ASPAVELI 1080mg 54mg / ml solution for infusion medication leaflet

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.

Therapy should be initiated under the supervision of a healthcare professional experienced in themanagement of patients with haematological disorders. Self-administration and home infusion shouldbe considered for patients who have tolerated treatment well in experienced treatment centres. Thedecision of a possibility of self-administration and home infusions should be made after evaluation andrecommendation from the treating physician.

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

Pegcetacoplan is administered twice weekly as a 1 080 mg subcutaneous infusion with a commerciallyavailable syringe system infusion pump that can deliver doses up to 20 mL. The twice weekly doseshould 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 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).

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).

If a dose of pegcetacoplan is missed, it should be administered as soon as possible, then the regularschedule should be resumed.

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 haemodialysis (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.

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. This medicinal product can be self-administered. Whenself-administration is initiated, the patient will be instructed by a qualified healthcare professional ininfusion techniques, the use of a syringe system infusion pump, the keeping of a treatment record, therecognition of possible adverse reactions, and measures to be taken in case these occur.

ASPAVELI should be infused in the abdomen, thighs, hips, or upper arms. Infusion sites should be atleast 7.5 cm apart from each other. The infusion sites should be rotated between administrations.

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 typical infusion time is approximately30 minutes (if using two sites) or approximately 60 minutes (if using one site). The infusion should bestarted promptly after drawing this medicinal product into the syringe. Administration should becompleted within 2 hours after preparing the syringe. For instructions on the preparation and infusionof 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, 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 are no or 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.

The most commonly reported adverse reactions in patients treated with pegcetacoplan were injectionsite reactions: injection site erythema, injection site pruritus, injection site swelling, injection site pain,injection site bruising. Other adverse reactions reported in more than 10% of patients during clinicalstudies 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 were haemolysis andsepsis.

Table 1 gives the adverse reactions observed from the clinical studies and postmarketing experiencewith pegcetacoplan in patients with PNH. 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), andnot known (cannot be estimated from available data).

Within each frequency 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 Adverse reaction

Infections and infestations Very common Upper respiratory tract infection

Common Sepsis2

COVID-19

Gastrointestinal infection

Fungal infection

Skin infection

Oral infection

Ear infection

Infection

Respiratory tract infection

Viral infection

Bacterial infection

Vaginal infection

Eye infection

Uncommon Cervicitis

Groin infection

Nasal abscess

Oesophageal candidiasis

COVID-19 pneumonia

Anal abscess

Blood and lymphatic system disorders Very common Haemolysis

Common Thrombocytopenia

Metabolism and nutrition disorders Common Hypokalaemia

Nervous system disorders Very common Headache

Dizziness

Vascular disorders Common Hypertension

Respiratory, thoracic and mediastinal Very common Coughdisorders Common Dyspnoea

Epistaxis

Oropharyngeal pain

Nasal congestion

Gastrointestinal disorders Very common Abdominal pain

Common Nausea

Skin and subcutaneous tissue disorders Common Erythema

Urticaria3

Musculoskeletal and connective tissue Very common Arthralgiadisorders Back pain

Pain in extremity

Common Myalgia

Muscle spasms

Renal and urinary disorders Common Acute kidney injury

Chromaturia

MedDRA System Organ Class Frequency Adverse reaction

General disorders and administration Very common Injection site erythemasite conditions Injection site pruritus

Injection site bruising

Injection site pain

Common Injection site reaction

Injection site induration

Investigations Common Alanine aminotransferase increased

Bilirubin increased

Injury, poisoning and procedural Very common Vaccination complication4complications1Studies APL2-308, APL2-302, APL2-202, APL2-CP-PNH-204, and APL-CP0514 in PNH patients.

Medically similar terms are grouped, where appropriate, on the basis of similar medical concept.2Sepsis includes one case of septic shock.3Estimated from both clinical trial- and postmarketing experience.4Vaccination complications were related to the mandatory vaccinations.

Based on its mechanism of action, the use of pegcetacoplan may potentially increase the risk ofinfections, particularly infections caused by encapsulated bacteria including Streptococcuspneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae (seesection 4.4). No serious infection caused by encapsulated bacteria was reported during Study

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

APL2-302 were non-serious, 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. Eleven patients experienced an infection during study

APL2-308. All but one infection were reported as mild or moderate in intensity. One patient who hadan infection developed septic shock and died.

Haemolysis

Nineteen patients reported haemolysis during Study APL2-302 in patients treated with pegcetacoplan.

Seven cases were reported as serious, and 5 cases led to discontinuation of pegcetacoplan and the doseof pegcetacoplan was increased in 10 patients. There were 3 cases of haemolysis during study

APL2-308 in patients treated with pegcetacoplan. None of these cases were reported as serious or ledto discontinuation of pegcetacoplan. The dose of pegcetacoplan was increased in all 3 patients.

Anti-drug antibody (ADA) incidence (seroconverted ADA or boosted ADA from pre-existing level)were low, and when present, had no noticeable impact on the PK/PD, efficacy, or safety profile ofpegcetacoplan. Throughout studies APL2-302 and APL2-308, 3 out of 126 patients who were exposedto pegcetacoplan had confirmed positive anti-pegcetacoplan peptide antibodies. All 3 patients alsotested 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 seroconversionsand 9 were treatment-boosted.

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.

No case of overdose has been reported to date. In case of overdose, it is recommended that the patientbe monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatmentbe 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 andexert a broad inhibition of the complement cascade. The 40-kDa PEG moiety imparts improvedsolubility and longer residence time in the body after administration of the medicinal product.

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 Study APL2-302, the mean C3 concentration increased from 0.94 g/L at baseline to 3.83 g/L at

Week 16 in the pegcetacoplan group and sustained through Week 48. In Study APL2-308, the mean

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.

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 withhaemoglobin levels <10.5 g/dL. Eligible patients entered a 4-week run-in period during which theyreceived pegcetacoplan 1 080 mg subcutaneously twice weekly in addition to their current dose ofeculizumab. Patients were then randomised in a 1:1 ratio to receive either 1 080 mg of pegcetacoplantwice weekly or their current dose of eculizumab through the duration of the 16-week randomisedcontrolled 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 haemoglobin level. Baseline wasdefined as the average of measurements prior to the first dose of pegcetacoplan (at the beginning ofthe run-in period). Key secondary efficacy endpoints were transfusion avoidance, defined as theproportion of patients who did not require a transfusion during the RCP, and change from baseline to

Week 16 in absolute reticulocyte count (ARC), LDH level, and 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.

Haemoglobin normalisation was achieved in 34% of patients in the pegcetacoplan group versus 0% inthe eculizumab 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 withhaemoglobin levels less than the lower limit of normal (LLN). Eligible patients were randomised in a2:1 ratio to receive pegcetacoplan or supportive care (e.g., transfusions, corticosteroids, supplementssuch as iron, folate, and vitamin B12), hereafter referred to as the control arm through the duration ofthe 26-week treatment period.

Randomisation was stratified based on the number of packed red blood cell (PRBC) transfusionswithin the 12 months prior to Day -28 (<4; ≥4). At any point during the study, a patient assigned to thecontrol arm who had haemoglobin levels ≥2 g/dL below baseline or presented with a PNH associatedthromboembolic event was per protocol able to transition to pegcetacoplan for the remainder of thestudy.

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 haemoglobin 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 topegcetacoplan because their haemoglobin levels decreased by ≥2 g/dL below baseline. Of the 53randomised patients, 52 (97.8%) received prophylactic antibiotic therapy according to localprescribing guidelines.

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

In the group treated with pegcetacoplan, 30 out of 35 patients (85.7%) achieved haemoglobinstabilisation versus 0 patients in the control arm. The adjusted difference between pegcetacoplan andthe control arm 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

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 paroxysmal nocturnalhaemoglobinuria (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 weeklydosing at 1 080 mg in patients with PNH were achieved approximately 4 to 6 weeks following the firstdose. In complement inhibitor-experienced patients (Study APL2-302) the geometric mean (%CV)steady-state serum concentrations ranged between 655 (18.6%) and 706 (15.1%) µg/mL in patientstreated for 16 weeks. Steady-state concentrations in the patients (n=22) that continued to receivepegcetacoplan up to Week 48 were 623 µg/mL (39.7%), indicating sustainable therapeuticconcentrations 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. The bioavailability of a subcutaneous dose of pegcetacoplan isestimated to be 76% based on population PK analysis.

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

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.

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 (19-81 years), race orsex based on the results of population PK analysis.

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. Patients weighing 40 kg arepredicted to have a 45% higher average concentration. Minimal data are available on the safety profileof pegcetacoplan for 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.

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. There are no available clinical data for the use of pegcetacoplan inpatients with ESRD requiring haemodialysis. 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.

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 all theliquid.

* 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.

Follow the device manufacturer’s instructions to prepare the infusion pump and tubing.

Potential areas for infusion include the abdomen, thighs, hips, or upper arms. Rotate infusion sitesfrom one infusion to the next. If there are multiple infusion sites, they should be at least 7.5 cm apart.

The typical infusion time is approximately 30 minutes (if using two sites) or approximately 60 minutes(if using one site).

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.