient is on dialysis at baseline, then the first valid creatinine value to be used as the baseline value is the first assessment ≥ 6 days post dialysis. If a patient is on dialysis during the entire 26-week Initial Evaluation Period, then the baseline creatinine is not calculated.

Secondary endpoints included time to Complete TMA Response, Complete TMA Response status over time, dialysis requirement, CKD stage as evaluated by estimated glomerular filtration rate (eGFR), hemoglobin response and change from baseline in quality of life (QoL).

Complete TMA Response was observed in 30 of the 56 patients (53.6%) during the 26-week Initial Evaluation Period as shown in Table 11.

Table 11: 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 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). Table 12 summarizes the secondary efficacy results for Study ALXN1210-aHUS-311.

Renal function, as measured by eGFR, was improved or maintained during ravulizumab treatment. Two thirds of the patient population (32/47), who were mostly CKD Stage 4 or 5 at baseline, improved by 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. Seventeen 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. Patients reported improved health-related QoL.

Table 12:         Secondary Efficacy Outcome for Study ALXN1210-aHUS-311

Note: m: number of patients available at Day 183 visit. 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: Compared to CKD stage at baseline. Improved: Excluded those with Stage 1 at baseline as they cannot improve. *95% confidence intervals (95% CIs) are based on exact confidence limits using the Clopper-Pearson method. **95% confidence intervals (95% CIs) for the proportion are based on the asymptotic Gaussian approximation method with a continuity correction.***Excludes patients with Stage 5 at baseline as they cannot worsen.

Abbreviations: CI = confidence interval; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; FACIT = Functional Assessment of Chronic Illness Therapy; LDH = lactate dehydrogenase; SD = standard deviation; TMA = thrombotic microangiopathy.

There was no observable clinically meaningful difference in efficacy results in studies with ULTOMIRIS and SOLIRIS after 26 weeks of treatment.

5.1.3.2.2         Study in Pediatric Patients with Complement-Mediated TMA

The 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 complement-mediated TMA were enrolled of whom 18 were included in the full analysis set. Enrolment criteria excluded patient presenting with TMA due to ADAMTS13 deficiency, STEC-HUS and genetic defect in cobalamin C metabolism. Consequently, there is no information on the use of ravulizumab in these populations. 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 complement mediated

TMA was not confirmed. The mean age at the time of first infusion was 6.4 years. 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 Cm-TMA were enrolled. Patients had to have clinical response to SOLIRIS prior to enrollment.

Table 13 presents the baseline characteristics of the pediatric 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 hemolytic uremic syndrome; eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum; SD = standard deviation.

The primary endpoint was Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) 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. Secondary endpoints included time to Complete TMA Response, TMA response status over time, dialysis requirement, CKD stage as evaluated by eGFR, hemoglobin response and change from baseline in QoL.

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%) 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, LDH normalization, and renal function improvement.

Table 15 summarizes the secondary efficacy results for Study ALXN1210-aHUS-312.

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. Patients also reported improved health related QoL.

Table 15:         Secondary Efficacy Outcome for Study ALXN1210-aHUS-312

Note: m: number of patients available at Day 183 visit. 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: Compared to CKD stage at baseline. Worsened: Excluded those with Stage 1 at baseline as they cannot improve.*95% confidence intervals (95% CIs) are based on exact confidence limits using the Clopper Pearson method. **95% confidence intervals (95% CIs) for the proportion are based on the asymptotic Gaussian approximation method with a continuity correction.*** Excludes patients with Stage 5 at baseline as they cannot worsen.

Abbreviations: CI = confidence interval; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; FACIT = Functional Assessment of Chronic Illness Therapy; LDH = lactate dehydrogenase; SD = standard deviation; TMA = thrombotic microangiopathy.

The efficacy of ULTOMIRIS for the treatment of complement mediated TMA, including aHUS appear similar in pediatric and adult patients. There was no observable clinically meaningful difference in efficacy results in studies with ULTOMIRIS and SOLIRIS (C10-003) after 26 weeks of treatment.

In SOLIRIS-experienced patients, switching to ULTOMIRIS maintained disease control as evidenced by stable hematologic and renal parameters, with no apparent impact on safety.

1.1.3.3     Generalized Myasthenia Gravis (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) designed to demonstrate ULTOMIRIS superiority over placebo. Patients participating in this study were randomized 1:1 to either receive ULTOMIRIS or placebo for the 26-week Randomized-Controlled Period (RCP) and 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 Myasthenia Gravis Activities of Daily Living (MG-ADL) total score ≥ 6 were randomized to receive either ULTOMIRIS (N = 86) or placebo (N = 89). Prior treatment with immunosuppressant therapies (ISTs) (corticosteroids, azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate mofetil, or tacrolimus) was not required for enrollment. However, patients on ISTs 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 were balanced across the two treatment groups (Table 16).

Table 16:         Baseline Disease Characteristics in Study ALXN1210-MG-306

^a Prior MG crisis information were collected as part of medical history and not evaluated as per the clinical protocol definition.

^b Immunosuppressant therapies (ISTs) include corticosteroids, azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate mofetil, or tacrolimus.

^c Other immunosuppressant agents include azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate mofetil, or tacrolimus.

Abbreviations: Max = maximum; min = minimum; MG = myasthenia gravis; MG-ADL = Myasthenia Gravis Activities of Daily Living; MGFA = Myasthenia Gravis Foundation of America; QMG = Quantitative Myasthenia Gravis; SD = standard deviation

The primary endpoint was the change from baseline to Week 26 in the MG-ADL total score (a validated patient-reported assessment measuring relevant functional activities affected in patients with gMG).

The secondary endpoints, also assessed changes from baseline to Week 26, included the change in the Quantitative Myasthenia Gravis (QMG) total score (QMG - a validated clinician-reported assessment of muscle weakness in gMG), 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 primary endpoint, change in MG‑ADL total score from baseline to Week 26, as compared to placebo. Primary and secondary endpoint results are presented in Table 17.

The treatment effect of ULTOMIRIS on MG-ADL was rapid, with an improvement demonstrated as early as Week 1 (p = 0.0265) and sustained through Week 26.  The efficacy of ULTOMIRIS was consistent overall across prespecified subgroups (sex, age, body weight, region, immunosuppressant therapy use at baseline, and MGFA clinical classification).

Table 17:      Analysis of Primary and Secondary Efficacy Endpoints in Study ALXN1210-MG-306

*For QMG ≥ 5-point and MG-ADL ≥ 3-point improvement, the adjusted percentages within each treatment are displayed.

** The endpoint was not formally tested for statistical significance; a nominal p-value was reported.

Abbreviations: CI = confidence interval; LS = least squares; MG-ADL = Myasthenia Gravis Activities of Daily Living; MG-QoL15r = Revised Myasthenia Gravis Quality of Life 15 item scale; Neuro-QoL fatigue = Neurological Quality of Life Fatigue; QMG = Quantitative Myasthenia Gravis; SEM = standard error of mean

The proportion of clinical responders at higher response thresholds (≥4-, 5-, 6-, 7-, or 8-point improvement on MG-ADL, and ≥6-, 7-, 8-, 9-, or 10-point improvement on QMG) was consistently greater for ULTOMIRIS compared to placebo.

In patients treated with ULTOMIRIS, improvements were observed in all domain scores of the MG-ADL and in the ocular, bulbar, and limb domain scores of the QMG.

Other Efficacy Results

Overall, 25.6% of patients treated with ULTOMIRIS achieved minimal manifestation status as per the MGFA post-intervention status at Week 26 compared to 9.9% of patients treated with placebo.

Table 18 presents an overview of the patients with clinical deterioration and patients requiring rescue therapy over the 26-week RCP.

Table 18:       Clinical Deterioration and Rescue Therapy in Study ALXN1210-MG-306

^aRescue therapy included high-dose corticosteroid, plasma exchange/plasmapheresis, or intravenous immunoglobulin.

Long-Term Efficacy

At the time of the analysis, 79 of the 158 patients who entered the Open-Label Extension Period had completed or were projected to reach the Week 52 study visit. All patients received ULTOMIRIS in the Open-Label Extension Period and the original treatment assignment blind was maintained.

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 on all endpoints including MG-ADL and QMG (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 on all endpoints including MG-ADL and QMG (Figure 3) was observed.

Figure 3:          Change from Randomized-Controlled Period Baseline in MG-ADL Total Score (A) and QMG Total Score (B) through Week 52 (Mean and 95% CI) in Study ALXN1210-MG-306
 

Note: Randomized‑Controlled Period figures are based on data from 175 patients. Open‑Label Extension Period figures are based on data from 79 patients who completed the Week 52 Visit or were projected to reach the Week 52 Visit at the data cutoff date.

Abbreviations: CI = confidence interval; MG-ADL = Myasthenia Gravis Activities of Daily Living; QMG = Quantitative Myasthenia Gravis

Immunosuppressant therapies (IST)

In the OLE of the study, clinicians had the option to adjust IST. In patients followed for 26 weeks in the OLE, 32.9% of patients decreased their daily dose of corticosteroid therapy and 5.1% of patients stopped corticosteroid therapy. The most common reason for change in corticosteroid therapies was improvement in MG symptoms while on ULTOMIRIS treatment.

1.1.3.4     Neuromyelitis Optica Spectrum Disorder (NMOSD)

The efficacy and safety of ULTOMIRIS IV in adult patients with anti‑AQP4 antibody‑positive NMOSD was assessed in Study ALXN1210‑NMO‑307, which was designed as an open‑label, multicenter study using the placebo arm of Study ECU‑NMO‑301 (eculizumab versus placebo in patients with NMOSD) to demonstrate ULTOMIRIS superiority over placebo. Patients participating in Study ALXN1210‑NMO‑307 received ULTOMIRIS intravenously in the Primary Treatment Period that ended when the last enrolled patient completed (or discontinued prior to) 52 weeks on study, representing a median study duration of 73.5 weeks (minimum 13.7, maximum 117.7 weeks). Patients were subsequently allowed to enter a Long-Term Extension Period during which all patients continued to receive ULTOMIRIS for up to 2 years.

Study ALXN1210‑NMO‑307 enrolled 58 adult patients with NMOSD who had a positive serologic test for anti‑AQP4 antibodies, at least 1 relapse in the last 12 months prior to the Screening Period, and an Expanded Disability Status Scale (EDSS) score ≤ 7. Prior treatment with immunosuppressant therapies (ISTs) was not required for enrollment. However, patients on selected ISTs (ie, corticosteroids, azathioprine, mycophenolate mofetil, tacrolimus) were permitted to continue on therapy, with a requirement for stable dosing until they reached Week 106 in the study. At that point, changes could be made at the discretion of the Investigator. In addition, acute therapy for relapse treatment (including high‑dose corticosteroids, PE/PP, and IVIg) was allowed if a patient experienced a relapse during the study.

A total of 56 (96.6%) patients completed the Primary Treatment Period of Study ALXN1210‑NMO‑307. The demographics of patients were balanced across the 2 treatment groups (including age [median of 46.0 years for ULTOMIRIS versus 44.0 years for placebo], gender [89.7% female for ULTOMIRIS versus 89.4% female for placebo], and age at NMOSD initial clinical presentation [median of 42.5 years, ranging from 16 to 73 years, for ULTOMIRIS versus median of 38.0 years, ranging from 12 to 73 years, for placebo]). Baseline disease characteristics in both groups were indicative of a patient population with disability representative of the NMOSD population overall (Table 19).

Table 19:       Patient Disease History and Baseline Characteristics in the ULTOMIRIS Arm of Study ALXN1210-NMO-307 and Comparative Placebo Arm of Study ECU-NMO-301

Abbreviations: ARR = annualized relapse rate; EDSS = Expanded Disability Status Scale; HAI = Hauser Ambulatory Index; IST = immunosuppressant therapy; max = maximum; min = minimum; NMOSD = neuromyelitis optica spectrum disorder; SD = standard deviation

The primary endpoint of Study ALXN1210-NMO-307 was the time to first adjudicated on‑trial relapse as determined by an independent adjudication committee. The hazard ratio (95% confidence interval [CI]) for ULTOMIRIS compared with placebo was 0.014 (0.000, 0.103), representing a 98.6% reduction in the risk of relapse (p < 0.0001) (Figure 4). No adjudicated on-trial relapse was observed in ULTOMIRIS‑treated patients during the median Primary Treatment Period of 73.5 weeks, representing a statistically significant difference between the ULTOMIRIS and placebo treatment arms in time to first adjudicated on‑trial relapse (p < 0.0001). The proportion of relapse-free patients at Week 48 was 100% on ULTOMIRIS versus 63.2% on placebo. All ULTOMIRIS-treated patients remained relapse free at Week 72. ULTOMIRIS-treated patients experienced consistent improvement over patients in the placebo arm in time to first adjudicated on-trial relapse across all prespecified subgroups: demographics, no IST usage (ULTOMIRIS monotherapy), use of steroids alone, use of azathioprine, use of mycophenolate mofetil, any IST usage, use of rituximab in the year prior to Screening.

Figure 4:       Kaplan-Meier Survival Estimates for Time to First Adjudicated On-Trial Relapse in Study ALXN1210-NMO-307 and Comparative Placebo Arm of Study ECU-NMO-301

Note: The placebo group data were collected as part of the PREVENT trial, Study ECU-NMO-301. Patients who did not experience an adjudicated on-trial relapse were censored at the end of the study period. If a patient in the placebo group was followed longer than any of the patients in the ravulizumab arm, then that patient was censored at the longest ravulizumab follow-up time.

(1) Based on the Kaplan-Meier product limit method.

(2) Based on the complementary log-log transformation.

(3) Based on the log-rank test.

(4) Based on a Cox proportional hazards model, with Firth’s adjustment if no relapses observed in a treatment arm.

(5) Wald confidence interval or Profile Likelihood Confidence Limits, if no relapses observed in a treatment arm.

Abbreviation: CI = confidence interval

ULTOMIRIS-treated patients had an adjudicated on-trial annualized relapse rate (ARR) that was statistically significantly lower than an ARR of 0.25 (1 adjudicated on‑trial relapse per 4 patient ‑years) (p < 0.0001) (Table 20). The 0.25 comparator rate was chosen to represent a conservative ARR that may be experienced in the NMOSD patient population.

Table 20:       Adjudicated On-trial Annualized Relapse Rate in Study ALXN1210‑NMO‑307

^a Upper 95% confidence limit using exact methods is based on the chi-square distribution with 1 degree of freedom, divided by patient-years; the lower confidence limit is not defined for 0 relapses. The p-value is based on the Poisson distribution with 0 relapses and patient ‑years.

^b Based on a Poisson regression centered on the historical ARR in 24 months prior to Screening; p-value tests the significance of the difference from 0.25 relapses/patient-year. The model results could not be estimated when the relapse rate was 0.

Abbreviations: ARR = annualized relapse rate; CI = confidence interval; NA = not applicable

Patients in the ULTOMIRIS group were less likely to experience worsening in mobility‑related neurologic disability, as measured by Hauser Ambulatory Index (HAI) score, compared with patients in the placebo group (odds ratio [95% CI] p-value: 0.155 [0.031, 0.771] p = 0.0228]) (Table 21). Clinically important worsening from baseline in HAI score was reported for 2 (3.4%) patients in the ravulizumab group and 11 (23.4%) patients in the placebo group. Other secondary endpoints, while not statistically significant, favored the ULTOMIRIS group based on the European Quality of Life Health 5‑Dimension Questionnaire (EQ‑5D) Index Score (p = 0.0567), EQ‑5D visual analog scale (VAS; nominal p = 0.0297), and EDSS score (nominal p = 0.0588).

Table 21:       Change from Baseline in HAI, EQ-5D Index, EQ-5D VAS, and EDSS at the End of the Study Period of Study ALXN1210-NMO-307 and Comparative Placebo Arm of Study ECU-NMO-301

Note: A closed testing procedure was applied to control the type I error; if the primary endpoint was statistically significant and in favor of ravulizumab, the secondary endpoints was evaluated in rank order beginning with the ARR and followed by the above endpoints in the order presented in the table.

^a A nominal p-value was reported.

Abbreviations: EDSS = Expanded Disability Status Scale; EQ‑5D = European Quality of Life Health 5‑ Dimension Questionnaire; HAI = Hauser Ambulation Index; max = maximum; min = minimum; SD = standard deviation; VAS = visual analog scale

As compared with placebo-treated patients, ULTOMIRIS treated-patients had reduced annualized rates of both physician-reported on-trial relapse-related hospitalization (0.00 versus 0.34 for placebo, p < 0.0001) and acute relapse treatment (high dose oral steroid: 0.00 versus 0.13, p = 0.0005; IV methylprednisolone: 0.00 versus 0.47 for placebo, p < 0.0001; and plasma exchange: 0.01 versus 0.21 for placebo, p = 0.0002).

5.2.1        Absorption

Because the route of ULTOMIRIS administration is an IV infusion and the dosage form is a solution, 100% of the administered dose is considered bioavailable. 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).

5.2.2        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, and adult patients with gMG or NMOSD treated with ravulizumab IV, are presented in Table 22.

5.2.3        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, and adult patients with gMG or NMOSD treated with ravulizumab IV are presented in Table 22.

5.2.4        Pharmacokinetic Parameters

A linear, 2-compartment PK model was developed that adequately described the observed ravulizumab PK following intravenous 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, and adult patients with gMG or NMOSD, are presented in Table 22.

Table 22:         Estimated Central Volume, Distribution, Biotransformation and Elimination Parameters Following ULTOMIRIS Treatment

Abbreviations: gMG = generalized myasthenia gravis; IV = intravenous; NMOSD = neuromyelitis optica spectrum disorder; PNH = paroxysmal nocturnal hemoglobinuria; SC = subcutaneous; TMA = thrombotic microangiopathy

Therapeutic concentrations are achieved immediately following the first dose of ULTOMIRIS. In patients with PNH, complement-mediated TMA, gMG or NMOSD, 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, and NMOSD patient populations.

5.2.5        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, gMG, or NMOSD, 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.

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.

Sodium phosphate, monobasic

Sodium phosphate, dibasic

Sodium chloride

Polysorbate 80

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Reconstitution and dilution should only use sodium chloride 9 mg/mL (0.9%) solution for injection as diluent.

ULTOMIRIS vials must be stored under refrigerated conditions at 2°C – 8°C.

Vials must not be frozen or shaken.

Keep the vial in the outer carton to protect from light.

For storage conditions after dilution of the medicinal product, see Section 6.3.

30 mL of sterile concentrate in a vial (Type I glass) with a stopper and a seal

Each vial of ULTOMIRIS is intended for single use only.

ULTOMIRIS 10 mg/mL requires dilution to a final concentration of 5 mg/mL. Aseptic technique must be used.

Prepare ULTOMIRIS as follows:

1.      The number of vials to be diluted is determined based on the individual patient’s weight and the prescribed dose, see Section 4.2.

2.      Prior to dilution, the solution in the vials should be visually inspected; the solution should be free of any particulate matter or precipitation. Do not use if there is evidence of particulate matter or precipitation.

3.      The calculated volume of medicinal product is withdrawn from the appropriate number of vials and diluted in an infusion bag using sodium chloride 9 mg/mL (0.9%) solution for injection as diluent. Refer to the administration reference tables below. The product should be mixed gently. It should not be shaken.

4.      After dilution, the final concentration of the solution to be infused is 5 mg/mL for ULTOMIRIS 10 mg/mL.

5.      The prepared solution should be administered immediately following preparation. Do not administer as an intravenous push or bolus injection. Refer to the administration reference table in Section 4.2 for minimum infusion duration. Infusion must be administered through a 0.2 µm filter.

6.      If the medicinal product is not used immediately after reconstitution, storage times at 2°C – 8°C must not exceed 24 hours taking into account the expected infusion time.

The loading, maintenance and supplemental dose administration reference tables for ULTOMIRIS 10 mg/mL are provided in Table 23, Table 24 and Table 25, respectively.

Table 23:       Loading Dose Administration Reference Table for ULTOMIRIS 10 mg/mL

*For PNH and aHUS indications only.

^a Body weight at time of treatment.

^b ULTOMIRIS should only be diluted using sodium chloride 9 mg/mL (0.9 %) solution for injection.

Table 24:       Maintenance Dose Administration Reference Table for ULTOMIRIS 10 mg/mL

*For PNH and aHUS indications only.

^a Body weight at time of treatment.

^b ULTOMIRIS should only be diluted using sodium chloride 9 mg/mL (0.9 %) solution for injection.

Table 25: Supplemental Dose Administration Reference Table for ULTOMIRIS 10 mg/mL

^a Body weight at time of treatment.

^b ULTOMIRIS should be only diluted using sodium chloride 9 mg/mL (0.9 %) solution for injection.

Any unused medicinal product should be disposed of in accordance with local requirements.