Leaflet ASPAVELI 1080mg 54mg / ml solution for infusion

ASPAVELI 1 080 mg solution for infusion

Each 20 mL vial contains 1 080 mg of pegcetacoplan.

Each mL contains 54 mg of pegcetacoplan.

Each mL contains 41 mg of sorbitol.

Each vial contains 820 mg of sorbitol.

For the full list of excipients, see section 6.1.

Solution for infusion.

Clear, colourless to slightly yellowish aqueous solution with pH 5.0.

ASPAVELI is indicated as monotherapy in the treatment of adult patients with paroxysmal nocturnalhaemoglobinuria (PNH) who have haemolytic anaemia.

ASPAVELI is indicated for the treatment of adult and adolescent patients aged 12 to 17 years with C3glomerulopathy (C3G) or primary immune-complex membranoproliferative glomerulonephritis (IC-

MPGN) in combination with a renin-angiotensin system (RAS) inhibitor, unless RAS inhibitortreatment is not tolerated or contraindicated.

Therapy should be initiated under the supervision of a healthcare professional experienced in themanagement of patients with haematological or renal disorders. Self-administration and home infusionshould be considered for patients who have tolerated treatment well in experienced treatment centres.

The decision of a possibility of self-administration and home infusions should be made afterevaluation and recommendation from the treating physician.

Pegcetacoplan can be given by a healthcare professional or administered by the patient or caregiverfollowing proper instruction.

PNH

Adult patients with PNH

Pegcetacoplan is administered twice weekly as a 1 080 mg subcutaneous infusion with a commerciallyavailable syringe system infusion pump or on-body delivery system, that can deliver doses up to20 mL. The twice weekly dose should be administered on Day 1 and Day 4 of each treatment week.

PNH is a chronic disease and treatment with ASPAVELI is recommended to continue for the patient’slifetime, unless the discontinuation of this medicinal product is clinically indicated (see section 4.4).

Patients with PNH switching to ASPAVELI from a C5 inhibitor

For the first 4 weeks, pegcetacoplan is administered as twice weekly subcutaneous doses of 1 080 mgin addition to the patient’s current dose of C5 inhibitor treatment to minimise the risk of haemolysiswith abrupt treatment discontinuation. After 4 weeks, the patient should discontinue C5 inhibitorbefore continuing on monotherapy with ASPAVELI.

Switches from complement inhibitors other than eculizumab have not been studied. Discontinuingother complement inhibitors before reaching steady-state of pegcetacoplan should be done withcaution (see section 5.2).

Dose adjustment in PNH

The dosing regimen may be changed to 1 080 mg every third day (e.g., Day 1, Day 4, Day 7, Day 10,

Day 13, and so forth) if a patient has a lactate dehydrogenase (LDH) level greater than 2 x upper limitof normal (ULN). In the event of a dose increase, LDH should be monitored twice weekly for at least4 weeks (see section 4.4).

C3G and primary IC-MPGN

Pegcetacoplan is administered twice weekly as a subcutaneous infusion with a commercially availablesyringe system infusion pump or on-body delivery system, that can deliver doses up to 20 mL. Thetwice weekly dose should be administered on Day 1 and Day 4 of each treatment week.

C3G and primary IC-MPGN are chronic diseases. Discontinuation of this medicinal product is notrecommended unless clinically indicated.

Adult patients with C3G or primary IC-MPGN

Pegcetacoplan is administered twice weekly as a 1 080 mg subcutaneous infusion.

Adolescent patients with C3G or primary IC-MPGN

For adolescent patients, the dosing regimen is based on the patient´s body weight and consists of thefollowing:

Body weight First dose Second dose Maintenance dose(infusion volume) (infusion volume) (infusion volume)≥ 50 kg 1 080 mg twice weekly (20 mL)35 to < 50 kg 648 mg (12 mL) 810 mg (15 mL) 810 mg twice weekly (15 mL)30 to < 35 kg 540 mg (10 mL) 540 mg (10 mL) 648 mg twice weekly (12 mL)

If a dose of pegcetacoplan for treatment of PNH, C3G or primary IC-MPGN is missed, it should beadministered as soon as possible, then the regular schedule should be resumed even if this results in aninterval of less than 3 days between the replacement dose and the subsequent dose.

Patients with post-transplant recurrent C3G or primary IC-MPGN

Diagnosis of post-transplant recurrent C3G or primary IC-MPGN should be made based on a renalallograft biopsy. C3G or primary IC-MPGN recurrence may be detected in a routine post-transplantbiopsy; otherwise, a biopsy should be performed when clinical signs indicate recurrent disease. Asdone in study APL2-C3G-204 (see section 5.1), treatment with pegcetacoplan can be started before theonset of clinical signs such as estimated glomerular filtration rate (eGFR) decrease or urine to protein-to-creatine ratio (uPCR) increase. There is limited experience with the use of pegcetacoplan in patientswith recurrent C3G or primary IC-MPGN after transplantation in clinical studies (see section 5.1).

Although there were no apparent age-related differences observed in clinical studies, the number ofpatients aged 65 and over is not sufficient to determine whether they respond differently from youngerpatients. There is no evidence indicating any special precautions are required for treating an elderlypopulation.

Severe renal impairment (creatinine clearance <30 mL/min) had no effect on the pharmacokinetics(PK) of pegcetacoplan; therefore, pegcetacoplan dose adjustment in patients with renal impairment isnot necessary. There are no data available for the use of pegcetacoplan in patients with end-stage renaldisease (ESRD) requiring dialysis (see section 5.2).

The safety and efficacy of pegcetacoplan have not been studied in patients with hepatic impairment;however, no dose adjustment is recommended, as hepatic impairment is not expected to impactclearance of pegcetacoplan.

The safety and efficacy of ASPAVELI in children with PNH aged 0 to <18 years have not yet beenestablished. No data are available.

The safety and efficacy of ASPAVELI in children with C3G or primary IC-MPGN aged below12 years have not been established. No data are available.

This medicinal product should not be used in children <12 years of age, as non-clinical safety data arenot available for this age group.

ASPAVELI should only be administered via subcutaneous administration using a commerciallyavailable syringe system infusion pump or on-body delivery system.

This medicinal product can be self-administered. When self-administration is initiated, the patient willbe instructed by a qualified healthcare professional in infusion techniques, the use of a syringe systeminfusion pump or an on-body delivery system, the keeping of a treatment record, the recognition ofpossible adverse reactions, and measures to be taken in case these occur.

* When using a syringe system infusion pump, ASPAVELI should be infused in the abdomen,thighs, hips, or upper arms. Infusion sites should be at least 7.5 cm apart from each other. Theinfusion sites should be rotated between administrations. The infusion time is approximately30 minutes (if using two sites) or approximately 60 minutes (if using one site).

* When using an on-body delivery system, ASPAVELI should be infused at a site on theabdomen. The infusion site should be rotated between administrations following the devicemanufacturer´s instructions. The infusion time varies by patient and typically ranges from 30 to60 minutes.

Infusion into areas where the skin is tender, bruised, red, or hard should be avoided. Infusion intotattoos, scars, or stretch marks should be avoided. The infusion should be started promptly afterdrawing this medicinal product into the syringe. Administration should be completed within 2 hoursafter preparing the syringe. For instructions on the preparation and infusion of the medicinal product,see section 6.6.

Hypersensitivity to pegcetacoplan or to any of the excipients listed in section 6.1.

Pegcetacoplan therapy must not be initiated in patients:

* with unresolved infection caused by encapsulated bacteria including Neisseria meningitidis,

Streptococcus pneumoniae, and Haemophilus influenzae (see section 4.4).

* who are not currently vaccinated against Neisseria meningitidis, Streptococcus pneumoniae, and

Haemophilus influenzae unless they receive prophylactic treatment with appropriate antibioticsuntil 2 weeks after vaccination (see section 4.4).

Serious infections caused by encapsulated bacteria

The use of pegcetacoplan may predispose individuals to serious infections caused by encapsulatedbacteria including Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. Toreduce the risk of infection, all patients must be vaccinated against these bacteria according toapplicable local guidelines at least 2 weeks prior to receiving pegcetacoplan, unless the risk ofdelaying therapy outweighs the risk of developing an infection.

Patients with known history of vaccination

Before receiving treatment with pegcetacoplan, in patients with a known history of vaccination, itshould be ensured that patients have received vaccines against encapsulated bacteria including

Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilusinfluenzae Type B within 2 years prior to starting pegcetacoplan.

Patients without known history of vaccination

For patients without known history of vaccination, the required vaccines should be administered atleast 2 weeks prior to receiving the first dose of pegcetacoplan. If immediate therapy is indicated, therequired vaccines should be administered as soon as possible and the patient treated with appropriateantibiotics until 2 weeks after vaccination.

Monitoring patients for serious infections

Vaccination may not be sufficient to prevent serious infection. Consideration should be given toofficial guidance on the appropriate use of antibacterial agents. All patients should be monitored forearly signs of infections caused by encapsulated bacteria including Neisseria meningitidis,

Streptococcus pneumoniae, and Haemophilus influenzae, evaluated immediately if infection issuspected, and treated with appropriate antibiotics if necessary. Patients should be informed of thesesigns and symptoms, and steps taken to seek medical care immediately. Physicians must discuss thebenefits and risks of pegcetacoplan therapy with patients.

Hypersensitivity reactions have been reported. If a severe hypersensitivity reaction (includinganaphylaxis) occurs, infusion with pegcetacoplan must be discontinued immediately, and appropriatetreatment instituted.

Injection site reactions have been reported with the use of subcutaneous pegcetacoplan (seesection 4.8). Patients should be trained appropriately in proper injection technique.

PNH laboratory monitoring

Patients with PNH receiving pegcetacoplan should be monitored regularly for signs and symptoms ofhaemolysis, including measuring LDH levels, and may require dose adjustment within therecommended dosing schedule (see section 4.2).

There may be interference between silica reagents in coagulation panels and pegcetacoplan that resultsin artificially prolonged activated partial thromboplastin time (aPTT); therefore, the use of silicareagents in coagulation panels should be avoided.

Treatment discontinuation for PNH

If patients with PNH discontinue treatment with pegcetacoplan, they should be closely monitored forsigns and symptoms of serious intravascular haemolysis. Serious intravascular haemolysis is identifiedby elevated LDH levels along with sudden decrease in PNH clone size or haemoglobin (Hb), orreappearance of symptoms such as fatigue, haemoglobinuria, abdominal pain, dyspnoea, majoradverse vascular event (including thrombosis), dysphagia, or erectile dysfunction. If discontinuation ofthis medicinal product is necessary, alternate therapy should be considered. If serious haemolysisoccurs after discontinuation, consider the following procedures/treatments: blood transfusion (packed

RBCs), exchange transfusion, anticoagulation, and corticosteroids. Patients should be closelymonitored for at least 8 weeks from the last dose, representing more than 5 half-lives of this medicinalproduct, to allow for medicinal product washout (see section 5.2) to detect serious haemolysis andother reactions. In addition, slow weaning should be considered.

Contraception in women of childbearing potential

It is recommended that women of childbearing potential use effective contraception methods toprevent pregnancy during treatment with pegcetacoplan and for at least 8 weeks after the last dose ofpegcetacoplan (see section 4.6).

Polyethylene glycol (PEG) accumulation

ASPAVELI is a PEGylated medicinal product. The potential long-term effects of PEG accumulationin the kidneys, the choroid plexus of the brain, and other organs are unknown (see section 5.3).

Regular laboratory testing of renal function is recommended.

All physicians who intend to prescribe ASPAVELI must ensure they have received and are familiarwith the physician educational material. Physicians must explain and discuss the benefits and risks of

ASPAVELI therapy with the patient and provide them with the patient information pack and thepatient card. The patient should be instructed to seek prompt medical care if they experience any signor symptom of serious infection or hypersensitivity during therapy with ASPAVELI, especially ifindicative of infection with encapsulated bacteria.

Sorbitol content

ASPAVELI 1 080 mg contains 820 mg sorbitol in each vial.

Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say, essentially‘sodium-free’.

No interaction studies have been performed. Based on in vitro data, pegcetacoplan has low potentialfor clinical drug-drug interactions.

It is recommended that women of childbearing potential use effective contraception methods toprevent pregnancy during treatment with pegcetacoplan and for at least 8 weeks after the last dose ofpegcetacoplan. For women planning to become pregnant, the use of pegcetacoplan may be consideredfollowing an assessment of the risks and benefits (see Pregnancy).

There is a limited amount of data from the use of pegcetacoplan in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3).

Pegcetacoplan is not recommended during pregnancy and in women of childbearing potential notusing contraception.

It is unknown whether pegcetacoplan is excreted in human milk. The potential for absorption andharm to the breastfed infant is unknown. Animal data suggest a low excretion (less than 1%, notpharmacologically significant) of pegcetacoplan in monkey milk (see section 5.3). It is unlikely that abreastfed infant would have clinically relevant exposure.

It is recommended to discontinue breast-feeding during pegcetacoplan treatment.

No animal or human data on the effect of pegcetacoplan on fertility are available. In toxicity studies,there were no microscopic abnormalities in male or female reproductive organs in monkeys (seesection 5.3).

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

PNH

The most commonly reported adverse reactions in patients with PNH treated with pegcetacoplan wereinjection site reactions: injection site erythema, injection site pruritus, injection site swelling, injectionsite pain, injection site bruising. Other adverse reactions reported in more than 10% of patients duringclinical studies were upper respiratory tract infection, diarrhoea, haemolysis, abdominal pain,headache, fatigue, pyrexia, cough, urinary tract infection, vaccination complication, pain in extremity,dizziness, arthralgia and back pain. The most commonly reported serious adverse reactions werehaemolysis and sepsis.

C3G and primary IC-MPGN

The most commonly reported adverse drug reactions in patients with C3G or primary IC-MPGNtreated with pegcetacoplan were infusion site reactions and upper respiratory tract infections. The mostcommonly reported serious adverse reactions were acute kidney injury and pneumonia.

Table 1 gives the adverse reactions observed from the clinical studies and postmarketing experiencewith pegcetacoplan in patients with PNH, C3G and primary IC-MPGN. Adverse reactions are listed by

MedDRA system organ class (SOC) and frequency, using the following convention: very common(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100) or rare (≥1/10 000 to <1/1 000),very rare (<1/10 000), and not known (cannot be estimated from available data). Within eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions from clinical trials1 and postmarketing experience

MedDRA System Organ Class Frequency in PNH Frequency in C3G or

Adverse reaction primary IC-MPGN

Influenza Very common

Upper respiratory tract infections2 Very common Very common

Urinary tract infection Very common Common

Sepsis Common3

Opportunistic infections Common4

COVID-19, Gastrointestinal infection, Fungal Commoninfection, Skin infection, Oral infection

Ear infection Common Common

Infection, Respiratory tract infection5, Viral Commoninfection, Bacterial infection, Vaginal infection,

Eye infection

Cervicitis, Groin infection Uncommon

Pneumonia Uncommon Common

Nasal abscess, Tuberculosis, Oesophageal Uncommoncandidiasis, COVID-19 pneumonia, Anal abscess

Hypersensitivity reaction Very common6

Haemolysis Very common

Thrombocytopenia Common Common7

Neutropenia Common Common

Hypokalaemia Common Common

Headache Very common Very common

Dizziness Very common

Hypertension Common

Cough Very common Common

Dyspnoea, Oropharyngeal pain, Nasal congestion Common

Epistaxis Common Common

Abdominal pain Very common

Diarrhoea Very common Very common

Nausea Common Very common

Erythema, Rash, Urticaria Common

Arthralgia, Back pain Very common

Pain in extremity Very common Common

Myalgia Common Common

Muscle spasms Common

Acute kidney injury Common Very common

Chromaturia Common

Pyrexia Very common Very common

Fatigue Very common Common

Infusion site reactions8 Very common Very common

MedDRA System Organ Class Frequency in PNH Frequency in C3G or

Adverse reaction primary IC-MPGN

Alanine aminotransferase increased, Bilirubin Commonincreased

Vaccination complication Very common1Studies APL2-308, APL2-302, APL2-202, APL2-CP-PNH-204, and APL-CP0514 in PNH patients and Study

APL2-C3G-310, APL2-C3G-314, APL2-201 and APL2-C3G-204 in C3G and primary IC-MPGN patients.

Medically similar terms are grouped, where appropriate, on the basis of similar medical concept.2Include nasopharyngitis, upper respiratory tract infection, pharyngitis, rhinitis and sinusitis.3Sepsis includes one case of septic shock and one case with non-encapsulated Neisseria meningitidis.4Herpes zoster (including Herpes zoster meningoencephalitis), and Pneumocystis jirovecii infection.5Include respiratory tract infection and respiratory tract infection viral.6Include rash and eczema.7Includes platelet count decreased.8PTs included in Infusion site reactions: infusion site erythema, infusion site pruritus, infusion site swelling,infusion site bruising, infusion site pain, infusion site induration.

No serious infection caused by encapsulated bacteria was reported during PNH Study APL2-302.

Forty-eight patients experienced an infection during the study. The most frequent infections in patientstreated with pegcetacoplan during PNH Study APL2-302 were upper respiratory tract infection(28 cases, 35%). Most infections reported in patients treated with pegcetacoplan during PNH Study

APL2-302 were nonserious, and predominantly mild in intensity. Ten patients developed infectionsreported as serious including one patient who died due to COVID-19. The most frequent seriousinfections were sepsis (3 cases) (leading to discontinuation of pegcetacoplan in one patient) andgastroenteritis (3 cases); all of which resolved.

In C3G and primary IC-MPGN clinical studies, four serious respiratory tract infections caused byencapsulated bacteria were reported in patients treated with pegcetacoplan: an epiglottitis, apneumococcal pneumonia and an atypical pneumonia that led to drug interruption, and a pneumonia

Haemophilus with no dose adjustment. Events recovered and resolved except for the events ofpneumonia Haemophilus and the atypical pneumonia that resolved with sequelae. In addition, oneserious Escherichia urinary tract infection was reported, the event recovered and resolved with nodose adjustment.

Haemolysis

Nineteen patients reported haemolysis during PNH Study APL2-302 in patients treated withpegcetacoplan. Seven cases were reported as serious, and 5 cases led to discontinuation ofpegcetacoplan and the dose of pegcetacoplan was increased in 10 patients. There were 3 cases ofhaemolysis during PNH Study APL2-308 in patients treated with pegcetacoplan. None of these caseswere reported as serious or led to discontinuation of pegcetacoplan. The dose of pegcetacoplan wasincreased in all 3 patients.

Acute kidney injury

In C3G and primary IC-MPGN clinical studies, 10 serious events of acute kidney injury were reportedin 8 patients (5.7%) treated with pegcetacoplan, of which 5 events were observed in 4 post-transplantpatients. Of these serious events, only 1 led to drug withdrawal and 1 to dose interruption. All eventsrecovered and resolved, except the single event that led to drug withdrawal.

Patients with post-transplant recurrent C3G or primary IC-MPGN

In the patients with post-transplant recurrent C3G or primary IC-MPGN (N=22), included in Studies

APL2-C3G-310 and APL2-C3G-204, the safety profile appeared consistent with that of the overallpopulation, although with higher frequencies of severe and serious adverse events, as expected in thispatient population.

In adolescent patients with C3G or primary IC-MPGN (N=28, aged 12 years to 17 years) included in

Study APL2-C3G-310, the safety profile appeared consistent with the overall results. The mostcommon adverse reaction reported in this patient population were infusion site reactions.

The safety of pegcetacoplan has not been studied in paediatric patients less than 12 years of age.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the postmarketing setting, cases of overdose have been reported, with no new safety eventsobserved. In case of overdose, it is recommended that the patient be monitored for any signs orsymptoms of adverse reactions and appropriate symptomatic treatment be instituted.

Pharmacotherapeutic group: Immunosuppressants, Complement inhibitors, ATC code: L04AJ03

Pegcetacoplan is a symmetrical molecule comprised of two identical pentadecapeptides covalentlybound to the ends of a linear 40-kDa PEG molecule. The peptide moieties bind to complement C3 and

C3b and exert a broad inhibition of the complement cascade. The 40-kDa PEG moiety impartsimproved solubility and longer residence time in the body after administration of the medicinalproduct.

Pegcetacoplan binds to complement protein C3 and its activation fragment C3b with high affinity,thereby regulating the cleavage of C3 and the generation of downstream effectors of complementactivation. In PNH, extravascular haemolysis (EVH) is facilitated by C3b opsonisation whileintravascular haemolysis (IVH) is mediated by the downstream membrane attack complex (MAC).

Pegcetacoplan exerts broad regulation of the complement cascade by acting proximal to both C3b and

MAC formation, thereby controlling the mechanisms that lead to EVH and IVH.

In C3G and primary IC-MPGN, there is excessive deposition of C3 breakdown products in theglomeruli of the kidney leading to renal parenchymal damage and impairment of kidney function.

Pegcetacoplan targets upstream effectors of complement activation (C3 and C3b), thereby inhibitingactivation initiated by all (alternative, classical and lectin) complement pathways. By inhibiting C3,pegcetacoplan directly addresses the inappropriate C3 activation and modifies the underlying diseaseby reducing the excessive deposition of C3 breakdown products in the glomeruli of the kidney. Bytargeting C3b, pegcetacoplan also inhibits the activity of the alternative pathway (AP) C3 convertasethrough an additional mechanism of action in the complement cascade. This further preventsdeposition of C3 breakdown products in the glomeruli.

PNH

In Study APL2-302, the mean serum C3 concentration increased from 0.94 g/L at baseline to 3.83 g/Lat Week 16 in the pegcetacoplan group and sustained through Week 48. In Study APL2-308, the meanserum C3 concentration increased from 0.95 g/L at baseline to 3.56 g/L at Week 26.

In Study APL2-302, the mean percentage of PNH Type II + III RBCs increased from 66.80% atbaseline, to 93.85% at Week 16 and sustained through Week 48. In Study APL2-308, the meanpercentage of PNH Type II + III RBCs increased from 42.4% at baseline to 90.0% at Week 26.

In Study APL2-302, the mean percentage of PNH Type II + III RBCs with C3 deposition wasdecreased from 17.73% at baseline to 0.20% at Week 16 and sustained through Week 48. In Study

APL2-308, the mean percentage of PNH Type II + III RBCs with C3 deposition decreased from2.85% at baseline to 0.09% at Week 26.

C3G and primary IC-MPGN

In Study APL2-C3G-310, the mean serum C3 concentration increased from 0.62 g/L at baseline to3.71 g/L at Week 26 in the pegcetacoplan group and the effect was sustained up to Week 52. In theplacebo group, C3 concentrations remained stable up to Week 26 (0.57 g/L at baseline; 0.58 g/L at

Week 26) and increased upon switch to pegcetacoplan to 3.59 g/L at Week 52.

Mean serum sC5b-9 concentration decreased from 902.5 ng/mL at baseline to 290.2 ng/mL at

Week 26 in the pegcetacoplan group and the effect was sustained up to Week 52. In the placebo group,sC5b-9 concentrations remained stable (768.3 ng/mL at baseline; 759.9 ng/mL at Week 26) anddecreased upon switch to pegcetacoplan to 272.9 ng/mL at Week 52.

Clearance of glomerular C3 deposits at 6 months was observed based on a greater proportion ofpatients achieving a staining score of zero in the pegcetacoplan (71.4%) as compared to the placebo(8.8%) group.

PNH

The efficacy and safety of pegcetacoplan in patients with PNH was assessed in two open-label,randomised-controlled phase 3 studies: in complement inhibitor-experienced patients in Study

APL2-302 and in complement inhibitor-naïve patients in Study APL2-308. In both studies the dose ofpegcetacoplan was 1 080 mg twice weekly. If required, the dose could be adjusted to 1 080 mg every3 days.

Study in complement inhibitor-experienced adult patients (APL2-302)

Study APL2-302 was an open-label, randomised study with an active comparator-controlled period of16 weeks followed by a 32-week open label period (OLP). This study enrolled patients with PNH whohad been treated with a stable dose of eculizumab for at least the previous 3 months and with Hblevels <10.5 g/dL. Eligible patients entered a 4-week run-in period during which they receivedpegcetacoplan 1 080 mg subcutaneously twice weekly in addition to their current dose of eculizumab.

Patients were then randomised in a 1:1 ratio to receive either 1 080 mg of pegcetacoplan twice weeklyor their current dose of eculizumab through the duration of the 16-week randomised controlled period(RCP). Randomisation was stratified based on the number of packed red blood cell (PRBC)transfusions within the 12 months prior to Day -28 (<4; ≥4) and platelet count at screening(<100 000/mm3; ≥100 000/mm3). Patients who completed the RCP entered the OLP during which allpatients received pegcetacoplan for up to 32 weeks (patients who received eculizumab during the RCPentered a 4-week run-in period before switching to pegcetacoplan monotherapy).

The primary and secondary efficacy endpoints were assessed at Week 16. The primary efficacyendpoint was change from baseline to Week 16 (during RCP) in Hb level. Baseline was defined as theaverage of measurements prior to the first dose of pegcetacoplan (at the beginning of the run-inperiod). Key secondary efficacy endpoints were transfusion avoidance, defined as the proportion ofpatients who did not require a transfusion during the RCP, and change from baseline to Week 16 inabsolute reticulocyte count (ARC), LDH level, and functional assessment of chronic illness therapy(FACIT)-Fatigue scale score.

A total of 80 patients entered the run-in period. At the end of the run-in period, all 80 wererandomised, 41 to pegcetacoplan and 39 to eculizumab. Demographics and baseline diseasecharacteristics were generally well balanced between treatment groups (see Table 2). A total of38 patients in the group treated with pegcetacoplan and 39 patients in the eculizumab group completedthe 16-week RCP and continued into the 32-week open-label period. In total, 12 of 80 (15%) patientsreceiving pegcetacoplan discontinued due to adverse events. Per protocol 15 patients had their doseadjusted to 1 080 mg every 3 days. Twelve patients were evaluated for benefit and 8 of the 12 patientsdemonstrated benefit from the dose adjustment.

Table 2: Patient baseline demographics and characteristics in Study APL2-302

Parameter Statistics Pegcetacoplan Eculizumab(N=41) (N=39)

Age (years) Mean (SD) 50.2 (16.3) 47.3 (15.8)18-64 years n (%) 31 (75.6) 32 (82.1)≥65 years n (%) 10 (24.4) 7 (17.9)

Dose level of eculizumab at baseline

Every 2 weeks IV 900 mg n (%) 26 (63.4) 29 (74.4)

Every 11 days IV 900 mg n (%) 1 (2.4) 1 (2.6)

Every 2 weeks IV 1 200 mg n (%) 12 (29.3) 9 (23.1)

Every 2 weeks IV 1 500 mg n (%) 2 (4.9) 0

Female n (%) 27 (65.9) 22 (56.4)

Time since diagnosis of PNH (years) to Day -28 Mean (SD) 8.7 (7.4) 11.4 (9.7)

Haemoglobin level (g/dL) Mean (SD) 8.7 (1.1) 8.7 (0.9)

Reticulocyte count (109/L) Mean (SD) 218 (75.0) 216 (69.1)

LDH level (U/L) Mean (SD) 257.5 (97.6) 308.6 (284.8)

Total FACIT-Fatigue* Mean (SD) 32.2 (11.4) 31.6 (12.5)

Number of transfusions in last 12 months priorto Day -28 Mean (SD) 6.1 (7.3) 6.9 (7.7)<4 n (%) 20 (48.8) 16 (41.0)≥4 n (%) 21 (51.2) 23 (59.0)

Platelet count at screening (109/L) Mean (SD) 167 (98.3) 147 (68.8)

Platelet count at screening <100 000/mm3 n (%) 12 (29.3) 9 (23.1)

Platelet count at screening ≥100 000/mm3 n (%) 29 (70.7) 30 (76.9)

History of aplastic anaemia n (%) 11 (26.8) 9 (23.1)

History of myelodysplastic syndrome n (%) 1 (2.4) 2 (5.1)

*FACIT-Fatigue is measured on a scale of 0-52, with higher values indicating less fatigue.

Pegcetacoplan was superior to eculizumab for the primary endpoint of the haemoglobin change frombaseline (P<0.0001).

Figure 1. Adjusted mean change in haemoglobin (g/dL) from baseline to Week 16 in APL2-302

Non-inferiority was demonstrated in key secondary endpoints of transfusion avoidance and changefrom baseline in ARC.

Non-inferiority was not met in change from baseline in LDH.

Due to hierarchical testing, statistical testing for change from baseline for FACIT-Fatigue score wasnot formally tested.

The adjusted means, treatment difference, confidence intervals, and statistical analyses performed forthe key secondary endpoints are shown in Figure 2.

Figure 2. Key secondary endpoints analysis in APL2-302

Results were consistent across all supportive analyses of the primary and key secondary endpoints,including all observed data with post transfusion data included.

Hb normalisation was achieved in 34% of patients in the pegcetacoplan group versus 0% in theeculizumab group at Week 16. LDH normalisation was achieved in 71% of patients in the grouptreated with pegcetacoplan versus 15% in the eculizumab group.

A total of 77 patients entered the 32-week OLP, during which all patients received pegcetacoplan,resulting in a total exposure of up to 48 weeks. The results at Week 48 were generally consistent withthose at Week 16 and support sustained efficacy.

Study in complement inhibitor-naïve adult patients (APL2-308)

Study APL2-308 was an open-label, randomised, controlled study that enrolled patients with PNHwho had not been treated with any complement inhibitor within 3 months prior to enrolment and with

Hb levels less than the lower limit of normal (LLN). Eligible patients were randomised in a 2:1 ratio toreceive pegcetacoplan or supportive care (e.g., transfusions, corticosteroids, supplements such as iron,folate, and vitamin B12), hereafter referred to as the control arm through the duration of the 26-weektreatment period.

Randomisation was stratified based on the number of PRBC transfusions within the 12 months prior to

Day -28 (<4; ≥4). At any point during the study, a patient assigned to the control arm who had Hblevels ≥2 g/dL below baseline or presented with a PNH associated thromboembolic event was perprotocol able to transition to pegcetacoplan for the remainder of the study.

A total of 53 patients were randomised, 35 to pegcetacoplan and 18 patients to the control arm.

Demographics and baseline disease characteristics were generally well balanced between treatmentarms. The mean age was 42.2 years in the pegcetacoplan arm and 49.1 years in the control arm. Themean number of PRBC transfusions in the 12 months prior to screening was 3.9 in the pegcetacoplanarm and 5.1 in the control arm. Five patients in each arm (14.3% in the pegcetacoplan arm and 27.8%in the control arm) had a history of aplastic anaemia. Further baseline values were as follows: meanbaseline Hb levels (pegcetacoplan arm: 9.4 g/dL vs. control arm; 8.7 g/dL), ARC (pegcetacoplan arm:230.2 × 109/L vs. control arm: 180.3 × 109/L), LDH (pegcetacoplan arm: 2 151.0 U/L vs. control arm:1 945.9 U/L) and platelet count (pegcetacoplan arm: 191.4 × 109/L vs. control arm: 125.5 × 109/L).

Eleven of 18 patients randomised to the control arm transitioned to pegcetacoplan because their Hblevels decreased by ≥2 g/dL below baseline. Of the 53 randomised patients, 52 (97.8%) receivedprophylactic antibiotic therapy according to local prescribing guidelines.

The primary and secondary efficacy endpoints were assessed at Week 26. The two co-primary efficacyendpoints were Hb stabilisation, defined as avoidance of a >1 g/dL decrease in Hb concentration frombaseline in the absence of transfusion, and change in LDH concentration from baseline.

In the group treated with pegcetacoplan, 30 out of 35 patients (85.7%) achieved Hb stabilisationversus 0 patients in the control arm. The adjusted difference between pegcetacoplan and the controlarm was 73.1% (95% CI, 57.2% to 89.0%; p<0.0001).

The least-square (LS) mean (SE) changes from baseline in LDH concentration at Week 26were -1 870 U/L in the group treated with pegcetacoplan versus -400 U/L in the control arm(p<0.0001). The difference between pegcetacoplan and the control arm was -1 470 (95% CI, -2 113to -827). Treatment differences between the pegcetacoplan and the control arm were evident at

Week 2 and were maintained through Week 26 (Figure 3). LDH concentrations in the control armremained elevated.

Figure 3. Mean (±SE) LDH concentration (U/L) over time by treatment group in study

APL2-308

For the selected key secondary efficacy endpoints of haemoglobin response in the absence oftransfusions, change in haemoglobin level, and change in ARC, the group treated with pegcetacoplandemonstrated a significant treatment difference versus the control arm (Table 3).

Table 3: Key secondary endpoints analysis in study APL2-308

Parameter Pegcetacoplan Control arm Difference(N=35) (N=18) (95% CI)p-value

Haemoglobin response in the absenceof transfusionsa 25 (71%) 1 (6%) 54% (34%, 74%)n (%) p < 0.0001

Change from baseline to Week 26 inhaemoglobin level (g/dL) 2.9 (0.38) 0.3 (0.76) 2.7 (1.0, pct. 4.4)

LS Mean (SE)

Change from baseline to Week 26 in

ARC (109/L) -123 (9.2) -19 (25.2) -104 (-159, -49)

LS Mean (SE)a Haemoglobin response was defined as a ≥1 g/dL increase in haemoglobin from baseline at Week 26.

ARC = Absolute reticulocyte count, CI = Confidence interval, LS = Least square, SE = Standard error

C3G and primary IC-MPGN

The efficacy and safety of pegcetacoplan in patients with C3G or primary IC-MPGN was assessed inthe randomised, placebo-controlled, double- blinded phase 3 Study APL2-C3G-310, including adultsand adolescents with native kidney or post-transplant recurrent C3G or primary IC-MPGN.

The dose of pegcetacoplan was 1 080 mg twice weekly for adults or adolescents with body weights≥50 kg, or weight-based for adolescents with body weights <50 kg.

Study in adult and adolescent patients with C3G or primary IC-MPGN (APL2-C3G-310)

Study APL2-C3G-310 was a randomised, double-blinded study with a placebo-controlled period of26-weeks, followed by a 26-week OLP. This study enrolled adolescents from 12 years to 17 years ofage, and adults with C3G or primary IC-MPGN. This study enrolled patients with native kidney orpost-transplant recurrent disease who presented with proteinuria ≥1 g/day and eGFR≥30 mL/min/1.73 m2. Patients were on a stable and optimised dose regimen for C3G/primary

IC-MPGN treatment (e.g., RAS inhibitors, sodium-glucose cotransporter-2 [SGLT-2] inhibitors,immunosuppressants, systemic corticosteroids no higher than 20 mg/day of prednisone equivalent) forat least 12 weeks prior to randomisation.

Eligible patients were randomised in a 1:1 ratio to receive pegcetacoplan or placebo subcutaneouslytwice weekly during the 26-week RCP. Two stratification factors were applied to the randomisation;patients with post-transplant recurrence versus native kidney disease patients, and patients withbaseline renal biopsies (either collected during screening or within 28 weeks prior to randomisation)versus patients without baseline renal biopsies. During the RCP, changes to the baseline treatmentregimens for C3G/primary IC-MPGN were minimised and only made when required for the well-being of the patient. Patients who completed the RCP, entered the 26-week OLP, in which allparticipants were treated with pegcetacoplan twice weekly.

A total of 124 patients were randomised, 63 to pegcetacoplan and 61 to placebo. Demographics andbaseline disease characteristics were generally balanced between the two groups (see Table 4). A totalof 118 patients completed the 26-week RCP, of which 114 patients completed the OLP treatmentperiod with pegcetacoplan (N=59 pegcetacoplan-to-pegcetacoplan; N=55 placebo-to-pegcetacoplan).

Table 4: Patient baseline demographics and disease characteristics in study APL2-C3G-310

Parameter Statistics Pegcetacoplan Placebo(N=63) (N=61)

Age (years) Mean (SD) 28.2 (17.1) 23.6 (14.3)

Adolescents (12 - 17 years) n (%) 28 (44.4) 27 (44.3)

Adults ≥18 years n (%) 35 (55.6) 34 (55.7)

Sex

Male n (%) 26 (41.3) 28 (45.9)

Female n (%) 37 (58.7) 33 (54.1)

Type of disease at Screening

C3G n (%) 51 (81.0) 45 (73.8)

C3GN n (%) 45 (71.4) 41 (67.2)

DDD n (%) 4 (6.3) 4 (6.6)

Undetermined n (%) 2 (3.2) 0

IC-MPGN n (%) 12 (19.0) 16 (26.2)

Time since diagnosis of C3G/IC-MPGN (years) Mean (SD) 3.64 (3.47) 3.76 (3.62)

Prior kidney transplant n (%) 5 (7.9) 4 (6.6)

Time since last kidney transplant (years) Mean (SD) 11.4 (6.7) 5.8 (6.4)

Time since most recent post-transplant Mean (SD) 1.47 (1.49) 1.38 (1.64)recurrence (years)

Baseline triplicate FMU uPCR (mg/g) Mean (SD) 3124 (2408) 2541 (2015)

Baseline eGFR (mL/min/1.73 m2) Mean (SD) 78.5 (34.1) 87.2 (37.2)

C3c staining in baseline biopsy3+ n (%) 51 (81.0) 51 (83.6)2+ n (%) 12 (19.0) 10 (16.4)

Baseline serum albumin (g/dL) Mean (SD) 3.31 (0.61) 3.39 (0.70)

Baseline serum C3 (mg/dL) Mean (SD) 60.6 (45.7) 56.3 (35.6)

Disease manifestations

Oedema n (%) 45 (71.4) 32 (52.5)

Fatigue n (%) 16 (25.4) 8 (13.1)

Haematuria n (%) 37 (58.7) 39 (63.9)

High Blood Pressure n (%) 35 (55.6) 29 (47.5)

Nephrotic Syndrome n (%) 32 (50.8) 27 (44.3)

Use of other treatments at baseline*

Agents acting on the renin-angiotensin system n (%) 59 (93.7) 54 (88.5)

Immunosuppressants n (%) 49 (77.8) 45 (73.8)

Glucocorticoids n (%) 29 (46.0) 27 (44.3)

*Within 12 weeks prior to study entry.

C3G = C3 glomerulopathy, C3GN = C3 glomerulonephritis, DDD = Dense-deposit disease, IC MPGN =

Immune-complex membranoproliferative glomerulonephritis, FMU = First-morning urine, uPCR = Urineprotein-to-creatinine ratio, eGFR = Estimated glomerular filtration rate, SD = Standard deviation

The primary and key secondary efficacy endpoints were assessed at Week 26. The primary efficacyendpoint was the log-transformed ratio of first-morning urine (FMU) uPCR at Week 26 compared withbaseline.

Pegcetacoplan was superior to placebo, with a statistically significant 68.1% reduction (95% CI:57.3% to 76.2%, p<0.0001) in uPCR from baseline compared to placebo after 26 weeks of treatment (-67.2% [95% CI: -74.9% to -57.2%] and + 2.9% [95% CI: -8.6% to 15.9%] for pegcetacoplan andplacebo respectively. Efficacy of similar magnitude was observed in subgroups irrespective of age(adolescents vs. adults), disease type (C3G vs. primary IC-MPGN), disease status (native vs.post-transplant recurrent disease), and concomitant use of immunosuppressants/glucocorticoids (yesvs. no). The effect of pegcetacoplan on uPCR was sustained through Week 52 (-67.2 % frombaseline). Patients who switched from placebo to pegcetacoplan at Week 26 (Figure 4) experienced asimilar reduction (-51.3%) at Week 52.

Figure 4. Geometric mean ratio (95% CI) of FMU uPCR compared to baseline over time bytreatment group from MMRM model in Study APL2-C3G-310

Note: Geometric mean ratio calculated from re-exponentiated LS Means.

CI = Confidence interval, LS = Least square, FMU = First-morning urine, uPCR = Urine protein-to-creatinineratio, MMRM = Mixed model of repeated measure

Pegcetacoplan treatment for 26 weeks demonstrated statistically significant improvement in the keysecondary endpoint related to proteinuria reduction, with 60.3% of patients treated with pegcetacoplanachieving a ≥50% reduction in uPCR compared to 4.9% in the placebo group, a difference of 52.7%(95% CI: 29.2%-76.2%; p<0.0001).

Pegcetacoplan treatment for 26 weeks resulted in a higher proportion of patients achieving a reductionof two orders of magnitude or greater, on a scale of 0-3, in renal C3 staining intensity with 26 (74.3%)patients on pegcetacoplan vs. 4 (11.8%) on placebo and a difference of 64.3% (95% CI: 41.4% -87.2%, nominal p<0.0001).

Pegcetacoplan treatment for 26 weeks showed stabilisation in eGFR with a change from baseline of -1.497 (2.242) on pegcetacoplan vs. -7.808 (1.919) on placebo, and a treatment difference of6.312 mL/min/1.73m2 (95% CI: 0.501, 12.122, nominal p=0.0333). The effect of pegcetacoplan oneGFR was sustained through Week 52. Patients who switched from placebo to pegcetacoplan at

Week 26 experienced a similar stabilisation at Week 52.

Efficacy of similar magnitude was broadly observed for proteinuria reduction ≥50%, C3 stainingclearance and eGFR stabilisation in subgroups irrespective of age (adolescents vs. adults), disease type(C3G vs. primary IC-MPGN), disease status (native vs. post-transplant recurrent disease) andconcomitant use of immunosuppressants/glucocorticoids (yes vs. no) at Week 26.

Study in adult post-transplant recurrent C3G or primary IC-MPGN (APL2-C3G-204)

Study APL2-C3G-204 was a phase 2 open-label, randomised study in 13 adult patients withpost-transplant recurrent C3G (N=10) or primary IC-MPGN (N=3) for 52 weeks.

During the first 12 weeks of the study, 10 patients received pegcetacoplan, in addition to standard ofcare (SOC), and 3 only SOC. All patients received pegcetacoplan from Week 13 to Week 52.

The primary endpoint of reduction in C3 staining intensity on renal biopsy at Week 12 was observedin 50% of the patients treated with pegcetacoplan (5 of 10 patients; 4 of which, achieved a stainingscore of zero), and 33.3% of the patients in the control group (1 of 3 patients; with this patientachieving a staining score of 1).

In general, changes and percentage changes from baseline in eGFR (secondary endpoint) were small.

Mean (SD) eGFR changed from 52.3 (12.11) mL/min/1.73 m2 at baseline to 57.3 (25.12)mL/min/1.73 m2 at Week 52, and median eGFR changed from 50.5 mL/min/1.73 m2 at baseline to58.5 mL/min/1.73 m2 at Week 52. Most patients (9 of 13 patients [69.2%]) across groups achievedstabilisation or improvement in eGFR by Week 52.

Two different assays for the detection of anti-pegcetacoplan peptide anti-drug antibody (ADA) wereused in PNH and C3G or primary IC-MPGN clinical studies, respectively. The assay used for C3G orprimary IC-MPGN was more sensitive. Differences in assays preclude meaningful comparisons of theincidence of ADAs in the studies described below.

In PNH clinical studies, ADA incidence (treatment-emergent ADA or boosted ADA from pre-existinglevel) was low, and when present, had no noticeable impact on the PK/PD, efficacy, or safety profileof pegcetacoplan. Throughout studies APL2-302 and APL2-308, 3 out of 126 patients who wereexposed to pegcetacoplan had confirmed positive anti-pegcetacoplan peptide antibodies. All 3 patientsalso tested positive for neutralising antibody (NAb). NAb response had no apparent impact on PK orclinical efficacy. Eighteen out of 126 patients developed anti-PEG antibodies; 9 were treatment-emergent and 9 were treatment-boosted.

In C3G and primary IC-MPGN clinical studies, ADA incidence (treatment-emergent ADA or boosted

ADA from pre-existing level) in study APL2-C3G-310 was 23.6% for anti-PEG and 16.3% foranti-pegcetacoplan peptide. Based on population PK and PD analysis, ADAs had no clinicallymeaningful impact on efficacy or PK/PD in a pooled analysis population. Five patients also testedpositive for NAb. NAb response had no apparent impact on PK or clinical efficacy. Twenty-nine outof 123 patients developed anti-PEG antibodies;14 were treatment-emergent and 15 were treatment-boosted. In patients with post-transplant recurrent disease in study APL2-C3G-204, no patientdeveloped a positive ADA response (treatment-emergent ADA or boosted ADA from pre-existinglevel) to pegcetacoplan peptide or PEG. During the 26-week placebo-controlled period in study

APL2-C3G-310, there was no detectable impact of ADAs on the safety of pegcetacoplan treatment.

The European Medicines Agency has deferred the obligation to submit the results of studies with

ASPAVELI in one or more subsets of the paediatric population in PNH and C3G or primary IC-

MPGN, respectively (see section 4.2 for information on paediatric use).

Pegcetacoplan is administered by subcutaneous infusion and gradually absorbed into the systemiccirculation with a median Tmax between 108 and 144 hours (4.5 to 6.0 days) following a singlesubcutaneous dose to healthy volunteers.

Steady-state serum concentrations following twice weekly dosing at 1 080 mg in patients with PNHwere achieved approximately 4 to 6 weeks following the first dose. In complement inhibitor-experienced patients (Study APL2-302) the geometric mean (%CV) steady-state serum concentrationsranged between 655 (18.6%) and 706 (15.1%) µg/mL in patients treated for 16 weeks. Steady-stateconcentrations in the patients (n=22) that continued to receive pegcetacoplan up to Week 48 were623 µg/mL (39.7%), indicating sustainable therapeutic concentrations of pegcetacoplan through

Week 48. In complement inhibitor-naïve patients (Study APL2-308) the geometric mean (%CV)steady-state serum concentration at Week 26 was 744 µg/mL (25.5%) with twice weekly dosing. Thebioavailability of a subcutaneous dose of pegcetacoplan is estimated to be 76% based on population

PK analysis.

Steady-state serum concentrations following twice weekly dosing at 1 080 mg in C3G or primary IC-

MPGN patients were achieved approximately 4 to 8 weeks following the first dose and therapeuticconcentrations of pegcetacoplan were maintained through Week 52. In patients of study APL2-C3G-310, the steady-state mean (%CV) serum concentrations ranged between 715.8 (31.2%) and 765.7(23.2%) μg/mL up to Week 26 and remained between 670.1 (30.1%) and 726.6 (30.5%) μg/mL up to

Week 52.

The mean (%CV) volume of distribution of pegcetacoplan is approximately 3.98 L (32%) in patientswith PNH based on population PK analysis.

The mean (%CV) of central volume of distribution of pegcetacoplan is approximately 4.31 L (32.1%)in adult patients with C3G or primary IC-MPGN.

Metabolism/elimination

Based on its PEGylated peptide structure, the metabolism of pegcetacoplan is expected to occur viacatabolic pathways and be degraded into small peptides, amino acids, and PEG. Results of aradiolabelled study in cynomolgus monkeys suggest the primary route of elimination of the labelledpeptide moiety is via urinary excretion. Although the elimination of PEG was not studied, it is knownto undergo renal excretion.

Pegcetacoplan showed no inhibition or induction of the CYP enzyme isoforms tested as demonstratedfrom the results of in vitro studies. Pegcetacoplan was neither a substrate nor an inhibitor of the humanuptake or efflux transporters.

Following multiple subcutaneous dosing of pegcetacoplan in patients with PNH, the mean (%CV)clearance is 0.015 L/h (30%) and median effective half-life of elimination (t1/2) is 8.6 days asestimated by the population PK analysis.

The estimated mean (CV%) of clearance is 0.012 L/hour (43%) in adult patients with C3G or primary

IC-MPGN. The median terminal t1/2 is 10.1 days in adult patients with C3G or primary IC-MPGN.

Exposure of pegcetacoplan increases in a dose proportional manner from 45 to 1 440 mg.

No impact on the pharmacokinetics of pegcetacoplan was identified with age (12-81 years), race orsex based on the results of population PK analysis in patients with PNH, C3G or primary IC-MPGN.

Compared with a reference 70 kg patient, the steady-state average concentration is predicted to beapproximately 20% higher in patients with a body weight of 50 kg. PNH patients weighing 40 kg arepredicted to have a 45% higher average concentration. Minimal data are available on the safety profileof pegcetacoplan for PNH patients with a body weight below 50 kg.

Although there were no apparent age-related differences observed in these studies, the number ofpatients aged 65 years and over is not sufficient to determine whether they respond differently fromyounger patients. See section 4.2.

Based on population PK analysis, body weight in adolescent patients (12-17 years) has an impact onclearance and volume of distribution. The dosing regimen for adolescents with C3G or primary IC-

MPGN is based on the patient´s body weight. See section 4.2. The model-predicted exposure foradolescents with C3G or primary IC-MPGN is adequately matched to the adult reference exposure.

In a study of 8 patients with severe renal impairment, defined as creatinine clearance (CrCl) less than30 mL/min using the Cockcroft-Gault formula (with 4 patients with values less than 20 mL/min), renalimpairment had no effect on the pharmacokinetics of a single 270-mg dose of pegcetacoplan. Thereare minimal data on patients with PNH with renal impairment who have been administered the clinicaldose of 1 080 mg twice weekly. Based on population PK analysis, eGFR had no clinically meaningfulimpact on pegcetacoplan exposure in a pooled analysis population. There are no available clinical datafor the use of pegcetacoplan in patients with ESRD requiring dialysis. See section 4.2.

In vitro and in vivo toxicology data reveal no toxicity of special concern for humans. Effects observedin animals at exposure levels similar to clinical exposure levels are described below. These effectswere not observed in clinical studies.

Animal reproduction

Pegcetacoplan treatment of pregnant cynomolgus monkeys at a subcutaneous dose of 28 mg/kg/day(2.9 times the human steady-state Cmax) from the gestation period through parturition resulted in astatistically significant increase in abortions or stillbirths. No maternal toxicity or teratogenic effectswere observed in offspring delivered at term. Additionally, no developmental effects were observed ininfants up to 6 months postpartum. Systemic exposure to pegcetacoplan was detected in foetuses frommonkeys treated with 28 mg/kg/day from the period of organogenesis through the second trimester,but the exposure was minimal (less than 1%, not pharmacologically significant).

Long term animal carcinogenicity studies of pegcetacoplan have not been conducted.

Pegcetacoplan was not mutagenic when tested in in vitro bacterial reverse mutation (Ames) assays andwas not genotoxic in an in vitro assay in human TK6 cells or in an in vivo micronucleus assay in mice.

Animal toxicology

Repeat-dose studies were conducted in rabbits and cynomolgus monkeys with daily subcutaneousdoses of pegcetacoplan up to 7 times the human dose (1 080 mg twice weekly). Histologic findings inboth species included dose-dependent epithelial vacuolation and infiltrates of vacuolated macrophagesin multiple tissues. These findings have been associated with large cumulative doses of long-chain

PEG in other marketed PEGylated drugs, were without clinical consequence, and were not consideredadverse. Reversibility was not demonstrated in the pegcetacoplan animal studies after one month andwas not evaluated for a longer duration. Data from literature suggest reversibility of PEG vacuoles.

Renal tubular degeneration was observed microscopically in both species at exposures (Cmax and

AUC) less than or comparable to those for the human dose and was minimal and nonprogressivebetween 4 weeks and 9 months of daily administration of pegcetacoplan. Although no overt signs ofrenal dysfunction were observed in animals, the clinical significance and functional consequence ofthese findings are unknown.

Glacial acetic acid

Sodium acetate trihydrate

Sodium hydroxide (for pH adjustment)

Water for injection

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

30 months.

Store in a refrigerator (2 °C - 8 °C).

Store in the original carton to protect from light.

A Type I glass vial with a stopper (chlorobutyl or bromobutyl), and a seal (aluminium) with a flip-offcap (polypropylene) containing 54 mg/mL of sterile solution.

Each single pack contains 1 vial.

Multipack containing 8 (8 packs of 1) vials.

Not all pack sizes may be marketed.

ASPAVELI comes as a ready-to-use solution in single-use vials. Because the solution contains nopreservative, this medicinal product should be infused immediately after preparing the syringe.

ASPAVELI is a clear, colourless to slightly yellowish aqueous solution. Do not use if the liquid lookscloudy, contains particles, or is dark yellow.

Always bring the vial to the room temperature for approximately 30 minutes before use.

Remove the protective flip cap from the vial to expose the central portion of the gray rubber stopper ofthe vial. Clean the stopper with a new alcohol wipe and allow the stopper to dry. Do not use if theprotective flip cap is missing or damaged.

Preparing the syringe:

Option 1: If using a needleless transfer device (such as a vial adapter), follow the instructions providedby the device manufacturer.

Option 2: If transfer is done using a transfer needle and a syringe, follow the instructions below:

* Attach a sterile transfer needle to a sterile syringe.

* Pull back the plunger to fill the syringe with air, which should be about 20 mL.

* Make sure the vial is in upright position. Do not turn the vial upside down.

* Push the air-filled syringe with transfer needle attached through the centre of the vial stopper.

* The tip of the transfer needle should not be in the solution to avoid creating bubbles.

* Gently push the air from the syringe into the vial. This will inject the air from the syringe intothe vial.

* Invert the vial.

* With the transfer needle tip in the solution, slowly pull the plunger to fill the syringe with theprescribed dose of ASPAVELI.

* Remove the filled syringe and the transfer needle from the vial.

* Do not recap the transfer needle. Unscrew the needle and throw it away in the sharps container.

ASPAVELI should only be administered via subcutaneous administration using either a syringesystem infusion pump or an on-body delivery system:

* Follow the device manufacturer’s instructions to prepare the infusion pump and tubing. Whenusing an infusion pump, areas for infusion include the abdomen, thighs, hips, or upper arms.

Rotate infusion sites from one infusion to the next. If there are multiple infusion sites, theyshould be at least 7.5 cm apart. The infusion time is approximately 30 minutes (if using twosites) or approximately 60 minutes (if using one site).

* Follow the device manufacturer’s instructions to prepare the on-body delivery system. Whenusing the on-body delivery system, ASPAVELI should be administered at a site on theabdomen. Rotate the infusion site from one infusion to the next. The infusion time varies bypatient and typically ranges from 30 to 60 minutes.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Swedish Orphan Biovitrum AB (publ)

SE-112 76 Stockholm

Sweden

EU/1/21/1595/001

EU/1/21/1595/002

Date of first authorisation: 13 December 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.